Pi Is 1556086415336108

Journal of Thoracic Oncology t Volume 6, Number 6, Supplement 2, June 2011 14th World Conference on Lung Cancer
Session PRS: Presidential Symposium 377 coding mutations per sample and 180 overall
incl. Best Oral Presentations signiÀcantly mutated genes including TP53, BID,
SI, NFE2L2, LRB1B, NOTCH1, PTEN, PIK3CA,
CDKN2A, RB1, KEAP1, KDM6A, FGFR2 and
Wednesday, 6 July 2011
CTNNA2. Whole genome sequencing revealed
multiple in-frame fusions involving RB1, NOTCH1,
Presidential Symposium incl. Best Oral Presentations Wednesday, 6 PIK3CB, TP63, VHL and ETV6 (Fig 2).
July 2011 08:30-10:00
PRS.1 GENOMIC CHARACTERIZATION

AND TARGETED THERAPEUTICS IN
SQUAMOUS CELL LUNG CANCER
Peter Hammerman1, Andrey Sivachenko2, Nam
Pho2, Andrew Cherniak2, Alex Ramos2, Gad Getz2,
Matthew Meyerson1
1
Medical Oncology, Dana Farber Cancer Institute/
United States Of America, 2Cancer Program, Broad
Institute/United States Of America
Background: Recent advances in the molecular

classiÀcation of lung adenocarcinoma have led to
the development of novel cancer therapeutics which
are more effective and less toxic than chemotherapy
for patients who harbor speciÀc genetic alterations
in their tumors such as EGFR mutations and ALK
fusions. However, progress in squamous cell
lung cancer (lung SCC) has lagged behind lung
adenocarcinoma. Reports by our group and others in
the past year have identiÀed the DDR2 and FGFR1
tyrosine kinases as potential therapeutic targets in
lung SCC and we sought to extend these Àndings
with a more detailed genomic characterization of Conclusion: Together, these results provide an initial
lung SCCs. insight into the genomic abnormalities in lung SCCs
and suggest that therapeutic targets are likely to
Methods: We performed a detailed genomic analysis exist in this disease and include PIK3CA and FGFR
of 118 lung SCCs and matched normal controls family members among others.
as part of The Cancer Genome Atlas project. This
included copy number proÀling using SNP 6.0 Keywords: targeted therapies, squamous cell lung
arrays, next-generation whole exome sequencing of cancer, cancer genomics
all samples and whole genome sequencing of Àve
tumor/normal pairs. A revised/updated abstract may be included in
the Late Breaking Abstract Supplement, available
Results: Using the GISTIC 2.0 algorithm we at the 14th World Conference on Lung Cancer.
identiÀed signiÀcant focal copy number gains in 25
regions of the genome, including several genes likely
to be important in the pathogenesis of lung SCC
including CMYC, SOX2, FGFR1, CCND1, TP63
and NFE2L2. 14 focal deletion peaks were identiÀed
and include LRP1B, EPHA3, PTEN, RB1, CDKN2A
and CSMD1 (Fig 1). Mutational analysis of exome
sequencing from 64 samples with excellent coverage
and lack of hypermutation identiÀed an average of
Copyright © 2011 by the International Association for the Study of Lung Cancer S39
Presidential Symposium incl. Best Oral Presentations Wednesday, 6 Presidential Symposium incl. Best Oral Presentations Wednesday, 6
July 2011 08:30-10:00 July 2011 08:30-10:00
PRS.3 IMPROVEMENTS IN SURVIVAL PRS.7 THE EFFECTS OF INVESTING

OF ELDERLY PATIENTS WITH STAGE IN THORACIC SURGERY ON LUNG
I NSCLC IN THE NETHERLANDS CANCER RESECTION RATES
BETWEEN 2003-2009 Kelvin K.W. Lau1, David Waller2, Sridhar Rathinam2,
Cornelis J. Haasbeek1, Otto Visser2, David Palma3, Michael D. Peake2
Frank J. Lagerwaard1, Ben Slotman1, Suresh Senan1 1
Department Of Thoracic Surgery, GlenÀeld
1
Radiation Oncology, Vu University Medical Hospital/United Kingdom, 2GlenÀeld Hospital/
Center/Netherlands, 2Amsterdam Cancer Registry, United Kingdom
Comprehensive Cancer Centre Amsterdam/
Netherlands, 3Radiation Oncology, London Regional Abstract under Embargo - will be presented in a
Cancer Program/Canada press conference during WCLC 2011.
Abstract under Embargo - will be presented in a

press conference during WCLC 2011.
Presidential Symposium incl. Best Oral Presentations Wednesday, 6

July 2011 08:30-10:00
PRS.5 IN VIVO SELECTION OF NON-

SMALL CELL LUNG CANCER PATIENTS
WITH ACTIVATING MUTATIONS IN
THE TUMOR EPIDERMAL GROWTH
FACTOR RECEPTOR USING [11C]
ERLOTINIB AND POSITRON EMISSION
TOMOGRAPHY
Idris Bahce1, Mark Lubberink2, N H. Hendrikse3,
Astrid A. Van Der Veldt4, Maqsood Yaqub5, Albert D.
Windhorst4, R C. Schuit5, Erik Thunnissen6, Daniëlle
A. Heideman6, Pieter E. Postmus1, Adriaan A.L.
Lammertsma4, Egbert F. Smit1
1
Pulmonary Medicine, VU University Medical
Centre/Netherlands, 2Pet Centre, Uppsala University
Hospital/Sweden, 3Clinical Pharmacology &
Pharmacy, VU University Medical Center/
Netherlands, 4Nuclear Medicine & Pet Research, VU
University Medical Center/Netherlands, 5Nuclear
Medicine And Pet Research, VU University Medical
Center/Netherlands, 6Pathology, VU University
Medical Center/Netherlands

press conference during WCLC 2011.
S40 Copyright © 2011 by the International Association for the Study of Lung Cancer
PLENARY SESSIONS 5p15.33, 6p21.33 or 15q15.2 inÁuence smoking

behavior. That smoking causes lung cancer is
perhaps the most widely known result in the Àeld of
Session PL01: The Lung Cancer medical epidemiology(14-15). Smokers are ten times
Epidemic more likely to get lung cancer than lifetime non-
smokers, and the geographical and temporal patterns
in lung cancer incidence can largely be modeled
Monday, 4 July 2011
based on overall tobacco consumption(2). The
smoking induced risk of lung cancer is dose
The Lung Cancer Epidemic Monday, 4 July 2011 08:30-10:00 dependent , increasing with higher numbers of
cigarettes smoked per day and with the duration of
PL01.2 LUNG CANCER SUSCEPTIBILITY smoking as well(16-17), although other aspects of
GENES smoking such as the type of tobacco used, age at
Thorgeir E. Thorgeirsson onset of smoking, depth and duration of inhalation,
University Of California Santa Cruz/United States also come into play(2). Several smoking phenotypes
Of America are quite heritable, including smoking persistence
and nicotine dependence (18-19). The main variant
Abstract: Rapid progress in cancer genetics is at 15q25 does not appear to inÁuence the tendency to
expected to greatly impact clinical practice in the take up smoking, but associates with the amount
next decade, as the characterization of germline and smoked per day and with nicotine dependence(3).
tumor DNA at increasingly high resolution will Since the discovery of this locus additional studies
provide valuable insights into cancer, hopefully have been conducted, providing further evidence
opening new avenues for cancer prevention, early relating to the matter of how to explain the effect of
detection, and treatment. The mapping of cancer risk this locus on lung cancer. While reviewing these
regions represents an important step toward studies it is important to keep in mind that there are
understanding of the pathogenesis of cancer, and in three main possibilities when it comes to explaining
the last few years genome-wide association studies why this variant has a stronger effect on the
have yielded over 90 regions associating with consequences of smoking than on CPD. First, the
various cancers(1) including lung cancer(2). variant may associate with other aspects of smoking
Genome-wide association studies have identiÀed behavior – not adequately measured by CPD – that
sequence variants associating with risk of lung inÁuence risk of lung cancer and some other
cancer at four loci in populations of European smoking-related diseases. Second, the variant may
descent. Variants at chrs 15q25.1 in a region increase the vulnerability to the harmful effects of
containing genes encoding for three nicotinic tobacco smoke. Third, the variant may confer risk of
acetylcholine receptor (nAChR) subunits (CHRNA5, a smoking-related diseases in a manner that is
CHRNA3, CHRNB4) were discovered Àrst , and independent of smoking. In light of the key impact
shown to associate with the number of cigarettes that smoking has on lung cancer risk it is reasonable
smoked per day (CPD) (3-4), nicotine addiction(3, to expect at least some association with lung cancer
5), peripheral arterial disease(3) and lung cancer(3, for variants inÁuencing smoking behavior. Ideed, in
6-7). Three independent Àndings on lung cancer addition to the chrs 15q25 variants, recent meta-
were remarkably consistent with regard to the analyses of smoking behavior have identiÀed loci at
estimate of the effect on lung cancer risk at the 8p11 and 19q13 containing sequence variants
15q25 locus (odds ratios between 1.30-1.32)(3, 6-7), exhibiting genome-wide signiÀcant association with
but the studies differed with regard to the smoking quantity and nominally signiÀcant
interpretation of the results on smoking behavior(8). associations with lung cancer(20). Further studies are
By expanding various studies and building on meta required to verify the effects on lung cancer at these
analysis efforts(9) three additional loci have been loci. Variants at 15q25 have been the most signiÀcant
discovered, at 5p15.33 in a region encompassing the Àndings in three large meta analyses of smoking
TERT and CLPTM1L genes(10-12), 6p21.33 within behavior(20-22), and there is no doubt that the
the major histocompatabillity region (MHC)(7, 11), association with smoking behavior is real.The
and 15q15.2 near the TP53BP1 gene(13). There is original variant has been shown to confer risk of
currently no evidence indicating that the loci at additional smoking-related diseases, including
chronic obstructive pulmonary disease(23) and Àndings into account and considering that there are
cancers in the upper aerodigestive tract(24). Carriers at least three independent at-risk variants within the
of the variant not only smoke more, but also extract region, there is certainly need for further studies
more nicotine and more carcinogens from each before Àrm conclusions can be reached. The key
cigarette than non-carriers(25). Furthermore, the variant at chrs 15q25 clearly inÁuences nicotine
variant has been shown to associate with continued addiction and smoking behavior, and through these
smoking during pregnancy in two studies(26-27), effects it also confers risk of lung cancer and other
and progression to regular smoking and nicotine smoking related diseases. This variant provides a
dependence in young smokers may be inÁuenced by fascinating example of gene-environment
the variant(28). The last two Àndings suggest that the interactions involved in many disorders, and can be
variant may inÁuence smoking duration through an studied from that point of view alone for years to
effect on cessation, and potentially through come. At the present time it appears unnecessary to
facilitating early onset of regular smoking, but even invoke more complicated scenarios to explain the
a relatively small effect on smoking duration could effect the main variant has on risk of lung cancer and
be expected to explain the observed odds ratio for other smoking-related diseases. However, it is clear
lung cancer(16-17). Work on rodents has also that such effects cannot by any means be ruled out
delineated potential mechanisms within the brain, based on association studies alone, particularly when
including action of the alpha-5 subunit protein within it comes to other variants within the region that have
the habenula to inÁuence the brain’s reaction to not been as thoroughly studied. Large collaborative
aversive stimuli inÁuencing the motivational drive efforts will be required to reÀne the association
for nicotine intake(29), but the lateral habenula has signals already discovered in lung cancer, and to this
been implicated in negative reward end current whole genome sequencing efforts, such
mechanisms(30-31). Brain imaging studies have as the 1000 genomes project(39-40), will prove
been conducted in humans revealing that the variant invaluable as they are discovering a large number of
modulates an cingulated circuit previously shown to variants from various populations that can be
be involved in nicotine addiction(32) and to be imputed into these large datasets for further study, or
altered in psychiatric patients(33), but involvement when necessary studied by direct genotyping or
of the dorsal anterior cingulate cortex in reward- sequencing. References 1. Hosking FJ, Dobbins SE,
based decision making has been suggested Houlston RS. Genome-wide association studies for
before(34) . It had been argued that the results on the detecting cancer susceptibility. Br Med Bull.
risk conferred of lung cancer in never smokers have 2011;97:27-46. 2. Brennan P, Hainaut P, Boffetta P.
been inconsistent with some studies Ànding Genetics of lung-cancer susceptibility. Lancet Oncol.
association(7), and other not(6), but a recent large 2011 Apr;12(4):399-408. 3. Thorgeirsson TE, Geller
meta analysis with much larger sample size found no F, Sulem P, Rafnar T, Wiste A, Magnusson KP, et al.
association with lung cancer in never smokers of A variant associated with nicotine dependence, lung
European descent (35). However, several studies of cancer and peripheral arterial disease. Nature. 2008
Asian and African American populations have Apr 3;452(7187):638-42. 4. Berrettini W, Yuan X,
reported association of SNPs within the region in Tozzi F, Song K, Francks C, Chilcoat H, et al.
never smokers including a well powered study Alpha-5/alpha-3 nicotinic receptor subunit alleles
reporting four common 15q25 variants associating increase risk for heavy smoking. Mol Psychiatry.
with lung cancer in two Chinese case-control studies 2008 Apr;13(4):368-73. 5. Saccone SF, Hinrichs AL,
with similar effects among ever and never Saccone NL, Chase GA, Konvicka K, Madden PA, et
smokers(36). However, the relevance of these al. Cholinergic nicotinic receptor genes implicated in
Àndings remains unclear as some of the key markers a nicotine dependence association study targeting
have low frequencies in these populations(See (2, 348 candidate genes with 3713 SNPs. Hum Mol
37) and references therein). Additional arguments for Genet. 2007 Jan 1;16(1):36-49. 6. Amos CI, Wu X,
a more direct effect on lung cancer come from Broderick P, Gorlov IP, Gu J, Eisen T, et al. Genome-
studies of the effects of nicotine and various tobacco- wide association scan of tag SNPs identiÀes a
speciÀc carcinogens on nAChR signaling and cell susceptibility locus for lung cancer at 15q25.1. Nat
proliferation in bronchial mucosal cells(2), and a Genet. 2008 May;40(5):616-22. 7. Hung RJ, McKay
potential involvement of altered nAChR signaling in JD, Gaborieau V, Boffetta P, Hashibe M, Zaridze D,
lung cancer has been suggested(38). Taking these et al. A susceptibility locus for lung cancer maps to
nicotinic acetylcholine receptor subunit genes on reÀnes the association of 15q25 with smoking
15q25. Nature. 2008 Apr 3;452(7187):633-7. 8. quantity. Nat Genet. 2010 May;42(5):436-40. 22.
Chanock SJ, Hunter DJ. Genomics: when the smoke Genome-wide meta-analyses identify multiple loci
clears. Nature. 2008 Apr 3;452(7187):537-8. 9. associated with smoking behavior. Nat Genet. 2010
Broderick P, Wang Y, Vijayakrishnan J, Matakidou May;42(5):441-7. 23. Pillai SG, Ge D, Zhu G, Kong
A, Spitz MR, Eisen T, et al. Deciphering the impact X, Shianna KV, Need AC, et al. A genome-wide
of common genetic variation on lung cancer risk: a association study in chronic obstructive pulmonary
genome-wide association study. Cancer Res. 2009 disease (COPD): identiÀcation of two major
Aug 15;69(16):6633-41. 10. McKay JD, Hung RJ, susceptibility loci. PLoS Genet. 2009
Gaborieau V, Boffetta P, Chabrier A, Byrnes G, et al. Mar;5(3):e1000421. 24. Lips EH, Gaborieau V,
Lung cancer susceptibility locus at 5p15.33. Nat McKay JD, Chabrier A, Hung RJ, Boffetta P, et al.
Genet. 2008 Dec;40(12):1404-6. 11. Wang Y, Association between a 15q25 gene variant, smoking
Broderick P, Webb E, Wu X, Vijayakrishnan J, quantity and tobacco-related cancers among 17 000
Matakidou A, et al. Common 5p15.33 and 6p21.33 individuals. Int J Epidemiol. 2009 Sep 23. 25. Le
variants inÁuence lung cancer risk. Nat Genet. 2008 Marchand L, Derby KS, Murphy SE, Hecht SS,
Dec;40(12):1407-9. 12. Rafnar T, Sulem P, Stacey Hatsukami D, Carmella SG, et al. Smokers with the
SN, Geller F, Gudmundsson J, Sigurdsson A, et al. CHRNA lung cancer-associated variants are exposed
Sequence variants at the TERT-CLPTM1L locus to higher levels of nicotine equivalents and a
associate with many cancer types. Nat Genet. 2009 carcinogenic tobacco-speciÀc nitrosamine. Cancer
Feb;41(2):221-7. 13. Rafnar T, Sulem P, Besenbacher Res. 2008 Nov 15;68(22):9137-40. 26. Freathy RM,
S, Gudbjartsson DF, Zanon C, Gudmundsson J, et al. Ring SM, Shields B, Galobardes B, Knight B,
Genome-Wide SigniÀcant Association Between a Weedon MN, et al. A common genetic variant in the
Sequence Variant at 15q15.2 and Lung Cancer Risk. 15q24 nicotinic acetylcholine receptor gene cluster
Cancer Res. 2011 Feb 15;71(4):1356-61. 14. Doll R, (CHRNA5-CHRNA3-CHRNB4) is associated with a
Hill AB. Smoking and carcinoma of the lung; reduced ability of women to quit smoking in
preliminary report. Br Med J. 1950 Sep pregnancy. Hum Mol Genet. 2009 Aug
30;2(4682):739-48. 15. Wynder EL, Graham EA. 1;18(15):2922-7. 27. Thorgeirsson TE, Stefansson K.
Tobacco smoking as a possible etiologic factor in Commentary: Gene-environment interactions and
bronchiogenic carcinoma; a study of 684 proved smoking-related cancers. Int J Epidemiol. 2010 Feb
cases. J Am Med Assoc. 1950 May 27;143(4):329- 1. 28. Weiss RB, Baker TB, Cannon DS, von
36. 16. Doll R, Peto R. Cigarette smoking and Niederhausern A, Dunn DM, Matsunami N, et al. A
bronchial carcinoma: dose and time relationships candidate gene approach identiÀes the CHRNA5-
among regular smokers and lifelong non-smokers. J A3-B4 region as a risk factor for age-dependent
Epidemiol Community Health. 1978 Dec;32(4):303- nicotine addiction. PLoS Genet. 2008
13. 17. Peto R, Darby S, Deo H, Silcocks P, Whitley Jul;4(7):e1000125. 29. Fowler CD, Lu Q, Johnson
E, Doll R. Smoking, smoking cessation, and lung PM, Marks MJ, Kenny PJ. Habenular alpha5
cancer in the UK since 1950: combination of nicotinic receptor subunit signalling controls nicotine
national statistics with two case-control studies. intake. Nature. 2011 Jan 30. 30. Matsumoto M,
BMJ. 2000 Aug 5;321(7257):323-9. 18. Madden PA, Hikosaka O. Lateral habenula as a source of negative
Heath AC, Pedersen NL, Kaprio J, Koskenvuo MJ, reward signals in dopamine neurons. Nature. 2007
Martin NG. The genetics of smoking persistence in Jun 28;447(7148):1111-5. 31. Kimura M, Satoh T,
men and women: a multicultural study. Behav Genet. Matsumoto N. What does the habenula tell dopamine
1999 Nov;29(6):423-31. 19. Vink JM, Willemsen G, neurons? Nat Neurosci. 2007 Jun;10(6):677-8. 32.
Boomsma DI. Heritability of smoking initiation and Hong LE, Gu H, Yang Y, Ross TJ, Salmeron BJ,
nicotine dependence. Behav Genet. 2005 Buchholz B, et al. Association of nicotine addiction
Jul;35(4):397-406. 20. Thorgeirsson TE, and nicotine’s actions with separate cingulate cortex
Gudbjartsson DF, Surakka I, Vink JM, Amin N, functional circuits. Arch Gen Psychiatry. 2009
Geller F, et al. Sequence variants at CHRNB3- Apr;66(4):431-41. 33. Hong LE, Hodgkinson CA,
CHRNA6 and CYP2A6 affect smoking behavior. Yang Y, Sampath H, Ross TJ, Buchholz B, et al. A
Nat Genet. 2010 May;42(5):448-53. 21. Liu JZ, genetically modulated, intrinsic cingulate circuit
Tozzi F, Waterworth DM, Pillai SG, Muglia P, supports human nicotine addiction. Proc Natl Acad
Middleton L, et al. Meta-analysis and imputation Sci U S A. 2010 Jul 27;107(30):13509-14. 34. Bush
G, Vogt BA, Holmes J, Dale AM, Greve D, Jenike men at a ratio of 17:1 yet 20 years later ADC
MA, et al. Dorsal anterior cingulate cortex: a role in surpassed SCC as the most common lung cancer
reward-based decision making. Proc Natl Acad Sci U in many males populations. Currently ADC is up
S A. 2002 Jan 8;99(1):523-8. 35. Truong T, Hung RJ, to 1.5 times more common in cigarette-smoking
Amos CI, Wu X, Bickeboller H, Rosenberger A, et men and anywhere from 2 to 7 times more common
al. Replication of lung cancer susceptibility loci at in women than SCC. Outdated assertions from
chromosomes 15q25, 5p15, and 6p21: a pooled the mid 20th century cloud our impressions. Doll
analysis from the International Lung Cancer and Kreyberg described the relationship between
Consortium. J Natl Cancer Inst. 2010 Jul tobacco smoking and ADC of the lung as “slight,
7;102(13):959-71. 36. Wu C, Hu Z, Yu D, Huang L, if any,” in the late 1950s and early 1960s. At that
Jin G, Liang J, et al. Genetic variants on time their conclusion might have been correct since
chromosome 15q25 associated with lung cancer risk women had not yet begun to abuse cigarettes to
in Chinese populations. Cancer Res. 2009 Jun the same extent as men, and cigarettes were simply
15;69(12):5065-72. 37. Spitz MR, Amos CI, Dong made from tobacco leaves and smoked without
Q, Lin J, Wu X. The CHRNA5-A3 region on Àlters. The 10-fold increase in lung ADC incidence
chromosome 15q24-25.1 is a risk factor both for in men from 1959 through at least the early 1990s
nicotine dependence and for lung cancer. J Natl in the United States, Japan, and parts of Europe is
Cancer Inst. 2008 Nov 5;100(21):1552-6. 38. directly attributable to changes in cigarettes. The
Schuller HM. Is cancer triggered by altered market share of Àltertip cigarettes rose from less than
signalling of nicotinic acetylcholine receptors? Nat 1% in 1950 to 80% in 1970. Filters remove large
Rev Cancer. 2009 Mar;9(3):195-205. 39. Mills RE, particles from cigarette smoke, and thus reduce the
Walter K, Stewart C, Handsaker RE, Chen K, Alkan deposition of these particles in central airways where
C, et al. Mapping copy number variation by SCCs usually develop. The resultant decline in SCC
population-scale genome sequencing. Nature. 2011 incidence has not been subtle. Filters also allow
Feb 3;470(7332):59-65. 40. Durbin RM, Abecasis smokers to inhale more deeply than with unÀltered
GR, Altshuler DL, Auton A, Brooks LD, Gibbs RA, cigarettes. Deep inhalation carries tobacco-speciÀc
et al. A map of human genome variation from carcinogens beyond the main airways into peripheral
population-scale sequencing. Nature. 2010 Oct lung and into contact with bronchiolar and alveolar
28;467(7319):1061-73. epithelium, the site of adenocarcinogenesis. Low
Keywords: Nicotine Addiction, CHRNA5, tar and low nicotine cigarettes have also altered the
CHRNA3, Lung cancer smoking habits of abusers. While smokers in the
1930s and 1940s took approximately one 35 ml puff
per minute, current users take up to three puffs per
The Lung Cancer Epidemic Monday, 4 July 2011 08:30-10:00 minute with recorded volumes as high as 65 ml.
Blended reconstituted tobacco, also introduced in the
PL01.4 CHANGING 1950s, releases measurably higher concentrations of
HISTOPATHOLOGICAL PICTURE OF nitrosamines, a potent inducer of ADC in rodents,
LUNG CANCER? than tobacco leaf products. In women, ADC has
Douglas Flieder been the most frequent subtype of lung cancer since
Pathology, Fox Chase Cancer Center/United States reliable statistics were collected starting in the 1960s.
Of America Squamous histology might have been more prevalent
before the introduction of Àltered cigarettes, but
Abstract: Although one might be tempted to suggest given the relatively small number of women smokers
that we are experiencing an explosive 21st century in the Àrst decades of the past century and our
rise in the incidence of lung adenocarcinoma (ADC), current understanding of lung cancer risk factors
such is not the case. The slow and inexorable in women, it is difÀcult to imagine a time when
displacement of squamous cell carcinoma (SCC) squamous histology was more common than ADC.
by ADC as the most common lung cancer subtype Thus, when one speaks of a large-scale increase
began more than 50 years ago. Population- and in numbers of women with lung ADC, one should
hospital-based studies in the North America, Asia recognize that these incidence rates simply mirror the
and Europe support this contention. In the 1950s rapidly growing number of women smokers over the
SCC predominated over ADC in cigarette-smoking past Àfty years rather than a peculiar shift in female
lung cancer histology. Our heightened awareness of of adenocarcinoma subtypes appear stable since
lung cancer in non-smokers likely contributes to the WHO deÀnitional changes in 1999. Lung cancer
impression that we are experiencing a surge in ADC has risen from obscurity at the start of the 20th
cases. However, it is not certain whether lung cancer century to occupy the throne of deadly cancers one
incidence rates in non-smokers changed. ADC is century later. Equality among the sexes to partake
almost 3.5 times more frequent than squamous cell in unhealthy behaviors and the evolution of the
histology in non-smokers and globally this subset cigarette into a Ànely developed killing machine are
is more frequent in women, particularly Asian responsible for the ascendancy of ADC over SCC as
women. Increased smoking cessation, at least in the most common histologic subtype of lung cancer.
parts of the Western world, may also contribute to Purported biases did not play a large role.
a relative rise of adenocarcinoma cases since the Keywords: Adenocarcinoma, lung
risk of developing a pulmonary SCC drops faster
than the risk of developing an adenocarcinoma in
ex-smokers. While diagnostic advances, including Session PL02: Lung Cancer in
changes in tissue procurement techniques and Never-Smokers
tumor classiÀcations cannot be ignored, they are
not primarily responsible for the changing trend
Tuesday, 5 July 2011
in lung cancer histology epidemiology. Historical
confounders such as a 1970s European belief that
many ADCs in the lung were metastases rather Lung Cancer in Never-Smokers Tuesday, 5 July 2011 08:30-10:00
than primary malignancies, or the practice in many
nations not to subtype non-small cell carcinomas are PL02.1 ENVIRONMENTAL FACTORS
not responsible for the increase in adenocarcinoma CONTRIBUTING TO LUNG CANCER IN
cases. Furthermore, newer technologies introduced in NEVER-SMOKERS
the late 1960s through the 1980s, including Áexible Michael Thun
bronchoscopy and transthoracic needle aspirates, Epidemiology, American Cancer Society/United
allowed for relatively non-invasive sampling of States Of America
peripheral lesions but did not cause a rise in lung
cancer cases. With regard to histologic classiÀcation, Abstract: Environmental Factors Contributing to
pathologists until recently were encouraged to label Lung Cancer in Never-Smokers Michael J Thun
these cancers simply non-small cell carcinomas and American Cancer Society Although active tobacco
there is no evidence that peripheral lesions were smoking is by far the leading cause of lung cancer
misdiagnosed as ADCs. Only over the past few worldwide, the number of cases caused by other
years have pathologists used immunohistochemical factors is still substantial. For example, in the United
stains to subtype morphologically challenging States (U.S.) and Europe, exposure to factors other
non-small cell carcinomas and studies suggest that than active cigarette smoking are estimated to
proposed diagnostic algorithms lead to accurate account for about 10% of all lung cancer deaths in
diagnoses of localized and advanced lung cancer men and 15-20% in women. This corresponds to
on most small biopsies and cytologic specimens. approximately 19,000 to 23,000 of the more than
ModiÀcations and personal interpretations of lung 157,300 lung cancer deaths projected to occur in
cancer classiÀcation schemes hardly impact today’s the U.S. in 2010. If these deaths were considered
epidemiologic perspective on lung cancer histology. as a separate category, they would rank eighth
ClassiÀcation changes in the 1970s and 1980s shifted among most common fatal cancers in America.
signiÀcant numbers of SCCs into the large cell Environmental factors other than active smoking
carcinoma category, and cases previously considered that are known to cause lung cancer include
large cell carcinomas were diagnosed as solid occupational or residential exposure to secondhand
ADCs when mucin stain were positive. However, smoke, radon gas, asbestos (particularly among
several contemporary cohort reviews found that smokers), certain metals (chromium, cadmium.
such changes did not signiÀcantly alter overall arsenic), some organic chemicals, ionizing radiation,
results. More recent World Health Organization air pollution (particularly from burning coal), and a
classiÀcation modiÀcations did not alter fundamental history of tuberculosis or other chronic inÁammatory
diagnostic groupings. Furthermore, incidence rates conditions. Besides these established risk factors,
several other exposures have been proposed to than men who have never smoked. It merely reÁects
increase risk. These include infection with certain the reality that there are many more older women
stains of human papillomavirus and chronic than men who have never smoked regularly. Given
inhalation of cooking fumes and/or incense. Two the substantial disease burden from lung cancer
other characteristics that are consistently associated among never-smokers, more research is needed
with increased lung cancer risk are leanness and to understand the important causal factors and to
physical inactivity. However, these associations strengthen prevention efforts, especially in high risk
have been observed predominantly among smokers. populations.
Because cigarette smoking is strongly associated Keyword: lung cancer, never-smokers, second-hand
with leanness and physical inactivity as well as smoke, radon
lung cancer, these observations may represent
residual confounding by smoking rather than
causal relationships. The incidence of lung cancer Lung Cancer in Never-Smokers Tuesday, 5 July 2011 08:30-10:00
among women in certain areas of Northern China is
higher than that among female smokers in Europe PL02.2 MOLECULAR PATHOGENESIS
and North America for reasons that are currently OF LUNG CANCER IN NEVER-SMOKERS
unrelated to smoking. Less than Àve percent of Pierre P. Massion
all Chinese women smoke, and the prevalence Pulmonary Medicine, Vanderbilt University/United
of female smoking is generally under seven or States Of America
eight percent, even in the highest risk areas. The
remarkably high regional risk of lung cancer has Abstract: Although tobacco smoking is responsible
been attributed to indoor air pollution from cooking for the majority of lung cancers, up to 25% of lung
and heating with low quality coal, in conjunction cancers worldwide arise from individuals who never
with indoor exposure to second hand smoke from smoked. These tumors more commonly arise from
male smoking. While female smoking is actually the distal airways, among younger individuals and
decreasing among Chinese women at the national more commonly women. Familial genetic risk ,
level, the lung cancer burden among Chinese women hormonal, environmental and viral factors are being
is already large because of the high background discovered. The molecular pathology of these tumors
risk and massive population. WHO estimates that is clearly different and much light has been shed on
never-smokers currently account for 30% of lung these tumors in the last 5 years. Lung tumors from
cancers in China. Never smoking women in China non-smokers use biological pathways differently
will confront an even greater risk if and when the including differences in chromosomal segregation
cultural taboos that deter female smoking begin to and chromatin alterations to reach a malignant
erode in urban centers, as may already be happening phenotype. Typically a lower number of differently
in among young middle class women. Publications expressed genes, lower mutation rate are found
about lung cancer risk in relation to smoking status among them and with different pattern of mutations,
and gender often confuse proportions with rates particularly for EGFR, Kras p53 and EML4–ALK.
(per 100,000 people per year) and draw erroneous These differences raise the hypothesis that the Àeld
claims about risk. For example, while it is true that of cancerization is quite different in non-smokers.
adenocarcinoma comprises a larger proportion of This presentation will review the major discoveries
all lung cancers in women than men, this does not in the Àeld and discuss some unanswered questions
mean that the risk (or incidence rate) of developing and strategies to try to address them. What are the
pulmonary adenocarcinoma is higher in women mechanisms controlling overall genome instability
than men irrespective of smoking. In reality, the in non-smokers? Is the airway epithelium a surrogate
incidence rate is lower in women than men, but of lung cancer in non-smokers? What is the mutation
the proportion is higher because an even greater rate in the epithelium of smokers vs non-smokers?
gender difference in incidence of other histological Is the response to inÁammation different among
subtypes (particularly squamous and small cell nonsmokers with familial predisposition? What are
carcinomas) Similarly, while the proportion of lung the characteristics of cancer stem cells in never-
cancer patients who have never smoked regularly smokers? Recent discoveries already suggest that
is higher in women than men, this does not indicate some key molecular drivers have been identiÀed.
that women who have never smoked have higher risk These are the focus of targeted therapies with
impact on patients outcome. These results have risk factors for Chinese housewives to develop lung
important implications in urging the community to cancer(8-11). Cumulative exposure to cooking oil
offer genetic testing, to develop new personalized fumes from frying was associated with increased
therapeutic strategies and to answer the need for risk of lung cancer in never-smoking women.
improving our understanding of the molecular Additionally, meta-analysis studies conducted in
pathogenesis of this deadly disease. China consistently suggested that risk of lung cancer
Keywords: molecular pathogenesis, never smoker, increased as a consequence of the exposure to
personalized domestic coal used for heating and cooking, indoor
exposure to coal dust, chronic exposure to cooking
oil vapor, and ETS(12). In Japan, a high risk of
Lung Cancer in Never-Smokers Tuesday, 5 July 2011 08:30-10:00 lung adenocarcinoma in females was observed for
exposure to smoke in the workplace combined with
PL02.3 LUNG CANCER IN NEVER- exposure to husbands who smoke. Both endogenous
SMOKING ASIAN FEMALES and extraneous estrogen might be involved in the
Caicun Zhou etiology of lung cancer in Japanese never-smoking
Oncology, Shanghai Pulmonary Hospital, Cancer women (13).
Institute, School Of Medicine, Tongji University/China Single nucleotide polymorphisms (SNPS) of
many genes including IL 1ơ-31 T/T, IL -1RN,
Abstract: Lung cancer is a major health burden CYP 1B1, CYP 1A1, MPO, GSTP1, and XRCC1
worldwide, accounting for 12% of all new cancer have been studied to determine their relationship
cases (1). Most of lung cancer cases are associated with risk of lung cancer in Asian female patients
with a personal history of direct tobacco smoking (14,15). ERCC2 751 variant genotypes (AC/CC)
(DTS). But, the proportion of never-smoking patients were found to be associated with increased risk of
with lung cancer has been signiÀcantly increasing lung adenocarcinoma, especially in those without
over the past 30 years, from 15.9% in the 1970s to exposure to cooking oil fumes or to fuel smoke (16).
32.8% in the 2000s(1,2). Most studies on lung cancer Odds ratios of lung cancer across increasing levels
in never-smokers have emerged from Asia, as the of cooking dish-year were 1, 1.17, 1.92, 2.26 and
smoking prevalence rate in Asia is lower than that 6.15, respectively(17). A genome-wide association
in west. More and more evidence suggests that lung study of lung cancer in never-smoking women
cancer in never-smokers is a distinct disease in terms revealed that 5p15.33 locus was associated with risk
of carcinogenesis, clinical characteristics, molecular of lung adenocarcinoma(18). The most signiÀcant
biology, etc (3-5). This review summarizes some association was for rs2736100 on chromosome
data on lung cancer in non-smoking Asian women. 5p15.33. This Ànding was independently replicated
The majority of Asian women with non-small cell in 7 studies from East Asia(19,20). We compared
lung cancer (NSCLC) were never-smokers (76.3% frequencies of SNPs of 10 genes including 8 DNA
in women vs. 9.9% in men)(3). Never-smokers with repair genes among female and male NSCLC
NSCLC were found to be disproportionately Asian patients with or without smoking history. SNPs of
women with adenocarcinoma. Data from 6 different these genes were comparable between both genders
cohorts showed that the truncated age-adjusted and not different by smoking status.
incidence rates of lung cancer in never smokers Lung cancer in never-smoking Asian women
ranged from 14.4 to 20.8% per 100,000 person-years may have different molecular biology (21). It is
in women and 4.8 to 13.7% per 100,000 person- well known that smoking is associated with more
years in men, supporting earlier observations that frequent methylation of some genes such as p16
women were more likely than men to have never- and MGMT(22) or their different mutation proÀles
smoking-related lung cancer (5,6). such as epidermal growth factor receptor (EGFR),
Many factors including air pollution, cooking oil KRAS, EML4-ALK and cMET, etc(18-27). Lung
fumes, exposure to environmental tobacco smoke cancer, especially adenocarcinoma, in never-smokers
(ETS), and family history of lung cancer may is associated with more frequent mutations of
be related with increased risk of lung cancer in EGFR and EML4-ALK and less frequent mutations
never-smoking Asian women(1,5,7). Studies from of KRAS and c-MET. Studies from Hong Kong,
Shanghai, Shenyang, Gansu, and Taiwan have mainland China, and Taiwan showed incidence
demonstrated that cooking oil fumes were one of of KRAS mutation was 13-19% in men with
lung adenocarcinoma but 0% in women. This is EGFR tyrosine kinase inhibitor (TKI) proves to
not surprising, as it was now known that KRAS be more effective in Asian never-smoking women
mutation is due to the mutagenic effect of tobacco with NSCLC (35,36). Overall response rate to
smoking and the majority of Chinese female patients EGFR TKI was 52% in never-smoking women,
are never-smokers. EGFR mutation is reported to 33% in never-smoking men, 0% in smoking women
be over 60% in never-smoking female patients, and 12% in smoking men. According to the Asian
signiÀcantly higher than that in male patients. But subgroup analysis of TRUST study, progression
EGFR mutation is comparable in its incidence (over free survival (PFS) and overall survival were 9.2
60%) between never-smoking men and women in months and 20.3 months in never-smoking women
China and Japan (25,28-29). EGFR mutation was with nonsquamous tumors, respectively. Disease
also found to be highly associated with high copy control rate and response rate were higher in never-
numbers or over-expression of EGFR. Some studies smoking women. In the IPASS study, geÀtinib was
found that ETS exposure was inversely related to associated with signiÀcant improvement in response
incidence of EGFR mutation (38.5% vs. 61.4%). rate, PFS, toxicity proÀle, and quality of life (QOL)
Patients with ETS exposure also showed a lower when used as the 1st line treatment for never- or mild
response rate to EGFR TKI than patients without ever-smokers with adenocarcinoma compared with
ETS exposure (24.6% vs. 44.8%)(30). Moreover, doublet chemotherapy. Female patients accounted
EML4-ALK fusion is more often detected in for over 80% of the study population. Nevertheless,
the never-smoking adenocarcinoma of the lung. overall survival was not different between the 2
EML-4 ALK fusion was found in 16.13% of lung arms because of high post-study cross-over to EGFR
adenocarcinoma and 19.23% in never-smokers and TKI in chemotherapy arm (29). In the OPTIMAL
42.28% in adenocarcinoma lacking mutation of study, both female and male patients harboring
EGFR or KRAS (31). In another study, the incidence EGFR mutations obtained much more clinical
of EML4 ALK was 15.8% in never-smoking men, beneÀt from erlotinib therapy compared with
6.5% in never-smoking women, 1.5% in ever- chemotherapy (37). PFS was slightly better in the
smoking men, and 0% in ever-smoking women women than men (HR: 0.13 vs. 0.27). The response
(25). EGFR mutations were mutually exclusive with rate to chemotherapy was not different between
KRAS mutations or the EML4-ALK fusion gene. never-smoking women and men (20.2% vs. 23.8%),
The frequency of HER2 mutations was found to be but signiÀcantly different between ever-smoking
4.3% in the Oriental never-smoking women with women and ever-smoking men (31% vs. 23.6%).
lung adenocarcinoma and 11% in those lacking Women demonstrated modestly longer PFS than men
EGFR mutations (32). MET mutation was also often when treated with chemotherapy, with no difference
found in Asian patients with NSCLC. But it was observed in response rate, serious adverse events, or
less often observed in never-smokers than smokers QOL.
and less often in women than men, especially Never-smoking and Asian ethnicity have been
for MET N375S mutation, which was thought to found to be favorable factors for overall survival
be responsible for resistance to MET inhibitors in NSCLC (2,38). Japanese and Korea ethnicities
(33). In China, about 90% of never-smokers with had longer overall survival in NSCLC compared
adenocarcinoma harbored targetable oncogenic with Caucasians. Never-smoking Asian female
kinase mutations, including 78.8% with EGFR patients survived longer than never-smoking Asian
mutation, 5.8% with EML4-ALK fusion, 3.8% with men regardless of treatment (2,34). But some
HER2 mutation, and 1.9% with KRAS mutation study showed the prognosis of never-smoking men
(28). In another study, EGFR mutation was prevalent with adenocarcinoma was similar to that of never-
in never- smokers of both genders with lung smoking women (39).
adenocarcinoma (78.9 % vs. 74.1%) while KRAS In conclusion, lung cancer in never-smoking Asian
mutation was quite rare (0% vs. 3.7%) (25). women is a distinct disease. NSCLC is associated
Lung cancer in never-smoking Asian women has with high proportion of adenocarcinoma and higher
different clinical features. There were more cases of incidence of EGFR mutation and the EML4-ALK
adenocarcinoma (>80%), stage IA disease, and fewer fusion gene, but less K-ras mutation and cMET
co-morbidities (2). Never-smoking women with lung mutation. Some SNPs may be associated with
cancer were comparatively younger at the time of increased risk of lung cancer in never-smoking Asian
diagnosis compared with smoking women (34). women. Cooking oil vapor, ETS, etc., are believed to
be particular risk factors for these patients Because factors, hormone use and the risk of lung cancer
of the distinctive nature of their disease, never- among middle-aged never smoking Japanses women
smoking Asian women have a favorable prognosis. : a large scale population-based cohort study. Int J
Those harboring positive EGFR mutation should Cancer 2005; 117: 662-666
receive EGFR TKI in the 1st line setting. 14. Lim WY, Chen Y, Mohamed Ali S, et al.
References: Polymorphisms in inÁammatory pathway genes, host
1. Lam WK. Lung cancer in Asian women- the factors, and lung cancer risk in Chinese female never-
environment and genes. Respirology 2005; 10: 408- smokers. Carcinogenesis Advance 2011, Jan 20
417. 15. Yoon KA, Kim JH, Gil HJ, et al. CYP1B1,
2. Kawaguchi T, Matsumura A, Fukai S, et al. CYP1A1, MPO and GSTP1 polymorphisms and lung
Japanese ethnicity compared with Caucasian ethnicity cancer risk in never-smoking Korean women. Lung
and never-smoking status are independent favorable Cancer 2008; 60: 40-46
prognostic factors for overall survival in non-small 16. Yin Z, Su M, Li X, et al. ERCC2, ERCC1
cell lung cancer. A collaborative epideminologic study polymorphisms and haplotypes, cooling oil fume and
of the National Hospital Organization Study Group lung adenocarcinma risk in Chinese non-smoking
for Lung Cancer (NHSGLC) in Japan and a Southern females.
California Regional Cancer Registry Databases. JTO 17. Yu ITS, Chiu Y, Au JSK, et al. Dose-response
2010; 5: 1001 relationship between cooking fumes exposure and
3. Thun MJ, Hannan LM, Adams-Campbell LL, et al. lung cancer among Cchinese non-smoking women.
Lung cancer occurrence in never-smokers: an analysis Cancer Res 2006; 66: 4961
of 13 cohorts and 22 cancer registry studies. PLoS 18. Hsiung CA, Lan Q, Hong YC, et al. The 5p15.33
Med 2008; 5: 1357 locus is associated with risk of lung adenocarcinoma
4. Yano T, Miura N, Takenak T, et al. Never-smoking in never-smoking females in Asia. PLoS Genetics
nonsmall cell lung cancer as a separate entity. 2010; 6(8): 1
Clinicopathologic features and survival. Cancer. 2008 19. Jin G, Xu L, Shu Y, et al. Common genetic
Sep 1;113(5):1012-8. variants on 5p15.33 contribute to risk of lung
5. Scagliotti GV, Longo M, Novello S. Non-small cell adenocarcinoma in a Chinese population.
lung cancer in never smokers. Curr Opin Oncol 2009; Carcinogenesis. 2009 Jun;30(6):987-90.
21: 99-104 20. Kang JU, Koo SH, Kwon KC, et al.. Gain at
6. Wakelee HA, Chang ET, Gomez SL, et al. Lung chromosomal region 5p15.33, containing TERT, is
cancer incidence in never smokers. J Clin Oncol 2007; the most frequent genetic event in early stages of non-
25:472–478. small cell lung cancer. Cancer Genet Cytogenet. 2008
7. Zhao H, Gu J, Xu H, et al. Meta-analysis of the Apr 1;182(1):1-11.
relationship between passive smoking population in 21. Subramanian J, Govindan R,. Molecular genetics
China and lung cancer. Chin J Lung Cancer 2010, 13: of lung cancer in people who have never smoked.
617 Lancet Oncol 2008; 9: 676
8. Gao YT, Blot WJ, Zheng W et al. Lung cancer 22. Liu Ym Lan Q, Siegfridl JM, et al. Aberrant
among Chinese women. Int. J. Cancer 1987; 40: promoter methylation of p16 and MGMT genes in
604–9. lung tumors from smoking and never-smoking lung
9. Wang TJ, Zhou BS, Shi JP. Lung cancer in non- cancer patients. Neoplasia 2006; 8: 46-51
smoking Chinese women: a case-control study. Lung 23. Toyooka S, Matsuo K, Shigematsu, et al. The
Cancer 1996; 14 (Suppl. 1): S93–8. impact of sex and smoking status on the mutational
10. Metayer C, Wang Z, Kleinerman RA et al. spectrum of epidermal growth factor receptor gene in
Cooking oil fumes and risk of lung cancer in women non-small cell lung cancer.
in rural Gansu, China. Lung Cancer 2002; 35: 111–7. 24. Tam IYS,Chung LP,Suen WS,etal. Distinct
11. Ko YC, Cheng LS, Lee CH et al. Chinese food epidermal growth factor and KRAS mutation patterns
cooking and lung cancer in women nonsmokers. Am. in non-small cell lung cancer patients with different
J. Epidemiol. 2000; 151: 140–7. tobacco exposure and clinicopathologic features.
12. Zhang Y, Chen K, Zhang H, et al. Meta-analysis 25. Wong DWZ, Leung ELH, So KKT, et al. EML4-
of risk factors on lung cancer in non-smoking Chinese ALK fusion gene is involved in various histologic
female. Chin J Epidermiol 2001; 22(2): types of lung cancers from nonsmokers with wild-type
13. Liu Y, Inoue M, Sobue T, et al. Reproductive EGFR and KRAS.
26. Wang YC, Lee HS, Chen SK, et al. Analysis of versus carboplatin plus gemcitabine, in Chinese
K-ras gene mutations in lung carcinomas: correlation advanced non-small-cell lung cancer patients with
with gender, histological subtypes, and clinical EGFR activating mutations. Presented at European
outcome. J Cancer Res Clin Oncol 1998; 124: 517- Society of Medical Oncology meeting. 2010
522 [Abstract LBA13].
27. Wu YL, Zhong W, Li L, et al. Epidermal Growth 38. Ahn MJ, Lee J, Park YH, et al. Korean ethnicity
Factor Receptor Mutations and Their Correlation with as compared with white ethnicity is an independent
GeÀtinib Therapy in Patients with Non-small Cell favorable prognostic factor for overall survival in
Lung Cancer: A Meta-Analysis Based on Updated non-small cell lung cancer before and after the oral
Individual Patient Data from Six Medical Centers epidermal growth factor receptor tyrosine kinase
in Mainland China. Journal of Thoracic Oncology. inhibitor era. JTO 2010; 5: 1185
2(5):430-439 39. Hau LH, Chu NM, Liu CC, et al. Sex-associated
28. Sun Y, Fang R, Gao B, et al. Comparable differences in non-small cell lung cacner in the new
rate of EGFR kinase domain mutation in lung era : is gender an independent prognostic factor ?
adenocarcinomas from Chinese Male and female Lung Cancer. 2009; 66: 262
never-smokers. Acta Pharmacologica Sinica 2010; 31: Keywords: Non-small cell lung cancer, Asian,
647-648 Females, Never-smoking
29. Mok TS, Wu YL, Thongprasert S, et al.
GeÀtinib or carboplatin-paclitaxel in pulmonary
adenocarcinoma. N Engl J Med. 2009 Sep Lung Cancer in Never-Smokers Tuesday, 5 July 2011 08:30-10:00
3;361(10):947-57.
30. Lee YJ, Cho BC, Jee SH, et al. Impact of PL02.4 LUNG CANCER IN NEVER-
environmental tobacco smoke on the incidence of SMOKERS: PROGNOSTIC
mutations in epidermal growth factor receptor gene IMPLICATIONS
in never-smoker patients with non-small-cell lung Ping Yang
cancer. JCO Health Sciences Research, Mayo Clinic/United
31. Zhang X, Zhang S, Yang X,et al. Fusion of EML4 States Of America
and ALK is associated with development of lung
adenocarcinomas lacking EG Abstract: Never smokers in the context of lung
32. Shigematsu H, Takahashi T, Nomura M, et al. cancer have been commonly deÀned as people
Somatic mutations of the HER2 kinase domain in who have smoked less than 100 cigarettes in their
lung adenocarcinoma. Cancer Res 2005; 65: 1642- lifetime.1 Physicians and scientists have long
1646 recognized that lung cancer in never smokers
33. Krishnaswamy S, kanteti R, Duke-Cohan JS, et (LCINS) is a very different disease than lung cancer
al. Ethnic differences and functional analysis of MET in smokers.1-5 Much attention has been drawn to
mutations in lung cancer. Clin Cancer Res. 2009 Sep LCINS, credited to the rapidly gained knowledge
15;15(18):5714-23 from genomic changes to treatment responses.6
34. Hsu LH, Chu NM, Liu CC, et al. Sex-associated Following will be an overview of Àve key points:
difference in non-small cell lung cancer in the new Lung cancer mortality and survival in never smokers.
era: is gender an independent prognostic factor? Mortality of primary lung cancer in never smokers
Lung cancer 2009; 66: 262 has been rare, especially in western countries and
35. Lim ST, Wong EH, Chuah KL, et al.GeÀtinib is regions without other environmental carcinogens.
more effective in never-smokers with non-small-cell For powerful illustrations of pre-mature mortality
lung cancer: experience among Asian patients. Br J attributable to current cigarette smoking, never
Cancer 2005; 93: 23-28 smokers have much reduced mortality for major
36. Mok T, Wu YL, Au JS, et al. EfÀcacy and safety diseases, such as lung cancer by over 95%.7 Among
of erlotinib in 1242 East/South-East Asian Patients people who have developed lung cancer, those
with advanced non-small cell lung cancer. JTO 2010; unfortunate never smokers fortunately experience
5: 1609-1615 better prognosis from treatment responses to
37. Zhou C, Wu, YL, , Cheng G, et al. EfÀcacy survival proximities,8,9 which was more pronounced
results from the randomised phase III OPTIMAL in Far East Asian populations than in U.S. White
(CTONG 0802) study comparing Àrst-line erlotinib populations.9,10 In Japanese never smokers with
advanced stage non-small cell lung cancer (NSCLC), integrated multi-level genomic approaches become
being female, having a better performance crucial in concert with established prognostic and
score, and a diagnosis of adenocarcinoma were predictive markers. Another ongoing Mayo Clinic
signiÀcant favorable survival predictors.11 Never study utilizes a systems biology approach to identify
smokers and targeted therapy – EGFR-TKI drugs overall survival (OS) related networks and gene
– a few unanswered questions. The essence of the signatures. This study has six steps and results will
breakthrough in lung cancer targeted therapy was be presented: (1) to analyze whole genome gene
the remarkably better response to epidermal growth expression proÀles in lung adenocarcinoma tumor
factor receptor tyrosine kinase inhibitors (EGFR- tissues from never smokers and Ànd a signiÀcant
TKI) by never smoking female adenocarcinoma correlation of a top candidate expression module;
patients.12 Unanswered questions include, but not (2) to compare to the conventional model consisting
limited to, seemingly inconsistent results between of clinical variables for assessing OS prediction
disease-free and overall survival, true magnitude accuracy; (3) to use Gene Ontology enrichment
(effect size) of EGFR mutation (and other analysis to locate potential biological process of the
alterations) on NSCLC prognosis with all necessary top candidate expression module; (4) to investigate
confounding factors under control, and impact of the effect of the top candidate network module at
both EGFR alterations and various speciÀc-target the germline level; (5) to identify the top 30 genes in
drugs on subgroups of progression and recurrence. the OS-related module that overlapped between the
LCINS and treatment toxicities. Although EGFR- discovery and validation data sets, namely the “hub”
TKI drugs were generally well-tolerated, unusual genes that were highly connected to other genes;
toxicities have been sporadically reported from and (6) to test these 30 genes, being up- or down-
LCINS.13,14Whether these were speciÀc to never regulated in adenocarcinoma tumor compared to
smokers and possible mechanisms warrants further adjacent normal lung tissues, and the added value of
investigation. Anaplastic lymphoma kinase (ALK) the hub genes in predicting OS.18
alterations in never smoker adenocarcinoma patients. References:
The echinoderm microtubule-associated protein- 1. Subramanian J, Govindan R: Oncology 2010
like 4 (EML4)–ALK translocation was discovered 2. Rudin CM, Avila-Tang E, Samet JM: Clinic
in NSCLC in 2007 and results in constitutively Cancer Res 2009
active ALK kinase activity.15 Several studies have 3. Samet JM, Avila-Tang E, Boffetta, P. et al: Clin
reported ALK gene rearrangement being correlated Cancer Res 2009
with never or light/former smoking status, younger 4. Sun S, Schiller JH, Gazdar AF: Nature Reviews
age, adenocarcinoma histology, and very rarely Cancer 2007
coincide with EGFR mutations, while mutually 5. Scagliotti GV, Longo M, Novello S: Curr Opin
exclusive of KRAS mutation, as summarized by Oncol 2009
Yi and colleagues.16 An ongoing Mayo Clinic 6. Yang P: Seminars in Respiratory and Critical Care
study is accomplishing four speciÀc objectives Medicine (in press) 2011
and results will be presented: (1) to assess whether 7. KenÀeld SA, Stampfer MJ, Rosner BA, et al:
IHC can be a practical tool for ALK screening in Journal of the American Medical Association 2008
adenocarcinoma with a conÀrmatory FISH test; (2) 8. Ebbert JO, Yang P, Vachon CM, et al: Journal of
to estimate the prevalence of ALK-positivity in an Clinical Oncology 2003
enriched study cohort by either or both IHC and 9. Kawaguchi T, Matsumura A, Fukai S, et al:
FISH tests; (3) to describe clinical characteristics Journal of Thoracic Oncology 2010
of cases by IHC, FISH, and combined IHC and 10. Ou SH, Ziogas A, Zell JA: Journal of Thoracic
FISH results; and (4) to evaluate clinical outcomes Oncology 2009
of ALK+ vs. ALK- cases, while controlling for 11. Kawaguchi T, Takada M, Kubo A, et al: Journal
clinically important prognostic factors, in a naturally of Thoracic Oncology 2010
followed observational patient cohort, i.e., 303 12. Lee YJ, Kim HT, Han JY, et al: Journal of
never smokers with adenocarcinoma.17 Searching for Thoracic Oncology 2010
new markers for prognosis and therapy: integrated 13. Schacher-Kaufmann S, Pless M: Case Rep Oncol
genomic networks approach. Moving forward to new 2010
discovery and validation of biomarkers with high 14. Nanda A, Dias-Santagata DC, Stubbs H, et al:
value in outcome prediction and targeted treatment, Clin Lung Cancer 2008
15. Soda M, Choi YL, Enomota M, et al: Nature of sublobar resections in terms of survival and
2007 recurrence of lesser resections. Therefore, the present
16. Yi ES, Boland JM, Maleszewski JJ, et al: Journal gold standard for the parenchymal pulmonary
of Thoracic Oncology 2011 resection for lung cancer still remains “lobectomy
17. Yang P, Kulig K, Oliviera AM, et al: European with (systematic) lymph node sampling/dissection”.
Multidisciplinary Conference in Thoracic Oncology [Radical resection for lung cancer: prognostic
(EMCTO) Conference 2011 impact of LND] Very recently, the results of large,
18. Li Y, Tang H, Sun Z, et al: American Association randomized trial to see the difference in survival
for Cancer Research (AACR) 2011 between systematic LNS and LND (ACOSOG
Keywords: Lung cancer, Never smokers, EGFR- Z0030) was published [4]. As conclusions, it has
TKI, EML4-ALK been demonstrated that only 4% of patients had a
negative LNS and found to have a positive lymph
node at mediastinal LND and that mediastinal
Session PL03: State of the Art LOND did not improve the survival or disease-free
survival in early stage lung cancer if preresection
Thursday, 7 July 2011 surgical staging of mediastinal and hilar nodes is
negative [4]. However, as cautious notes, it needs
to be mentioned that the results of this study is not
State of the Art Thursday, 7 July 2011 08:30-10:00 generalized for resectable lung cancers of any stage,
and that LND is still recommended for accurate
PL03.1 STATE OF THE ART SURGERY IN staging to determine if postoperative therapy is
2011 indicated. [Extended indication of the adjuvant
Hisao Asamura treatment] Owing to the accumulation of the results
Division Of Thoracicsurgery, National Cancer of many important clinical trials, it is becoming
Center Hospital/Japan clearer that the postoperative adjuvant chemotherapy
does improve the survival for the patients who
Abstract: The evolution of lung cancer surgery has undergo pulmonary resections for early stage lung
been well described, featuring several epoch–making cancer. Recent meta-analyses have shown that the
surgical successes and important clinical trials. postoperative chemotherapy is able to improve the
These included the Àrst successful pneumonectomy survival by 4-5%. With the use of modern regimens
by Dr. Graham at the Barnes Hospital in St. of platinum doublet, the improvement is as high as
Louis, the concept of “radical pneumonectomy” 9% [5,6,]. The clear deÀnition of the patients who
[1] and “radical lobectomy” [2] by Dr. Cahan might beneÀt from toxic postoperative chemotherapy
at the Memorial Hospital in New York, and the and the sophistication of the regime are the future
randomized, phase III study comparing the surgical challenge of this topic. [Challenges for the less
outcome of lobectomy and sublobar resections by invasive surgery] As a technical challenge, the
North American Lung Cancer Study Group [3]. minimally invasive surgical approach is becoming
Through these studies and experiences, the standard more and more common in the surgical community.
mode of parenchymal pulmonary resection for lung In the past decade, video-assisted thoracoscopic
cancer has been evolved from “pneumonectomy” to lobectomy has been performed for early stage
“lobectomy with (systematic) lymph node sampling/ lung cancer with increasing frequency. Although
dissection (LNS/LND)”. In the last randomized little direct comparison to see the superiority/
study, the comparison was made between lobectomy equivalence of survival and perioperative parameters
and sublobar resections for patients with T1N0M0 between open and video-assisted procedures has
lung cancer less than 3 cm in diameter, and it was been made, the fact is being generally accepted
shown that the prognosis of patients undergoing that thoracoscopic lobectomy is feasible and could
sublobar resection was signiÀcantly worse, and the be performed in safe [8]. However, it is necessary
local recurrence rate for sublobar resection was three to clearly answer the questions such as whether it
times higher. Although the following retrospective is possible to use the thoracoscopic approach for
studies have suggested at least the equivalent more technically demanding surgery, what is the
outcome after sublobar resection, there has been advantage of thoracoscopic lobectomy with regard
no deÀnitive demonstration of non-inferiority to not only medical but also the cost aspects, what
is the future advance of endoscopic surgery with References: [1] Cahan WG, Watson WL, Pool
the use of robotic technology. [Challenges for the JL. Radical pneumonectomy. J Thorac Surg
lesser resection] Owing to the advent of reÀned 1951;22:449-73.
chest CT images with higher resolution and CT [2] Cahan WG. Radical lobectomy. J Thorac
screening programs, smaller lung cancers are being Cardiovasc Surg 1960;5:555-72.
encountered in our practice more frequently [7]. [3] Lung Cancer Study Group, Ginsberg RJ,
Furthermore, the preoperative work-up for the Rubinstein LV. Randomized trial of lobectomy
surgical candidates has been sophisticated together versus limited resection for T1N0 non-small cell
with new technologies such as PET scan. In these lung cancer. Ann Thorac Surg 1995;60:615-23.
situations, we have become able to deal with [4] Randomized trial of mediastinal lymph node
patients with the “true” early stage lung cancers, and sampling versus complete lymphadenectomy during
therefore, the clinical signiÀcance and importance pulmonary resection in the patient with N0 or N1
of sublobar resection need to be revised by (less than hilar) non-small cell carcinoma: results of
deÀnitive clinical trials. The prognostic equivalence the American College of Surgery Oncology Group
of segmentectomy against lobectomy could be Z0030 Trial.
demonstrated only through the scientiÀc, non-biased [5] Douillard JY, Tribodet H, Aubert D, et al.;
comparison despite the recent accumulation of LACE Collaborative Group. Adjuvant cisplatin and
retrospective studies in favor of segmentectomy. For vinorelbine for completely resected non-small cell
these reasons, two large scaled studies are underway lung cancer: subgroup analysis of the Lung Adjuvant
(Table). Both studies are targeting peripheral Cisplatin Evaluation. J Thorac Oncol. 2010;5:220-8.
lung cancers less than 2 cm in diameter without [6], et al. Adjuvant chemotherapy, with or without
nodal involvement, and the accrual of more than postoperative radiotherapy, in operable non-small-
1,000 patients is planned. The future international/ cell lung cancer: two meta-analyses of individual
regional collaboration must be encouraged to patient data. Lancet. 2010;375:1230-1.
draw meaningful conclusions from these studies. [7] International Early Lung Cancer Action Program
Otherwise, the indication of segmentectomy Investigators, et al. Survival of patients with stage I
for peripheral lung cancers will continue to be lung cancer detected on CT screening. N Engl J Med.
undetermined. Randomized, phase III Trials 2006;355:1763-71
comparing lobectomy and sublobar resections. Keywords: Lung cancer, Minially invasive surgery,
lymph node dissection, Surgery
CALGB140503 JCOG0802/WJOG
Peripheral small Peripheral small (2cm or State of the Art Thursday, 7 July 2011 08:30-10:00
(2cm or less) less) NSCLC without non-
Patients
NSCLC without invasive lung cancer on
pure GGO lesion Chest CT-scan
PL03.2 STATE OF THE ART
Randomized phase
RADIOTHERAPY IN 2011
Randomized phase III / Dirk De Ruysscher
Trial design III / non-inferiority
non-inferiority trial
trial Department Of Radiation Oncology (MAASTRO),
Target number.
1297 cases Grow, Maastricht University Medical Centre/
(908 cases after 1100 cases / 3 years / 5 Netherlands
/ Entry period /
randomization) / 5 years
follow-up
years / 3.25 years
Abstract: SigniÀcant improvements have been
Standard arm Lobectomy Lobectomy
Wedge resection or
realised in radiotherapy techniques and results for
Investigational arm Segmentectomy lung cancer. Stereotactic body radiotherapy (SBRT)
Segmentectomy
Primary endpoint Overall survival Overall survival has become a routine treatment for patients with
DFS, Local Postope. pulmonary inoperable stage I-II NSCLC with local tumour
recurrence rate, functions at 3 months and 1 control rates of 90 % with few side effects. SBRT
Distant recurrence year, DFS, Local recurrence has therefore the potential to compete with surgery
rate, Postope. rate, Adverse events,
Secondary endpoints in operable patients with early stage disease.
pulmonary hospitalization, chest
function at 6 drainage term, Operative From a meta-analysis based on individual patient
months (FEV1.0, time, bleeding amount, data, it is clear that the concurrent administration
FVC) number of auto-staplers of chemotherapy and radiotherapy resulted in a
signiÀcant improvement of the 5-year survival of This is most convincingly demonstrated in patients
patients with locally advanced, stage III NSCLC. with brain metastases, but is explored in other parts
Most of these patients had multi-level N2 or N3 of the body as well. PCI was shown to increase
disease and had bulky nodes that most would survival in patients with stage IV SCLC and is now
consider to be irresectable. The role of radiotherapy considered to be standard care. SBRT has also a role
in patients with resectable N2 disease still fuels hot to play in the treatment of metastases from other
debates. These patients were randomized between tumours than lung cancer. Most studied is SBRT
surgery and deÀnitive chemo-radiation after to treat lung- or liver metastases from colo-rectal
induction concurrent chemo-radiation in the Lung cancer. The results are comparable with surgical
Intergroup Trial 0139. 75 % of the patients had resection with the same low incidence of side effects
single nodal station NSCLC. There was no difference as with SBRT for early stage NSCLC. Standard
in survival between the two arms. Although the study radiotherapy still provides palliative beneÀt for the
has often been criticised because of the high rate of majority of individuals suffering from incurable
pneumonectomies and toxic deaths in the surgery disease with e.g. bleeding, obstruction, pain,
arm, the overall median survival as well as the 5-year neurological symptoms … These achievements
survival, about 24 months and 25 %, respectively, is could only be made by a truly multi-disciplinary
at least as good as single-institutional surgical series approach involving clinicians from different
that reported on an intention to treat basis. Indeed, specialities, physicists, biologists, technicians and
a major caveat in surgical series is beside patient colleagues from imaging and computer sciences.
selection that often only patients that indeed went on Examples include the incorporation of imaging
to surgery are reported, which is mostly only 70-80 such as 4D-CT and Positron Emission Tomography
% of the initial population that initiated therapy. In (PET) in radiotherapy treatment planning, the
the same trial, a hypothesis-generating non-planned development of more accurate dose calculation
subgroup analysis was performed of patients that algorithms, and use of more sophisticated imaging
were treated with concurrent chemo-radiation (45 and dose treatment veriÀcation techniques on the
Gy) followed by lobectomy. As expected, the median treatment machine. These developments allow
survival increased to 34 months and the 5-year treatment adaptation for individual patients during a
survival to 36 %, but this is analogous as what course of radiotherapy based on changes in tumour
has been achieved with concurrent chemotherapy anatomy. These technical and biological reÀnements
and radiotherapy without surgery in patients with parallel increased standardisation, quality assurance
single nodal station N2 disease. Patients with small and patient safety at all levels of radiotherapy. As
volume disease (< 50 ml) may even have better most patients still die of their cancer, due to both
survival rates with systemic treatment concurrently distant and local relapses, there is much room
with radiotherapy. In conclusion, radiotherapy is an for improvement at all sites. This includes better
integral part in the management of stage III NSCLC. treatment options for the old and/ or frail patient,
The most signiÀcant advances that were achieved characterisation of the tumour by Àne needle
for small cell lung cancer came from radiotherapy. biopsies, circulating tumour cells and imaging,
Meta-analyses done with individual patient data tailoring systemic treatment and radiotherapy
showed that the addition of chest radiotherapy and according to these characteristics, taking into account
prophylactic cranial radiotherapy (PCI) improved intra-tumour heterogeneity, including stem cells, for
5-year survival in patients with stage I-III disease. e.g. selective boosting of these areas, heterogeneity
Further more, phase III trials and meta-analyses within organs at risk and the role of prophylactic
demonstrated that the 5-year survival increased cranial irradiation (PCI) to decrease the incidence of
from 15 % to 26 % by delivering early, accelerated brain metastases. In all these and other areas, the role
chest radiotherapy concurrently with chemotherapy. of radiotherapy is likely to increase. Finally, even
Historically, in patients with distant metastases, with these developments radiotherapy is still the
radiotherapy was considered not to inÁuence cheapest anti-cancer treatment.
survival. This is not longer the case. In selected cases Keywords: Radiotherapy, state of the art
with 1-4 distant metastases (“oligometastases”),
high-dose stereotactic radiotherapy results in local
tumour control rates of 90 % and more and a small,
but signiÀcant proportion of long-term survivors.
State of the Art Thursday, 7 July 2011 08:30-10:00 TKIs in 1st. line therapy for advanced NSCLC. A
remaining question is what the most optimal assay
PL03.3 STATE OF THE ART method for EGFR mutation testing is and what will
(MOLECULAR) PATHOLOGY IN 2011 be the most cost-effective screening test in the future.
Fred R. Hirsch Direct sequencing is considered the “gold standard”,
Department Of Medicine, Division Of Medical but more sensitive PCR-based methods for detection
Oncology, University Of Colorado, Denver/United of the most frequent mutations in exon 19 and 21 are
States Of America developed. (i. e DxS Scorpion). Another remaining
question is the clinical relevance of the less frequent
Abstract: Personalized medicine has Ànally come minor mutations found in exons 18-21. EGFR
to lung cancer and is based on molecular pathology. Resistant Mutations are reported mainly in exon
This development requires a multidisciplinary 20; T790 M mutations are the most important ones.
approach to diagnosis and management of lung This mutation accounts for about 50% of acquired
cancer patients. Many individual prognostic markers resistance to EGFR TKIs, but occurs also more rarely
often based on protein expression (IHC) have been in pretreatment specimens. The exact frequency
published, particularly in early stage NSCLC. of this mutation in pretreatment specimens is not
Similarly, many multigene classiÀers based on clear. Other EGFR Resistant Mechanisms: Several
gene expression array sets or multiple PCR gene other mechanisms for either intrinsic resistance or
expression classiÀers have shown prognostic value acquired resistance to EGFR TKIs are suggested.
in test sets, but none of them have yet been sufÀcient MET-ampliÀcation, particularly in EGFR mutation
validated for clinical use. Some predictive molecular positive tumors and IGFR has been hypothesized
markers have been established and changed as intrinsic-and/or acquired resistant mechanisms.
practice. Many candidate markers are in prospective EGFR Protein expression: has been studied in many
validation studies. New “drugable” molecular trials by IHC, and no clear association to sensitivity
abnormalities are continuously detected and multiple to EGFRTKis has been established. However, the
speciÀc targeted agents are rapidly being developed. role of EGFR IHC for cetuximab therapy is still
This development is demanding standards for tissue under investigation, and most recent data from the
acquisition, assay developments and implementation FLEX study indicate a predictive role for EGFR
into clinical practice. For tissue acquisition it is IHC at least in prediction of response to therapy.
mandatory to secure sufÀcient tissue for exact EGFR gene copy number: While EGFR gene
histopathological diagnosis and subtyping as some copy number detected by FISH has demonstrated
‘standard” chemotherapeutic agents are histological some predictive association to EGFR TKIs, its
restricted in use. While the IASLC/WHO role for clinical practice in not clear. More studies,
international histopathological classiÀcation still is particularly in EGFR wt patients are necessary.
based on conventional morphological assessment, Preliminary studies indicate a potential predictive
IHC markers are widely used for supporting the role for cetuximab, and ongoing prospective phase
histopathological subtyping and to reduce the III study (SWOG 0819) is validating this Àndings.
NSCLC NOS diagnosis. Molecular testing of the Proteomics: several prospective studies are currently
tumor tissue, particularly for EGFR mutations and ongoing for validation of the proteomic classiÀer,
ALK-gene-rearrangement, is today mandatory for Veristrat® (Biodesix, Colorado, USA). ALK-
choice of 1. line therapy for advanced NSCLC, and Gene Rearrangement: This gene abnormality (or
sufÀcient tissue (preferentially core biopsy) should abnormalities) occurs in 3-5 % of unselected patients
be secured. In many institutions this will be done with NSCLC and occurs mostly in younger females,
by having a pathologist’s assessment in conjunction never smokers with adenocarcinoma histology.
with the diagnostic procedure. While cytology are Although, a few cases are reported where both
today frequent diagnostic specimens, it is rarely ALK-gene rearrangement and EGFR-mutations
sufÀcient for both primary diagnosis and molecular occur, those are practically mutual exclusive.
testing, unless ‘tissue” blocs are made thereof. Treatment with the ALK-inhibitor, crizotinib®
Predictive biomarkers: Epidermal Growth Factor (PÀzer), demonstrated in patients with tumors
Receptor Mutations: Several prospective clinical harboring this abnormality had a response rate of
trials demonstrated the crucial role of activating 60% and DCR around 80% with a median PFS> 9
EGFR mutation testing for selection of EGFR months, despite progression on previous therapy.
The “break-apart” FISH (Abbot Diagnostics) has relatively static over the same period and will not
been standard diagnostic assay for the crizotinib® be addressed in this presentation. 1) Regarding
studies, but more and more data are reported on tumor histology, molecular proÀling studies conÀrm
other diagnostic platforms (e. g PCR and IHC). that NSCLC represents a heterogeneous group of
Encouraging data are reported for IHC compared to malignancies, linked primarily by site of origin,
FISH, and 100% correlations are reported for FISH rather than one disease. From the standpoint of
negative and IHC negative ones and for IHC 3+ and pathologic subtyping, NSCLC can be differentiated
FISH, while some discrepant results are reported into adenocarcinoma (which can be further sub-
for IHC 1+/2+. However, by standardizing the IHC classiÀed) squamous cell carcinoma, large cell
and optimization of antibodies and IHC techniques, carcinoma (neuroendocrine and non-neuroendocrine)
this assay might be more clinical useful for routine and a variable group classiÀed by pathologists
pathology screening of the ALK-gene rearrangement. as non-otherwise speciÀed (NOS). While
Other Predictive Biomarkers: Prospective clinical adenocarcinoma histology is known to correlate with
trials are currently ongoing or planned to validate a higher likelihood of response to EGFR TKIs, this
c-MET IHC and FISH (e.g MetMab, Genentech/ association does not directly translate into superior
Roche) and E-cadherin IHC (Entinostat, Syndax). survival, absent other factors such as predictive
Many other biomarkers are currently under clinical biomarkers. For example, in the BR.21 trial testing
investigations. Multigene Analyses: For future the EGFR TKI erlotinib, the hazard ratios for
individualized therapy of patients with NSCLC survival were virtually identical for adenocarcinomas
multigene analyses seems to be the “way to go”, versus squamous cell histology. For the Àrst time
and several mass mutation assays are already in use in recent history, randomized clinical trials in
(i. e SnapShot®, Sequenom®), which in the future NSCLC now suggest that histologic subtyping can
work-up might be combined with other assays, i. also be used as a chemotherapy selection factor.
e gene copy number or protein expression. Large However, even these data are primarily restricted
prospective studies are currently ongoing among to a single chemotherapeutic agent: pemetrexed.
multiple institutions in the US (e.g. the Lung In the randomized trial of Scagliotti, Gandara et al,
Cancer Mutation Consortium) performing mass comparing pemetrexed-cisplatin versus gemcitabine-
mutation analyses of patients with advanced NSCLC cisplatin, survival was superior in those patients with
with speciÀc clinical trials linked to the different non-squamous histology receiving the pemetrexed-
mutations found. based regimen. Conversely, gemcitabine-cisplatin
resulted in superior survival in patients with
squamous histology tumors. These data, combined
State of the Art Thursday, 7 July 2011 08:30-10:00 with retrospective analyses of other pemetrexed trials
in NSCLC, suggest that histologic subtype can now
PL03.4 STATE OF THE ART MEDICAL be used to select individual patients who may beneÀt
TREATMENT IN 2011 more or less from different chemotherapy regimens.
David R. Gandara From a regulatory standpoint, these Àndings have
Oncology, UC Davis Cancer Center/United States Of led the FDA in the USA to limit pemetrexed therapy
America to NSCLC patients with non-squamous histology.
Of note, analysis of the large SWOG data base,
Abstract: Systemic treatment of non-small cell among others, supports the conclusion that the
lung cancer (NSCLC) has rapidly evolved over activity of chemotherapeutic drug classes such as
the last 10 years. While platinum-based doublet the microtubule-targeted agents taxanes and vincas
chemotherapy continues to be generally accepted as is not histology-speciÀc, and that these drugs are
a standard of care in advanced stage NSCLC patients equally effective regardless of histologic subtype of
with a good performance status, with one notable NSCLC. In contrast, emerging evidence suggests
exception described below, interlinking themes of that platinum compounds are generally more active
1) histology-based therapy, 2) predictive biomarkers adenocarcinomas than squamous cell cancers, based
and 3) maintenance therapy have emerged as on differences in DNA repair capacity as discussed
dominant factors in therapeutic decision-making below, but that there is high variability between
for individual patients. In stark contrast, therapy of individual patient cancers. 2) Predictive Biomarkers:
extensive stage small cell lung cancer has remained It is quite likely that underlying molecular factors
are responsible for histology-based differences in cetuximab-containing therapy in colorectal cancer,

chemotherapy efÀcacy in NSCLC, and that testing this does not appear to be the case in NSCLC. One
at the individual patient level will be required of the most important advances of the last few years
in the future to optimize therapeutic outcomes: is development of crizotinib, a selective inhibitor
hence personalized medicine. In fact, recent data of ALK-fusion gene-positive NSCLC. It is likely
suggest that histology is at best a crude method that in the future, this paradigm of selective therapy
of molecular selection, and that tumor molecular for a molecularly-deÀned population will become
proÀling will supplant histology in the near future more the rule rather than the exception. Lastly, one
for selecting chemotherapy in individual NSCLC of the largest unmet needs in lung cancer therapy is
patients. For example, for pemetrexed a number identiÀcation of molecular selection factors for anti-
of possible predictive molecular biomarkers have angiogenic therapies, where bevacizumab represents
been described. The largest body of evidence a prime example of “untargeted use of targeted
relates to thymidylate synthase (TS), an enzyme therapy”. 3) Maintenance therapy: It is a tribute
important in DNA biosynthesis and a molecular to recent advances by lung cancer investigators
target of Áuropyrimidine- and pemetrexed-based that a discussion of maintenance therapy (deÀned
therapies. Lower TS expression levels have been as what we do after a patient has derived clinical
associated with a greater likelihood of response beneÀt from Àrst-line therapy) in advanced NSCLC
to Áuoruracil (5FU)-containing therapies in is even possible. Here, there are data in support of
gastrointestinal cancers, and to pemetrexed in “switch maintenance” chemotherapy (pemetrexed
NSCLC, mesothelioma and breast cancer. Although after Àrst-line therapy with a platinum plus non-
TS mRNA expression is statistically lower in groups pemetrexed regimen) and also for an EGFR TKI.
of patients with NSCLC of adenocarcionoma How strong the evidence is for these approaches
or large cell subtypes, compared with those of remains “in the eye of the beholder”, as well as
squamous histology, there is tremendous overlap the particulars of exactly which patients derive the
of expression ranges in individual patient tumors. greatest beneÀt. Clearly, “watch and wait” of therapy
Conversely, it should be also noted that pemetrexed with close monitoring remains a viable option in
shows limited activity in small cell lung cancer, a many patients who have responded and are then
histiology associated with characteristically high asymptomatic from their disease. An important
levels of TS expression. As noted above, even more research question to be addressed in future trials
data are emerging regarding ERCC1 and RRM1 as is whether “switch maintenance” is truly superior
molecular selection factors for platinum compounds to “early second line therapy” at the time of Àrst
and/or gemcitabine, respectively. Although a variety evidence of progressive disease. In Summary, much
of different methodologies have been employed to progress has been made in the management of
measure protein or mRNA expression of these genes, advanced NSCLC patients in the last few years. At
cross-study results are consistent in demonstrating present, integrated decision-making, supplementing
both prognostic and predictive value. A number of clinical factors with, histology and molecular factors
clinical trials are in progress worldwide attempting is now feasible. Further, it is desirable that patients
to validate these biomarkers. While the issue of how themselves engage their physicians in this decision-
to integrate these data into clinical decision-making making process, empowered by as much knowledge
outside of a clinical trial remains “in Áux”, the as possible about their own cancer and their own
presence of commercially available assays demands clinical situation. The next few years will determine
that Oncologists be up-to-date on relevant literature the pace of this transition from empiricism to
and ready to answer patient questions about use in integrated and personalized medicine.
day-to-day practice. Even more relevant in 2011 is
mutation status for EGFR as a molecular predictor
of increased efÀcacy of EGFR TKIs. Activating
EGFR mutations are typically associated with a
never-smoking history in NSCLC. Of interest, EGFR
mutation status does appear to predict for activity of
the EGFR-directed monoclonal antibody cetuximab
in NSCLC. Further, while KRAS mutations are
established as a negative predictor for beneÀt of
MINI SYMPOSIUM SESSIONS growth factor 2 (c-erbB-2)), regulation of cell

cycle (cyclins, p16, p21, retinoblastome (Rb)),
apoptosis (p53, Bax, B cell leukemia 2 (Bcl2),
Session M01: Signaling in Lung Cancer (fragile histidin triad (FHIT), survivin, mouse
double minute 2 (MDM2), p14arf, semaphorins),
Monday, 4 July 2011 inÁammation (cyclo-oxygenase 2 (COX-2), nuclear
factor kappa-light-chain-enhancer of activated B
cells (NF-KB)), invasion (metallopeptidases, tissue
Signaling in Lung Cancer Monday, 4 July 2011 10:30-12:00 inhibitors of metallopeptidases), angiogenesis
(vascular endothelial growth factor (VEGF) and
M01.3 PATHWAYS PATHOGENESIS VEGF recepteur e.i. neuropilins), cell adhesion
Céline Mascaux1, Fred R. Hirsch2 (E-cadherin, E catenin), DNA repair (checkpoint
1
Department Of Medicine, Division Of Medical 2 (CHK2), Ataxia telangiectasia mutated (ATM),
Oncology, University Of Colorado, Denver/United p53, histone H2A gene (H2AX)). We performed
States Of America, 2Division Of Medical Oncology gene expression analyses accross all stages of lung
And Pathology, University Of Colorado, Denver/ squamous carcinogenesis. Canonical pathways
United States Of America described in invasive lung carcinomas were
already activated in pre-invasive lesions, eg hepatic
Abstract: The three major histological subtypes Àbrosis/hepatic stellate cell activation, leukocyte
of lung cancer are lung squamous cell carcinoma extravasation signaling, complement system, acute
(SCC), lung adenocarcinoma (ADC) and small-cell phase responding, coagulation system, PXR/RXR
lung carcinoma (SCLC). Precursors lesions have and LXR/RXR activation, NFB signaling, cell cycle
been identiÀed for these three lesions: dyplasia G2/M DNA damage checkpoint regulation and role
and carcinoma in situ (CIS), atypical adenomatous of BRCA1 in DNA damage response. In canonical
hyperplasia (AAH) and diffuse idiopathic pulmonary pathways analyses, the activation of immune
neuroendocrine cell hyperplasia (DIPNECH) response at step 2 was also an important pattern,
are the supposed precursors of SCC, ADC and i.e. antigen presentation pathway, IL-4, IL-8 and
SCLC, respectivelly. Little is know about the IL-10 signaling, T-cell receptor signaling, natural
molecular biology of the precursors of SCLC, killer cell signaling, TREM-1 signaling, Interferon
DIPNECH. This presentation will focus on the signaling and complement system. We found by
molecular pathology and pathways of SCC and gene expression analyses that the most signiÀcant
ADC pathogenesis. Pathways pathogenesis of pathway involved in the transition between the
SCC. Morphological changes in the bronchial lesion at low risk to progress (metaplasia, mild and
epithelium preceeding the development of SCC moderate dysplasia) versus the lesion at high risk
include basal cell hyperplasia, squamous metaplasia, (severe dysplasia) was immune response including
dysplasia at three degrees (mild, moderate and tumor growth factor B (TGFB) family, tumor
severe) and carcinoma in situ (CIS). As detected necrosis factor (TNF) family, immune receptors
with a good sensitivity by using autoÁuorescence (toll-like receptors, interleukine receptors, integrin
bronchoscopy, the molecular biology of these receptors) chemokine ligands, interleukines,
lesions have been studied. Various mechanism of complement components, supressor of cytokine
molecular abnormalities are involved at the earliest signaling (SOCS) family, Sry-related HMG box
steps of SCC pathogenesis: chromosomes (loss of (SOX) family. The signiÀcant and early involvment
heterozygocity, aneuploidy), genes (mutations), of immune response in SCC development indicates
epigenic (methylations), transcriptomic changes the importance of microenvironment and the
(changes in expression level expression for mRNA potential interest of discovery interesting targets in
and miRNA), proteic changes (expression level). this pathway for chemoprevention and/or therapy.
The molecular functions and pathways that are Pathways pathogenesis of ADC. AHH are considered
altered in SCC pathogenesis include differenciation to be the precursors of ADC. These lesions are very
(cytokeratines), cell immortalization (telomerase, rare to diagnose through CT guided transthoracic
RNA component telomerase reverse transcriptase biopsies and they are mainly found on resected
(hTERT)), cellular proliferation (Ki-67, PCNA, specimens next to the tumors. Because AHH is
epidermal growth factor (EGFR) and epidermal more difÀcult to sample than SCC precursors, less
markers have been studied in the former than in structure. Remodelers work with other chromatin
the later. However it is easier to study them on factors to control packaging and unpackaging
mouse models than precursors of SCC. Many of the as the DNA elements that control chromosomal
molecular abnormalities have been found in those processes (enhancers, promoters, replication
lesions as in SCC precursors: chromosomes (loss origins) must be exposed in a regulated manner
of heterozygocity, aneuploidy), genes (mutations), to properly execute various processes, such as
epigenic (methylations), proteic changes (expression gene transcription,DNA replication, DNA repair,
level). At the early stages, in AHH, through and DNA recombination. Therefore, chromatin
studies in human samples or in mouse models, structure not only provides a packaging solution,
early molecular abnormalities have been identiÀed but also an opportunityfor regulation. There are
including cell cycle regulation (cyclines, Rb, p21), four different families of chromatin remodeling
cell proliferation (Ki-67, EGFR, c-erbB-2, K-Ras), complexes. All four utilize ATP hydrolysis to alter
apoptosis (p53, survivin), inÁammation (COX-2) histone-DNA contacts and, in addition to the ATPase
and cell immortalization (telomerase). Conclusions. domain, are able to bind to DNA and histones, and
More is know about pathways of early pathogenesis to modify and alter histones. The Àrst isolated and
in SCC than in ADC because the Àrst one is best studied of the remodeler families is the SWI/
accessible in vivo. But more therapeutic applications SNF complex. Of the 20 odd family members, 10-
of signaling pathways have practical impact on 12 form large (~2 kDa) complexes. The proteins
patients with invasive ADC so far and further have a different nomenclature from the genes. Each
development of ongoing research in biomarkers are complex contains one of the two ATPase proteins
expected to provide more therapeutic targets and (SMARCA2 gene or BRM protein, or SMARCA4
more predictive markers for response or resistance or BRG1 protein), three core proteins essential for
to speciÀc therapies for both SCC and ADC. basic remodeling activity, and several accessory
Targeting immune pathways could be interesting for proteins that determine cell and gene speciÀcity ().
chemoprevention and/or therapy in SCC. Because of its crucial role in controlling chromatin
Keywords: Carcinogenesis, pathways remodeling and histone modiÀcation which in turn
regulate cell cycle, development, differentiation
and transcription, the complex components may
Signaling in Lung Cancer Monday, 4 July 2011 10:30-12:00 function as tumor suppressor genes (TSGs) () and
mutations of SMARCA4 (mainly homozygous
M01.4 DEREGULATION OF CHROMATIN deletions) are present in lung cancer cell lines
REMODELING IN LUNG CANCER and tumors while SMARCA2 may be silenced
Adi F. Gazdar by epigenetic effects (). Some members may be
Hamon Center For Therapeutic Oncology Research, mutated in other cancers including ovarian, renal
UT Southwestern Medical Center/United States Of cell and malignant rhabdoid tumors (), including the
America accessory protein BAF250A (ARID1A). Because
preliminary data indicated that the SWI/SNF
Abstract: There exists a dynamic balance between complex was deregulated by multiple mechanisms
genome packaging and genome access. The we undertook a comprehensive analysis of the
linear length of chromosomal DNA presents a entire complex in NSCLC cell lines and tumors,
signiï¬cant topological challenge, as nearly two using multiple platforms. Such a comprehensive
meters of DNA must be packaged into a nucleus examination has never been applied to any tumor
that is about 200,000 fold smaller. The solution type. Our preliminary data indicates that multiple
involves chromatin,the collaboration among members of the complex are deregulated in a variety
specialized DNA packaging proteins (primarily of individual samples, often in concordance. Our
histones), factors for histone deposition and preliminary data are: · About half of the members
removal, histone modiï¬cation enzymes, and a set of the 20 gene complex display a wide variety of
of chromatin remodeling complexes (remodelers) homozygous or heterozygous mutations or are
().Remodelers use the energy of ATP hydrolysis inactivated by epigenetic phenomena in about 75%
to change the packaging state of chromatin by of the cell lines. Cell lines frequently have multiple
moving, ejecting, or restructuringthe nucleosome, mutations, up to 5, in individual cases. More detailed
which is the primary repeating unit of chromatin analysis of three genes, the ATPases SMARCA2
(protein = BRM), SMARCA4 (protein = BRG1) and Keywords: SWI/SNF complex, Tumor Suppressor
the accessory protein ARID1A (protein = BAF250A) Genes
indicates high levels of protein inactivation by
multiple mechanisms &ndash histone deacetylation
(SMARCA2), homozygous deletions (SMARCA4), Session M02: K-Ras Role in NSCLC
mutations (ARID1A) or DNA methylation (PHF10).
However, protein loss (Western blot analysis of Monday, 4 July 2011
nuclear fractions) indicates that these mechanisms
explain only part of loss, and that other mechanisms
probably operate at the transcriptional/translational K-Ras Role in NSCLC Monday, 4 July 2011 10:30-12:00
level. · Allelic loss of the entire complex occurs more
frequently than by chance in tumors (p = 0.002) and M02.1 K-RAS BIOLOGY
cell lines (p = 0.01), compared to the same number Rafael Rosell
of randomly selected genes (1000 permutations Hospital Germans Trias I Pujol, Catalan Institute Of
tested). Pair by pair comparisons indicate that Oncology/Spain
several gene pairs demonstrate concordant loss
at highly signiÀcant rates. Thus our preliminary Abstract: K-ras mutations alone do not signiÀcantly
data indicates widespread, frequently concordant predict response to chemotherapy or mTOR
inactivation or allelic loss of multiple members of inhibitors. Earlier studies demonstrated a relationship
the SWI/SNF complex in most if not all tumors. with chemotherapy response or prognosis by K-ras
Inactivation patterns show major differences with mutation type. Recently, different K-ras mutations in
our previous concepts regarding tumor suppressor lung cancer cell lines exhibit varying sensitivity to
genes: 1) inactivation may be uni- or biallelic and chemotherapy drugs such as cisplatin, pemetrexed,
2) multiple members of the same large functioning taxol and sorafenib . We recently observed that
unit are inactivated concordantly. Of interest, elevated levels of AEG-1 and NFKBIA correlate
haploinsufÀciency of the ARID1A gene results in with the presence of K-ras mutations (unpublished
peri-implantation embryonic lethality and prevents data). We have also examined other genes that
ES cell differentiation (). These Àndings are of modulate the activity of K-ras mutations, such as
considerable biological and possibly of clinical galectin-3 and nucleophosphamin-1 (NPM1) (See
interest. Figure). NPM1 speciÀcally interacts with K-ras on
Bibliography: 5. Rodriguez-Nieto S, Canada A, the plasma membrane and stabilises K-ras plasma
Pros E, Pinto AI, Torres-Lanzas J, Lopez-Rios F, et membrane levels. Recruitment of Gal-3 drives
al. Massive parallel DNA pyrosequencing analysis K-rasGDP nanoclustering, leading to increased
of the tumor suppressor BRG1/SMARCA4 in lung ERK activation . Mutations in exon 12 of NPM1
primary tumors. Hum Mutat. 201132:E1999-2017. 6. have been found in AML and predict response to
Medina PP, Romero OA, Kohno T, Montuenga LM, chemotherapy (See Figure). We have also examined
Pio R, Yokota J, et al. Frequent BRG1/SMARCA4- SIAH2 expression which can drive K-ras activation.
inactivating mutations in human lung cancer cell We observed that EZH2, an oncogene which
lines. Hum Mutat. 200829:617-22. 7. Varela I, activates NFÐšB and RAS, closely correlated with
Tarpey P, Raine K, Huang D, Ong CK, Stephens BRCA1 expression in a series of 60 metastatic
P, et al. Exome sequencing identiÀes frequent NSCLC patients (Santarpia et al. submitted to BJC).
mutation of the SWI/SNF complex gene PBRM1 However, in this small series of patients correlation
in renal carcinoma. Nature. 2011. 8. Wiegand KC, between levels of EZH2 and K-ras mutations was
Shah SP, Al-Agha OM, Zhao Y, Tse K, Zeng T, et not found. Due to the relevance of EZH2 in K-ras
al. ARID1A mutations in endometriosis-associated signalling, further research on this gene should be
ovarian carcinomas. The New England journal of conducted as part of the K-ras mutations project.
medicine. 2010363:1532-43. 9. Gao X, Tate P, Hu P, EZH2 mutations (Try641) have been reported in
Tjian R, Skarnes WC, Wang Z. ES cell pluripotency follicular and diffuse large B-cell lymphomas.
and germ-layer formation require the SWI/SNF BRAF mutations have been identiÀed in NSCLC,
chromatin remodeling component BAF250a. more frequently in women (9%), and only V600E
Proceedings of the National Academy of Sciences of had prognostic signiÀcance in a series of 1000
the United States of America. 2008105:6656-61. lung cancers screened (Marchetti et al. conÀdential
unpublished data) (See Figure). In addition, MEK1 cancer according to K-ras genotypes. Clin Cancer
mutations have been described at low frequencies Res 1996;2:1083-6. 3. Garassino MC, Marabese
, which could be susceptible to treatment with M, Rusconi P, et al. Different types of K-Ras
selective inhibitors. MAP3K8 (the gene encoding mutations could affect drug sensitivity and tumour
COT) is a MAPK pathway agonist driving resistance behaviour in non-small-cell lung cancer. Ann Oncol
to RAF inhibition in BRAF (V600E) cell lines 2011;22:235-7. 4. Inder KL, Hill MM, Hancock
(See Figure). Other downstream components that JF. Nucleophosmin and nucleolin regulate K-Ras
can inÁuence clinical behaviour of tumors with signaling. Commun Integr Biol 2010;3:188-90. 5.
K-ras mutations is the recently described model for Shalom-Feuerstein R, Plowman SJ, Rotblat B, et al.
PKCƣ regulation of apoptosis and survival in K-ras K-ras nanoclustering is subverted by overexpression
dependent NSCLC (See Figure). Overexpression of the scaffold protein galectin-3. Cancer Res
of PKCƣ promotes tumor progression in pancreatic 2008;68:6608-16. 6. Falini B, Mecucci C, Tiacci
cancer . Therefore, in tumors with K-ras mutations E, et al. Cytoplasmic nucleophosmin in acute
many genetic modiÀers can be relevant in delivering myelogenous leukemia with a normal karyotype.
prognostic information and for predicting response N Engl J Med 2005;352:254-66. 7. House CM,
to selective inhibitors, including MEK inhibitors , Moller A, Bowtell DD. Siah proteins: novel drug
or mTOR inhibitors. Interestingly, overexpression targets in the Ras and hypoxia pathways. Cancer
of the atypical PKCƨ confers poor prognosis in Res 2009;69:8835-8. 8. Morin RD, Johnson NA,
early NSCLC and is ampliÀed in squamous cell Severson TM, et al. Somatic mutations altering
lung cancer . LKB1/STK11 is also one of the most EZH2 (Tyr641) in follicular and diffuse large B-cell
frequently mutated tumor suppressor genes in lymphomas of germinal-center origin. Nat Genet
NSCLC . LKB1 mutations can occur concomitantly 2010;42:181-5. 9. Marks JL, Gong Y, Chitale D, et
with the presence of K-ras mutations and tumors al. Novel MEK1 mutation identiÀed by mutational
with double mutations are reported to be more analysis of epidermal growth factor receptor
sensitive to mTOR and MEK inhibitors . LKB1 signaling pathway genes in lung adenocarcinoma.
mutations are widespread but three hotspot regions Cancer Res 2008;68:5524-8. 11. Johannessen CM,
were described . LKB1 forms complexes with Boehm JS, Kim SY, et al. COT drives resistance
STE20-related adaptor (STRAD) and mouse protein to RAF inhibition through MAP kinase pathway
25 (MO25), phosphorylates and activates 13 kinases, reactivation. Nature 2010;468:968-72. 12. Symonds
including AMPK. Activated AMPK phosphorylates JM, Ohm AM, Carter CJ, et al. Protein Kinase C
TSC2, activating TSC1-2 complex, which inhibits {delta} Is a Downstream Effector of Oncogenic
RAS homologue enriched in brain (RHEB), K-ras in Lung Tumors. Cancer Res 2011;71:2087-97.
preventing activation of mTOR . 13. Mauro LV, Grossoni VC, Urtreger AJ, et al. PKC
Delta (PKCdelta) promotes tumoral progression
of human ductal pancreatic cancer. Pancreas
2010;39:e31-41. 14. Regala RP, Weems C, Jamieson
L, et al. Atypical protein kinase C iota is an oncogene
in human non-small cell lung cancer. Cancer Res
2005;65:8905-11. 15. Ding L, Getz G, Wheeler DA,
et al. Somatic mutations affect key pathways in lung
adenocarcinoma. Nature 2008;455:1069-75. 16.
Mahoney CL, Choudhury B, Davies H, et al. LKB1/
KRAS mutant lung cancers constitute a genetic
subset of NSCLC with increased sensitivity to
MAPK and mTOR signalling inhibition. Br J Cancer
2009;100:370-5. 17. Sanchez-Cespedes M. A role
References: 1. Mitsudomi T, Steinberg SM, Oie for LKB1 gene in human cancer beyond the Peutz-
HK, et al. ras gene mutations in non-small cell Jeghers syndrome. Oncogene 2007;26:7825-32. 18.
lung cancers are associated with shortened survival Marcus AI, Zhou W. LKB1 regulated pathways in
irrespective of treatment intent. Cancer Res lung cancer invasion and metastasis. J Thorac Oncol
1991;51:4999-5002. 2. Rosell R, Monzo M, Pifarre 2010;5:1883-6.
A, et al. Molecular staging of non-small cell lung Keywords: K-ras, EGFR mutations, oncogene, LKB1
K-Ras Role in NSCLC Monday, 4 July 2011 10:30-12:00 worse outcome (HR 1.09, p=0.39; adenocarcinoma
HR 1.03, p=0.93). KRAS as a Predictive Marker
M02.3 SYNTHETIC LETHAL The role of KRAS in activating the AKT pathway
APPROACHES TO TACKLE RAS suggests a potential role as a predictive marker for
MUTANT NSCLC resistance. JBR.104 that compared adjuvant cisplatin/
Ji Luo vinorelbine to observation in resected stage IB-
Medical Oncology Branch, National Cancer II NSCLC included prospective evaluation and
Institute/United States Of America stratiÀcation by RAS status. The 333 patients with
WT-RAS enjoyed signiÀcant survival beneÀt from
Abstract: NSCLCs with Ras mutation present chemotherapy (HR=0.69, p=0.03). In contrast among
a major therapeutic challenge. Agents targeting 117 patients with mutated RAS, there was no beneÀt
Ras farnesyl transferase or Ras effectors such (HR 0.95, p=0.87). However, the interaction test of
as MEK have only met with limited success. To chemotherapy effect in WT versus mutant RAS was
better understand the mechanism of Ras-driven non-signiÀcant (interaction p=0.29). Similar results
oncogenesis and identify additional therapeutic were found in the LACE-Bio analysis. Patients
targets, we and others recently carried out RNAi with WT-KRAS derived modest beneÀt from
synthetic lethal screens to evaluate the genetic adjuvant chemotherapy (HR 0.89, p=0.20); those
dependencies of cancer cells with Ras mutation. with mutations did not beneÀt (HR 1.02, p=0.91)5.
These studies have identiÀed a number of genes However, once again the interaction p-value was
operating in diverse cellular pathways that are more not signiÀcant (interaction p=0.50). This poses
critical for the viability of Ras mutant cells compared an important clinical dilemma. In the absence of
to Ras wild type cells. This reÁects the cancer cell’s signiÀcant interaction (in the statistical sense),
enhanced need for stress-relief and survival genes – a do the results justify making adjuvant treatment
phenomenon we call “non-oncogene addiction” that decisions based on KRAS status? The answer likely
can be exploited for cancer therapeutics. is “No” at this time. The oncology community
Keywords: ras, synthetic lethality, RNAi, genetic must be held to a very high level of evidence in
screen order to withhold a treatment, and in the absence
of prospectively validated studies, this remains a
question of research interest. In advanced NSCLC,
K-Ras Role in NSCLC Monday, 4 July 2011 10:30-12:00 data on the impact of KRAS on chemotherapy are
limited. Trials have been retrospective, frequently
M02.4 CLINICAL APPROACH TO K-RAS with imbalance in other prognostic factors between
MUTANT NSCLC patients with WT and mutated KRAS. Because
Frances A. Shepherd the studies were underpowered and not performed
Department Of Medical Oncology, University Health in randomized patient populations controlled for
Network, Princess Margaret Hospital And University potential confounding factors, the results remain
Of Toronto/Canada insufÀcient for use in clinical practice. Small
molecule EGFR tyrosine kinase inhibitors (EGFR-
Abstract: Clinical Approach to KRAS Mutant TKIs) now have demonstrated clinical activity in
Non-Small Cell Lung Cancer KRAS as a Àrst to third-line treatment of NSCLC6. Eberhard
Prognostic Marker Slebos et al1 were the Àrst to et al7, in their retrospective analysis of KRAS from
report that KRAS mutations occurred in ~30% of TRIBUTE, were the Àrst to suggest that KRAS
adenocarcinoma and were associated with poorer mutation might predict outcome in patients treated
prognosis. Since then, >50 retrospective studies with EGFR TKIs. Decreased survival was seen
have been reported, but with contradicting results. in patients who received erlotinib/chemotherapy
A meta-analysis of 23 studies (n=2632) and 11 compared to patients with mutations who received
restricted to 1170 adenocarcinoma reported worse chemotherapy alone and patients with WT-KRAS
outcome with RAS mutation: hazard ratio (HR) 1.39 who received chemotherapy +/- erlotinib (p=0.02).
(p=0.03) and 1.50 (p=0.1), respectively2. A meta- Among the patients with mutant KRAS, the hazard
analysis involving 1721 patients from studies of ratio for survival of erlotinib/chemotherapy versus
platinum-based adjuvant chemotherapy (LACE-Bio)3 chemotherapy was 2.1 (CI 1.1-3.8). In chemotherapy
reported KRAS mutation in 19.7%, and a modestly alone patients, KRAS mutation status did not affect
outcome. These data must be interpreted with caution vinorelbine and cisplatin post non-small cell lung
because of the small patient numbers (25 erlotinib/ cancer resection. New Engl J Med 352:2589-
chemotherapy; 30 chemotherapy). In BR.21, that 97,2005. 5. Tsao MS, Hainaut P, Bourredjem A, et
compared erlotinib to placebo, patients with WT- al. LACE-Bio pooled analysis of the prognostic and
KRAS derived signiÀcant beneÀt from erlotinib predictive value of KRAS mutation in completely
(HR 0.69, p=0.03) whereas those with mutated resected non-small cell lung cancer. Proc ESMO,
KRAS derived no beneÀt (HR 1.67, p=0.30)8. 2010 6. Wheatley-Price P, shepherd FA. Epidermal
However, the interaction was not signiÀcant growth factor inhibitors in the treatment of lung
(interaction p=0.09). Subsequent studies in the cancer: reality and hopes. Curr Opin Oncol 20:162-
maintenance and second-line settings have failed to 75,2008. 7. Eberhard DA, Johnson BE, Amler LC,
demonstrate a signiÀcant predictive role for KRAS. et al. Mutations in the epidermal growth factor
Surprisingly, unlike colon cancer, this also is true receptor and in KRAS are predictive and prognostic
for the monoclonal antibody cetuximab. Whether indicators in patients with non-small-cell lung cancer
this is due to the types of KRAS mutations seen in treated with chemotherapy alone and in combination
smoking-related NSCLC (different from those of with erlotinib. J Clin Oncol 23:5900-9,2005. 8.
colorectal cancer) remains to be explored. Therefore, Zhu CQ, da Cunha Santos G, Ding K, et al. Role
at this time, KRAS mutational status should not be of KRAS and EGFR as biomarkers of response to
used to select patients for EGFR inhibitor therapy. erlotinib in National Cancer Institute of Canada
Targeting KRAS To date, attempts to target KRAS Clinical Trials Group Study BR.21. J Clin Oncol
directly or indirectly, for the most part, have been, 26:4268-75,2008.
unsuccessful. A decade ago, numerous farnesyl Keywords: Kras, Non-small cell lung cancer,
transferase inhibitors were evaluated in combination Molecular markers
with chemotherapy. Addition of these agents led
only to increased toxicity with no improvement
in important activity or efÀcacy endpoints. More Session M03: Carcinogenesis and
recent attempts have focused on trying to block the Metastasis
effects of KRAS activation by interfering with the
pathway at various points downstream of RAS itself.
Monday, 4 July 2011
Targets under investigation include RAF, MEK,
MET, AKT and PI3K. Although some pre-clinical
studies have produced “promising” results, the Carcinogenesis and Metastasis Monday, 4 July 2011 10:30-12:00
clinical trials are too early to draw Àrm conclusions.
Summary Despite two decades of research, the true M03.1 MOLECULAR PATHOGENESIS OF
prognostic and predictive roles of KRAS mutation SQUAMOUS CELL CARCINOMA AND
status remain somewhat unclear. Furthermore, only ITS PRECURSOR LESIONS
with pooling of large well-powered studies, will it Wilbur Franklin
be possible to determine whether individual RAS Pathology, University Of Colorado, Anschutz
mutations exert different effects. At this time, there Medical Center/United States Of America
is insufÀcient evidence to select or exclude patients
from speciÀc treatment based on KRAS mutation Abstract: Since the 1960’s, it has been recognized
status. References 1. Slebos RJC, Kibbelaar RE, that in smokers at risk for lung cancer, normal
Dalesio O, et al. K-RAS oncogene activation as a mucociliary mucosa of the central airways may
prognostic marker in adenocarcinoma of the lung. replaced by squamous epithelium. This squamous
New Engl J Med 323:561-5,1990. 2. Mascaux transformation is accompanied by variable
C, Iannino N, Martin B, et al. The role of RAS cytological atypia (dysplasia) and is associated with
oncogenes in survival of patients with lung cancer: profound increases in epithelial proliferative rate
a systematic review of the literature with meta- and EGFR and HER2 expression1. In some cases,
analysis. Br J Cancer 92:131-9,2005. 3. Pignon evidence of angiogenesis is detected2. SpeciÀc
JP, Tribodet H, Scagliotti GV et al. Lung Adjuvant proteomic proÀles can be used to distinguish
cisplatin evaluation: a pooled analysis by the lACE dysplastic mucosa from epithelium3. It is postulated
collaborative group. J Clin Oncol 26:3552-9,2008. 4. that these lesions represent precursors of invasive
Winton T, Livingston R, Johnson D, et al. Adjuvant squamous carcinoma. Molecular changes that
underlie squamous dysplasia in the in the airways status and predictive power of candidate biomarkers.
of smokers are increasingly better deÀned. It is now Cytology: Sputum squamous atypia detected by
possible to construct a multistep molecular model conventional cytological examination increases the
for the central airway carcinogenesis that we discuss risk for incident cancer in smokers with a hazard
below. ratio (HR) of 2.4 overall and 10.3 for those subjects
tested 5 months before the appearance of carcinoma6.
A model for molecular progression to squamous Sputum cytology alone is therefore a standard
carcinoma against which other markers should be measured.
Gene methylation: Nested case control studies have
The initial phase of carcinogenesis is purely indicated that methylation of tumor suppressor genes
chemical with direct damage to DNA occurring as a may be predictive of lung carcinoma with 6.5 fold
result of exposure to the highly reactive compounds increased risk for carcinoma7 in a high risk cohort.
mainly in tobacco smoke that give rise to DNA FISH: Aneuploidy indicated by FISH is the most
bulky adducts and DNA methylation. Adducts and strongly predictive biomarker for lung cancer risk
methylation may interfere with DNA repair and evaluated to date. In initially cancer-free subjects
resulting double stranded breaks may results in who subsequently develop lung cancer, aneuploidy is
chromosomal recombination or partial loss. These highly correlated with clinical detection lung cancer
changes are recognized as loss of heterozygosity (HR 29.9) within 18 months. FISH aneuploidy is
(LOH) and can now be detected at high density currently being validated as a clinical early detection
throughout the genome using SNP arrays. Losses tool8.
may be small or extensive, involving a major part of
individual chromosomal arms. This phenomenon has High Throughput Approaches to Squamous
been referred to as somatic recombination, mitotic Carcinogenesis
recombination, or most recently as uniparental
disomy (UPD). Recombination may occur Increasingly studies of carcinogenesis and
continuously through the life of the premalignant premalignancy are driven by data-dense high
cell. Mutation may also occur in premalignant cells throughput techniques and several of these are
and some of these mutations may have an important described below. GWAS: GWAS studies involving
impact on the fate of the affected cells. In particular, 40,000 to 60,000 individuals have identiÀed loci
TP53 may result in increased resistance to apoptosis in three chromosomal regions (8p11, 15q25 and
and to a proliferative advantage that results in a 19q13) harboring nicotine associated genes that
spreading of tumor cells over the airways. Ongoing may affect smoking behavior9 and a locus at
mitotic recombination may result in further LOH chromosome 15q15.2 that is associated lung cancer
in genes that are important in lung carcinogenesis. risk10. This latter variant is distinct from coding
Loss of the normal copy of TP53 in a cell with variants of TP53BP that are also located at 15q15.2.
one mutant copy may result in complete loss of a To date GWAS studies have not emphasized risk
mitotic checkpoint and may lead to the complicated associations for speciÀc histological subtypes of
karyotypes that are characteristic of invasive carcinoma or premalignant lesions. Gene expression
squamous. The extent of genomic damage in fully (mRNA):Similarly, microarray technology has
formed squamous carcinoma is being revealed been used to discover predictive gene expression
by the ongoing sequencing studies. These studies changes in bronchial epithelial brushings of patients .
have identiÀed not only molecular changes that are These studies have provided an 80 gene indicator of
important in squamous carcinogenesis but also new lung cancer distinguishes smokers with from those
therapeutic targets including FGF1 ampliÀcation4 without prevalent lung cancer. These mRNA changes
and DDR25. are have not yet been used to predict lung cancer
prospectively nor predict speciÀc lung tumor types
Biomarkers of Squamous Carcinogenesis in in subjects who do not yet have cancer. Microarray
Sputum gene expression signatures have also been derived
for dysplastic lesions and have been correlated
A readily available surrogate for biopsy tissue is with dysplasia grade in squamous lesions11. We
sputum and data regarding cellular and molecular have found that gene expression changes may be
changes in sputum have been used to assess the divided into those that are related to epidermalization
of the epithelium and other changes that may be cells with mild to moderate atypia lining the
related to increased proliferative potential. miR involved alveoli and respiratory bronchioles, and is
signatures: Recent studies have evaluated miR levels considered to be a precursor lesion of peripheral-type
in dysplastic squamous lesions and identiÀed miR adenocarcinoma. At this point, abnormality of the
signatures associated with progression of dysplastic EGFR gene occurs in about 50% of cases of AAH.
changes to invasive carcinoma12. These promising AAH develops to AIS (adenocarcinoma in situ, pure
results suggests that it may be possible to use miR bronchioloalveolar carcinoma, and Noguchi type A
signatures to support histological interpretations and and B) over a long period, and meanwhile apoptotic
perhaps ultimately as a surrogate for histology. The function, such as that mediated by the p16 gene,
biological signiÀcance of these changes is currently becomes perturbed and expression of Bax inhibitor 1
being evaluated. appears. The tumor cells also acquire several allelic
Conclusions inbalances such as 13q13. At this stage, the main
Despite the availability of impressive new genetic alterations are EGFR gene mutation and anti-
technologies to assess molecular changes in apoptotic abnormality. Therefore, the tumor cells can
premalignant bronchial epithelium, clinical survive, but their growth rate is still very low. AIS
applications remain distant. New software tools for then progress to early but invasive adenocarcinoma
mapping and recording of cellular and molecular (EIA, Noguchi Type C), during which time the tumor
changes and assembly of large, properly followed acquires a malignant stroma (active Àbroblastic
cohorts may help to better deÀne the natural history proliferation) showing a characteristic phenotype. At
of central airway premalignancy. this stage, the tumor cells acquire various additional
References genetic abnormalities, such as p53 mutation and
1. Clin Cancer Res 12: 2281-8, 2006 2. Clinical allelic imbalances at 17p12-p13, 18p11, and
Cancer Research 6:1616-1625, 2000. 3. Am J Respir 11p11-p12. In particular, allelic imbalance at 8p21
Crit Care Med, 172: 1556-62, 2005 4. Sci Translat is closely associated with prognosis. Recently we
Med 2: 62 62ra93, 2010 5. Cancer Discovery compared the expression proÀles of AIS with those
doi:10.1158/2159-8274.CD-11-0005, 2011 6. Cancer of EIA showing lymph node metastasis or a fatal
Epidemiol Biomarkers Prev 17:158-62, 2008 7. outcome, and screened the differentially expressed
Cancer Res 66: 3338-44, 2006 8. Cancer Prev Res genes by cDNA microarray to identify those related
3:447-53, 2010 9. Nature genetics 42: 448-453, to tumor progression. This revealed abnormal
2010 10. Cancer Research 71:1356-1361, 2011 11. demethylation of stratiÀn (SFN) in the course of
Nature Medicine 13:362-366, 2007 12. Eur Respir J malignant progression from AIS to EIA. SFN was
33:352&ndash359, 2009 originally identiÀed as a p53-inducible gene that
causes G2 arrest and allows the repair of damaged
DNA. Real-time methylation-speciÀc PCR (MSP)
Carcinogenesis and Metastasis Monday, 4 July 2011 10:30-12:00 showed that while normal lung tissue and AIS
bore a completely methylated SFN promoter, the
M03.2 MOLECULAR PATHOGENESIS promoter regions of most EIAs (more than 95%)
OF ADENOCARCINOMA AND ITS were at least partially methylated. Demethylation-
PRECURSOR LESIONS induced overexpression of SFN occurs during the
Masayuki Noguchi course of progression of early lung adenocarcinoma,
Department Of Pathology, Graduate School Of and aberrantly overexpressed SFN is thought to be
Comprehensive Human Sciences, University Of one of the accelerators of malignant progression by
Tsukuba/Japan conferring proliferative ability on the tumor cells.
Abstract: Studies of the histology, cytology

and molecular biology of pulmonary
adenocarcinogenesis have suggested that it is a
multistep process. Multi-potential epithelial cells
located in the terminal respiratory unit (TRU)
acquire atypical adenomatous hyperplasia (AAH)
as a result of exposure to various carcinogens.
AAH is characterized by local proliferation of
among metastases. The presentation will also review

the frequency and the signiÀcance of pathologic
variables between primary tumor and metastases.
Keywords: lung cancer, metastases, biology
Session M04: Issues Surrounding the

Use of PFS as a Primary Endpoint
Monday, 4 July 2011
Issues Surrounding the Use of PFS as a Primary Endpoint Monday, 4

July 2011 10:30-12:00
Keywords: AIS, EIA, AAH
M04.1 THE STATISTICIAN
PERSPECTIVE
Carcinogenesis and Metastasis Monday, 4 July 2011 10:30-12:00 Sumithra J. Mandrekar
Department Of Health Sciences Research, Mayo
M03.4 BIOLOGY OF METASTASIZING Clinic/United States Of America
LUNG CANCER
Lucian R. Chirieac Abstract: Overall Survival (OS), deÀned as the time
Pathologie, Brigham And Womens Hospital/United to death from any cause, remains the gold standard
States Of America endpoint that unequivocally assesses the beneÀt
of a new treatment relative to the current standard
Abstract: Non-small cell lung carcinoma (NSCLC) of care. OS sometimes requires more follow-up
remains the leading cause of death from cancer making it a “long” endpoint to assess, especially
in both men and women. Distant relapse remains in a phase II setting where time is of the essence.
the major cause of morbidity and mortality in the Progression-free survival (PFS), deÀned as the time
patients with lung cancer. The term metastasis is to the earlier of disease progression or death from
deÀned as the transfer of disease from one organ any case, is thus a desirable outcome measure in
to part or to another not directly connected to it. this setting. In a disease with poor prognosis such
Metastasis is the primary clinical challenge as it is as advanced lung cancer, the true endpoint of OS
unpredictable in onset and it exponentially increases is also mostly determined by the progression status
the clinical impact to the host. Tumor metastasis of the disease (Mandrekar et al., 2010). PFS is a
is a multistage process in which malignant cells direct measure of the effect of the treatment on the
spread from primary tumor to discontiguous organs. tumor burden process, unaffected by subsequent
It involves a rest and growth in different micro- treatments the patient may receive (Mandrekar
environments, which are treated clinically with et al., 2010; Buyse et al., 2008; Lara et al., 2008;
different strategies depending on the tumor histotope Foster et al., 2011; Fleming et al., 2009). PFS has
and metastatic location. Some isolated metastases become an accepted alternate endpoint in assessing
may be resected, whereas metastases to other organs treatment efÀcacy in lung cancer especially in a
may be treated with radioisotopes and are virtually Phase II setting, as it includes a patient who achieves
unresectable. Because of the cellular heterogeneity stable disease for an extended period of time as a
therapies have varying degrees of efÀcacy that are success, in addition to those who achieve complete
challenging not only for the oncologist but also or partial response (Lara et al., 2008; Mandrekar et
for our understanding of the metastatic process. al., 2010). PFS-based endpoints are controversial and
This presentation will focus on differences challenging for several reasons. PFS considers all
regarding morphology and biomarker expression patients “similarly” although progressive disease is
between the primary tumor and metastases of lung inherently different from one patient to the next, i.e.,
adenocarcinoma. The mutation status of metastases all patients, regardless of the size of their baseline
can differ from that of the primary tumor and also tumor burden, are considered to have progressive
disease if there is a 20% increase in the sum of the PFS estimates in lung cancer, an analysis utilizing
largest diameters of target lesions from baseline individual patient data from 14 NCCTG and 7
(Fleming et al., 2009). The accuracy and validity SWOG trials was performed (Mandrekar et al.,
of PFS as an endpoint is also impacted by the 2011). Reported progression date (RPD) was deÀned
imbalance in assessment schedules across different as either the scan date or the clinical deterioration
arms, treatment holidays, missing assessments, and date. Disease progression date was determined
occurrence of progression in the middle of a long using one of the 4 approaches: RPD (M1), one day
disease evaluation interval. In an open label trial, after last progression-free scan (M2), midpoint
investigator evaluation of progression can cause between last progression-free scan and RPD (M3),
substantial ascertainment bias. While a blinded or interval censoring (M4). PFS was estimated using
independent review can address this issue, they have the method of Kaplan-Meier (M1-3) or maximum
to occur in real time so that scans oare obtained on likelihood (M4). As expected, PFS estimates using
the patient until progression decision is conÀrmed the reported progression date was the highest, with
by the independent committee. If not, it leads to method 2 being the most conservative. Methods 3
informative censoring, which is often ignored and 4 were similar since majority of DP occurred
when analyzing these data. Panageas et al. (2007) during treatment (frequent disease assessments). All
discussed the issues related to assessment times and 4 methods resulted in the same overall conclusion
progression date determination. Tumor assessment for randomized trials. PFS estimates were thus
is normally repeated every few cycles while patients signiÀcantly impacted by the approach used for
are on study. Clearly, patients may have progressed declaring DP date with the magnitude of difference
anytime between a non-progression scan and the large enough to alter trial conclusions (Table 1). In
following scan indicating disease progression, summary, to obtain reliable evidence about the effect
referred to as interval censoring. Typically, the Àrst of a treatment on PFS and OS, randomized trials
documented progression date is used as a surrogate where all patients are followed to progression and
for the true progression date, which, to a large death are essential. The magnitude of the treatment
extent, overestimates the median PFS. In Panageas effect on PFS in addition the statistical reliability
et al.’s (2007) study, a close relationship between of this evidence are both important to understand
cycle length and progression date declaration was the clinical beneÀt. Clear standards for declaring
also observed. In extreme cases, if the assessment progression date and sensitivity analysis are critical
interval is wide, the overestimation could result in when reporting efÀcacy or comparing trial results.
a positive trial outcome, while in fact the observed based on PFS.
efÀcacy is just a false positive conclusion arising Table 1: Median PFS estimates by the disease
from the length of the assessment interval. This is progression date determination method.
particularly concerning in single-arm phase II trials
without a concurrent control arm. In a randomized Disease Progression Median PFS (months)
Date Method
trial, due to treatment delays from adverse events, NSCLC SCLC
progression date may be reported later in the NCCTG SWOG NCCTG (n =116 ) SWOG (n=131 )
(n =660 ) (n =297 )
more toxic treatment arm, even if the true PFS is 1 4.3 3.1 2.7 1.3
identical between the treatment arms. In addition, 2 1.8 1.5 0.03 0.03
when evaluations are performed between scheduled 3 3.3 2.2 1.8 0.7
assessments out of concern for lack of efÀcacy, or 4 (lower, upper) 3.52, 3.55 2.86, 2.89 1.45, 1.48 0.03, 0.16
signs of clinical progression, patients on the arm % Difference 58% 23% 52% 29% 99% 33% 98% 46%
Method 1 vs. 2
with inferior efÀcacy may have more frequent Method 1 vs. 3
measurement compared to those with treatment
of superior efÀcacy, the so-called evaluation-bias. Keywords: PFS, endpoint, disease assessments
Consequently, the efÀcacy of the superior arm is
overestimated to some extent (Bhattacharya, 2009).
Simulation studies have also shown that variations
in the timing of tumor assessment can signiÀcantly
bias trial conclusions based on PFS analyses
(Panageas 2007; Friedlin, 2007). To understand the
impact of disease progression date determination on
Issues Surrounding the Use of PFS as a Primary Endpoint Monday, 4 could subsequently be carried out (3). Another
July 2011 10:30-12:00 strategy proposes an unbiased estimate of BICR PFS
based on LE and a sample of BICR PFS data(4).
M04.4 ISSUES SURROUNDING THE USE Importantly, whereas the main purpose of BICR is
OF PFS AS A PRIMARY ENDPOINT: THE to address the bias associated with the assessment of
REGULATORY PERSPECTIVE (EUROPE) progression by investigators, BICR may introduce
Francesco Pignatti, Iordanis Gravanis an equally intractable problem of informative
Oncology, Haematology And Diagnostics, European censoring when BICR is carried out retrospectively.
Medcines Agency (EMA)/United Kingdom The optimal solution to this may require even more
complex real-time BICR to be implemented(5).
Abstract: While overall survival (OS) remains the Another issue with PFS is bias due to unscheduled
most objective and clinically convincing endpoint evaluations. There is a risk, for example, that toxicity
in registration trials in the advanced or metastatic may prompt for more screening detected progression
cancer setting, other efÀcacy endpoints have been in one of the treatment arms, introducing a bias,
explored in the hope of gaining earlier insight about often in favour of the experimental treatment group.
the beneÀt of new drugs. Regulators have recently Furthermore, skipped or otherwise unavailable
shown wider acceptance of progression-free survival evaluations generate a missing data problem that
(PFS) as the primary endpoint in registration has no easy solution. Currently these issues are
trials. In a recent EMA series (2006-2010), PFS addressed through various imputation methods in
was the primary endpoint for registration in 39% sensitivity analyses. Another proposal is to analyse
of applications, up from 10.5% in the previous 5 PFS data as interval-censored survival data as this
years. The wider acceptance did not come without may be more robust to bias due to unscheduled
extensive debate, and was often tied with conditions evaluations(6). Although there are a number of open
obliging companies to submit further data to conÀrm methodological questions about interval-censored
the effect on OS with data from longer follow-up or data(7), more efÀcient statistical approaches of
from trials in related indications. The use of PFS is handling this problem may soon become part of
complicated by several non-trivial methodological the standard set of supportive analyses of PFS. To
issues associated with measuring progression in an what extent PFS can be considered as a convincing
unbiased way. The EMA has issued methodological measure of clinical beneÀt in pivotal registration
guidance on using PFS as primary endpoint in trials, is still the subject of debate. In particular,
conÀrmatory trials, which is currently under the clinical interpretation of this endpoint, which
review(1-2). An important issue from a regulatory is based on radiological deÀnitions intended for
perspective is that the local evaluation (LE) of phase II trials, is often problematic in the context of
PFS attributed by may be subject to measurement the beneÀt-risk assessment at the time of approval.
error and more importantly bias. Regulators have Also, regardless of bias and efÀciency of BICR,
traditionally been requesting systematic complete regulators face a dilemma of interpretation when the
blinded independent radiological evaluation (BICR) results of BICR and LE differ signiÀcantly. Whilst
as a more reliable evaluation in the context of BICR may estimate PFS in a less biased and more
registration trials. The requirement for BICR has precise way, the LE reÁects clinical practice and
been relaxed somewhat for double-blinded trials may be equally relevant under real conditions of
although the real effectiveness of the blinding for use. Wide differences between BICR and LE due
cancer drugs can always be questioned. BICR, to measurement error would necessarily question
however, comes with its own set of problems. From the correctness of the local adjudication and the
the perspective of developers and investigators it relevance of PFS as an endpoint to change clinical
adds signiÀcant complexity and cost to the trial. practice. In conclusion, there is an opportunity to
Several proposals have been made to improve the develop more efÀcient risk-based approaches for
efÀciency of BICR when the primary concern is measuring PFS whilst ensuring reliable estimation
investigator bias in the adjudication of progression of treatment effect. However, more experience needs
due to knowledge of the assigned treatment group. to be gained before considering the applicability of
For instance, the risk of bias could be measured some of these methods. Further work is also needed
based on a sample of patients (“audit”). If bias in order to deÀne more objectively the clinical
became apparent from the audit, a complete BICR relevance of progression in different settings also
taking into account the perspectives of different Session M05: Tracheal Tumors
stakeholders. The EMA Oncology Working Party
is currently discussing these approaches in view Monday, 4 July 2011
of a revision of its methodological guideline on
PFS. Publication disclaimer The views presented
here are personal and should not be understood Tracheal Tumors Monday, 4 July 2011 10:30-12:00
or quoted as those of the European Medicines
Agency. References 1. European Medicines Agency. M05.1 ENDOBRONCHIAL TREATMENT
Guideline On The Evaluation Of Anticancer Herve Dutau
Medicinal Products In Man (CPMP/EWP/205/95/ Thoracic Oncology, Pleural Disease And
Rev.3). [Internet] London: European Medicines Interventional Pulmonology Departement, North
Agency; 2006; Available from: http://www.ema. University Hospital/France
europa.eu/ema/pages/includes/document/open_
document.jsp?webContentId=WC500017748. 2. Abstract: Trachea can be affected by malignant and
European Medicines Agency. Appendix 1 to the benign tumors. Malignant tracheal involvement of
guideline on the evaluation of anticancer medicinal the trachea can be divided into primary, secondary
products in man - methodological considerations for and regional involvement from mediastinal
using progression-free survival (PFS) as primary structures.. Among primary tracheal tumors,
endpoints in conÀrmatory trials for registration. squamous cell carcinomas account for 45%,
[Internet] London: European Medicines Agency; adenoid cystic carcinoma for 31%, carcinoïds for
2008; Available from: http://www.ema.europa.eu/ 4.3%, muco-epidermoïd carcinomas for 2.4%,
ema/pages/includes/document/open_document. adenocarcinoma for 2% and rare tumors (small
jsp?webContentId=WC500017749. 3. Amit O, and large cell carcinomas, Kaposi, Àbrosarcoma,
Mannino F, Stone AM, Bushnell W, Denne J, etc,…) for less than 1%. Secondary lesions can
Helterbrand J, Burger HU. Blinded independent be originated from colonic, renal, melanoma, or
central review of progression in cancer clinical trials: breast malignancies. Involvement of the trachea can
Results from a meta-analysis. Eur J Cancer2011 occur during the course of cancers from regional
Mar 21. 4. Dodd LE, Korn EL, Freidlin B, Gray R, structures (oesophagus, thyroid, lung, thymus) and
Bhattacharya S. An Audit Strategy for Progression- from Hodgkin and non Hodgkin lymphomas of the
Free Survival. Biometrics2011 Jan 6. 5. Dodd mediastinum. Benign tumors can also affect the
LE, Korn EL, Freidlin B, Jaffe CC, Rubinstein trachea: lipoma, neuroÀbroma, Àbroma, hamartoma,
LV, Dancey J, Mooney MM. Blinded independent chondroma, schwannoma, plasmocytoma,
central review of progression-free survival in leiomyoma or glomic tumor. Bronchoscopy plays
phase III clinical trials: important design element an important diagnostic role in obtaining tissues
or unnecessary expense? J Clin Oncol2008 Aug for pathologic examination and also in order to
1;26(22):3791-6. 6. Stone AM, Bushnell W, Denne thoroughly precise the localization and the extension
J, Sargent DJ, Amit O, Chen C, Bailey-Iacona R, of the disease, this is important in case of surgical
Helterbrand J, Williams G. Research outcomes and management. Moreover, bronchoscopy has an
recommendations for the assessment of progression important therapeutic impact either as a neoadjuvant
in cancer clinical trials from a PhRMA working treatment before surgery or alone in cases of
group. Eur J Cancer2011 Mar 22. 7. Zhang Z, Sun non operable patients and of benign conditions.
J. Interval censoring. Stat Methods Med Res2010 Bronchoscopic management depends on the type
Feb;19(1):53-70. of tumoral involvement (extrinsic compression,
Keywords: PFS, EMA endoluminal obstruction or both). Symptomatic
external compression can be relieved by the use
of stents. Endoluminal obstruction is generally
treated by mechanical debulking assisted by laser,
electrocauthery, cryotherapy, argon plasma,or
microdebrider. In case of respiratory distress, rapid
techniques have to be used: laser, electrocauthery,
argon plasma,or microdebrider. Cryotherapy has
a delayed action and is not indicated in this case.
The rigid bronchoscope is the technique of choice lymph nodes are involved, bilateral paratracheal
because it allows rapid mechanical debulking and subcarinal lymphatic regions are included.
by coring large pieces of tumors. A stent can be For distal tracheal lesions, the carina, bilateral
inserted in order to prevent recurrences after optimal paratracheal soft tissue and the medial half of the
desobstruction in some cases. Tracheal tumors main bronchi are included. For proximal tracheal
management requires a multidisciplinary approach lesion, a generous margin of bilateral supraclavicular
involving thoracic surgeons, pulmonologists, regions is included as clinical target volume. Of 108
endoscopists, oncologists and radiologists. consecutive patients with adenoid cystic carcinoma,
Keywords: tumors, Endoscopy, bronchoscopy, 89 (82%) received radiation 2. Extramural tumor
trachea extension and microscopically positive airway
margins were common. The disease-free survival
of 92 patients with extramural tumor was 47% at
Tracheal Tumors Monday, 4 July 2011 10:30-12:00 10 and 29% at 15 years, compared to 93 and 85%
in 16 patients without transmural disease. In 59
M05.3 ROLE OF ADJUVANT patients with microscopically positive margins,
RADIOTHERAPY IN THE SURGICAL disease-free survival was 48% and 24% at 10 and
TREATMENT OF TRACHEAL 15 years, compared to 63 and 56% in 40 patients
CARCINOMA with negative tracheal margins. In a study of 50
Henning A. Gaissert consecutive squamous cell carcinomas, tumor
Surgery, Massachusetts General Hospital/United characteristics were identiÀed to predict survival 3.
States Of America Prior radiotherapy occurred in 24% of patients, either
for the same disease or separate, prior lung cancer.
Abstract: The two most common primary Only 42% received post-resection radiation. Overall
malignancies of the trachea are squamous and survival was 46% at 5 and 27% at 10 years. Tumor
adenoid cystic carcinoma, while other bronchogenic extension into thyroid and lymphatic invasion were
carcinomas or sarcomas are rare. Surgical resection associated with worse survival, while keratinization,
is the preferred treatment for localized tracheal dyskeratosis, acantholysis, necrosis, and tumor
tumors. However, transmural tumors and lymphatic thickness had no association with survival. An
invasion are common, while radical resection is earlier study had shown poor long-term survival
limited by the narrow conÀnes of the mediastinum when tracheal resection margins were involved with
1
. Margins are often close and additional resection tumor 1. Postoperative radiotherapy for tracheal
of microscopic tumor-bearing tracheal margins may tumors follows treatment principles established
exceed safe levels of tension at the anastomosis. in other thoracic malignancies, with particular
Preoperative radiation is avoided because the attention to successful healing of the anastomosis.
radiated trachea tolerates poorly anastomotic tension Long-term survival observed after resection with
following reconstruction. For these reasons, adjuvant microscopically positive tracheal margins is in part
postoperative radiotherapy is administered to most attributed to adjuvant radiotherapy, even though
patients. Treatment is begun 6 to 8 weeks after its precise contribution to overall survival remains
resection, following bronchoscopic conÀrmation unknown. Given the low incidence of these tumors,
of anastomotic healing, at a dose of 54 to 63 Gray alternatives to postoperative radiation have not been
(Gy). A majority of patients were treated with 2 D evaluated. References 1. Gaissert HA, Grillo HC,
conformal therapy. Currently, a typical treatment Shadmehr MB, Wright CD, Gokhale M, Wain JC,
protocol consists of 3D conformal, intensity- Mathisen DJ. Long-term survival after resection
modulated radiation therapy to maximize sparing of primary adenoid cystic and squamous cell
of lungs and esophagus with weekly preportal carcinoma of the trachea and carina. Ann Thorac
imaging for veriÀcation of set-up and isocenter. Surg. 2004;78:1889-96. 2. Honings J, Gaissert
Daily fractions of 1.8 Gy are administered for a total HA, Weinberg AC, Mark EJ, Wright CD, Wain
of 35 treatments and a total dose of 63 Gy. A typical JC, Mathisen DJ. Prognostic value of pathologic
target volume includes the tracheal anastomotic site characteristics and resection margins in tracheal
with a margin of 3-4 cm of remaining proximal and adenoid cystic carcinoma. Eur J Cardiothorac
distal treachea for potential microscopic disease Surg. 2010;37:1438-44. 3. Honings J, Gaissert HA,
and peritracheal soft tissues at the tumor bed. If Ruangchira-Urai R, Wain JC, Wright CD, Mathisen
DJ, Mark EJ. Pathologic characteristics of resected Session M06: Global Lung Cancer
squamous cell carcinoma of the trachea: prognostic Coalition (GLCC) and Longkanker
factors based on an analysis of 59 cases. Virchows Informatiecentrum: Lung Cancer -
Arch. 2009;455:423-9. Effecting Change
Keywords: squamous cell carcinoma, Trachea,
Trachel tumor, Adenoid cystic carcinoma
Monday, 4 July 2011
Tracheal Tumors Monday, 4 July 2011 10:30-12:00

Global Lung Cancer Coalition (GLCC) and Longkanker
M05.4 TRACHEAL TRANSPLANTS Informatiecentrum: Lung Cancer - Effecting Change Monday, 4 July
Emmanuel Martinod 2011 10:30-12:00
Chirurgie Thoracique, Chu Avicenne. AP-HP, Paris/
France M06.1 GLOBAL ATTITUDES TO LUNG
CANCER
Abstract: After more than Àfty years of research, Robert Worcester
airway transplantation remains a major surgical and Ipsos Mori/United Kingdom
biological challenge in the Àeld of thoracic surgery.
Five principal types of tracheobronchial substitutes Abstract: Ipsos MORI were commissioned by the
including synthetic prostheses, bioprostheses, Global Lung Cancer Coalition to explore perceptions
allografts, autografts and bio-engineering conduits of which cancers kill the greatest number of people
have been experimentally evaluated in numerous within countries; and sympathy towards people with
studies. More recently, few clinical attempts have lung cancer. Two questions were asked: » Which of
provided encouraging results with bio-engineered the following cancers do you think kills the most
airways, tracheal allografts implanted after people in your country? You may choose up to two
heterotopic revascularization, and aortic allografts. (Bowel or Colon cancer/Breast cancer/Lung cancer/
In-vivo or ex-vivo regeneration of epithelium Prostate cancer/Skin cancer); and » Lung cancer
and cartilage has been demonstrated with these is mainly caused by smoking cigarettes and other
substitutes. Cryopreserved aortic allografts present tobacco products. Bearing this in mind, to what
major advantages because they are available in tissue extent do you agree or disagree with the following
banks and do not require immunosuppressive therapy statement…I have less sympathy for people with
which is contraindicated in cancer lesions. These lung cancer than people with other types of cancer. A
favorable results have to be conÀrmed in larger quantitative survey was conducted across: Argentina,
series of patients with extensive tracheobronchial Australia, Brazil, Bulgaria, Canada, Denmark,
diseases. Great Britain, Italy, Japan, Norway, Slovenia, Spain,
Keywords: airway transplantation, tracheobronchial Sweden, Switzerland, the Netherlands, and the
diseases, Surgery, tissue regeneration USA. This compares the Àndings across countries,
highlighting common sub-group differences.
Methodology: A nationally representative quota
sample for each country of c. 1,000 adults was
interviewed from 25 January – 16 May 2010, using
the Ipsos Omnibus (although exact ages varied
slightly between countries). Face-to-face in-home
interviewing was used where possible (in Brazil,
Bulgaria, Great Britain, Italy, Japan, Spain and
Slovenia), and telephone (CATI) interviewing
elsewhere (in Argentina, Australia, Canada, Norway,
Denmark, Switzerland, Sweden, The Netherlands,
and the USA). Data have been weighted to the
known adult population proÀle of each country.
Discussion of Findings: Which cancer is perceived
to be the biggest killer? In 13 of the 16 countries
surveyed, lung cancer is thought to be the cancer

responsible for the greatest number of deaths in their
country. The exceptions are: Japan, where a broadly
equal proportion cite lung cancer and bowel cancer;
Australia where a greater proportion cite breast and
skin cancer; and Bulgaria where a greater proportion
cite breast cancer. Of all the countries surveyed,
people in Japan and Norway are most likely to
believe that lung cancer is the biggest killer in their
country, although, as mentioned, in Japan there is
also a perception that bowel/colon cancer is on a par However, in all the countries surveyed, the majority
with lung cancer (67% and 65% respectively). reject the idea that they are less sympathetic for
people with lung cancer, despite its link to smoking
– for example, 52% of Australians disagree that they
are less sympathetic. Demographic differences in
opinion In most countries there is no difference in
sympathy towards people with lung cancer by age,
but in others there are some notable differences.
Older people have less sympathy than average in
Argentina though in the Netherlands and Norway
younger people have less sympathy than average.
Sympathy levels are lower among men than women
in six of the countries surveyed (Australia, Canada,
Demographic differences in perceptions In seven Denmark, Great Britain, Norway and Slovenia).
countries surveyed (Australia, Canada, Japan, Furthermore people with lower educational
Norway, Spain, Sweden, and the USA) younger attainment are less likely to feel sympathy for people
people (under 34 years old) are more likely than with lung cancer than those educated to higher levels
older people (aged 55+) to perceive lung cancer as in Bulgaria, Slovenia Switzerland, and the USA.
the cancer type responsible for the most deaths in
1
their country. ReÁecting the higher incidence rates Smoking is responsible for 90% of all lung cancer
of lung cancer among men than women, in a number according to the World Health Organisation.
of countries (Argentina, Brazil, Denmark, Japan,
Norway, Slovenia and Switzerland) men are more
likely than women to believe lung cancer kills the Global Lung Cancer Coalition (GLCC) and Longkanker
greatest number. Attitudes towards lung cancer In Informatiecentrum: Lung Cancer - Effecting Change Monday, 4 July
line with prevailing medical opinion1, respondents 2011 10:30-12:00
were told: “Lung cancer is mainly caused by
smoking cigarettes and other tobacco products.” M06.3 LUNG CANCER AND THE NEW
They were then asked whether or not, bearing this in MEDIA
mind, they have less sympathy for people with lung Tracy Fischer
cancer than other types of cancer. There is signiÀcant Communications, National Lung Cancer
variation between countries in the proportion of Partnership/United States Of America
adults who admit that they have less sympathy for
people with lung cancer – from one in ten (10%) Abstract: This presentation will focus on how
Argentineans to around three in ten Australians and lung cancer advocacy groups can use new media,
Brazilians (29% and 28% respectively). particularly social media, to advance awareness of
and commitment to the cause. To drive awareness
of lung cancer, and to raise funds for research,
education, legislative and awareness programs,
advocacy groups have the opportunity to reach out
to their constituents and connect using technology
now commonplace in personal interaction.
Utilization of the new bottom-up information the state of the relevant technology and for scaling
stream the internet propagates can assist advocacy technological infrastructure to support the successful
groups in effecting change for lung cancer patients. implementation of this new service. Using US
This presentation will provide examples of social Census data, there are about 72 million adults
media: media designed to be disseminated through over age Àfty-Àve. Between 32-40% were either
social interaction, created using highly accessible current or former smokers, so about 30 million
and scalable publishing techniques. As online may be candidates for CT-based lung cancer
fundraising and communication has showed steady screening. Using prior cancer screening experience
growth in recent years despite numerable economic only a fraction of those individuals would avail
challenges, this type of communication channel is themselves to this new service. If initially 25% of
increasing in importance. Recommended strategies the target population availed themselves to lung
for advocacy groups will be presented, including cancer screening, then that would entail following
steps to take when implementing a social media about 7.5 million at-risk adults. Since the risk of
initiative: research, plan, post, integrate and evaluate. developing lung cancer in a smoker is continuous,
Examples of methods for speciÀc social networks optimal care would involve serial follow-up of the
will be discussed, as well as common measurement at-risk cohort for the balance of their lives. The
and evaluation tools. challenge for lung cancer screening is to develop an
Keywords: advocacy, new media, internet, social informatics backbone that can organize the capture,
media analysis and distribution of this vast amount of new
data. Fortunately, the emergence of economical,
distributed biomedical informatics resources is
Global Lung Cancer Coalition (GLCC) and Longkanker happening at an opportune time to enable the
Informatiecentrum: Lung Cancer - Effecting Change Monday, 4 July establishment of a web-based system that could
2011 10:30-12:00 tie all screening institutions together. A system
developed by Anthony Reeves currently has the data
M06.4 NEW TECHNOLOGY TO for 55,000 screening subjects including DICOM
EFFECT CHANGE IN LUNG CANCER Àles of all screening CT images as well as digitized
OUTCOMES version of all the diagnostic pathology of the lung
James L. Mulshine cancer cases and becomes a valuable resource for
Internal Medicine, Rush University/United States Of enabling screening research. This systematic capture
America of lung cancer screening data and images allows for
real time analysis which could enable continuous
Abstract: The Director of the NCI recently process improvement to optimize all aspects of the
announced the completion of the National Lung screening process as proposed in recent publications
Screening Trial in light of Ànding a 20% lung cancer by the Institute of Medicine on the rapid learning
mortality reduction beneÀt in that randomized healthcare system. The remarkable improvement in
screening trial comparing CT to chest X-ray in a CT image resolution witnessed over the last decade
high risk for lung cancer cohort (). Additionally, is expected to continue for the foreseeable future.
recent reports have documented mortality reduction This provides a number of research options to
beneÀt over the range of 37-60% based on a improve lung cancer detection and also to integrate
comparative analysis of lung cancer mortality image processing tools that could assist the speed,
outcomes with a New York state I-ELCAP cohort or accuracy while reducing the cost of lung cancer
with CISNET models of I-ELCAP outcomes. Such screening. With existing manpower shortage for
remarkable results have re-deÀned the dialogue clinical radiologists, measures to improve the
about improving lung cancer outcomes. Other productivity of lung cancer screening are essential.
results suggest improvements in clinical screening The Quantitative Imaging Biomarker Alliance
management such as with better diagnostic work- of RSNA has assembled a large community of
up approach reported with the NELSON trial; so researchers that are already committed to address
that a time may come when national public health this challenge. A major task is the downstream
agencies conclude that CT-based lung cancer clinical management challenge of segregating the
screening is an effective and essential population- potentially benign lung nodules from the potentially
based cancer service. This presentation reviews clinically aggressive lung nodules. This was the
subject of a recent report in the NEJM, where the the essential public health research is required to
NELSON investigators followed a carefully deÀned responsibly support these directions. Finally, the
imaging protocol for suspicious nodules based on evolution of imaging technology is providing an
the growth rate of those nodules on repeat high opportunity for broader collaboration of the disparate
resolution CT imaging after a wait of three months. communities of health care providers involved in
The software tool used for this study resulted different tobacco-related diseases. Integration of
in an over 90% accuracy of identifying clinical efforts may accelerate improvement of the early
signiÀcant lung cancers and there was a low number detection of all major tobacco-related diseases of
of cases picked up outside of scheduling imaging the thorax so that we can rapidly and economically
on long term follow up. A low rate of incorrect provide these new preventive services as they are
lung cancer diagnoses is a critical determinant of demonstrated to be effective.
the overall screening success. Having objective Keywords: Lung cancer, CT screening, Image
software tools to evaluate the aggressiveness of Processing, screening management
cancer cases is a critical measure to address the
potential for over-diagnosis that plagues other
cancer screening. The rapid evolution of minimally Global Lung Cancer Coalition (GLCC) and Longkanker
invasive surgical techniques for curative resection Informatiecentrum: Lung Cancer - Effecting Change Monday, 4 July
of early lung cancers is profoundly re-sculpting 2011 10:30-12:00
outcome expectations with the surgical management
of lung cancer. Video-assisted minimally invasive M06.5 LUNG CANCER SPECIALIST
lobectomy approaches are being reported in large NURSES - SHOWING THEIR WORTH
multi-center studies to have lower operative Beth Ivimey
mortality rates (2% vs. 0.1%), shorter hospital stays Dept. Medical Oncology, Prince Of Wales Hospital/
and lower complication rates. This development Australia
greatly enhances the potential therapeutic beneÀt
of lung cancer screening and research to deÀne the Abstract: Introduction. The Lung Cancer Nurse
optimal approaches to the surgical care of screen- is viewed as an integral member of the Lung
detected lung cancers is an important priority. Based Cancer Multi Disciplinary Team, being responsible
on success with lung cancer screening, we may for coordinating the care of patients who have
Ànally be making this transition from late to early been diagnosed with a thoracic malignancy. The
stage care. Systemic side-effects limited the use deÀnition of the nursing role varies across the globe,
of corticosteroids in the treatment of asthma. With whether it be as a Lung Cancer Nurse Specialist,
both intravenous and oral lung cancer drugs, the Practitioner or Consultant in the U.K, Lung Cancer
occurrence of systemic side-effects is a barrier for Nurse Navigator in the U.S or Lung Cancer Nurse
success with existing lung cancer therapies especially Coordinator in Australia. All embrace the intricacies
in the adjuvant setting. Aerosolized drug delivery of managing and supporting the care of people
was used to deliver corticosteroids to the lung diagnosed with a thoracic malignancy, steering the
epithelium while reducing side effects for asthma. patient through the diagnostic and investigative
Aerosol drug delivery strategy may be a key step for phase, assisting with informed decision making,
allowing safe delivery of new molecularly-deÀned treatment and follow up, survivorship or end of life
therapeutics to enhance the cure of early lung cancer. care. The lung cancer nurse will be supportive to the
In closing, the success of CT screening to routinely patient and their carer(s) assessing their physical,
Ànd early curable cancer in conjunction with rapidly psychosocial, emotional and geographical situation
improving imaging, image processing, diagnostic and needs. The lung cancer nurse becomes a primary
work-up algorithms and surgical management contact and link for the patient and members of the
approaches brings great hope to the entire lung lung multi disciplinary team and facilitates timely
cancer community. Cooperation across institutions referral and appointments. The worth or value that
like IASLC and the GLC along with many other this highly experienced nurse brings to the team
potential collaborators is essential to ensure the has traditionally been difÀcult to deÀne. Patient
maximum dissemination of the information about satisfaction and outcomes for people diagnosed with
the potential for improving lung cancer outcomes. In lung cancer were poor prior to the lung cancer nurse
addition, coordination of strategic efforts to advance position commencing. Lead Clinicians with the lung
cancer multi disciplinary teams now state that their Session M07: Tumor and Host
team is incomplete without a lung cancer nurse and
that the Lung Cancer Nurse is highly valued by all Monday, 4 July 2011
members of the team. Lung Cancer patient access to
best practice, satisfaction and outcomes have been
enhanced by the implementation of the lung cancer Tumor and Host Monday, 4 July 2011 16:30-18:00
nurse role. Enrollment for patients into lung cancer
clinical trials has increased since the development M07.1 EPITHELIAL-MESENCHYMAL
of the Lung Cancer Nurse position and there has TRANSITION: FROM DIAGNOSIS TO
been greater interest in evaluating the quality of life THERAPY
for patients with lung cancer and for their carers. Giuseppe Pelosi
Lung Cancer Nurse Specialist follow up clinics have Department Of Pathology And Laboratory Medicine,
shown to be safe, acceptable, and cost effective. National Cancer Institute And University Of Milan,
Lung Cancer Nurses undertake other hidden work School Of Medicine/Italy
in addition to their complex clinical work. DeÀning
the value of time organizing care via telephone, Abstract: The term epithelial-mesenchymal
assessment, face to face consultation, referral, transition (EMT) refers to the loss of epithelial
crisis interventions and education has been difÀcult cell traits and the acquisition of a mesenchymal
because capturing the data referring to every instance phenotype by cells with motile properties. This
of service is time consuming. The evidence that phenomenon is deemed to be pivotal in a variety
has come forth describes the complexities well and of normal and pathological conditions, including
suggests that more research is necessary to further ontogenesis, Àbrosis, wound healing, inÁammation,
enhance and validate our role. The development and tumorigenesis 1, 2. In lung cancer pathology,
of national and international Lung Cancer Nurse carcinomas containing variable amounts of sarcoma/
Forums is the cornerstone to Lung Cancer Nurses sarcoma-like elements in the form of spindle and/
working collaboratively across the globe with these or giant cells or entirely made up of these tissues are
issues in mind. Moore S,Corner J, Haviland J, Wells rare but well-recognized entities 3, although many
M, Salmon E, Normand C, Brada M, O’Briend M, conventional lung tumors may undergo EMT during
SmithI. BMJ;2002;1145-1147. Nurse Led Follow up progression. As a whole, carcinomas with sarcoma/
and conventional medical follow up in management sarcoma-like elements are collectively classiÀed as
of patients with lung cancer; randomized trial. sarcomatoid carcinomas and include Àve histologic
Excellence in Care: The Contribution of the Clinical patterns, namely pleomorphic carcinoma, spindle
Nurse Specialist Optimising Cancer Care in Australia cell carcinoma, giant cell carcinoma, carcinosarcoma
(2003) Clinical Oncology Society of Australia. and pulmonary blastoma, which show quite similar
The Cancer Council Australia Leary A et al (008) clinical presentation and behavior 3. They are
Dimensions of clinical work in the UK. Treating deemed to have a monoclonal origin from a common
Lung Cancer in NSW. NSW Cancer Institute. ancestor lesion undergoing sarcomatoid metaplasia
December 2010. The National Lung Cancer Forum of full-blown carcinoma cells during tumor
for Nurses. 2009 Good Practice Guide. Evaluation progression (conversion paradigm) 4. Recent genetic
of the Western Australian Cancer Nurse Coordinator studies have also raised the possibility of separating
Role. Yates P, (2004) Cancer Care Coordinators: the various members of this tumor family on the
Realising the Potential for Improving the Patient basis of their chromosome proÀle, supporting once
Journey, Cancer Forum 28 (3);128-132 again the notion that these tumors are more akin to
Keywords: Lung Cancer Nurse, Forum, value each other than to conventional NSCLC 5. Although
the pathogenetic bases of pulmonary sarcomatoid
carcinomas are still largely unknown, the activation
of an EMT program is felt to play a pivotal role in
the process of epithelial trans-differentiation into
sarcoma/sarcoma-like cells 1, 2, 6. In particular, EMT
program in these tumors could be initiated by an
upregulation of c-Jun, a nuclear transcription factor 5
and a consecutive overexpression of vimentin, fascin
7
and osteonectin 8. Another well-known activator C. Tumours of the lung, pleura, thymus and heart.
of EMT, the Wnt pathway 9, has been consistently Lyon: IARC Press; 2004. 4. Pelosi G, Sonzogni A, De
demonstrated in pulmonary blastoma, inasmuch as Pas T, et al. Review article: pulmonary sarcomatoid
b-catenin gene mutation and consequent aberrant carcinomas: a practical overview. Int J Surg Pathol
nuclear/cytoplasmic localization of the protein 2010;18:103-20. 5. Blaukovitsch M, Halbwedl I,
occur in this tumor type 10, 11 but not in other types of Kothmaier H, Gogg-Kammerer M, Popper HH.
sarcomatoid carcinoma 5. Depending on the extent Sarcomatoid carcinomas of the lung--are these
and timing of EMT, the proportion of epithelial histogenetically heterogeneous tumors? Virchows
vis a vie mesenchymal cells may vary widely from Arch 2006;449:455-61. 6. Gotzmann J, Mikula M,
tumor to tumor 10. The composition of the metastases Eger A, et al. Molecular aspects of epithelial cell
of pulmonary sarcomatoid carcinomas has been plasticity: implications for local tumor invasion and
assessed in cases of carcinosarcoma 12, 13 and metastasis. Mutat Res 2004;566:9-20. 7. Pelosi G,
pleomorphic carcinoma 4, 13, revealing an exclusive Fraggetta F, Nappi O, et al. Pleomorphic carcinomas
or partial epithelial composition in most cases. This of the lung show a selective distribution of gene
may implicate that epithelial cells could contribute products involved in cell differentiation, cell cycle
more effectively than sarcomatous elements to control, tumor growth and tumor cell motility: a
metastasis formation, as suggested experimentally clinicopathological and immunohistochemical study
in murine models 14 and clinically by the lack of 31 cases. Am J Surg Pathol 2003;9:1203-15. 8.
of prognostic implications of the percentage of Siddiq F, Sarkar FH, Wali A, Pass HI, Lonardo F.
sarcomatoid component in the primary tumors 4, 15. Increased osteonectin expression is associated with
The activity and efÀcacy of systemic chemotherapy malignant transformation and tumor associated
in patients with pulmonary sarcomatoid carcinoma Àbrosis in the lung. Lung Cancer 2004;45:197-205.
has not been well deÀned thus far but probably 9. Ilyas M. Wnt signalling and the mechanistic basis
is poor with conventional drugs. No prospective of tumour development. J Pathol 2005;205:130-
clinical trial has been published on the subject, and 44. 10. Nakatani Y, Miyagi Y, Takemura T, et al.
the results obtained from conventional NSCLC Aberrant nuclear/cytoplasmic localization and
enrolling clinical trials cannot be extrapolated for gene mutation of beta-catenin in classic pulmonary
sarcomatoid carcinoma, inasmuch as the latter were blastoma: beta-catenin immunostaining is useful for
not analyzed separately. The few available data distinguishing between classic pulmonary blastoma
for these tumors are derived from retrospective and a blastomatoid variant of carcinosarcoma. Am J
studies, which showed a substantial failure of the Surg Pathol 2004;28:921-7. 11. Sekine S, Shibata T,
standard chemotherapy regimens commonly used Matsuno Y, et al. Beta-catenin mutations in pulmonary
for NSCLC, although single sarcomatoid carcinoma blastomas: association with morule formation. J Pathol
patients had beneÀted by postoperative combination 2003;200:214-21. 12. Koss M, Holzer L, Frommelt
chemotherapy of carboplatin and paclitaxel. R. Carcinosarcomas of the lung. A clinicopathologic
In this scenario of ineffective or disappointing study of 66 patients. Am J Surg Pathol 1999;23:1514-
therapy options, targeting EMT could become a 26. 13. Humphrey P, Scroggs M, Roggli V, Shelburne
useful therapeutic strategy by interfering with the J. Pulmonary carcinomas with a sarcomatoid
development of these tumors. It could include the element: an immunocytochemical and ultrastructural
E-cadherin expression restoration or the c-Jun analysis. Hum Pathol 1988;19:155-65. 14. Barsky
or RAS pathway inactivation that are frequently S, Xiao Y, Ye Y, Ostler J, Leone G. Carcinosarcoma
engaged in sarcomatoid carcinoma 1, 2. E-cadherin, exhibit EMT - A phenomenon of tumor progression
a transmembrane glycoprotein involved in Ca2+- unrelated to metastsis (abstract #1485). Mod Pathol
dependent epithelial cell–cell homophylic adhesion 2008;21:325A. 15. Nakajima M, Kasai T, Hashimoto
at the adherens junctions 16, 17 is downregulated in H, Iwata Y, Manabe H. Sarcomatoid carcinoma
most sarcomatoid carcinoma. of the lung. A clinicopathologic study of 37 cases.
References 1. Thiery J. Epithelial-mesenchymal Cancer 1999;86:608-16. 16. Huber A, Weis W. The
transitions in tumour progression. Nat Rev Cancer structure of the b-cetenin/E-cadherin complex and
2002;2:442-54. 2. Thiery JP, Sleeman JP. Complex the molecular basis of diverse ligand recognition by
networks orchestrate epithelial-mesenchymal b-catenin. Cell 2001;105:391-402. 17. Takeichi M.
transitions. Nat Rev Mol Cell Biol 2006;7:131-42. 3. Cadherin cell adhesion receptors as a morphogenetic
Travis W, Brambilla E, Muller-Hermelink H, Harris regulator. Science 1991;251:1451-5.
Tumor and Host Monday, 4 July 2011 16:30-18:00 G. Immunocytological detection of bone marrow
micrometastasis in operable non-small cell lung
M07.2 CIRCULATING TUMOR CELLS cancer. Cancer Res 1993;53: 1027-31. Passlick B,
AND THE METASTATIC PROCESS Izbicki JR, Kubuschok B, Nathrath W, Thetter O,
Klaus Pantel Pichlmeier U, Schweiberer L, Riethmuller G, Pantel
Department Of Tumor Biology, University Medical K. Immunohistochemical assessment of individual
Center Hamburg-Eppendorf/Germany tumor cells in lymph nodes of patients with non-
small-cell lung cancer. J Clin Oncol 1994;12: 1827-
Abstract: Early spread of tumor cells is usually 32. Pantel K, Izbicki J, Passlick B, Angstwurm M,
undetected by current imaging technologies. Haussinger K, Thetter O, Riethmuller G. Frequency
Therefore, in patients with cancer and no signs and prognostic signiÀcance of isolated tumour cells
of overt metastases, sensitive methods have been in bone marrow of patients with non-small-cell lung
developed to detect circulating tumor cells (CTC) in cancer without overt metastases. Lancet 1996;347:
the peripheral blood and disseminated tumor cells 649-53. Pantel K, Brakenhoff RH, Brandt B.
(DTC) in the bone marrow. These technologies can Detection, clinical relevance and speciÀc biological
be classiÀed into cytometric and/or immunological properties of disseminating tumour cells. Nat Rev
and molecular approaches. Interestingly, the bone Cancer 2008;8: 329-40. Wrage M, Ruosaari S, Eijk
marrow seems to be a common homing organ PP, KaiÀ JT, Hollmen J, Yekebas EF, Izbicki JR,
for cells derived from various epithelial tumors Brakenhoff RH, Streichert T, Riethdorf S, Glatzel
including non-small cell lung cancer (NSCLC). M, Ylstra B, Pantel K, Wikman H. Genomic proÀles
Sequential peripheral blood analyses, however, are associated with early micrometastasis in lung cancer:
more convenient for patients than BM analyses in relevance of 4q deletion. Clin Cancer Res 2009;15:
patients with solid tumors and many research groups 1566-74. Pantel K, Alix-Panabieres C. Circulating
are currently assessing the clinical utility of CTC for tumour cells in cancer patients: challenges and
assessment of prognosis and monitoring of systemic perspectives. Trends Mol Med 16 (2010) 398–406.
therapy. In view of the plethora of prognostic Keywords: CTC, circulating tumor cells, DTC
indicators—especially in breast cancer—monitoring
of CTC during and after systemic adjuvant therapy
might provide unique information for the clinical Tumor and Host Monday, 4 July 2011 16:30-18:00
management of the individual cancer patient and
allow an early change in therapy years before the M07.3 HARNESSING THE IMMUNE
appearance of overt metastases signals incurability. SYSTEM TO TREAT CANCER
There is an urgent need for biomarkers for real-time Lee M. Krug
monitoring of the efÀcacy of systemic adjuvant Thoracic Oncology, Memorial Sloan-Kettering
therapy in individual patients. At present, the success Cancer Center/United States Of America
or failure of anti-cancer therapies is only assessed
retrospectively by the absence or presence of overt Abstract: Dendritic cell-derived exosomes (Dex)
metastases during the post-operative follow-up are nanovesicles originating from late endosomes.
period. However, overt metastases are, in general, These vesicles are secreted by living dendritic
incurable by most current therapies. The monitoring cells (DCs) in the extracellular milieu and have
of CTC as “liquid biopsy” will provide new insights demonstrated the capacity to activate innate and
into the selection of tumor cells under biological adaptive immunity. These immuno-stimulatory
therapies. Molecular characterization of DTC properties have stimulated researchers to use Dex as
and CTC opens a new avenue for understanding a cell free vaccine. The development of a production
metastatic spread of tumor cells with important process following good laboratory practices has
implications for future therapies. The use of CTC allowed the use of Dex in vaccination protocols in
analyses in clinical trials testing new anti-cancer patients in the early 2000s. However, no modulation
agents as companion diagnostics has the potential of adaptive immune responses was observed in
to speed up the cumbersome and expensive drug these clinical trials. Thus the scientiÀc community
validation process in oncology. attempted to decipher mechanisms of action involved
References Pantel K, Izbicki JR, Angstwurm M, in the establishment of an effective immune response
Braun S, Passlick B, Karg O, Thetter O, Riethmuller after Dex vaccination. The results stressed that
the immunogenicity of Dex reÁects the state of shown to inhibit Treg cell activity. Therefore, we
maturation of DCs. Taking into account these new investigated the combined effects of CTX and
knowledge, our team developed a new generation of iDex to elicit antitumor immunity leading to tumor
Dex capable of inducing immune cellular responses rejection in the poorly immunogenic B16F10
against tumor antigens. We have engineered human melanoma model in mice. iDex-mediated anti-tumor
mDex, respecting good laboratory processes (GLP), effects were improved in CTX treated animals. CTX
harboring a phenotype with increased expression administrated 6 days before iDex vaccination was
of MHC complexes and co-stimulatory molecules able to boost peptide speciÀc secondary responses
suggesting potent adaptive immunity. These second as assessed by immunomonitoring using speciÀc
generation mDex are currently tested in a phase II Áuorescent tetramers and IFNƢ secretion by T
clinical trial in non small cell lung cancer (NSCLC) cells after in vitro stimulation. Modulation of Dex
bearing patients. The interest for Dex began in 1998 bioactivity through modulation of DCs maturation
when it was shown that these vesicles secreted into stage was Àrst described in 2005. This Àrst study
the culture supernatant of immature dendritic cells shows that Dex derived from DC treated with IL-
(immature Dex or “iDex”) could induce stabilization 10 are tolerogenic, resulting in the suppression
and regression of tumors in mice. These antitumor of inÁammation and collagen-induced arthritis in
effects induced by iDex pulsed with tumor antigens mice. Conversely, it appears that exosomes secreted
were dependant on CD8+ T cells in mice. These by mature DCs are immunogenic (mDex). Indeed,
results provide a rational for the use of iDex as a Dex produced from LPS-matured DC showed
therapeutic vaccine in patients bearing advanced enrichment with and CD86 leading to activation
cancer. of CD4+ and CD8+ T cells. Although the full
Two phase I clinical trials using autologous iDex understanding of the signiÀcance of Dex requires
pulsed with MAGE-3 peptides in patients with additional studies, these vesicles proved to be a
stage III/IV (French trial) and (US trial) allowed us naturally occurring minimal antigen presenting unit
to monitor immunological responses. These trials that could orchestrate immune responses according
aimed at evaluating the feasibility of Dex production to various signals received by producing DCs.
by autologous monocyte-derived DCs and the safety Exosomes are secreted in large quantities by DCs
of Dex inoculation. Secondary endpoints were in the absence of any stimulation (steady state), in
the immunomonitoring of peptide speciÀc CD4+ this context exosomes might play a role mainly in
and CD8+ T cell responses restricted by exosomal tissue homeostasis in promoting apoptotic body
MHC class II and I molecules. Fifteen patients clearance and avoiding harmful inÁammation that
were included in the french trial and thirteen in could lead to autoimmune diseases development.
the US trial. Feasibility and tolerance were good; By cons, in an anti-inÁammatory or a pro-
however, no T cell responses were pointed out after inÁammatory context, the molecular composition
iDex vaccinations. The discrepancy between some of Dex could play a fundamental role in shaping
clinical responses and the lack of any detectable immune responses. Indeed, in vivo the targeting
T cell responses prompted the search for alternate to one or the other exosomes presenting cell, the
effector mechanisms accounting for the tumoricidal expression of molecules that can regulate immunity,
activity. We studied NK activity in patients enrolled the presence of inÁammation mediators in Dex but
in these clinical trials and we could show that iDex also mRNAs or microRNAs content could dictate
were able to restore NK cell activity in half of in vivo bioactivity of Dex. The role of Rab27a and
treated patients. All of these preclinical and clinical Rab27b in regulating the secretion of exosomes
studies have led to improve this vaccine approach in has recently been identiÀed; this should enable us
order to obtain Dex that could activate an effective to build tools for the understanding of exosomes’
adaptive immune response in vivo. Three strategies role in different pathophysiological contexts. Our
were explored to improve the antitumor efÀcacy of growing knowledge of the effects of Dex on immune
Dex: - concomitant injection of an immunological responses and their potential use as therapeutic
adjuvant - inhibition of regulatory T cells (Treg) - the agents led us to develop second generation mDex in
use of mature DC to produce Dex (mDex). The role order to propose a maintenance immunotherapy in
of Treg in restricting T cell based-immune responses patients with advanced cancer. During this phase II
has gained renewed recognition. Cyclophosphamide clinical trial, we will have a unique opportunity to
(CTX) at immuno-potentiating doses has been analyze the immunostimulatory capacity of mDex
in a dynamic study in patients, to investigate their of the symptom of breathlessness in people who
protein and nucleic acid content and to correlate are not severely hypoxaemic is more controversial
those parameters with a potential and expected a systematic review that brings together all of the
clinical efÀcacy in patients. Together, these studies relevant papers in people with cancer and dyspnoea
should allow us to identify molecules essential for who do not qualify for long term home oxygen
the bioactivity of mDex in vivo in cancer patients does not demonstrate a symptomatic beneÀt. By
and to pave the way for the production of synthetic contrast, in chronic obstructive pulmonary disease
exosomes that would have a tailor-made content for there appears to be appreciable symptom beneÀt in
the induction of a speciÀc immune response. people who do not have hypoxaemia but are severely
Keywords: immunotherapy, exosomes breathless. The most promising intervention is the
use of heliox (28% O2/He 72%). This markedly
reduces the work of breathing therefore helping to
Session M08: Symptom Control - reduce breathlessness. Its expense however precludes
Translating Basic Research to Bedside it in use in clinical practice. A recently published
multi-site international study did not demonstrate
symptomatic beneÀt for people who do not
Monday, 4 July 2011
qualify for long term home oxygen with refractory
breathlessness over a one week period. Both
Symptom Control - Translating Basic Research to Bedside Monday, 4 medical air and oxygen delivered a similar level of
July 2011 16:30-18:00 symptomatic beneÀt. The science around the use of
opioids has continued to improve. In a double-blind
M08.1 SCIENTIFIC BASIS FOR THE randomised cross-over study of people with mild to
MANAGEMENT OF DYSPNEA moderate chronic obstructive pulmonary disease,
David Currow the use of a centrally acting opioid antagonist
Palliative And Supportive Services, Flinders demonstrated increased breathlessness when opioid
University/Australia receptors were blocked without changing the
exercise tolerance. Functional magnetic resonance
Abstract: Dyspnoea is a subjective sensation. It is imaging (fMII). This conÀrms the widespread
fundamentally a mismatch between afferent drive activation of opioid receptors with the initiation
to breath and the body’s efferent response to this. of stimuli that caused breathlessness in healthy
At a population level, at least one in 100 people in volunteers and in people with underlying lung
the population are chronically breathless despite disease. Adequately powered studies demonstrate an
optimised treatment of the underlying causes of adequately powered study and a systematic review
breathlessness. This group of people with refractory conÀrmed clinical efÀcacy of opioids for the relief
or intractable breathlessness require symptomatic of breathlessness. A long term effectiveness study
treatment. The other important distinction to make conÀrms the safety (no episodes of respiratory
is between breathlessness at rest and breathlessness depression in a patient population predominately
on exertion. There are a group of people breathless made up of people with COPD) and no tachyphylaxis
at rest or on absolutely minimal exertion (dressing, demonstrated (follow-up up to 22 months). Other
preparing a cup of coffee). Clinically, although interventions investigated include the use of selective
there are different descriptors that help delineate serotonin reuptake inhibitors, promethazine,
breathlessness, these are not pathognomonic. nebulised frusemide (not for its diuretic properties)
There are two clear components of breathlessness and a number of other medications. All of these
however. The Àrst is the intensity of breathlessness. studies are still investigational. Future questions
The second is an affective component measured as also need to be answered about whether all opioid
how unpleasant the sensation is. The symptomatic agonists are the same in their ability to inÁuence
treatment of breathlessness includes the use of breathlessness. Non-pharmacological interventions
oxygen, pharmacological interventions (focussed do have a strongly emerging evidence base with
around the use of chronic low dose opioids) and non- a number of therapies that have been shown to
pharmacological interventions. Although oxygen reduce breathlessness and improve people’s quality
has been shown to prolong survival in people with of function. These allow self management for a
severe hypoxaemia, its use in people for the relief number of people whose symptoms are ameliorated
somewhat the education and support that is offered consequences include negative nitrogen balance,
through these programs. hypo-albuminaemia and weight loss. In addition,
Keywords: dyspnoea, oxygen therapy, opioids, Non- because of the systemic inÁammation patients
pharmacological have an increased cortisol, hyperlipidemia and
hyperinsulinemia. These nutritional consequences
result in metabolic alterations in cachexia affecting
Symptom Control - Translating Basic Research to Bedside Monday, 4 protein, lipid and carbohydrate metabolism. This
July 2011 16:30-18:00 results in changes in body composition in cachexia
and speciÀcally there is reduced fat free mass
M08.3 CACHEXIA AND LUNG CANCER (skeletal muscle) as well as reduced fat. However,
Robert Milroy extra cellular water is maintained. There are a
Respiratory Medicine, Glasgow Royal InÀrmary/ range of clinical sequelae associated with cancer
United Kingdom cachexia. These include anorexia and weight loss as
well as wasting of muscle mass and loss of fat. In
Abstract: Lung Cancer remains one of the addition, anaemia and fatigue are common features.
commonest malignancies worldwide with a Consequently patients with cancer cachexia have
rising incidence in developing countries. Despite reduced function and reduced quality of life and
advances in treatment it continues to have an they have also been shown to have reduced survival.
overall poor prognosis. Lung Cancer is a cancer Up to 35% of skeletal muscle may be lost and
where the symptom burden is particularly high patients with lung cancer particularly are prone to
and these include both local symptoms such as respiratory muscle weakness and immobility which
breathlessness, cough, haemoptysis and pain, can result in DVT and PTE. Moreover, the chronic
symptoms of metastatic disease and also systemic systemic inÁammation seen in cancer cachexia down
symptoms – speciÀcally fatigue and cachexia. regulates the cytochrome P450 enzyme system. The
This lecture will focus on lung cancer cachexia. systemic inÁammatory response has been reviewed
Cachexia is deÀned as involuntary weight loss and in inoperable non small cell lung cancer by the
loss of skeletal muscle and derives from the Greek Glasgow group and a Glasgow prognostic score has
for poor condition Cachexia is a common symptom been described by this group. In addition a Montreal
at presentation and may in fact be the presenting Score has been described by McDonald et al in
symptom. It is increasingly common with increasing Canada. Therapeutic interventions in lung cancer
stage and is increasingly common as the disease cachexia remain a signiÀcant challenge to clinicians,
progresses. Cachexia is often associated with fatigue. and various treatment modalities will be reviewed.
The patho-physiology of lung cancer cachexia is not Regrettably research into cancer cachexia in lung
fully understood. It is not simply related to anorexia cancer and other cancers remains limited. End
and reduced intake. There are major metabolic points for future research in cancer inÁammation
changes with signiÀcant clinical consequences. and cachexia should include not only survival
The metabolic changes relate to a chronic systemic but symptoms, quality of life and performance
inÁammatory response with increased synthesis of status as well as function and anthropometrics. In
proteins involved in the response to tissue injury summary, cachexia is common in lung cancer. It is
(acute phase proteins). This inÁammatory response often associated with fatigue. It is commoner with
appears to be mediated by Cytokines. This results in increasing stage and disease progression. Systemic
redistribution of body protein, depletion of skeletal inÁammation mediated by cytokines has major
muscle and elevated resting energy expenditure. metabolic consequences which results in loss of
The consequences of this chronic systemic skeletal muscle and fat, reduced function and poorer
inÁammation fall into four categories: behavioural, survival.
physiological, nutritional and metabolic. Behavioural Keyword: cachexia, systemic inÁammation
consequences include anorexia, fatigue, malaise
and altered sleep. Physiological consequences
comprise increased resting energy expenditure and
skeletal muscle wasting but also include increased
body temperature, bone marrow suppression
and trace mineral sequestration. The nutritional
Symptom Control - Translating Basic Research to Bedside Monday, 4 1931 (9), NK1-receptors described in 1981 (10)
July 2011 16:30-18:00 and the Àrst clinical trial published in 1997 (11).
The development of these agents included use
M08.4 CHEMOTHERAPY-INDUCED of a new imaging technique, positron emission
NAUSEA AND VOMITING: FROM tomography (PET). This enabled an estimation of
TRANSMITTERS AND RECEPTORS the percentage of receptor binding necessary to
TO EVIDENCE-BASED CLINICAL obtain optimal antiemetic effect and to correlate
GUIDELINES this to relevant plasma trough concentrations (12).
Jørn Herrstedt Nausea and vomiting were decades ago inevitable
Oncology, Odense University Hospital And side effects of chemotherapy, but today effective
University Of Southern Denmark/Denmark antiemetic prophylaxis has been developed and
vomiting is successfully prevented in most patients,
Abstract: The physiology of nausea and vomiting meaning that nausea has overtaken vomiting as the
has been of scientiÀc interest for more than 100 most feared side effect of chemotherapy (13). The
years. Using the dog brain Thumas in 1891 proposed Multinational Association of Supportive Care in
the existence of an anatomical area, called the Cancer (MASCC) has developed evidence-based
vomiting center (VC) (1). This was further explored antiemetic guidelines. Chemotherapeutic agents
by Hatcher in 1923 (2), who demonstrated that are grouped according to emetic risk potential as
apomorphine-induced vomiting could be abolished having minimal (< 10% risk of vomiting), low (10-
by ablation of the nucleus of the tractus solitarius. 30%), moderate (30-90%) or high (> 90%) risk. The
Borison and Wang (3) made a series of studies corresponding recommended antiemetic prophylaxis
in the 1950s and demonstrated two regions. The (14) is; minimal risk, no routine prophylaxis; low
VC was located in the lateral reticular formation risk, a single dose of dexamethasone; moderate
and the chemoreceptor trigger zone (CTZ) at the risk including the combination of an anthracycline
area postrema, outside the blood-brain barrier, plus cyclophosphamide (AC), a combination of
and therefore capable of sensing both blood- and a 5-HT3-receptor antagonist plus dexamethasone
cerebrospinal Áuid-borne emetic stimuli. Miller plus the NK1-receptor antagonist, aprepitant (or
and Wilson in 1983 questioned the existence of the fosaprepitant); moderate risk (no AC included),
VC (4) and today we consider the VC as a system a combination of the 5-HT3-receptor antagonist,
connecting neural networks penetrating into the palonosetron, plus dexamethasone; high risk, a
nucleus of the tractus solitarius. Autoradiography combination of a 5-HT3-receptor antagonist plus
technique was soon used to demonstrate dopamine, dexamethasone plus the NK1-receptor antagonist,
muscarine cholinergic and histamine receptors in aprepitant (or fosaprepitant). Both 5-HT3-receptor
the gastrointestinal tract, the VC and the CTZ, and antagonists and the NK1-receptor antagonist,
radioligand-binding studies linked receptors to the fosaprepitant (15) can be administered as single
emetic reÁex arch (5). Today we know that most doses together with a single dose of dexamethasone
antiemetics act as antagonists at receptors, thereby before initiation of chemotherapy. The single
abolishing the emetic effect of neurotransmitters dose regimen optimizes compliance, because
such as dopamine and histamine. Two groups of only dexamethasone has to be administered for an
drugs, the serotonin (5-HT)3 receptor antagonists additional 2-3 days after chemotherapy. Tolerability
and the neurokinin (NK)1 receptor antagonists, of combination antiemetic prophylaxis is very
were speciÀcally developed as antiemetics. These good with headache and constipation being drug
developments disclosed the long timeframe from class adverse effects of 5-HT3-receptor antagonists
isolation of a substance (serotonin and substance (16) and no speciÀc drug class adverse effects
P), the Ànding of the corresponding receptors (5- allocated to aprepitant (17). This presentation will
HT3 and NK1), the hypothesis of a clinical relevant brieÁy summarize the development of antiemetics
application (using speciÀc receptor antagonists from basic research to clinical use go through
as antiemetics) and clinical drug development. recommendations from evidence-based guidelines,
Thus, serotonin was isolated in 1948 (6), 5-HT3- focusing on antiemetic prophylaxis in lung
receptors described in 1957 (7) and the Àrst clinical cancer patients. References 1. Thumas LJ. Über
trial with a 5-HT3-receptor antagonist published das Brechcentrum und über die Wirkung einiger
in 1987 (8), whereas substance P was isolated in pharmakologischer Mittel auf dasselbe. Archieves
für Patologische Anatomie1891;123:44-69. 2. vomiting. Expert Opin Drug Safety (published online
Hatcher RA, Weiss S. Studies on vomiting. J March 2011).
Pharmacol Exp Ther 1923;22:139-193. 3. Borison Keyword: antiemetics, nausea, vomiting, supportive
HL, Wang SC. Physiology and pharmacology of care
vomiting. Pharmacol Rev 1953;5:193-230. 4. Miller
AD, Wilson VJ. ”Vomiting center” reanalyzed: an
electrical stimulation study. Brain Res 1983;270:154- Session M09: Developments in High
158. 5. Davis C.J. Emesis research: a concise Dose Radiotherapy for Lung Cancer
history of the critical concepts and experiments.
In: Reynolds, D.J.M., Andrews, P.L.R., Davis, C.J
Monday, 4 July 2011
(Eds.), Serotonin and the ScientiÀc Basis of Anti-
Emetic Therapy. Oxford Clinical Communications,
Oxford, U.K., 1995, 9–24. 6. Rapport MM et al. Developments in High Dose Radiotherapy for Lung Cancer Monday, 4
Crystalline serotonin. Science 1948;108: 329–330. July 2011 16:30-18:00
7. Gaddum JH and Picarelli ZP. Two kinds of
tryptamine receptor. Br J Pharmacol Chemother M09.1 HEAVY ION RADIOTHERAPY IN
1957;12:323–328. 8. Leibundgut U and Lancranjan LUNG CANCER
I. First results with ICS 205-930 (5-HT3 receptor Hirohiko Tsujii, Naoyoshi Yamamoto, Masayuki
antagonist) in prevention of chemotherapy-induced Baba
emesis. Lancet1987; 329: 1198. 9. Von Euler VS and Research Center For Charged Particle Therapy,
Gaddum JH. An unidentiÀed depressor substance National Institute Of Radiological Sciences/Japan
in certain tissue extracts. J Physiol (Lond)1931; 66:
577–583. 10. Leander S et al. A speciÀc substance Abstract: (Introduction) In radiotherapy of non-
P antagonist blocks smooth muscle contractions small cell lung cancer (NSCLC), carbon ion beams
induced by non-cholinergic, non-adrenergic nerve offer improved dose distributions as compared
stimulation. Nature 1981; 294: 467–469. 11. Kris to photon beams and thus enable dose escalation
MG et al. Use of a NK1 receptor antagonist to within a target while sparing the surrounding normal
prevent delayed emesis after cisplatin. J Natl Cancer tissues. Furthermore, carbon ions being heavier than
Inst 1997; 89: 817–818. 12. Hargreaves J. Imaging protons provide a higher biological effectiveness,
substance P receptors (NK1) in the living human which increases with depth, reaching the maximum
brain using positron emission tomography. J Clin at the end of the range. At the National Institute of
Psychiatry 2002;63 (suppl 11):18-24. 13. Herrstedt J. Radiological Sciences (NIRS), clinical research on
Antiemetics: An update and the MASCC guidelines carbon ion radiotherapy (C-ion RT) was started in
applied in clinical practice. Nature Clin Practice 1994 using carbon-ions generated by Heavy Ion
2008;5:32-43. 14. Roila F, Herrstedt J, Aapro M Medical Accelerator in Chiba (HIMAC). So far,
et al. Guideline update for MASCC and ESMO in almost 6,000 patients have been treated, where the
the prevention of chemotherapy- and radiotherapy- beneÀt of C-ion RT over other modalities has been
induced nausea and vomiting: results of the Perugia demonstrated in terms of high local control rates and
consensus conference. On behalf of the ESMO/ a signiÀcant reduction in overall treatment time with
MASCC Guidelines Working Group. Ann Oncol acceptable toxicities in most cases. In this paper,
2010:21 (suppl 5);232-243. 15. Grunberg SM, Chua the results of treatment for Stage I NSCLC using 9
D, Maru A et al. Single-Dose Fosaprepitant for and 4 fractions are reviewed, as well as preliminary
the Prevention of Chemotherapy -Induced Nausea results of single fraction treatment is described.
and Vomiting Associated With Cisplatin Therapy: Also, results of other RT reported in the literatures
Randomized, Double-Blind Study Protocol—EASE. are compared. (Methods and materials) Stage I
J Clin Oncol 2011;Epub ahead of print March lung cancer is divided into two types depending on
7. 16. Ruhlmann C, Herrstedt J. Palonosetron tumor location: peripheral-type and central-type.
hydrochloride for the prevention of chemotherapy- This classiÀcation is made on the assumption that
induced nausea and vomiting. Expert Rev Anticancer the two types may tolerate radiation differently.
Therapy 2010;10:137-148. 17. Ruhlmann C, Therefore, different fractionation regimens were
Herrstedt J. Safety evaluation of aprepitant for the investigated for each type. The patients eligible for
prevention of chemotherapy-induced nausea and either treatment are those for whom surgery was
not indicated due to medical reasons or refusal. fractions over 3 weeks, 4 fractions over one week,
From 1999 to 2003, a total of 131 tumors in129 and eventually to a single fraction treatment. The
patients received C-ion RT with 9 fractions and 4 preliminary data suggested favorable local control
fractions, including 94 males and 37 females with and very few toxic reactions with a median follow up
an average age of 74.5 years. Out of the 131 foci, time of about 16 months. Compared with pulmonary
there were 72 T1 tumors and 59 T2 tumors. There damage reported for stereotactic radiotherapy in
were 85 adenocarcinomas, 43 epidermoid cancers stage I lung cancer, the incidence and severity in
and 3 other types. Regarding dose fractionations, our patients seemed to be remarkably low. The
51 cases were treated with 72.0GyE/9 fractions, and decreased adverse effects on the lung are likely
80 cases were treated with 52.8GyE/4fr for stage IA achieved due to the small volume irradiated. When
and 60.0GyE/4fr for stage IB. Since 2003, a dose- comparing proton vs C-ion RT, local control results
escalation study using single fraction treatment has are comparable for T1 tumors, but for T2 tumors
been conducted for peripheral-type NSCLC. The 2-5 year local control rates are higher in C-ion RT.
initial dose was 28.0 GyE, which was then escalated It is of note that in most reported data for proton
at increments of 5%. At each dose level, about 10 to therapy, follow-up periods are short relative to
30 patients were registered for evaluation of toxicity the time required for full evaluation of TCP, late
and local control with carbon ions. C-ion RT has NTCP and survival. Considering that the average
also been applied to locally advanced lung cancers age of the patients receiving C-ion RT was about
and hilar-type cancers, and case studies are being 75 years, about 10 years older than that of 65 years
accumulated. The locally advanced lung cancers in the operated patients, the results of C-ion RT for
included Pancoast tumors and mediastinal-type stage-I lung cancer may be comparable to surgical
tumors in stages II-IIIA. (Results) All of the patients results. Thus, the single-fraction irradiation method
treated with 9 fractions/3 weeks (50 patients) and 4 may be described as the ultimate type of treatment
fractions/1 week (79 patients) developed no evidence using carbon ion, and would be a valid alternative
of severe toxicities. The 5-year local control rates to surgery, especially for elderly and inoperable
were 98.6% for stage-IA cases and 89.7% for stage- patients.
IB cases, and the 5-year survival rates were 63.1% Keywords: Particle, Carbon ion, Radiotherapy,
for stage-IA cases and 50.0% for stage-IB cases. In Hypo-fraction, Lung, NSCLC
single fraction treatment, a total of 218 patients have
been registered, in which the total dose has been
escalated from 28.0 to 48.0 GyE. So far, no serious Developments in High Dose Radiotherapy for Lung Cancer Monday, 4
adverse events have been observed, and local control July 2011 16:30-18:00
appears to be improving with increasing total dose.
For skin reactions, six grade 2 toxicity (3.3%) but M09.2 ARC-THERAPIES AND OTHER
no grade 3 or higher was observed. For radiation APPROACHES FOR IMRT
pneumonitis, only one grade 1 was reported, and Wilko F.A.R. Verbakel
no toxicities greater than grade 2 occurred. The Radiation Oncology, Vu University Medical Center/
overall local control rate was 91.8%, and the cause- Netherlands
speciÀc survival rate at 5-years was 71.8%. The
superÀcial lesions arising at the hilar region have Abstract: RapidArc (Varian Medical Systems) is a
been successfully treated with acceptable toxicities. form of volumetric modulated arc therapy which has
Similarly, in the preoperative radiotherapy for been clinically used at VUmc since its Àrst release
patients with chest wall invasion, high anti-tumor in May 2008 for over 1400 patients, 500 treated
effect was conÀrmed in the pathological Àndings with SBRT. In comparison with Àxed beam IMRT,
after the lung was surgically removed. (Discussion) RapidArc reduces treatment time for all treatment
Only at NIRS, Japan, NSCLC has been treated sites. For SBRT for stage I lung tumours, RapidArc
with carbon ions. For peripheral tumor, we have can achieve better dose conformity than conventional
been conducting clinical studies to establish a 10 static Àeld plans. Use of 2 sequentially optimized
short-course, hypo-fractionated radiotherapy. We arcs allows overcoming the problem of the different
Àrst performed a dose-escalation study using 18 dose engines in the optimizer and Ànal dose
fractions/6 weeks. The number of fractions and calculation. Radiation delivery time for a fraction
treatment times were subsequently reduced to 9 of 18 Gy takes less than 6 minutes and a fraction of
7.5 Gy is delivered in less than 3 minutes. The fast advantages, but also important limitations: they are
treatment reduces the risk of intrafraction motion often resource-intensive and expensive, with a long
of the patient. The high dose conformity allowed lag-time from study initiation until results, and can
us to treat also large PTVs. Early toxicity results have limited generalizability. Many questions are
were collected from 14 patients with large St I not amenable to RCTs, due to concerns about ethics,
tumors (PTV range 87-286 cc) treated with risk practicality, and important barriers to accrual. In
adapted fractionation schemes of 5x11 Gy or 8x7.5 many cases, a pressing scientiÀc question cannot
Gy, prescribed to the 80% isodose. All patients be answered in the context of a randomized trial,
with a contralateral lung V5>26% developed CP and physicians must look to other sources in order
and contralateral V5 was the best predictor for CP to practice EBM. In the absence of controlled
(p<0.001). Total lung V10 had a weaker correlation trials, population-based studies provide the highest
to CP (p=0.02) and total lung V15 and V20 showed level of evidence for medical decision making. By
no signiÀcant correlation with CP. Our early clinical deÀnition, such studies include all patients from a
data showed that CL V5 is the best predictor for CP well-deÀned population, most commonly deÀned
and should be kept lower than 26%. This can be by a geographic boundaries (province, state, or
achieved applying partial arcs or avoidance sectors. country), but occasionally deÀned differently
Use of moving leaves in combination with moving (e.g. by occupation or membership in a health-
(lung) tumours can raise the fear of dosimetric maintenance organization). Although population
interplay effects. This has been studied for different studies are not able to control for confounders
levels of plan complexity and tumour amplitudes as well as randomization, they have several
using Gafchromic Àlm measurements in a moving important advantages: they are inherently the
phantom, showing that the dosimetric effect in most generalizable of studies, they reÁect real-
the tumour itself is limited to 3%. 3D conformal world outcomes, and reduce or eliminate selection
planning can be time consuming, especially for large bias. Population-based studies have advanced the
PTVs overlapping with organs at risk. Full IMRT understanding and treatment of non-small cell lung
provides better opportunities to spare OAR with cancer. Overall, progress in lung cancer has been
a lower dose and achieve a more conformal dose slow, with 5-year survival improving marginally
distribution, but it prolongs delivery time. A Hybrid from 13% in 1975-1977 to 16% in 1999-2005,
solution of a combination of 3D conformal plan with based on U.S. population data, a gain of only 3%.
a small IMRT component allows for fast planning In contrast, breast cancer patients achieved a 15%
and more conformal dose distributions. improvement and prostate-cancer patients a 30%
Keywords: SBRT, treatment planning, Radiotherapy improvement over the same time period. Population
studies have also revealed important international
disparities among developed countries: the age-
Developments in High Dose Radiotherapy for Lung Cancer Monday, 4 standardized 5-year survival in Sweden is nearly
July 2011 16:30-18:00 double the survival in England for both men and
women, and this difference in mortality is evident
M09.3 LUNG SBRT AND POPULATION- within the Àrst 3 months after treatment, suggesting
BASED COMPARATIVE- that early detection and treatment effects play a
EFFECTIVENESS RESEARCH major role in survival. Geographic variation also
David Palma occurs within individual countries, with major
Radiation Oncology, London Regional Cancer regional differences in resection rates and operative
Program/Canada mortality demonstrated in several population studies.
Stage I NSCLC in the elderly is a particularly
Abstract: The goal of Evidence-Based Medicine challenging clinical scenario: although the disease is
(EBM) is to apply the best-available evidence from theoretically curable, often treatment is hampered by
scientiÀc discovery to clinical decision making. patient co-morbidity, frailty, or physician perception
EBM was deÀned by Sackett as “the conscientious, of lack of efÀcacy. High-level evidence is limited,
explicit and judicious use of current best evidence since RCTs tend to restrict enrollment by elderly
in making decisions about the care of individual patients. Canadian population-based data have
patients.” The randomized control trial (RCT) demonstrated that in elderly patients with stage
is the gold-standard of EBM. RCTs have many I NSCLC treated with radical intent, survival is
predicted by tumor and treatment factors (such as allow treatment with this fractionation scheme
stage, sex, and radiotherapy dose), and physiological to lesions within 2 cm of the central pulmonary
factors (ECOG status), but is not predicted by age, structures. Central tumors are currently the subject
suggesting that elderly patients should not be denied of a cooperative group investigation utilizing a
radical treatment based on age alone. The impact lower dose per fraction (9 to 11.5 Gy) for Àve
of implementing stereotactic ablative radiotherapy fractions. Dose constraints for speciÀc organs vary
(SABR) for elderly patients with stage I NSCLC by institution. For the lungs, some institutions use a
has now been measured at the population level. dose constraints to the V20 of approximately 10 –
Emerging evidence suggests that the implementation 12% for the lung as a paired organ. Other institutions
of SABR is associated with a signiÀcant increase in try to keep the dose to 1000 cc of lung less than 12.4
radiotherapy utilization, and a signiÀcant decline in Gy and the 1500 cc less than 11.6 Gy. Other organs
the number of patients going untreated. As a result, such as the proximal bronchial tree, esophagus,
potentially curative therapy is now being offered spinal cord, heart, great vessles and brachial plexus
to patients who previously went untreated, and this are subject to a maximum dose constraint, usually
is reÁected in improved overall survival in patients in the range of 20 – 35 Gy. The chest wall has
treated with radiotherapy at the population level. recently been identify as an organ at risk for fracture
The development of several national administrative and persistent chest wall pain. Most institutions try
cancer databases has facilitated increased population- to limit the volume of chest wall receiving 30 Gy
based oncology research over the past decade. Future regardless of fraction size.
research should continue to focus on comparative Keywords: stereotactic body radiation therapy,
effectiveness issues, including survival outcomes, SBRT, toxicity, dose constraints
resource utilization and cost effectiveness. Although
randomized studies remain the gold standard of
EBM, population-based studies provide important Session M10: Molecular Screening
evidence, especially for questions that cannot be
answered by randomized trials. Monday, 4 July 2011
Keywords: Non-small cell lung cancer,
Epidemiology, Comparative effectiveness
Molecular Screening Monday, 4 July 2011 16:30-18:00
Developments in High Dose Radiotherapy for Lung Cancer Monday, 4 M10.1 EARLY DETECTION AND
July 2011 16:30-18:00 SCREENING OF LUNG CANCER VIA
VOLATILE BIOMARKERS
M09.4 NORMAL TISSUE CONSTRAINTS Hossam Haick1, Nir Peled2, Meggie Hakim1, Orna
FOR SBRT Barash1, Jane Mettei2, Ulrike Tisch1, Paul Bunn2,
Kenneth Rosenzweig Fred R. Hirsch2
1
Department Of Radiation Oncology, Mount Sinai Department Of Chemical Engineering, Technion -
School Of Medicine/United States Of America Israel Institute Of Technology/Israel, 2Cancer Center,
University Of Colorado/United States Of America
Abstract: Stereotactic body radiation therapy
(SBRT) is increasingly used in the treatment of Abstract: An emerging approach for diagnosing
early-stage non-small cell lung cancer (NSCLC), cancer relies on volatile biomarkers that are emitted
particularly in patients with medical conditions from cells membranes. These volatile biomarkers can
precluding surgical management. Although many be detected either directly from the headspace of the
of the side effects of SBRT are similar to those cancer cells or via the exhaled breath. The principle
seem for conventionally fractionated lung cancer of the latter is that cancer related changes in blood
treatment, there are other toxicities unique to SBRT chemistry are reÁected in measurable changes in the
that reÁect its use of high dose per fraction treatment. breath through exchange via the lung.
In one study, patients treated with doses of 20 Gy Methods: Based on these principles, we have
per fraction to central lesions had a greater risk of developed and tested a highly-sensitive, inexpensive,
treatment related mortality than peripheral lesions. and fast-response, non-invasive tool for early
As a result of this, newer SBRT protocols do not detection of volatile biomarkers. This tool is based
on an artiÀcial (electronic) nose, which makes use

of cross-selective and chemical nanosensor arrays
that are trained in their ensemble to detect cancer
biomarkers. The signals from all the sensors in
the array are analyzed using standard principal
component analysis (PCA) or discriminant factor
analysis (DFA). We term this new concept as NA-
NOSE. The NA-NOSE concept was applied to
(i) breath testing, using collected breath samples
from lung cancer (LC) patients and various control
groups, and to (ii) headspace sampling from LC cell
lines. RESULTS Clinical studies on breath samples
collected from 177 volunteers demonstrated the
discriminative power of the NA-NOSE breath test A series of complementary in-vitro studies3 have
to distinguish LC patients from healthy controls1 shown the feasibility of the NA-NOSE concept for
and from patients having colon cancer (CC), breast distinguishing the LC sub-histologies. The NA-
cancer (CC) or prostate cancer (PC) with >95% of NOSE clearly distinguished NSCLC from the control
diagnosis accuracy (see Fig. 1).2 The NA-NOSE medium, with relatively high accuracy. Furthermore,
distinguished between the breath of cancer patients the NA-NOSE could clearly distinguish patterns
and that of healthy individuals with high accuracy of volatile biomarkers emitted from cell lines that
and in the presence of confounding factors (e.g., exhibited EGFR mutation (mut) from cell lines that
age, gender, ethnic origin, family cancer history, exhibited EGFR wild type (wt), as shown in Fig.
intake of food additives, drug treatment, exposure 2 (p < 0.0001). The accuracy of the method was
to environmental toxins and smoking habits, etc.). determined as 85-89% through cross-validation.
The unambiguous detection of LC within a mixed Auxiliary chemical analysis of the headspace
population of healthy persons and persons suffering samples was performed using gas chromatography in
from the four most widespread cancers in a single combination with mass spectrometry (GC-MS) and
breath test could form the basis of a future cancer solid phase micro extraction (SPME). The results
screening test for the general population. showed statistically signiÀcant differences in the
average abundance of several biomarkers in each cell
category.
Conclusions: The NA-NOSE concept has the
potential to reduce cancer mortality, by enabling
widespread, trustworthy screening, especially for
high-risk populations, through non-invasive point-
In a complementary study we showed that the NA- of-care breath testing. It would be suitable for use
NOSE could identify and distinguish speciÀcally outside of specialist settings and would signiÀcantly
between LC and head-and-neck cancer (HNC) reduce costs in health budgets. The same tool
that are both closely related to tobacco smoking, could be used after biopsy in laboratory settings to
and, therefore occur in the same population. The assist treatment decisions. It would allow the easy,
results showed excellent separation between inexpensive and fast detection of the cancer subtype
LC patients, HNC patients and healthy controls. and/or cancer related genetic mutations that can
The differential diagnosis of LC and HNC could beneÀt from oral targeted therapy (e.g. EGFR tyrosin
lead to the development of a routine breath test kinase inhibitors). The easy-to-use NA-NOSE
for the at-risk population of tobacco smokers. technology detects cancer and identiÀes cancer-
related EGFR mutilations based on a change in the
blood chemistry and/or metabolic activity rather
than by tumor imaging, thus permitting earliest
cancer detection i.e. before a tumor of detectable
size has formed, and/or assists the swift choice of the
therapeutic approach.
References: 1. Peng G, Tisch U, Adams O, et al.
Diagnosing lung cancer in exhaled breath using gold of seropositivity to ANXA1, YWHAQ, and LAMR1
nanoparticles. Nature Nanotechnol 2009;4:669-673. for the early detection of lung cancer based on
2. Peng G, Hakim M, Broza YY, et al. Detection of blinded validation using pre-diagnostic sera. The
lung, breast, colorectal, and prostate cancers from goal of our current studies has been to identify
exhaled breath using a single array of nanosensors. additional antigens that augment the performance of
Br J Cancer 2010;103:542 – 551. our previously established panel. One such antigen
3. Barash O, Peled N, Hirsch FR, et al. SnifÀng the is ANGPTL3 a protein not previously associated
unique “odor print” of non-small-cell lung cancer with lung cancer. Our studies have demonstrated
with gold nanoparticles. Small 2009;5:2618-2624. signiÀcant autoantibody reactivity against ANGPTL3
Keywords: diagnosis, Screening, Breath, biomarker in the sera of newly diagnosed NSCLC patients
compared to control sera (p=0.0013). Importantly,
addition of ANGPTL3 to our previously published
Molecular Screening Monday, 4 July 2011 16:30-18:00 panel of ANXA1, YWHAQ, and LAMR1 improved
the predictive performance of the panel to
M10.2 AUTOANTIBODY DETECTION IN discriminate cases from controls in sera collected
SERUM prior to the onset of symptoms and diagnosis of
Sam M. Hanash lung cancer providing further support for the utility
Molecular Diagnostics, Fred Hutchinson Cancer of harnessing the immune response against tumor
Center/United States Of America antigens for the early detection of lung cancer.
Keywords: Early Detection, immune response
Abstract: The development of lung cancer is a
multi-step process. IdentiÀcation of antigens that
are expressed at early stages of tumor development Molecular Screening Monday, 4 July 2011 16:30-18:00
and that induce a humoral response would lead to
the development of simple non-invasive detection M10.3 ANALYSIS METHYLATED DNA IN
strategies. A humoral response to tumor antigens SPUTUM
results in an ampliÀed signal detected as a Steven Belinsky
seropositive response based on antigen-autoantibody Lovelace Respiratory Research Insititute/United
reactivity. While progress has been made in States Of America
identifying an immune response to deÀned antigens
in lung cancer using a multitude of technologies Abstract: Gene promoter hypermethylation is a
and some tests based on an immune response are major mechanism in the etiology of lung cancer with
becoming available, there are several challenges hundreds of genes epigenetically silenced during
that need to be overcome for this strategy to be initiation and progression of this disease. The fact
widely accepted as a means for early detection of that gene methylation can be detected in sputum
lung cancer. Antigens need to be identiÀed that are (as Àrst shown by our group) and that methylation
expressed at early stages. Most work done to date is reversible by pharmacological intervention led
is based on identiÀcation of seropositivity to tumor us to initiate translational studies to assess whether
antigens at the time of diagnosis. Given that different methylation in sputum could be used as a biomarker
antigens may be expressed at different stages and the for early lung cancer detection. A second goal of
balance between amount of antigen vs antibody may these studies was to identify genetic determinants
also be substantially altered with tumor progression, that inÁuence the propensity for methylation in the
the search for antigens and the development of aerodigestive tract or are associated with lung cancer
related biomarker tests would beneÀt substantially and to integrate these key variants with methylation
from a study design in which the intended clinical biomarkers for establishing the most sensitive
application drives discovery and validation studies. and speciÀc risk proÀle for early lung cancer
Given that a robust test would have to include detection. A nested, case-control study was initially
multiple antigens, there is a need for validation conducted in the Colorado cohort to determine the
studies that allow comparison of performance of sensitivity and speciÀcity of 16 genes interrogated
individual antigens on aliquots from the same study for methylation in sputum collected 3–18 months
samples as appropriate for the intended application. prior to diagnosis of clinical disease. A panel of six
We have previously reported the utility of assessment genes whose concomitant methylation in sputum
was associated with a 6.5-fold increased risk for cohort. We are assessing several different models
lung cancer and a sensitivity and speciÀcity of 65% that incorporate this genetic index and clinical risk
for classiÀcation of incident cases was identiÀed. factors with the methylation index to determine
Those studies were extended to evaluate 60 genes in their effect on sensitivity and speciÀcity for lung
sputum from incident lung cancer cases and controls cancer detection. (Supported by P50 CA58184, P50
from the Colorado SPORE and identiÀed a 17-gene CA58187, and R01 CA097356)
panel. Five genes (DAL1, PCDH20, KIF1A, P16, Keywords: Early Detection, Sputum, genetic
and DAPK) showed signiÀcantly increased odds polymorphisms, Promoter methylation
for methylation in cases compared to controls and
in total 14 genes were associated with a 2-fold or
more increased lung cancer risk. A diagnostic test Molecular Screening Monday, 4 July 2011 16:30-18:00
for lung cancer should have high speciÀcity and
sensitivity for identifying early stage disease where M10.4 MICRO RNA DETECTION IN
curative resection and possibly adjuvant therapy SPUTUM
could reduce mortality. Thus, sputum obtained from Feng Jiang, Nevins Todd
patients with Stage I lung cancer that are generally Thoracic Surgery, Cancer Hospital Of Jiangsu
asymptomatic for disease should be an appropriate Province/China
specimen for reÀning our gene panel for prospective
studies. Stage I lung cancer patients identiÀed from Abstract: Non-small cell lung cancer (NSCLC)
our New Mexico (NM) cancer registry cohorts is the most common type of lung cancer and the
(n = 45) were matched 1:2 with controls by age number-one cancer killer in the United States and
(± 5 yr), gender, smoking status, and enrollment worldwide. NSCLC mainly consists of two major
site and evaluated for methylation of the same 17- histological types: adenocarcinoma (AC) and
gene panel. Twelve genes were validated in this squamous cell carcinoma (SCC). The disease is
study. Concomitant methylation of 4 or 5 genes frequently diagnosed at advanced stages, resulting
from panels of 7 or 8 genes was associated with in an overall 5-year survival rate of about 14%.
sensitivity and speciÀcities of approximately 70 Conversely, the 5-year survival rate in stage I
and 75%, respectively. In addition, several exciting NSCLC patients who have received effective
new genes recently discovered by our group that treatments can be as high as 83%. Therefore,
are methylated in lung cancer that function as Ànding NSCLC earlier may reduce the mortality.
chemokines, CXCL12 and CXCL14 were evaluated The sensitivity of chest X -ray and sputum
in the NM cases and controls. Odds ratios of 1.6 cytology for early detection of NSCLC is low.
(CI, 0.7, 3.3) and 2.9 (CI, 1.7, 7.3) were seen for Bronchoscopy excels at detecting centrally occurring
CXCL12 and CXCL14, respectively suggesting lung tumors. However, it is invasive. Although
these genes could also be promising biomarkers CT provides excellent anatomic information and
for early lung cancer detection. A gene panel is can noninvasively detect NSCLC earlier at small
being Ànalized for validation in a nested, case- size, the improved sensitivity is associated with
control study of participants from the National Lung over-diagnosis. Therefore, developing minimally
Screening Trial. An additional goal is to develop and invasive techniques by taking advantage of recent
then integrate a genetic index of sequence variants developments in molecular genetics for diagnosis of
associated with lung cancer or methylation with the early stage NSCLC is clinically important. Because
panel of methylation biomarkers. As a Àrst step we morphological changes of exfoliated bronchial
genotyped the six single nucleotide polymorphisms epithelium from sputum are associated with incident
(SNPs) identiÀed and validated through genome- of NSCLC, cytological analysis of sputum has been
wide association studies in the cases and controls used clinically for its diagnosis. However, it was
from New Mexico and Colorado. These include two no more effective than chest radiographs in early
SNPs on chromosome 15 (nAChR gene cluster), diagnosis of lung cancer in several large prospective
one within 6p21.31 (HLA-DQA1 gene), one within randomized trials. The molecular genetic alterations
6p21.33 (BAT3-MSH5) and two within 5p15.33 detected in sputum may correlate with those exist in
(CLPTM1L-TERT locus). An odds ratio of 2.2 lung tumors, and even occur before morphological
(CI: 0.85, 5.64; p = 0.11) was seen for subjects changes that can be found by a cytological test.
carrying more than 3 risk alleles in the New Mexico Therefore, molecular study of sputum could be
more sensitive than cytology in diagnosis of lung in diagnosis of lung SCC patients. However, the
cancer. MicroRNA (miRNSs) are emerging as sensitivities of the gene panel were 72.0% and 92.0%
potential biomarkers in cancer diagnosis. The in diagnosis of lung AC patients. Additionally, there
objective of this study was to develop a panel of was an association of the changes of the genes with
miRNAs that can be used as a sputum-based test smoking packer-year of cancer patients (All p<0.05).
for early stage NSCLC. Patients and Methods We However, the changes were not related to the age,
Àrst used a microarray platform to analyze primary gender, and ethnic of the participants (All p >
lung tumor tissues from 32 stage I NSCLC patents 0.05). Taken together, the validation data conÀrmed
to deÀne miRNAs signatures whose expressions that the identiÀed sputum-based miRNAs had the
are associated with stage I lung cancer. We then potential to be used as biomarkers for NSCLC,
determined if miRNAs are stably present in sputum particularly lung SCCs in the airways of the lungs.
by quantitative real-time reverse transcriptase PCR We further compared the panel of the miRNA genes
(qRT-PCR) assay and deÀned a panel of miRNAs with cytology in distinguishing early stage NSCLC
that can provide potential biomarkers for lung patients from healthy individuals. 36.7% of early
cancer in a training set of 36 stage I NSCLC patents stage NSCLC patients were diagnosed to be positive
and 36 healthy controls. We Ànally validated the by cytological examination. All cytologically
deÀed miRNAs in a testing set of 49 case and 49 positive specimens also exhibited aberrations of
healthy individuals. Results Identifying miRNA the genes, thus were positive for the genetic test.
signatures whose aberrant expression levels were Interestingly, of the cytologically negative sputum
associated with lung adenocarcinoma. When P samples from the NSCLC patients, 19 were positive
value <0.01 was used as a cutoff, of the 377 miRNA for the miRNAs. Therefore, the composite of use of
targets, 26 miRNAs were either underexpression the miRNA genes had higher diagnostic sensitivity
or overexpression showed high expression in lung as compared with sputum cytology for early stage
tumor compared with matched lung tissues with NSCLC (P< 0.01). Conclusion The sputum miRNA
1.5 fold-change. Using a predeÀned criterion of biomarkers demonstrated the potential to improve
a fold-change 2, we identiÀed seven miRNAs the early detection of NSCLC, particularly lung
that statistically differently expressed between the SCC. However, future identifying more informative
paired lung tumors and normal lung tissues. These miRNAs that can be added to the current panel
included seven miRNAs . The miRNAs can be will improve accuracy for the early detection
reliably measured in sputum samples and a set of of NSCLC. Furthermore, the future use of the
miRNA are identiÀed in the training set of case miRNA biomarkers with CT scan will complete
and control. In the sputum samples, all the seven CT to improve efÀcacy to screen NSCLC in a high
miRNAs can be reliably measured. In the training risk population. Finally, evaluating whether the
set of cohort, four genes (miR-21, miR-485, and biomarkers can distinguish lung cancer patients
miR-205) were selected, which in combination from chronic respiratory disease and heavy smokers
produced the best prediction in distinguishing remains to be investigated.
lung cancer patients from normal subjects with Keywords: miRNA, Sputum, NSCLC, diagnosis
overall sensitivity and speciÀcity at 80.6% and
94.4% respectively. Furthermore, the panel of
biomarkers has higher sensitivity in detection SCC
compared with AC (P<0.05) at similar speciÀcity.
Validation of the marker panel in the independent
populations The genes displayed higher abnormal
levels in the lung cancer patients compared with
all non-cancer individuals (All p<0.05). We used
the optimal thresholds established in the training
set to determine diagnostic value of the genes for
lung cancer in the testing set. Overall, the panel of
the genes produced 81.6% and 93.9% sensitivities
in differentiating NSCLC patients from healthy
individuals. Furthermore, the genes used together
generated 87.5% sensitivity and 95.8% speciÀcity
Session M11: Design of Phase II Clinical multiple endpoints and Bayesian approaches have
Trials: Single Arm, Randomized, Multi been proposed. Typically the single-arm studies
Arm? enroll 30-70 patients in total. The shift in oncology
drug development from the evaluation of traditional
cytotoxic agents to new approaches directed at the
Monday, 4 July 2011 processes of angiogenesis, invasion, metastases
and other host-tumor interactions have challenged
Design of Phase II Clinical Trials: Single Arm, Randomized, Multi the traditional phase II with objective. For these
Arm? Monday, 4 July 2011 16:30-18:00 innovative cancer therapies, the optimal dose may
not be the most toxic, the traditional parameters of
M11.1 RANDOMIZED DESIGN tumor regression that are used to assess response
Harm Van Tinteren may not apply and reliable surrogates of true
Department Of Biostatistics, The Netherlands clinical beneÀt may simply be not available. With
Cancer Institute - Antoni Van Leeuwenhoek Hospital, an excess of options to explore and restrictions on
Amsterdam/Netherlands the availability of patients and study budgets, the
issue of prioritizing approaches and selecting ‘the
Abstract: Phase II Clinical Trials Designing optimal winner’ for further testing on large scale, stimulated
phase II trials continues to be a major challenge the development of randomized selection designs.
with an increasing number of potential (molecular In principle, the design is usually is equivalent
targeted) agents, alternative endpoints and an to running two-stage single-arm studies for each
increasing number of design options on the one regimen (or schedule), with the beneÀt of obtaining
hand and a rather poor track record of successfully a greater degree of comparability between the
screening out inactive agents on the other hand. treatments. Given some constraints, the regimen
This session is intended to give an overview of that results in the highest response rate is selected
options for the design of phase II clinical trials for for further study. The selection design has also
different types of cytotoxic and cytostatic agents been adapted for use with progression-free survival
in oncology. After a phase I trial has determined or overall survival. Where the phase II selection
a tolerable dose for a new agent or combination, design is appropriate, it can often be conducted
in the cancer drug development process, the main with modest sample size. For example, 30-40
goals of phase II trials are to screen out inactive patients per arm may yield 90% power to detect a
agents (sometimes referred to as phase IIA) and to regimen that has response rate superior by 15% (or
select promising therapies for (large-scale) phase corresponding hazard ratio of 1.5) in a two-armed
III trials (phase IIB). Historically, the design of study. Studies without a simultaneously randomized
phase II oncology trials can be divided into three standard-treatment control arm (either single-arm
categories: single-arm trials, randomized trials with or randomized) rely on an implicit comparison
multiple experimental regimens but no prospective to historical controls in terms of level of activity.
control arm and randomized trials with a concurrent However, rapidly changing standards in many
standard-treatment arm. The single-arm trial has diseases in therapy, imaging and supportive care
been the most frequently applied approach to the imply that historical data may not be reÁective of
efÀcacy evaluation at the phase II level in oncology the results observed in current clinical practice.
(phase IIA). The single-arm methodology includes Due to that reason, some investigators feel more
single-stage designs, in which a predetermined comfortable with a randomized phase II study with
number of patients are recruited, and two-stage a prospective control. This is the standard approach
designs, in which patients are recruited in two stages, to drug development in other therapeutic areas.
with stage 2 being sequential on the results observed Within this setting, the control arm is sometimes
in stage 1. The main objective of multi-stage designs used informally as to check on the similarity
is to minimize the number of patients treated with to historical controls. However, in general the
ineffective regimens. Amongst these latter designs, reference arm is too small to assure comparability
Gehan’s-, Simon’s- and Fleming’s two-stage designs and it may be difÀcult to interpret differences if
are the most commonly used. Multiple variations, they may occur. Alternatively, the control arm can
including optimal selection of interim analysis time be analyzed with the explicit intent of comparing
points, additional stages of accrual, consideration of treatment arms. Such design, sometimes referred
to as phase II screening trials, allow for selecting resource and time following unreliable leads. Even
promising regimens for further studying by adjusting when trials were positive for new single agents, it
especially the signiÀcance (false-positive rate) while has taken many additional years (sometimes 10 or
keeping the trial fully powered. The design will have more) to complete combination therapy trials that
low probability of failing to identify active agents may deÀne optimal standard regimens for clinical
and allows the sample size to remain restricted. use. In the end, the inefÀciency of this paradigm is
Randomized phase II studies, and especially when unsatisfactory to patients and health systems and
including a standard-treatment control arm, should also contributes to the burdensome cost of oncology
however be designed and interpreted with caution drugs by leaving few remaining years of patent life
because of the unavoidable issues such as high for companies to recoup their costs and realise a
false-negative and positive rate, unstable p-values proÀt. In this presentation I shall introduce a move
and the risk that these studies, whether negative of towards improving both the speed and reliability of
positive, may (incorrectly) preclude later deÀnitive oncology trials through the multi-arm, multi-stage
studies. In conclusion, phase II studies are important (MAMS) designs. This design randomises patients
screening tools in drug development, but require a to many new treatments, in a seamless phase II/
thoughtful design appropriate for each individual III setting and adaptively focuses recruitment
agent. Some situations may favor single-arm studies, resources onto arms selected according to emerging
especially in rare tumors and for single agents with intermediate data from the trial, supplemented by
tumor response endpoints, while randomized designs any available external data. The implementation
may be preferable for combination therapy, time- of this design will be illustrated through the
to-event endpoints and when the number of patients STAMPEDE trial, a 6-arm, 5-stage trial for men
is of lesser concern. Nevertheless, more innovative with prostate cancer. This trial has now ceased
designs are needed to cope with issues such as the recruitment two of its arms, continuing with the
selection and validation of the most appropriate remaining 4. We are also in the process of adding a
target-based endpoints, dynamic and adaptive new and 5th arm to these remaining 4. The beneÀts
randomization and stopping rules, Áexible study and difÀculties with designing and running this sort
accrual and population enrichment. of trial will be discussed.
Keyword: Multi-arm Multi-stage randomised phase
II/III
Design of Phase II Clinical Trials: Single Arm, Randomized, Multi
Arm? Monday, 4 July 2011 16:30-18:00
Design of Phase II Clinical Trials: Single Arm, Randomized, Multi
M11.2 MULTI-ARM MULTI-STAGE Arm? Monday, 4 July 2011 16:30-18:00
RANDOMISED TRIALS
Mahesh Parmar M11.3 BIOMARKER-BASED BAYESIAN
Clinical Trials Unit London, Medical Research ADAPTIVE DESIGNS FOR TARGETED
Council/United Kingdom AGENT DEVELOPMENT
J. J. Lee
Abstract: Oncology has made tremendous strides Biostatistics, UT M.D. Anderson Cancer Center/
in improving clinical outcomes - but often very United States Of America
slowly. Until quite recently, potential new therapies
have been empirically identiÀed (based on general Abstract: Advances in biomedicine have fueled the
antineoplastic effects rather than mechanisms development of targeted agents in cancer therapy.
relevant to speciÀc cancers) and developed and With better understanding of the disease’s etiology
tested via an inefÀcient and protracted process. and mechanism, many targeted agents are being
Nearly every candidate drug has been through developed to tackle the root cause of problems
sequential phase I, II and III testing over many with the hope to offer more effective and less toxic
years and in cohorts of patients typically unselected therapies. Targeted agents, however, do not work for
for anything but their disease, despite the plethora everyone. Hence, the development of target agents
of designs, phase II trials as currently designed requires the evaluation of prognostic and predictive
and run have proved poor predictors of clinical markers. In addition, upon the identiÀcation of
beneÀt in randomised phase III trials, wasting both each patient’s marker proÀle, it is desirable to
treat patients with best available treatments in with use of historical controls. The complexity of
the clinical trial accordingly. We have developed implementing a phase II study relative to a single
biomarker-based Bayesian adaptive designs to arm study is greater. In addition, randomized phase
(1) identify prognostic and predictive markers II studies are often two to four times larger than
for targeted agents, (2) test the treatment efÀcacy, single arm phase II studies, and therefore simply
and (3) provide better treatments for patients take longer to complete. Given these considerations
enrolled in the trial. In contrast to the frequentist it has been suggested that a more efÀcient approach
equal randomization designs, Bayesian adaptive would be to combine the randomized phase II and
randomization designs can treat more patients phase III study into one study; a so-called phase II/
with more effective treatments via outcome-based III study. The objective of the phase II component
adaptive randomization based on the available of a phase II/II study is essentially to make a go/no-
data at the time. They allow more frequent interim go decision as to whether the trial should continue
monitoring so ineffective treatments can be stopped on to the phase III as is done with separate phase II
early for futility and effective treatments can and phase III studies. The difference in this setting
graduate early due to efÀcacy. Through simulations, is that there is a seamless transition. Goldman,
the operating characteristics of different Bayesian LeBlanc, and Crowley (2008) proposed including
and frequentist designs are compared and contrasted. an early interim analysis for futility using an
By carefully choosing the design parameters, types I intermediate endpoint to increase the probability of
and II errors can be controlled for Bayesian designs. a trial stopping early when there is no beneÀt. Their
By incorporating adaptive randomization and early suggested implementation was based on amount
stopping rules, the proposed designs incorporate of information and used relatively conservative
rational learning from the interim data to make likelihood of stopping for futility. Hunsberger, Zhao,
informed decisions. Bayesian design also provides a and Simon (2009) further developed the early look
formal way to incorporate relevant prior information. to be more akin to a randomized phase II design. As
Compared with previously published designs, the in Hunsberger et. al, here we deÀne a phase II/III
proposed design can be more efÀcient, more ethical, trial to be a trial design which implements an early
and is also more Áexible in the study conduct. interim analysis that has the operating characteristics
However, outcome-based adaptive randomization of a randomized phase II. SpeciÀcally, the “phase
requires the efÀcacy outcome to be assessed in a II” interim analysis is performed on an intermediate
relatively short time period. Additional infrastructure outcome that is measured earlier than the primary
must be set up to allow timely and more frequent outcome and the stopping time is deÀned based
monitoring of interim results. Bayesian adaptive on the phase II design. As such, the likelihood of
randomization designs are distinctively suitable for stopping at this analysis both under no true treatment
the development of multiple targeted agents and effect and under a true treatment effect is greater
the identiÀcation of multiple biomarkers in phase II than the usual interim analysis. In this talk we
settings. Examples and lessons learned from recent discuss the properties of combining randomized
trials will be given. phase II and phase III clinical trials. In particular,
Keywords: Bayesian adaptive designs, Biomarkers, we will highlight the importance of the randomized
outcome-based adaptive randomization, interim phase II design properties on the overall study and
analysis the importance intermediate outcome used in the
phase II component as representing a true surrogate
for the primary outcome of the phase III study. We
Design of Phase II Clinical Trials: Single Arm, Randomized, Multi then apply the phase II interim analysis to completed
Arm? Monday, 4 July 2011 16:30-18:00 phase III trials in the Southwest Oncology group
and discuss how well the more aggressive phase II
M11.4 PHASE II INTO PHASE III analysis would have predictived the success (or lack
Mary W. Redman, Bryan Goldman, Michael Leblanc thereof) of these trials.
Public Health Sciences, Fred Hutchinson Cancer Keywords: trial design, futility monitoring,
Research Center/United States Of America surrogate endpoints
Abstract: Randomized phase II studies have become

the norm in oncology due to concerns about bias
Session M12: Novel Therapies in NSCLC mutations are detected in exon 20 of HER2 and
NSCLC patients with these mutations are clinically
Wednesday, 6 July 2011 resistant to EGFR kinase inhibitors geÀtinib and
erlotinib. Preclinical in vitro and in vivo studies
suggest that NSCLC harboring HER2 ampliÀcations
Novel Therapies in NSCLC Wednesday, 6 July 2011 10:30-12:00 and mutations could be effectively treated with
HER2 kinase inhibitors. Agents in clinical
M12.1 NOVEL TARGETS AND development include PF299804, HKI-272 (neratinib)
THERAPIES IN NON-SMALL CELL and BIBW-2992 (afatinib). These are all irreversible
LUNG CANCER inhibitors of both EGFR and HER2. These agents
Pasi A. Janne are currently being evaluated speciÀcally in NSCLC
Lowe Center For Thoracic Oncology, Dana Farber patients harboring genomic alterations in HER2
Cancer Institute/United States Of America and the clinical trials and available data will be
presented. Although most genomic alterations to date
Abstract: The treatment of non-small cell lung have been limited to adenocarcinomas, recent studies
cancer (NSCLC) is rapidly shifting away from a suggest that there may be therapeutically targetable
“one-size Àts all” treatment approach to a disease genetic alterations also in squamous cell lung cancer.
where therapy is based on genomic characteristics of AmpliÀcations in FGFR and somatic mutations in
the individual patient’s cancer. At the current time, DDR2 have been identiÀed and clinical trials are
for adenocarcinoma patients, there are effective underway to determine whether kinase inhibitors,
molecular targeted therapies for approximately effective in pre-clinical studies, are clinically
20% patients. These therapeutic successes are effective in squamous cell lung cancer patients
currently limited to cancers harboring epidermal whose tumors harbor these somatic changes. The
growth factor receptor (EGFR) activating mutations evolving incorporation of patient’s tumor speciÀc
or chromosomal rearrangements in the anaplastic genomic alterations into their therapeutic algorithm
lymphoma kinase (ALK). There is an increasing requires a systematic approach to identifying these
interest in identifying other genomic alterations in different patient subsets. The systematic genomics
NSCLC for which there may be effective targeted approaches currently being used in routine clinical
therapies analogous to what has been observed for practice at Dana Farber Cancer Institute will be
EGFR and ALK. Two other subsets, NSCLCs with discussed.
BRAF mutations and those with HER2 mutations Keywords: Somatic Mutation, Non-small cell lung
and/or ampliÀcations, are actively being actively cancer, kinase inhibitor, HER2
investigated. BRAF mutations have been detected in
~3% of NSCLC patients and have been exclusively
detected in adenocarcinomas. Unlike melanoma, Novel Therapies in NSCLC Wednesday, 6 July 2011 10:30-12:00
about 50% of BRAF mutations in NSCLC are
V600E while the remainder are exon 11 mutations. M12.2 NOVEL THERAPIES
Preclinical studies, both in vitro and in vivo, suggest Tony Mok
that for V600E BRAF mutations, MEK inhibitors Department Of Clinical Oncology, The Chinese
may be effective therapies. The clinical development University Of Hong Kong/China
and success of BRAF and MEK inhibitors in
melanoma provides the opportunity to study these Abstract: EGFR mutation at exon 19 and 21 in
agents in BRAF mutant NSCLC. A clinical trial patients with pulmonary adenocarcinoma was the
of the BRAF inhibitor GSK2118436 is currently novel Ànding in 2004, and only Àve years later the
underway for V600E BRAF mutant NSCLC. A role of geÀtinib in Àrst-line therapy for patients
second trial of MEK inhibitor, GSK1120212, is also with known EGFR mutations was conÀrmed in the
underway and will include NSCLC patients with randomized phase 3 Iressa Pan-Asia Study (IPASS).
both exon 11 and 15 BRAF mutations. Genomic Other Japanese studies also conÀrmed a higher
alterations in HER2 in NSCLC involve both tumor response rate and longer PFS when patients
ampliÀcations in HER2 and somatic mutations in with EGFR mutation are treated with EGFR TKI. In
HER2. Both occur at a frequency of 2-5% and are view of this success, numerous potential molecular
exclusive to adenocarcinomas. HER2 kinase domain targets are under investigation. A molecular target
should drive cancer growth. An ideal molecular comparing Stimuvax with placebo after standard
target should be speciÀc to the cancer cell and drive Àrst line chemotherapy. Two phase III studies are
cell proliferation such that inhibition of the mutated ongoing. One is a global registration phase III study
pathway would result in cessation of cancer growth. (START) comparing Stimuvax with placebo after
Preclinical studies should be able to demonstrate standard chemo-radiotherapy for patient with stage
differential growth rates in tumor cells with and IIIa and IIIb NSCLC. Second is a study of similar
without the target mutation. In this symposium we design (INSPIRE) in Asian population with the
shall discuss the promising targets and its respective assumption of higher incidence of EGFR mutation.
therapies that may become available to clinicians MAGE-A3 is an antigen related to melanoma that
in near future. EML4-ALK is a fusion gene that may over-express in about 30 to 40% of NSCLC.
juxtaposes the echinoderm microtubule-associated Phase II study on this vaccine as an adjuvant
protein-like 4 (EML-4) gene to the tyrosine kinase therapy to respectable lung cancer patients has
domain of anaplastic lymphoma kinase gene (ALK). shown promising result. MARGRIT is the world
This fusion gene occurs in about 2% to 7% of largest adjuvant study with intended accrual of 2270
lung cancer patients and almost solely in patients patients with MAGE-A3 expression. To date, about
without EGFR mutation. Crizotinib is an ALK-MET 1700 patients have been accrued. Belagenpumatucel
kinase inhibitor that was found to induce dramatic (Lucanix) is a tumor cell vaccine intended to block
tumor response in patients harboring the EML4- the TGF-ơ2 secretion. The current phase III study
ALK fusion gene in a phase I study. An extended targeted patients who attain tumor response or stable
phase I/II study reported a tumor response rate of disease after Àrst line chemotherapy and randomized
57% and disease control rate of 77% in patients to either the Belagenpumatucel or supportive care.
selected by Áuorescence in-situ hybridization In summary, multiple targeted therapies are under
(FISH) using a break-apart probe to ALK. The investigation and many have entered phase III.
encouraging Ànding will be conÀrmed in a global Biomarker is the key to the success of these studies.
phase III study comparing crizotinib with single Keyword: Targeted therapy, C-MET, ELM-4 ALK,
agent chemotherapy as second line therapy, and a Cancer vaccine
phase III Àrst line study is being planned. C-MET is
the receptor for Hepatocyte Growth Factor (HGF)
and plays an important role in oncogenesis. A long Novel Therapies in NSCLC Wednesday, 6 July 2011 10:30-12:00
list of drugs are under intensive investigation.
Among which the most promising ones include the M12.3 PREDICTIVE FACTORS
AVEO 299, ARQ 197 and MetMab. AVEO 299 is Jean-Charles Soria
a mono-clonal antibody against the ligand of HGF. Val De Marne, Institut Gustave Roussy/France
An ongoing randomized phase II compares the
combination of AVEO plus geÀtinib with geÀtinib Abstract: Lung cancer is the leading cause of
alone in an Asian population with high incidence cancer-related deaths worldwide. NSCLC is
of EGFR mutation. ARQ 197 is a tyrosine kinase currently being revisited on the basis of modern
inhibitor for C-MET. A recent randomized phase II molecular portraits that allow the identiÀcation
study reported promising improvement in PFS and of new molecular subtypes. To date, the
efÀcacy appeared to be most signiÀcant in patients &ldquoquest&rdquo for the perfect predictive
with KRAS mutation. MetMab is a mono-clonal molecular marker has been mainly based on 2
antibody against C-MET. Spiegel et al reported technological approaches. (1) High throughput
that the combination of MetMab and erlointib was technology Despite huge efforts and millions
superior to erlotinib alone as second line therapy for of Euros spent worldwide each year to identify
patients with high C-MET expression. This Ànding predictive biological signatures, there has been
needs to be validated in a phase III study. Cancer limited progress and the only signature (Metagene)
vaccine is also being actively pursued. Among being evaluated prospectively has recently been
which, the most promising agents include anti- challenged in terms of scientiÀc validity (2) single
MUC-1, anti-MAGE A3 and Belagenpumatucel. biomarker approach we may distinguish such a
The anti-MUC-1 vaccine (Stimuvax) was shown to biomarker in 3 categories of therapeutic agents:
have a trend in OS beneÀt in the subgroup analysis cytotoxic agents, tyrosine kinase inhibitors and
of stage IIIb patients in a randomized phase II study antiangiogenic agents In the &lsquocytotoxic
setting&rsquo, DNA repair pathways have provided Session M13: Methodological Aspects
the most promising biomarkers for cisplatin of Mutation Analysis
resistance, such as the expression of ERCC1 &
MSH2 or the level of BRCA1. Others candidate
biomarkers such as the cell cycle regulator p27,
class III &beta-tubulin or thymidylate synthase
had been linked to a beneÀt of chemotherapy. With Methodological Aspects of Mutation Analysis Wednesday, 6 July
regard to targeted therapies, speciÀc activating 2011 10:30-12:00
mutations located in the tyrosine kinase domain of
the epidermal growth factor receptor (EGFR) are M13.2 HANDLING OF DIFFERENT
associated with an improved response to EGFR- SAMPLES: CYTOLOGY, BIOPSIES,
directed tyrosine kinase inhibitors (TKIs) in NSCLC RESECTION SPECIMEN
patients. The majority of EGFR mutations occurred Koji Tsuta
in exon 19 (small deletion) or in exon 21 (single Pathology, National Cancer Center/Japan
point mutation, L858R). These activating mutations
are associated to responsiveness to tyrosine kinase Abstract: The development of new molecular
inhibitors. On the other hand, several mutations targeted therapies and less invasive diagnostic
in exon 20 (T790M or small insertion) seem to approaches—producing small biopsy and cytology
confer resistance to such treatments. Epidemiologic specimens for diagnosis—for lung tumors require
characterization of EML4-ALK translocations is precise molecular analysis and/or immunostaining of
ongoing but it seems to be a rare aberration, most such small samples to achieve personalized therapy.
common in non-smokers or light-smokers with the In general, surgically resected and biopsy specimens
adenocarcinoma subtype of NSCLC (and signet ring are Àxed with formalin, whereas cytologic specimens
features) , forming a distinct subgroup from patients are Àxed with alcohol. Formalin Àxes tissue by
harbouring EGFR, KRAS, mutations. The frequency cross-linking the proteins, primarily the residues of
of EML4-ALK fusion transcripts is around 5% the basic amino acid lysine. Formalin Àxation is the
or less in Caucasians patients. Crizotinib (PF- best method for assessing cell morphology, and most
02341066) is an ALK and MET inhibitor that has commercially available antibodies are optimized
demonstrated outstanding activity in monotherapy for formalin-Àxed tissues. However, formalin-Àxed
in patients with EML4-ALK translocations: 57% tissues more frequently exhibit nonreproducible
objective response in 82 patients with a median sequence alterations in nucleic acids than frozen
duration of treatment of 5,7 months and a predicted tissues. This is because formalin can cross-link
67% PFS rate at 6 months. Many other abnormalities cytosine nucleotides on either strand of the DNA.
linked to tyrosine kinase receptors could be used for On the other hand, alcohol Àxation reduces the
selection of speciÀc therapy such as ampliÀcation or solubility of protein molecules and disrupts the
activation mutation of HER2, HER3, HER4, FGFR hydrophobic interactions that confer a tertiary
1, FGFR2, KDR&hellipHowever correlation of structure to many proteins. The precipitation and
presence of such abnormalities and clinical response aggregation of proteins that occur during alcohol
are still not Àrmly documented, although some Àxation are very different processes from the cross-
interesting case reports have been documented.. linking that occurs with the use of formalin Àxatives.
Table 1 provides a summary of speciÀc alterations Most commercially available antibodies are not
and their potential corresponding drug. used for alcohol-Àxed materials without changes
Table 1 in staining protocols. However, ethanol causes
Molecular alteration Potential Drugs very little chemical change and therefore preserves
EGFR mutation Erlotinib, geÀtinib New pan-HER inhibitors
(afatinib, PF 299804 ) nucleic acids better than formalin. Frozen materials
EML4-ALK translocation Crizotinib are most suitable for nucleic acid isolation. However,
HER2 mutation or Trastuzumab Lapatinib, PF 299804
ampliÀcation cell morphology is better preserved in formalin-Àxed
PI3K mutation or GDC-0941 tissues than in frozen tissues. In addition, storing
ampliÀcation XL-147
XL-765 PX-866 frozen materials for a long time is both expensive
BEZ-235 and space consuming. Furthermore, degradation
BKM120
MET ampliÀcation XL184 ARQ917 Metmab of nucleic acids may occur during long-term
RAS and RAF mutations Sorafenib AZD6244 GSK1120212 AS703026 preservation.
FGFR1 ampliÀcation BJG398, AZD4547, TKI258
The best way to help patients select more appropriate also archival, formalin-Àxed tissue samples. Highly
treatment options is collection of formalin- and sensitive and speciÀc rabbit monoclonal antibodies
alcohol-Àxed tissues and frozen materials. We collect against the 2 most common mutations were recently
formalin- and alcohol-Àxed parafÀn-embedded developed for detecting epidermal growth factor
blocks and ethanol-Àxed imprint cytology smears receptor mutations. The excellent speciÀcities of
obtained from a fresh-cut surface, as well as frozen these antibodies will provide a reliable marker for
tissues from surgically resected tumor specimens the initial screening for epidermal growth factor
in our hospital. However, biopsy or cytologic receptor mutational status, similar with human
materials whose tumor amount may be small are epidermal growth factor receptor 2 status for breast
difÀcult to obtain using the above-mentioned storage carcinoma.
materials. In addition, frequent recutting from A diagnosis resulting from a combination of the
small samples such as biopsy specimens should be above-mentioned techniques will help patients select
avoided because repeated cutting from the same more appropriate treatment options. In addition, an
block can result in loss of tumor cells. This problem exchange of knowledge between pathologists and
may be resolved by preparing many unstained clinicians is of utmost importance.
slides immediately after biopsy. However, this Keywords: biopsy, cytology, surgically resected
approach bears the problem of protein and/or gene specimen
degradation with the passage of time. To prevent
molecular degradation, thinly spreading parafÀn on
unstained slides is useful. The number of slides for Methodological Aspects of Mutation Analysis Wednesday, 6 July
cytologic analysis is usually limited. In such cases, 2011 10:30-12:00
the cell block approach and cell transfer technique
can yield some slides for molecular analysis and M13.3 DETECTION IN BLOOD/SERUM
immunostaining. Another approach to circumvent the Miquel Taron
small number of unstained slides is use of multicolor Laboratory Of Molecular Biology, Medical
immunohistochemical techniques, which can obtain Oncology Service-Ico; Hospital Germans Trias I
information on multiple protein expression on the Pujol/Spain
same slide. In addition, this approach can detect not
only protein expression but also gene status through Abstract: In the last 30 years, different analyses
bright-Àeld in situ hybridization. have shown that cell-free circulating nucleic acids
To detect gene mutations, direct sequencing is containing tumor-associated genetic alterations can
performed as the gold standard. However, to obtain be detected in peripheral blood of cancer patients.
precise data, high-quality DNA and RNA extracted The development of sensitive and speciÀc methods
from an adequate amount of pure tumor cells are together with the new technologies for the detection
required, which necessitates an expensive and of minimal quantities of DNA or RNA have made it
time-consuming process. Other indirect methods possible to isolate and characterize tumor associated
have recently been developed to detect gene alterations in blood (point mutations, microsatellite
mutations, including the peptide nucleic acid–locked alterations, epigenetic alterations, etc)(1). In
nucleic acid PCR clamp system, mutant-enriched contrast to its huge potential clinical application, the
PCR, the smart ampliÀcation process, and high- characterization of circulating nucleic acids has not
resolution melting analysis. These methods have received much attention. We and others have focused
high sensitivities and can be applied to specimens on the analysis of gene mutations at blood sample
with low cancer cell content. We revealed a high level as a potential diagnostic tool in Non-Small
concordance rate of epidermal growth factor Cell Lung Cancer (NSCLC). It is well known that in
mutations between small biopsy materials and NSCLC patients, the screening of sensitizing EGFR
matched surgically resected materials by using high- mutations in tumor samples is becoming mandatory
resolution melting analysis. Another approach for to treat patients with EGFR tyrosine kinase inhibitors
detecting gene mutations is developing mutation- (TKIs). However, one of the most important
speciÀc antibodies. Compared to molecular limitations is the lack of available tumor cells in
techniques, immunohistochemistry is a fast and tumor tissues (biopsies or cytologies) in around 30%
cost-effective method that can be performed in of patients, and the difÀculty to perform re-biopsies
most pathology laboratories on not only fresh, but at baseline or during the follow-up of the patient.
In this sense, the use of strategies to genotype related to new strategies of massive sequencing
patients using cell-free circulating DNA could be a (9) and nanotechnology (10). One recent example
crucial tool. There are different studies in literature has been the use of next generation sequencing of
(2-7) showing that plasma- and serum-based serum circulating nucleic acids from patients with
EGFR mutation testing is not only feasible but has invasive ductal breast cancer that reveals clear
considerable value as well. In our experience, (8) we differences between healthy and nonmalignant
have analyzed paired serum and tissue samples from controls providing the basis for the development
164 EGFR mutated (exon 19 deletions and L858R) of a serum test for breast cancer screening and
patients. Starting from isolated serum/plasma monitoring (11). In conclusion, the analysis of gene
samples, cell-free circulating DNA was puriÀed and mutations at the serum or plasma level is a useful
analyzed for the presence of the mutations. Deletions diagnostic tool that should be used to genotype and
in exon 19 were determined by length analysis after treat patients. 1.- Fleischhacker M and Schmidt B.
PCR ampliÀcation with the use of FAM labeled Cancer Biomark, 2010; 6(3-4):211 2.- Yung T, et al.
primer in an ABI Prism 3130 DNA analyzer. Exon Cancer Res, 2009; 15:2076 3.- Kuang Y, et al. Clin
21 L858R point mutations were analyzed with a 5’ Cancer Res, 2009; 15(8):2630 4.- Kimura H, et al.
nuclease PCR assay (TaqMan assay) using FAM and Clin Cancer Res, 2006; 12:3915 5.- He C, et al. Int J
VIC MGB labeled probes for the wild-type and the Cancer, 2009 ; 125 : 2393 6.- Mack PC, et al. Journal
mutant sequences respectively. Both reactions were Thoracic Oncol, 2009; 4(12):1466 7.- Bai H, et al.
done in the presence of a protein nucleic acid (PNA) Journal Clin Oncol, 2009; 27(16): 2653 8.- Rosell R,
designed to inhibit the PCR ampliÀcation of the wild et al. NEJM, 2009; 361(10): 958 9.- Lo D and Chiu
type allele. Of the 164 EGFR positive patients (in R. Clinical Chemistry, 2009; 55(4):607 10.- Kim B,
tissue) in whom EGFR mutations were assessed in et al. NEJM, 2010; 365(25): 2434 11.- Beck J, et al.
serum, 97 carried mutations: exon 19 deletions in 64 Mol Cancer Res, 2010; 8:335
patients and L858R in 33 patients. Importantly, in Keywords: NSCLC, gene mutation, serum or
the multivariate analysis of this study, the adjusted plasma, EGFR
hazard ratios for the duration of progression-free
survival were 2.94 for men (P<0.001); 1.92 for the
presence of the L858R mutation, as compared with Methodological Aspects of Mutation Analysis Wednesday, 6 July
a deletion in exon 19 (P = 0.02); and 1.68 for the 2011 10:30-12:00
presence of the L858R mutation in paired serum
DNA, as compared with the absence of the mutation M13.4 HETEROGENEITY EGFR IN LUNG
(P = 0.02). Interestingly, we found that EGFR CANCER
mutation status in the serum or plasma matched that Erik Thunnissen
in the tumor tissue in 45% of patients with PS 0, in Pathology, VUMC/Netherlands
57% of patients with PS 1, and in 75% of patients
with PS 2 (P=0.01), showing the importance of Abstract: Heterogeneity of EGFR mutations is
tumour burden in this analysis. In addition, in our used in context of variation i) between different
study we found a sensitivity of 60%. In previous samples taken within one tumor, ii) between different
studies, we also analyzed the speciÀcity of our tumors within one patient comparing iia) tumors
technique and we have shown a speciÀcity higher from different sites in the lung, iib) primary tumor
than 98%. Altogether, this data reÁects the need and metastases or iic) between tumor sample before
to incorporate new and more sensitive diagnostic and after treatment. Examples iia) and iic) are
tools in the clinical practice when working with usualy not considered to be part of heterogeneity,
cell-free circulating DNA, to increase the sensitivity but represent the question of clonal relationship and
without a detriment effect on the speciÀcity of the changes within the tumor population, respectively.
tests. New techniques and technologies are being For each sample holds that the fraction of EGFR
implemented today to increase the sensitivity of mutated allele is determined by fraction of tumor
this technique to allow genotyping of all patients cells within the sample and amount of mutated
for EGFR, but also for common mutations such as alleles within these tumor cells. AmpliÀcation occurs
BRAF1 or k-Ras among others in serum and plasma in lung cancer a later phase of malignant process,
in order to Ànd the “needle in the haystack”. Among and therefore will not be distributed equally over the
these techniques, the most salient ones are those tumor: some areas show ampliÀcation while others
don’t. The EGFR test outcome is determined by a) Session M14: Image Guided Tissue
estimation of fraction of tumor cells in the sample Characterization
and b) analytical sensitivity of EGFR mutation test.
The analytical sensitivity provides a threshold when
a test will be positive and is related to minimum
input of DNA (1 ng DNA = ~approximately 200
tumor cells for many techniques). In selecting Image Guided Tissue Characterization Wednesday, 6 July 2011 10:30-
sample area for DNA extraction, the number of 12:00
tumor cells need to be high and areas of tumor
necrosis, inÁammatory cells and other stromal M14.1 NAVIGATIONAL TARGETING
components are avoided. To this end manual macro Fumihiro Asano
dissection or microdissection is used. The estimation Pulmonary Medicine, Gifu Prefectural General
of tumor cells fraction (representativity of the Medical Center/Japan
sample) is quite variable between pathologists.
Comparing different areas (i) within a tumor may Abstract: Bronchoscopic diagnosis of peripheral
reveal a negative test in one area that does not pulmonary lesions With the recent increase in
have ampliÀcation (i.e. 1 mutated allele) and a low lung cancer, the percentage of the peripheral type
fraction of tumor cells (e.g. 10% tumor cells = 5% in the lung Àeld has been particularly increasing.
mutated alleles) in case of analytical sensitivity of Although various imaging modalities have been
10%, while in another area with ampliÀcation an clinically applied, the pathological diagnosis of cell/
EGFR mutation may be demonstrated (e.g. mutated tissue specimens collected from the lesion is still a
allele ampliÀed 10x, and 10% tumor cells =~30% gold standard for lung cancer diagnosis. Methods
mutated alleles threshold of the technique). to collect samples for pathological diagnosis
This is a form of pseudoheterogeneity, but not include transbronchial biopsy under bronchoscopy,
true heterogeneity. In some studies intratumor CT-guided percutaneous biopsy, and biopsy by
heterogeneity has been suggested. In at least one surgery. Percutaneous biopsy relatively frequently
of these studies subsequent analysis with EGFR causes complications such as pneumothorax and
mutation speciÀc antibodies were positive in the hemorrhage, and lethal complications including
initially negative sample. In hindsight suggestive dissemination and air embolism have also been
of pseudoheterogeneity. An additional argument reported. Although surgery is the most reliable
against heterogeneity within one tumor is the fact method, it is highly invasive. In addition, smaller
that EGFR mutation is a driver mutation: i.e. this lesions are likely to be benign. In contrast,
mutation is an early event and present in the primary transbronchial biopsy has few complications and
tumor and with a clonal relation also present in all is less invasive. However, the diagnostic yield of
daughter cells. In comparing (iia) different tumors bronchoscopy for peripheral pulmonary lesions
within the lung and Ànding a different mutation in is unsatisfactory. The 2007 Guidelines of the
both tumors is more an argument for two different American College of Chest Physicians (ACCP)
primary tumors than for a clonal relationship. showed a diagnostic yield of 34% for lesions < 2
Many studies reveal discrepancies comparing (iib) cm in diameter. A major problem with this method
primary tumor and metastases to a variable extend. is difÀculty in the guidance of the bronchoscope
Here the abovementioned technical issues may and biopsy tools. Presently, many bronchoscopists
also play a role. In summary, although some papers mentally reconstruct the 3D bronchial arrangement
in the literature reports suggest the existence of based on 2D planar axial slices of CT performed
heterogeneity in EGFR mutations, the evidence for before bronchoscopy, and select a bronchial
this is not strong enough to support this notion. path. However, since this method is inaccurate,
Keywords: EGFR mutation, heterogeneity the diagnostic yield depends on the operator’s
experience and skill. For this, navigational
targeting to the lesion during bronchoscopy has
been developed. The methods of navigational
bronchoscopy that can be clinically employed at
present are electromagnetic navigation (EMN)
and virtual bronchoscopic navigation (VBN).
EMN EMN is a procedure in which a steerable Although further improvement in performance is

probe with an electromagnetic sensor is navigated necessary, VB images automatically synchronize
to the lesion based on electromagnetic positional with real images. However, unlike Bf-NAVI,
data in the EM Àeld generated from a board on LungPoint does not have the function to conÀrm
which the patient is placed. The superimposition areas of which VB images could not be produced
of positional data on previously acquired CT data because of the absence of the automatic extraction
on the patient allows the display of the site of the of bronchi, and to add VB images of these areas by
sensor probe in 3 MPR images. The operator guides manual extraction. Therefore, the range of peripheral
the probe to the lesion based on these images and bronchi of which VB images can be produced
the probe tip view. For the superimposition of tends to be smaller using the LungPoint than using
electromagnetic and CT data, VB images of the the Bf-NAVI. VBN has been used concomitantly
proximal bronchus are used. However, EMN differs with CT-guided ultrathin bronchoscopy and
from the below VBN since the bronchoscope is endobronchial ultrasonography with a guide-sheath
not guided based on VB images themselves. As (EBUS-GS), and satisfactory results have been
EMN systems, iLogicTM (superDimension) is used, reported. The diagnostic yield was 65.4-86% by
and SPiN DriveTM (Veran Medical Technologies) CT-guided ultrathin bronchoscopy, 63.3-84.4% by
was clinically introduced recently. Previous EMN EBUS-GS, 62.5% by Áuoroscopy, and 73.6% by all
studies have generated diagnostic yields for various techniques combined. Moreover, randomized studies
sized peripheral pulmonary lesions ranging from have shown that the use of VBN under EBUS-GS
69-76%. There have been reports using or not improves the diagnostic yield and shortens the
using X-ray Áuoroscopy, but the diagnostic yield time until the arrival of the bronchoscope to the
appears to be similar. A randomized study showed target, and, thus, the total examination time. No
that EMN-assisted bronchoscopy combined with complications of VBN itself have been reported.
EBUS is more sensitive than either EBUS or The advantage of VBN is simplicity. In VBN, only
EMN alone (diagnostic yield, 88 vs. 69 and 59%, the bronchoscope is advanced according to the VB
respectively). There are also the following problems. images. Since the procedure is similar to that of
It is necessary to learn the steps of the procedure conventional bronchoscopy, even inexperienced
differing from conventional bronchoscopy such operators can guide the bronchoscope to the target
as landmark registration and manipulation of the in a short time. In addition, since VBN requires
steerable probe based on 3D-MPR images and no special apparatus except software, the cost is
the tip view. The diagnostic yield is signiÀcantly not generally prohibitive. A problem is that arrival
affected by CT-to-body divergence. In addition, at the lesion cannot be conÀrmed by VBN itself,
the steerable probe with an electromagnetic sensor unlike EMN. Its combination with Áuoroscopy,
probe is for single use and expensive. VBN Virtual CT, or EBUS is necessary to conÀrm arrival. If a
bronchoscopic navigation (VBN) is a method in thin or ultrathin bronchoscope is used, its guidance
which images from virtual bronchoscopy (VB) to a site near the lesion is possible. Therefore, in
of the bronchial path to a peripheral lesion are most patients, the guidance of biopsy instruments is
produced and used as a guide for the navigation not necessary. A recent study reported a diagnosis
of a bronchoscope. Since the bronchial branching rate of 80% using VBN alone without employing
pattern on VB images is similar to that on real Áuoroscopy. Conclusions Navigational bronchoscopy
bronchoscopic images, the bronchoscope can be has increased the rate of diagnosing pulmonary
advanced close to the target lesion according to peripheral lesions. Considering a low complication
the bronchial path to the lesion displayed on VB rate compared with transthoracic needle aspiration,
images. Bf-NAVITM (KGT, Olympus Medical navigational targeting is a promising diagnostic
Systems) as a VBN system was developed and method for pulmonary peripheral lesions, and is
clinically introduced in 2008 in Japan. This system expected to be more widely used in the future.
is characterized by the automatic production of VB Keywords: Bronchoscopic diagnosis, Virtual
images along the bronchial path and the display of bronchoscopic navigation, Electromagnetic
VB matched with real images for bronchoscopic navigation, Transbronchial biopsy
navigation. In 2009, LungPointTM (Broncus) as
another VBN system was clinically introduced
in the U.S. LungPoint is straightforward to use.
Image Guided Tissue Characterization Wednesday, 6 July 2011 10:30- while simultaneously giving excellent anatomical
12:00 resolution. Put simply, PET shows what is happening
(but only at one process of interest at a time, while
M14.4 TUMOUR-PROFILING: THE CT maps out where). However, in aiming for the
EVOLVING ROLE OF PET, CT AND MRI. long-term goal of a minimally invasive “virtual
Otto S. Hoekstra, Anton Ussi, Guus A. Van Dongen, biopsy” there remains the challenge of being able
Frederik Barkhof, Adriaan A.L. Lammertsma to visualise the action of molecular mechanisms
Nucl Med & Pet Research, VU University Medical and their resulting physiological processes. This
Center/Netherlands is where the combination of PET and MRI comes
in, due to its expected proÀciency in delivering
Abstract: Biomedical imaging delivers added both physiological and high-deÀnition anatomical
value in the clinical management of cancer, as well information. In part the power of MRI lies in its
as in the research underpinning pharmaceutical superior soft tissue contrast compared to CT, but it
therapies. Continuous innovations in the fundamental can also bring physiological information. Much like
understanding of the science behind the disease, PET tracers elucidate on function at a molecular
combined with advances in the technology behind level by attaching to speciÀc receptors, MRI can
imaging leads to a constant cycle of improvements give detailed information on a wide variety of
to the scope and depth of the capabilities of processes, and unlike PET can do so for several
imaging techniques. In oncology, three techniques processes in the same scan. MRI techniques can be
stand at the forefront of clinical utility. Magnetic used to assess blood Áow and vessel permeability
resonance imaging (MRI) and X-ray computed (but cannot differentiate between the two at this
tomography (CT) are two very different methods in stage of development), diffusion (the mobility of
the radiological domain. MRI has the added value water within tissues, which, subject to validation
of being able to also elucidate upon physiological in a research setting, may be able to tell us whether
processes in the body, while CT offers mostly cancer cells are being killed by a drug – apoptosis
anatomical information and poorer tissue type – or whether tumour blood vessels are being
discrimination than MRI. The third technique, destroyed), and other areas of interest outside of
positron emission tomography (PET) uses target- the oncological domain. Although some of these
speciÀc radiopharmaceuticals to visualize and capabilities overlap those of PET, such as tumour
measure biochemical processes. Both individually blood Áow and water distribution, the increased
and in a combined setting these techniques provide versatility of imaging choices offered by overlapping
essential information for cancer diagnosis, treatment and complementary capabilities means that these
and monitoring. However, since the inception of innovations are by no means redundant. For human
combined PET & CT imaging, it has become clear applications, the sensitivity of PET is unchallenged,
that multi-modal imaging truly can offer much more and pharmacokinetics at minute tracer doses are
clinical value than the sum of their parts. Introduced much more likely to mimic the actual molecule
into the clinic in 2001, PET-CT has since become pharmacokinetics than will ever be possible with
essential in pulmonary oncology, and this is borne MRI. Even though the clinical viability of PET-MR
out by the fact that currently all PET scanners sold is remains to be proven, the research possibilities
are PET-CT combination machines, and sales of are manifold. These new additions to the functional
the scanners have increased ten-fold since 2001. imaging landscape have the potential to yield ever
The value of this is due to the complementary more detailed insights into tumour characteristics
range of capabilities of the two systems. PET is a and therapeutic effects by increasing the range of
highly sensitive means of quantitatively measuring processes that can simultaneously be measured. In so
a speciÀc molecular process. The range of potential doing, we can expect to gain a greater understanding
tracers is enormous, meaning that many different of fundamental both disease processes, individual
processes can be studied highly selectively. By patients’ speciÀc disease characteristics and
combining PET and CT, much more information prognosis, and even insights into the mechanism of
can be extracted regarding the stage of disease action of therapy.
and its precise location, to the beneÀt of patient Keyword: PET, PET-CT, MRI, PET-MRI
management. PET and CT combined offer detailed
insights into metabolic and molecular processes
Session M15: Nodule Management scan (in those who are candidates for surgery) and
consideration of prompt resection. CalciÀcation
Wednesday, 6 July 2011 in a benign pattern is an excellent indicator that
a nodule is a granuloma and needs no further
pursuit. Eccentric calciÀcation should maintain
Nodule Management Wednesday, 6 July 2011 10:30-12:00 concern for malignancy. Ground-glass opacities
(GGO) are nodules of low density (attenuation)
M15.1 GUIDELINES FOR CT-DETECTED that are generally only visible by CT scan. They
NODULES deserve special mention as they may represent
David Midthun low-grade adenocarcinomas (bronchioloalveolar
Pulmonary And Critical Care Medicine, Mayo cell carcinoma) which behave differently than
Clinic/United States Of America most malignancies presenting as solid nodules.
Malignant GGOs typically exhibit slow growth with
Abstract: The Ànding of a solitary pulmonary doubling times on average over 400 days and, for
nodule (SPN) or multiple nodules on CT presents this reason, the 2-year stability rule for solid nodules
a decision point for the patient and physician. The doesn’t apply and a longer period of follow-up is
vast majority of such nodules are benign; however needed. PET scanning is not helpful to distinguish
the detection of a nodule may be the Àrst and only malignancy due to the low density of the lesions,
point in time of a chance of cure in the patient with and needle biopsy is often nondiagnostic. GGOs
lung cancer. In the absence of a completely sensitive may show growth or stay the same size yet change
and speciÀc non-invasive test for malignancy, the to becoming solid or part solid in the process of
physician and patient must weigh the options for progression. PET scanning uses the injection of the
management. Guidelines for nodule evaluation by glucose analog 18F-2-Áuorodeoxyglucose (FDG)
the American college of Chest physicians (ACCP) and identiÀes nodules with high metabolic activity.
and the Fleischner Society can help guide the Nodule enhancement is an indication that a nodule
decision making. The single arm, observational is more likely malignant than benign, and absence
studies have shown that CT screening leads to a high of enhancement is a strong predictor that a nodule is
rate of detection of small parenchymal nodules. The benign. In a multicenter prospective study reported
rate of nodule detection is, in part, a function of the that FDG-PET had an overall sensitivity of 92%
CT slice thickness (collimation) used. Screening and a speciÀcity of 90% for detecting malignant
with 10 mm collimation results in detection of nodules, yet the sensitivity fell to only 80% when
one or more nodules in approximately 20-25% of nodules of 15 mm or smaller were analyzed. A meta-
participants, 5 mm collimation increases this to analysis of pulmonary nodules showed that PET had
40-50% of participants, and 1.25 mm collimation a sensitivity of 94% and a speciÀcity of 86%. The
raises detection to as high as 60%. A review of the lower limit of nodule size for PET applicability using
data from 8 CT studies in high risk patients (current current techniques is about 8-10 mm. A growing
or former smokers, age 50 or above) reported that nodule that is shows no enhancement on PET should
likelihood of malignancy was 0 to 1% for nodules still be considered suspicious for malignancy and
< 5 mm, 6 to 28% for nodules 5 to 10 mm, 33 to prompt needle biopsy or resection. If multiple
60% for nodules > 11-20 mm, and 64 to 82% for nodules are present, then follow-up is dictated by
nodules > 20-30 mm. The Ànding of a nodule on the largest nodule. Observation may be appropriate
CT should Àrst prompt review of any available old for patients with nodules that are larger than 8-10
images that might include the nodule for comparison. mm and have a low likelihood of malignancy.
Review of old images may show that the nodule is Whether or not an indeterminate nodule > 8-10
growing or establish that it has been stable for 2 or should be biopsied is the subject of considerable
more years. The Ànding of nodule stability in size debate and practices vary. The two biopsy techniques
over a two-year period has been established as an for assessment of SPNs are bronchoscopy and
excellent indicator of benignancy. If old images are transthoracic needle aspiration (TTNA). A number
not available, nodules < 8 mm may be observed with of series have shown that bronchoscopy with
follow-up CT at an interval determined by the nodule Áuoroscopy has a yield is a function of nodule
size. Evidence for nodule growth is a hallmark of size and may be as less than 20% in the setting
malignancy and should lead to a staging PET-CT of malignant nodules less than 2 centimeters and
in the range of 40-60% when the nodule is 3 cm. in CT screening programs. SpeciÀcally, FDG-PET
Yield rises with increasing nodule size, however, may have a useful diagnostic role in the evaluation
preoperative diagnosis is generally not needed for of screen-detected nodules by reducing the number
lesions greater than 3 centimeters due to the high of patients undergoing interventional procedures
likelihood of malignancy in nodules of this size. to establish the diagnosis. The potential reduction
Bronchoscopic yield increases if the CT shows that a in the biopsy rate due to the incorporation of FDG-
bronchus is present within the nodule. Studies using PET imaging into the management algorithm of
CT, endobronchial ultrasound, or electromagnetic patients with nodules is important because, despite
guidance have shown marked improvements in rigorous criteria determining biopsy of a lung
diagnostic yield over standard Áuoroscopic guidance. nodule, approximately 10% of biopsied nodules
Studies using one or more of these techniques in detected by a CT screening trial are benign.
combination have shown yields of 60 to 80% of However, FDG-PET has been reported to have poor
peripheral nodules of a mean diameter of 2- to 25 sensitivity in diagnosing lung cancer in nodules
mm. A meta-analysis of 47 studies evaluating small detected on screening CT and raises questions
peripheral nodules with TTNA reported yields of about its usefulness in preoperative management
approximately over 90% for nodules < 2 cm and i.e. FDG-PET can be negative in approximately a
95% for nodules > 2 cm (Àgure 7). Likelihood of third of lung cancers detected by screening CT. This
obtaining a speciÀc diagnosis in the setting of a poor sensitivity may be because screening detects
benign lesion is greater than with bronchoscopy a higher percentage of small tumors and low-grade
but is still problematic. Pneumothorax is the most tumors, and thus the inherent limitations of FDG-
frequent complication of TTNA. Resection is the PET in diagnosing lung cancer are ampliÀed in a
ultimate management for many lesions that remain screened population. The limitations of diagnosis
indeterminate after imaging evaluation especially aside, FDG-PET has the potential to reduce the
in a high risk individual. Unfortunately there risk of unnecessary treatment. In this regard, FDG
are currently too many benign nodules removed uptake has the potential to indicate biologic behavior
surgically. Recent series of video assisted thoracic and prognosis. FDG uptake has been reported to
surgery (VATS) have reported benign nodules be highly correlated with 5-year survival i.e. 100%
representing 50-86% of nodules resected. Reduction for SUV 2.5 and 20% for SUV 8. In summary,
in benign nodule resections may be achieved by there are limitations to FDG-PET imaging in the
observing smaller nodules, by utilizing PET-CT, and diagnosis of non-small cell lung cancer and in the
by performing biopsy by TTNA or bronchoscopy determination of management of patients with lung
when information is discordant. cancer detected by screening CT. However, by
Keywords: Nodule guideline, Pulmonary nodule, addressing the issue of potential over diagnosis and
CT screening over treatment, PET has the potential to improve the
clinical management of patients with lung cancers
detected by CT screening trials. This talk will review
Nodule Management Wednesday, 6 July 2011 10:30-12:00 the current experience as it pertains to the use of
FDG-PET in the evaluation and management of
M15.3 ROLE OF PET IN SCREEN- nodules detected in CT screening programs.
DETECTED NODULES Keyword: Nodules; Lung cancer; Screening; PET
Jeremy J. Erasmus
Radiology, The University Of Texas MD Anderson
Cancer Center/United States Of America
Abstract: Positron emission tomography (PET)

using the radiopharmaceutical 18F-2-deoxy-D-
glucose (FDG), a d-glucose analog improves the
accuracy of staging in non-small cell lung cancer
and may have an important role in the assessment of
therapeutic response and the prediction of prognosis.
Additionally, FDG-PET may be valuable in the
evaluation and management of nodules detected
Session M16: The Use of Biomarkers in The Use of Biomarkers in Clinical Trial Design Wednesday, 6 July 2011
Clinical Trial Design 10:30-12:00
M16.2 BIOMARKERS IN CLINICAL

TRIAL DESIGN – ROLE OF THE
MOLECULAR PATHOLOGIST/
The Use of Biomarkers in Clinical Trial Design Wednesday, 6 July 2011 BIOLOGIST
10:30-12:00 Ming S. Tsao
Pathology, Princess Margaret Hospital/Canada
M16.1 THE STATISTICIAN
PERSPECTIVE Abstract: Most clinical trials in oncology are
Marc Buyse designed largely to test the efÀcacy of new
Consultants, IDDI/Belgium treatment modalities, such as drugs, radiation or
surgery. As patients and tumors are genetically
Abstract: A biomarker is a characteristic heterogeneous, responses are also expected to be
that is objectively measured and evaluated as heterogeneous, with some patients beneÀting while
an indicator of normal biological processes, other do not. A biomarker has been deÀned as a
pathogenic processes, or pharmacologic responses characteristic that can be measured objectively
to a therapeutic intervention. Biomarkers can be and evaluated as an indicator of normal biologic
contrasted with clinical endpoints, which capture processes, pathogenic processes, or pharmacologic
information on how a patient feels, functions or responses to a therapeutic intervention. Biomarkers
survives. Biomarkers may be imaging-based or that predict the outcome (usually survival) of the
physiological indicators, but with the advent of the patients independent of treatment administered
targeted therapy era, cellular, molecular and genetic are prognostic marker. In contrast, biomarkers that
biomarkers have been identiÀed that hold far better predict the response of patients (e.g. survival) or
potential for being either prognostic or predictive. their tumors (e.g. shrinkage in size) to treatment
Prognostic biomarkers can potentially be used to administered are predictive markers. Biomarkers
better predict the course of disease while predictive that can be evaluated and potentially adopted as
biomarkers are critical to identify patient subsets clinical tests include DNA, RNA, microRNA
of patients who beneÀt from, or are harmed by new and protein. At the DNA level, such markers are
therapies. Both types of biomarker require statistical usually mutations, loss or gain in the copy number
validation, usually in prospective trials, often but of speciÀc genes. There are many ways to detect
not always randomized trials. Hence biomarkers are mutations; most commonly used and regarded by
becoming an integral part of trial design, and can be many as the gold standard method is sequencing
used to stratify or select patients, to adapt treatment of the DNA of the target gene. Mutations occur by
allocation, to modify treatment, or to predict clinical single nucleotide substitution or the loss of single
outcomes. Many designs have been proposed to or several such nucleotides. Copy number of the
integrate known or putative biomarkers alongside target genes may also be lost or gained. Biologically
standard or experimental treatments in clinical signiÀcant gene losses are those involving tumor
trials. The purpose of this session will be to discuss suppressor genes, e.g. P16, RB, P53 or PTEN,
clinical trial designs such as clinical utility, cross- while gene copy number gains usually involve
over, Bayesian adaptive, randomize-all, interaction, oncogenes, such as EGFR and MYC. High level
biomarker-based strategy, targeted (selection), gains greater than the chromosomal gains on which
adaptive parallel, tandem two-stage, enrichment, the gene is located are referred as ampliÀcation;
and prospective subset designs. The operating while copy number gains secondary to chromosomal
characteristics of some of these designs will be gain is called polysomy. The “gold standard” to
explored, and their relative merits and limitations detect gene copy aberrations is Áuorescence in situ
contrasted. hybridization (FISH). Other detection methods
Keywords: biomarker, statistical validation, trial include chromogenic in situ hybridization (CISH)
design and polymerase chain reaction (PCR) that assess
the relative abundance of the target gene. As tumor
tissue includes also normal host cells with normal
gene sequences/copy number, techniques that do not the trial protocols, these are commonly referred to
identify the aberration at an individual cell level are as “integral” biomarker studies as they are necessary
prone to reduced sensitivity. In contrast, FISH or for the trials to proceed. In contrast, biomarkers
CISH are more accurate but labour intensive. Many studies (a) are largely exploratory and are usually
believe that proteins should represent the ultimate included in the trial protocols as “integrated” studies;
and most biologically meaningful biomarkers of these could be conducted using less or not yet
disease. There are many methods to detect proteins, validated assays in research laboratories. Such that
the standard methods are based on immunological positive results from exploratory studies could be
assays requiring the generation and availability validated in other studies, design of the biomarker
of speciÀc antibodies. Liquid assays including studies should include pre-speciÀed evidence based
enzyme-linked immunosorbent assay (ELISA) are assay methods and scoring criteria, with assays
used to measure protein levels in serum, plasma and conducted independent and blinded to the clinical
body Áuid, or in tissue homogenate. Bright Àeld data. An important aspect of designing clinical
immunohistochemistry (IHC) or immunoÁuorescent trials with biomarker studies is the prevalence of
microscopy is used to detect proteins at tissue level. the biomarkers, as this would greatly inÁuence the
These are already standard techniques in routine sample size. Low prevalence markers require greater
laboratory medicine practices. Nevertheless, newer sample size for overcoming statistical requirement,
assay techniques that lend greater throughputs and/ thus prior knowledge of such prevalence will be
or sensitivity are continually being investigated, very useful in the trial design. One of the most
including the mass spectrometry methods (MALDI- crucial and controversial issues in biomarker
TOF). Sample pre-processing are critical elements studies is the method to determine cut-points for
that need careful attention in their implementation in classifying tumors as marker positive or negative.
studies. These include standardization of protocols While this is relatively straight forward for changes
for sample collection, storage, Àxation, antibody that are qualitative and clear cut (e.g. wild type vs
speciÀcity, assay reliability, scoring system, etc. mutant), for biomarkers that are quantiÀed in some
To date limited efforts have been devoted to these kind of continuous variables (e.g. 0 to 100% or
critical issues, which may impact greatly on the 0,1,2,3), determining cut-points can be challenging.
reliability, hence reproducibility of study results. Arbitrarily chosen cut-points usually lead to over-
There are several ways that biomarkers can be Àtting, thus a difÀculty to reproduce results in other
studied or incorporated into the design of clinical sample cohorts. While medians could be the most
trials. These include: (a) retrospective studies to stringent approach, they may not make biological
explore the prognostic and/or predictive value sense. SigniÀcant efforts and studies devoted to
of markers of interest, (b) prospective studies to this issue are necessary. Such studies should be
validate prognostic/predictive value of markers of multi-disciplinary that include biostatisticians and
interest, (c) prospective studies using the biomarkers biologists and pathologists who can provide the
to select patients for eligibility of participating in the biological meaning and interpretation of the data. In
trial or assignment to treatment arms, and (d) clinical summary, the molecular pathologists and biologists
trials that are conducted to validate prospectively play crucial roles in the design of biomarker and
the predictive value of the biomarkers (biomarker correlative science studies in clinical trials, thus
trials). Among these, (c) and (d) have the greatest should be an integral member of each clinical trial
and most direct impacts on patients during the trial, committee evaluating novel targeted therapies.
as treatments are entirely dependent on the results Keywords: prognostic markers, predictive markers,
of the biomarker studies, while (b) may have some tumor markers, validation
impact by inÁuencing the patient randomization.
Consequently, (b) (c) and (d) demand the most
stringent requirement for designing biomarker
studies in the trial, including standard operating
protocols for specimen handling and processing,
assay robustness, validated scoring algorithm and
turnaround time; these assays should be conducted
in accredited pathology laboratories as their impacts
on patient are equivalent to routine clinical care. In
Session M17: New Kids on the Block incision was performed just above the suprasternal
notch. Once the pre-tracheal fascia was elevated,
Wednesday, 6 July 2011 after digital dissection, the videogastroscope was
introduced through the cervical incision and a
total mediastinal exploration was performed. The
New Kids on the Block Wednesday, 6 July 2011 10:30-12:00 second step was the creation of mediastinal pleural
windows. On the right side, a digital dissection of the
M17.1 CERVICAL INCISION THORACIC right mediastinal pleura posteriorly to the superior
ENDOSCOPIC SURGERY (CITES): THE vena cava was performed, creating a communication
USE OF FLEXIBLE SCOPE between the mediastinum and the right pleural
Jalal Assouad1, Dominique H. Grunenwald2 cavity. On the left side, the pleurotomy was also
1
Department Of Thoracic Surgery. Hopital Tenon/ digitally performed between the left commun carotid
France, 2Thoracic Surgery, Hopital Tenon. and subclavian artery. Then the videogastroscope
University Of Paris VI/France was introduced into the pleural cavities. Mediastinal
lymph nodes: 2R, 4R, 7 and 4L were consistently
Abstract: Despite the development of new identiÀed and biopsies were easy to perform. The
techniques for mediastinal exploration in lung introduction of the videogastroscope into both
cancer staging, as transbronchial needle aspiration pleural cavities was easy and allowed a wide
(TBNA), endoscopic ultrasound-guided Àne- exploration allowing numerous pleural biopsies.
needle aspiration (EUS-FNA), and endobronchial At the end, a chest tube was placed through pleural
ultrasound-guided Àne-needle aspiration (EBUS- window and exteriorised from the cervical incision.
FNA), still mediastinoscopy and video-thoracoscopy The use of Áexible endoscope through a natural
remain the more commonly performed invasive oriÀce (NOTES) into thoracic cavity remains still
techniques for mediastinal and pleural staging [1, ethically doubtful in their human being application
2]. In some cases both mediastinal and pleural as much through transoesophageal approach as
explorations are needed and required two separate transgastric or vaginal [12, 13]. CITES seems to be
procedures in the same patient. Pleural exploration more adapted for thoracic speciÀcities (eg. chest tube
and biopsies are commonly performed by the meand placement). Bilateral pleural access using CITES
of videothoracoscopy. The need of thoracic ports approach associated to the extreme Áexibility of the
and chest tube still remains the major cause of endoscope offer the possibility of a complete pleural
postoperative pain [3]. Several minimally invasive inspection and could be used for biopsies in several
procedures have been recently described for thoracic sites and in other potential applications
performing thoracic surgical interventions through a (ex. Bilateral diaphragm pacing, lung biopsies, hilar
cervical incision [4-6]. Now there is a trend in favour lymph nodes dissection, thoracic sympathectomy).
of the use of Áexible endoscopy in general surgery Nevertheless, the access to the left hemi thorax
[7]. Few series in the literature reported the use of through the mediastinum remains challenging. Few
a Áexible endoscope in NOTES (Natural OriÀce series in the literature [14, 15] demonstrated that
Transluminal Endoscopic Surgery) particularly in aortic arch makes the advancement of the video-
abdominal surgery [8-10]. Up to now NOTES was mediastinoscope into the left hemi thorax difÀcult
never applied in thoracic surgery on human patients, and dangerous. Flexible endoscope used in CITES
because the risk of major mediastinal complications, could be more secure in left side approaches. In
and therefore ethical limitations. In 2010, we conclusion, we believe that our bilateral approach
conducted an experimental work on human subject (CITES) through a single cervical incision with
in the aim to evaluate the feasibility of using a the use of a Áexible endoscope, as a surgical tool,
Áexible endoscope as surgical tool for simultaneous and novel instrumentation designed for NOTES
exploration of mediastinum and both pleura could have rapidly wide applications in thoracic
[11]. We used the same surgical approach as for surgery. References 1. Detterbeck FC, Jantz
mediastinoscopy. The scope was a standard double- MA, Wallace M, Vansteenkiste J, Silvestri GA.
channel Áexible videogastroscope (STORZ®) and Invasive mediastinal staging of lung cancer: ACCP
KARL STORZ Cold Light Fontaine Xenon 100W, evidence-based clinical practice guidelines (2nd
TELE PACK™ endoscopic video and 15”Flat Screen edition). Chest 2007;132:202S-220S 2. Carlens.
Monitor. A conventional cervical mediastinoscopy E. Mediastinoscopy: a method for inspection and
tissue biopsy in the superior mediastinum. Dis Chest Mediastinopleuroscopy: a new approach to the
1959;36: 343-352 3. Rusch VW, Bains MS, Burt diagnosis of intrathoracic diseases. Ann Thorac Surg
ME, McCormack PM, Ginsberg RJ. Contribution of 1976;22:265-9
videothoracoscopy to the management of the cancer Keywords: minimally invasive surgery,
patient. Ann Surg Oncol 1994;1:94-8 4. Zielinski thoracoscopy, Mediastinoscopy, Lung Cancer
M, Pankowski J, Hauer L, Kuzdzal J, Nabialek Staging
T. The right upper lobe pulmonary resection
performed though the transcervical approach. Eur
J Cardiothorac Surg. 2007;32(5):766-9. 5. Fowkes New Kids on the Block Wednesday, 6 July 2011 10:30-12:00
L, Lau KK, Shah N, Black E. A Cervical Approach
to Investigating Pleural Disease. Ann. Thorac. Surg M17.2 CERVICAL APPROACH: STAGING
2009; 88: 315 – 317. 6. Chamberlain MH, Fareed AND RESECTIONS
K, Nakas A, Martin-Ucar AE, Waller DA. Video- Marcin Zielinski1, Tomasz Nabialek1, Artur
assisted cervical thoracoscopy: a novel approach Szlubowski1, Juliusz Pankowski2
1
for diagnosis, staging and pleurodesis of malignant Thoracic Surgery, Pulmonary Hospital/Poland,
2
pleural mesothelioma. Eur J Cardiovasc Surg Pulmonaru Hospital/Poland
2008;34:200-3 7. Swanstrom LL, Dunst Cm, Spaun
GO. Future applications of Áexible endoscopy in Abstract: Most of general thoracic surgical
esophageal surgery.J Gastrointest Surg. 2009 Sep operations is performed through the traditional
12.[Epud ahead of print]. 8. Sanchez-Margallo FM, thoracotomy or sternotomy or with modern
Asencio JM, Tejonero MC, Perez FJ, Sanchez MA, videos-assisted (VATS) approach. SigniÀcant
Uson J, Pascual S. Technical feasibility of totally severity of pain is a common disadvantage of all
natural oriÀce cholecystectomy in a swine model. these procedures, even in case of VATS. In the
Minim Invasive Ther Allied Technol 2008;17:361- recent years our team developed the transcervical
4 9. Perreta S, Dallemagne B, Coumaros D, extended approach for various thoracic surgical
Marescaux J. Natural oriÀce transluminal endoscopic procedures, originally introduced by Cooper et
surgery : transgastric cholecystectomy in a survival al for thymectomy [1]. The aim of these study
porcine model. Surg Endosc 2008;22:1126-30 10. is to summarize our experience regarding the
Marescaux J, Dallemagne B, Perreta S, Wattiez use of the extended transcervical approach in
A, Mutter D, Coumaros D. Surgery without scars: thoracic surgery. Material and Methods Surgical
report of transluminal cholecystectomy in a human technique of an extended transcervical approach
being. Arch Surg 2007;142:823-6 11. Assouad J, Transcervical extended approach utilizes a typical
Steltzlen C, Masmoudi H, Vignes S, Gounant V, a 5-8 centimeters collar incision in the neck. The
Delmas V, Grunenwald D. Cervical incision thoracic critical technical point enabling a wide access to
endoscopic surgery: a minimally invasive endoscopic the chest is an elevation of the sternal manubrium
approach in thoracic surgery. Interact Cardiovasc with a special retractor (modiÀed Rochard frame,
Thorac Surg 2010;10:967-70 12. Fritscher-Ravens Asculap-Chifa company). A bilateral visualization of
A, Patel K, Ghanbari A, Kahle E, von Herbay A, the laryngeal recurrent and vagus nerves is usually
Fritscher T, Niemann H, Koehler P. Natural oriÀce performed to avoid injury of these structures [2].
transluminal endoscopic surgery (NOTES) in the We used the transcervical extended approach for
mediastinum: long-term survival animal experiments several types of procedures, including thymectomy,
in transesophageal access, including minor surgical transcervical extended mediastinal lymphadenetomy
procedures. Endoscopy 2007;39:870-5 13. Clark (TEMLA), resection of the mediastinal tumors and
J, Sodergren M, Correia-Pinto J, Zacharakis E, the mediastinal metastases, pulmonary resection
Teare J, Yang GZ, Darzi A, Athanasiou T. Natural of the right and left upper lobes, closure of the
oriÀce translumenal thoracoscopic surgery: does bronchial Àstula after pneumonectomy and as a part
the slow progress and the associated risks affect of the esophageal resection. In case of thymectomy,
feasibility and potential clinical applications? Surg the trascervical approach is usually combined with
Innov 2009;16:9-15 14. Ginsberg RJ. Extended a subxiphoid incision and bilateral single-port VATS
cervical mediastinoscopy. Chest Surg Clin N to achieve a maximal extensiveness of dissection
Am 1996;6:21-30 15. Deslauriers J, Beaulieu M, (we call the procedure “transcervical-subxiphoid
Dufour C, Michaud P, Despres JP, Lemieux M. VATS maximal thymectomy”)[3]. In case of small
thymomas and thymic cysts the entire procedure is TEMLA (unrelated causes) and 1 patients died
performed through the neck without opening of the after transcervical-VATS left upper lobectomy
mediastinal pleura. TEMLA is performed entirely because of pulmonary embolism. Complications
through the neck approach. Most part of TEMLA occurred in 85/1335 patients (morbidity 6.4%).
is an open procedure, with exception of dissection Our late institutional results of presented technique
of the subcarinal, station 7, periesophageal, station of thymectomy has been very favourable –
8 nodes and the left lower paratracheal, station 4 5-years complete remission rates 53.1% 20.0%
nodes which are dissected in the mediastinoscopy- in comparison the basic trassternal thymectomy
assisted fashion with aid of the linder-Dahan two- (p<0.0001) which can be only explained by the
blade mediastinoscope (Wolf Company, Germany) removal of ectopic foci of the thymic tissue from
[4]. The paraaortic, station 6 and aorta-pulmonary the neck and the mediastinum in these patients [3].
window, station 5 nodes are sometimes dissected In our current study presented to WCLC diagnostic
with aid of videothoracoscope introduced to the yield of TEMLA at our institution was signiÀcantly
mediastinum through the operative wound. Bilateral better than combined Endobronchial Ultrasound
supraclavicular lymphadenectomy and even deep (EBUS)/Endoesophageal Ultrasound. Sensitivity and
cervical lymph node dissection is possible during Negative Predictive Value (NPV) for TEMLA and
TEMLA through the same incision. In case of the EBUS/EUS were88.9% and 84.1% versus 98.6% and
mediastinal tumors and the mediastinal metastases 99.7% respectively (p<0.0001 for both parameters)
the surgical approach is dependent on the location [4]. In our recent study on restaging of NSCLC after
of the lesion. In most of the patients an entire neoadjuvant treatment TEMLA was found to have
procedure is performed solely through the neck signiÀcantly better sensitivity and NPV (p<0.05)
incision but in some patients an additional VATS or than other series of restaging including PET/CT,
subxiphoid incision might be necessary. The right EBUS, EUS and remediastinoscopy [6]. Conclusions
and left upper pulmonary resctions were performed Transcervical extended approach with elevation
throught the transcervical incion combined with of the sternal manubrium enables performance of
1-, or 2-port VATS. The technique and preliminary various thoracic surgical procedures with minimal
results of this operation were described elsewhere invasiveness, low mortality and morbidity and very
[5]. The closure of the main bronchial Àstula and high effectiveness. References
the dissection of the esophagus were performed 1. Cooper J, Al-Jalaihawa A, Pearson F, Humphrey
solely through the neck. Results Starting from J, Humphrey H: An improved technique to facilitate
1.9.2000 to 30.2.2011 there were 1335 transcervical transcervical thymectomy for myasthenia gravis.
operations including 391 transcervical-subxiphoid Ann Thorac Surg 1988;45:242-7
VATS maximal thymectomies for myasthenia gravis 2. Zielinski M, Ku‚ J, Szlubowski A, Soja J: A
(MG), 20 thymectomies for thymoma, 781 TEMLA safe and reliable technique for visualization of the
procedures for staging of Non-Small Cell Lung laryngeal recurrent nerves in the neck. Am J Surg
Cancer (NSCLC), 52 resections of the mediastinal 2005;189:200-202
tumors, 65 resections of the mediastinal metastases 3. Zielinski M, Hauer L, Hauer J, Pankowski J,
(mostly from the thyroid cancer), 5 right upper Nabialek T, Szlubowski A. Comparison of complete
lobectomies and 3 left upper lobectomies combined remission rates after 5 year follow-up of three
with TEMLA for NSCLC, 15 esophageal dissections different techniques of thymectomy for myasthenia
(combined with laparotomy in 13 patients and with gravis. 2010;37:1137-43.
laparoscopy in 2 patients) and 3 attempts of closure 4. Zielinski M, Hauer L, Hauer J, Nabiaek T,
of the right main bronchus postpneumonectomy Szlubowski A, Pankowski J. Eur J Cardiothorac
Àstula. 5/1335 (0.4%) patients had to be converted Surg. 2010;37:776-80
because of technical difÀculties, in no case for 5. Zielinski M, Pankowski J, Hauer L et al: The right
major bleeding or other severe intraoperative upper lobe pulmonary resection performed through
complications or deaths. 8/1335 (0.6%) patients the transcervical approach. 2007;32:766-769.
required revision because of postoperative bleeding 6. Zielinski M, Szlubowski A, Koodziej M,
(through the original incision in all but one patient, Orzechowski S, Laczynka E, Pankowski J,
who necessitated thoracotomy) There were 6 Jakubiak M, Obrochta A. Comparison of diagnostic
postoperative deaths with 30-day postoperative yield of endoscopic ultrasound staging of Non-
mortality 0.4% (6/1346) with 5 patients died after Small Cell Lung Cancer (NSCLC) performed
with use of Endobronchial Ultrasound (EBUS) in maneuverability, 3-dimensional visibility and

and/or Endoesophageal Ultrasound (EUS) with occasional difÀcult hand-eye coordination which
invasive staging of NSCLC performed with may hinder general acceptance. For surgery in the
use of Transcervical Extended Mediastinal chest, this can present severe risks to the patient.
Lymphadenectomy (TEMLA). Submitted to WCLC, Computer-assisted surgical systems or surgical
Amsterdam 2011. robotics has its origins in the early 1980s, when the
Keyword: Lung cancer, Mediastinal lymph nodes, Àrst institutions began to investigate the potential
mediastinal tumors of simulating a surgeon’s movements. Computer
Motion (Santa Barbara, CA) developed the Àrst
FDA-approved surgical robot, the Aesop, initially
New Kids on the Block Wednesday, 6 July 2011 10:30-12:00 foot controlled and later evolved to voice activated
video system. Then, in a giant leap forward, two
M17.3 VATS SLEEVE-RESECTIONS California-based robotic companies developed two
Bernward Passlick surgical robots, the Zeus by Computer Motion and
Thoracic Surgery, University Of Freiburg/Germany the daVinci by Intuitive Surgical, Inc. (Sunnyvale,
CA). Both have similar features, high-deÀnition
Abstract: Video-assisted minimal-invasive visual clarity, 3-dimensional visibility, multiple
resections for early-stage lung cancer are nowadays degrees of rotational freedom and tremor control.
performed throughout the world. However, overall, The Àrst robotic general surgical procedure was
there are only a few specialized centers in every performed by Cadiere in 1998. Chitwood performed
region or country which are performing these the Àrst mitral valve repair in 2000. The da Vinci
procedures routinely. In most of the institutions, in was approved by the FDA for the use in general
addition to small incisions for the thoracoscopic thoracic surgical procedures in March 2001.
instruments and utility incisions are used for the Since that time there has been continued growing
direct manipulation of the lung hilus and for the interest. To perform an efÀcient case the surgeon
removal of the specimen. In addition to anatomical must possess a thorough understanding of the
resections there are also a few reports on video- anatomy, the pathology and the robotic technology.
assisted sleeve resections of primary lung cancers or Placement of the ports and the machinery, and
other malignant tumors of the bronchial system. Due organization of the assistant(s) can determine the
to the technical limitations of the minimal-invasive efÀciency of the planned procedure. As with the
approach (no palpation) video-assisted sleeve VATS technique, there are 3 basic approaches using
resections are technically possible and oncologically the surgical robot. Given the greater visibility and
acceptable in only a few circumstances. In general, precision, one approach is to perform the hilar and
these are clearly deÀned tumors without lymphatic mediastinal lymph node dissection alone performing
inÀltration and with clear margins on frozen sections. the remainder of the procedure with VATS. This
Overall results are promising so far. may or may not be performed using a mini-
Keywords: Lung cancer, Thoracic surgery thoracotomy or “utility incision.” Others perform
the procedure completely robotically with from 4 to
6 ports, increasing the skin incision to remove the
New Kids on the Block Wednesday, 6 July 2011 10:30-12:00 specimen. To date, the published reports demonstrate
a conversion rate of approximately 2% with an
M17.4 ROBOTIC RESECTIONS operating room time of 3.6 hours and a postoperative
Kemp Kernstine length of stay of 7 days with an approximately 20
Valencia/United States of America % morbidity and 1% operative mortality. The role
of robotics in lung resection is unclear. In general
Abstract: For lung cancer, minimally invasive robotics in thoracic surgery offers numerous
surgery or video-assisted thoracoscopic surgery opportunities for resection and reconstruction with
(VATS) appears to be safe with comparable short- excellent visibility and precision. As the technology
and long-term outcomes to the open thoracotomy continues to be reÀned and with greater the surgical
approach. VATS has reduced pain, length of hospital experience, the efÀciency and the cost of the
stay, improved lung function and quicker return to procedures will continue to improve. It is likely
preoperative status. Though there are limitations that many of the video-assisted procedures will be
replaced with robotic technology. An educational treatments directed against cancer stem cells should
process is necessary to optimize early outcomes. be targeted to subsets of patients grouped according
to their oncogenotype. We have recently obtained
global gene expression data from the Sca1-sorted
Session M18: Stem Cells in the Mouse populations of murine lung tumor cells, as well as
their normal wild-type counterparts, to uncover
Wednesday, 6 July 2011 the molecular pathways responsible for tumor
propagation in lung adenocarcinoma. I will also
discuss new avenues we have taken to understand the
Stem Cells in the Mouse Wednesday, 6 July 2011 16:30-18:00 connections between TPCs and metastasis in mouse
models as well as translating the importance of our
M18.2 STEM CELLS IN MURINE Àndings in human lung cancer cells and patient
NORMAL LUNG AND LUNG CANCER samples.
Carla Kim
Stem Cell Program, Children’s Hospital Boston/
United States Of America Stem Cells in the Mouse Wednesday, 6 July 2011 16:30-18:00
Abstract: Lung cancer is the major cause of death M18.3 HEDGEHOG SIGNALLING IN
from cancer worldwide. The Àve-year survival CANCER STEM CELLS
rate for the majority of lung cancer patients is Neil Watkins
only 16% because their tumors are refractory to Monash Institute Of Medical Research, Monash
chemotherapeutics or quickly become resistant to University/Australia
therapeutic response. Also contributing to morbidity,
most lung cancer patients already have advanced, Abstract: In development and homeostasis, the
metastatic disease at the time of diagnosis or develop property of long-term self renewal is restricted to a
metastases after surgical removal of early stage small subset of somatic stem cells. It is now clear
primary lung tumors. The cancer stem cell (CSC) that maintenance of this property is dependant on a
hypothesis, is an attractive explanation for tumor small number of developmental pathways that are
growth, recurrence after treatment, and metastasis distinct from those that regulate growth, apoptosis
in some cancers, yet the precise role of CSCs and senescence. These œstemness pathways are an
in lung tumors has not been established. Since evolutionarily conserved set of genes that regulate
successful cancer therapy requires the elimination cell fate and patterning in metazoans, and have the
or incapacitation of all tumor cells capable of capacity to regulate all the functional components
regenerating a tumor, it is crucial to characterize of self-renewal in development and repair. One of
the cells that are able to propagate a tumor in vivo. the most important of these pathways is Hedgehog
We refer to these functionally important cancer cells (Hh) signalling, named after the characteristic
as tumor-propagating cells (TPCs). Importantly, phenotype of the Drosophila mutant in which
understanding the identity and molecular nature the cuticle of Hh null embryos develop a marked
of TPCs will provide new opportunities for early expansion in the number of denticle hairs, hence a
detection, treatment and prevention of metastatic hedgehog-like appearance. This is caused by a loss
disease, whether or not they Àt the CSC model of segmental polarity in the developing Áy, because
in each type of cancer. My laboratory recently the Hh protein is a diffusible morphogen secreted in
showed that murine lung adenocarcinomas, the the posterior compartment of each segment of the
most prevalent lung cancer subtype, contain a embryo, and its concentration gradient is required
TPC population. In mice bearing tumors initiated for the normal striped pattern of denticles that is
with oncogenic Kras and deletion of p53, the cell lost in the Hh mutant. In mammalian development,
surface marker Sca1 identiÀes cancer cells with Hh proteins specify cell fate in the same way, and
stem cell properties. In contrast, TPCs are Sca1- are particularly important for axial patterning of the
negative in lung tumors that express a mutant EGFR. central nervous system, limb buds and foregut. More
Thus, the predominant driving oncogenotype is an recently, Hh signalling now known to be required for
important determinant in the identiÀcation of TPC the maintenance of somatic stem cell populations in
phenotype in lung cancer. This Ànding suggests that the central nervous system, skin, cartilage and other
organs. Mutations that lead to aberrant activation of small molecule Hh pathway inhibitors), tumour
of the Hh pathway result in medulloblastoma and formation in this model was dramatically reduced.
basal cell carcinoma. In these tumours, a naturally By using genetic mouse models, these experiments
plant-derived Hh pathway antagonist, cyclopamine, establish that Smo is a validated pharmacologic
is highly effective in blocking growth of these target in SCLC. Although we have been unable to
tumours. Cyclopamine is a competitive antagonist associate a distinct stem cell phenotype in small
of Smoothened (Smo), a transmembrane protein cell lung cancer (SCLC), we have shown that
that is required for all Hh signalling in metazoans. inhibition of Hh signalling is able to block self-
Pharmacologic targeting of Smo has formed the basis renewal capacity in this tumour model. Although
for the development of small molecule inhibitors Hh inhibitors have no effect on the growth of
of Hh signalling as potential cancer therapeutics. established SCLC tumours, they are highly effective
Our work is based on the premise that self-renewal in blocking long term clonal capacity in vitro and in
is a unique property restricted in nature to the germ vivo. Since SCLC is characteristically sensitive to
line, embryonic and somatic stem cells, and cancer. platinum-based chemotherapy, we then reasoned that
Furthermore, we believe that the acquisition of the population of tumour cells that can regenerate
aberrant self-renewal is functionally distinct from the tumour following chemotherapy, a surrogate
the hallmarked of cancer, such as uncontrolled marker of self-renewal, would be more dependant on
growth and the escape from apoptosis. Based on Hh signalling than bulk tumour cells. Experiments
the evidence in development and repair, we have in vitro and in vivo show that the self-renewal
explored the idea that cells within tumours that capacity in innately chemoresistant SCLC cells was
possess self-renewal properties, so called “cancer a thousand fold more efÀcient than chemonaive
stem cells”, are dependant on the same embryonic cells, and that this cell population was dramatically
signalling pathways that maintain stemness in more sensitive to Hh pathway inhibitors. These
normal tissues. We were Àrst able to characterise data support the idea that cancer stem cells
this phenomenon in small cell lung cancer (SCLC), possess the properties of self-renewal and innate
where cyclopamine was able to block clonal growth chemoresistance, and that targeting pathways that
in vitro. Since we were unable to identify a robust regulate self-renewal may be effective in depleting
marker for SCLC stem cells, we turned to other populations of tumour cells that evade conventional
tumour stem models to explore this idea. In multiple chemotherapy.
myeloma, in which a distinct tumour stem cell Keywords: Small cell lung cancer, Hedgehog, stem
population can be isolated, we found that the stem cells
cell compartment was extremely sensitive to Hh
pathway inhibition. These stem cells, which resemble
normal B cells, undergo terminal differentiation Stem Cells in the Mouse Wednesday, 6 July 2011 16:30-18:00
along a plasma cell lineage when treated with
cyclopamine, and in doing so lose their capacity M18.4 STEM CELLS
to self-renew. By contrast, mature myeloma cells CHEMORESISTANCE
are totally resistant to Hh pathway blockade. These Luca Roz, Giulia Bertolini, Gabriella Sozzi
Àndings have since been conÀrmed in other tumour Experimental Oncology, Fondazione IRCCS Istituto
stem cell models, including glioblastoma and chronic Nazionale Tumori/Italy
myeloid leukaemia. DeÀnitive conclusions based
on experiments using small molecule inhibitors are Abstract: The cancer stem cells (CSC) model
hampered by concerns over off-target effects. One carries fundamental implications for cancer therapy.
way to resolve this issue is the use of genetically One implication of this model is that, regardless of
modiÀed mouse models, in which targeted deletion the origin of CSCs (either from transformation of a
of a therapeutic target using a conditional knockout normal stem cells or from acquisition of stem like
approach can be used to validate a therapeutic properties during cancer evolution), only a fraction
target in vivo. To address this question, we studied of the cells in a given tumor might have tumor
a genetic mouse model of SCLC in which deletion initiating potential and that those cells should be
of the p53 and Rb tumour suppressors is targeted to targeted to achieve complete remission. Several lines
the adult airway epithelium. When crossed with a of evidence, Àrst in hematological tumors and more
conditional knockout of Smo (the molecular target recently in solid tumors, demonstrate an intrinsic
resistance of CSC to conventional chemotherapeutic before cisplatin treatment, the residual cells
agents and ionizing radiation, because of their recovered after tumor relapse were depleted in tumor
low proliferation rate and of defense mechanisms, initiating capability in a serial transplantation assay.
including the expression of multidrug transporters Additionally, treatment of tumorgrafts with cisplatin
of the ATP-binding cassette (ABC) superfamily. resulted in dissemination of CD133+CXCR4+ cells
In lung cancer evidence for the presence of CSC to the lungs implicating these cells also in the
has been obtained in transgenic animal models and metastatic spread. This process could be inhibited by
primary tumors. Their prospective identiÀcation combined treatment with retinoic acid derivatives.
and characterization may provide new insights to Finally a tendency towards shorter progression free
identify novel prognostic markers and targets for survival was observed in CD133+ NSCLC patients
therapeutic intervention. This could represent an treated with platinum-containing regimens indicating
innovative strategy to completely eradicate tumors of possible clinical relevance of these Àndings. Taken
and potentially lead to cure, even in advanced-stage together these results indicate that chemoresistant
disease. We previously showed that a subpopulation populations with highly tumorigenic and stem-like
of lung cancer cells expressing the stem cells marker features are present in lung tumors. The molecular
CD133 displayed higher tumorigenic potential in features of these cells may provide the rationale for
immunocompromised mice and increased expression more speciÀc therapeutic targeting and for deÀning
of genes involved in stemness, adhesion, motility predictive factors in clinical management of this
and drug efÁux than the CD133- counterpart. lethal disease.
Cisplatin treatment of lung cancer cells in vitro Keywords: chemoresistance, CD133, tumorgrafts,
resulted in enrichment of the CD133+ fraction both stem cells
after acute cytotoxic exposure and in cells with a
stable cisplatin-resistant phenotype. Expression of
transporters of the ABC family was also upregulated Stem Cells in the Mouse Wednesday, 6 July 2011 16:30-18:00
in the residual population. For in vivo studies
we established several models of primary tumor M18.5 EPITHELIAL PROGENITOR
xenografts (tumorgrafts), derived from direct CELLS AND THEIR REGULATION IN
implant of patient biopsies. Tumorgrafts can be THE NORMAL AND REPAIRING LUNG.
serially propagated, have been shown to recapitulate Barry Stripp
closely the phenotype of the original tumor and Departments Of Medicine And Cell Biology, Division
to be useful tools to evaluate response to therapy. Of Pulmonary Allergy And Critical Care Medicine,
Complete similarity between parental tumors and Duke University/United States Of America
tumorgrafts was conÀrmed for a panel of lung
cancer antigens, as well as for the CD133+ESA+ Abstract: Epithelial remodeling and dysfunction
fraction that was maintained over time in serial is pathognomonic of chronic lung disease and
transplantations. In tumorgraft models the highly directly contributes to declining lung function
tumorigenic lung tumor CD133+ cells, endowed that accompanies disease progression. This can be
with stem-like features, were spared by cisplatin demonstrated by dramatic declines in the abundance
treatment and reverted to the original values after of low molecular weight secretory products of
chemotherapy cessation, indicating that these cells nonciliated bronchiolar epithelial cells in serum
might represent a chemoresistant sub-population and/or airway lining Áuid of patients with asthma,
responsible for tumor re-growth after treatment. chronic obstructive pulmonary disease, early
In tumorgrafts with high content of CD133, transplant rejection, and other chronic inÁammatory
only the subpopulations of CD133+ABCG2+ and lung diseases. We have developed both in vivo and
CD133+CXCR4+cells were strongly enriched after in vitro models of epithelial cell injury and repair to
the in vivo cisplatin treatment, indicating that highly better understand cellular and molecular mechanisms
resistant cells could represent only a subset within of epithelial maintenance and remodeling in
the CSC compartment. Cisplatin-treated tumors lung disease. Epithelial tissues are maintained in
consistently expressed higher levels of stemness adulthood through the action of tissue-speciÀc
genes and ABC transporters compared to untreated progenitor cells that can be hierarchically organized
control. When tumorgrafts were treated with retinoic according to their capacity for proliferation,
acid derivatives to induce CSC differentiation differentiation and resistance to environmental
stress. Using a chimeric mouse model and sequential cell secretory protein-expressing cells of the airway
labeling of proliferating cells with halogenated neuroepithelial body microenvironment include a
thymidine analogues we show that normal epithelial label-retaining subset and are critical for epithelial
maintenance is achieved through the random renewal after progenitor cell depletion. Am J Respir
participation of abundant Clara cells. However, Cell Mol Biol 2001; 24:671-681. 5. Giangreco A,
Clara cells are the principal site for detoxiÀcation Reynolds SD, Stripp BR. Terminal bronchioles
of lipophilic environmental pollutants in the lung, harbor a unique airway stem cell population that
a function that renders this abundant progenitor localizes to the bronchoalveolar duct junction. Am
pool sensitive to injury by environmental agents. J Pathol 2002; 161:173-182. 6. Kim CF, Jackson
Airway injury that depletes the abundant Clara EL, Woolfenden AE, Lawrence S, Babar I, Vogel S,
cell pool results in activation of a rare population Crowley D, Bronson RT, Jacks T. IdentiÀcation of
of chemically resistant reparative cells. We show bronchioalveolar stem cells in normal lung and lung
that the clonal origins of specialized epithelial cell cancer. Cell 2005; 121:823-835. 7. Giangreco A,
types within airways differ dramatically between Arwert EN, Rosewell IR, Snyder J, Watt FM, Stripp
normal maintenance versus repair following injury, BR. Stem cells are dispensable for lung homeostasis
a concept that is of fundamental importance in but restore airways after injury. Proc Natl Acad Sci
understanding mechanisms leading to the expansion U S A 2009; 106:9286-9291. 8. Rawlins EL, Okubo
of progenitor cells carrying founding mutations that T, Xue Y, Brass DM, Auten RL, Hasegawa H, Wang
impact cancer susceptibility. We have developed F, Hogan BL. The role of scgb1a1+ Clara cells in the
fractionation and culture methods allowing clonal long-term maintenance and repair of lung airway,
analysis of airway epithelial progenitor cells to gain but not alveolar, epithelium. Cell Stem Cell 2009;
a more comprehensive understanding of mechanisms 4:525-534. 9. Reynolds SD, Zemke AC, Giangreco
regulating their renewal and differentiation. Using A, Brockway BL, Teisanu RM, Drake JA, Mariani
a clonal 3D organotypic culture model we show T, Di PY, Taketo MM, Stripp BR. Conditional
that functionally distinct epithelial progenitor cell stabilization of beta-catenin expands the pool of
types can be recovered from intralobar airways, lung stem cells. Stem Cells 2008; 26:1337-1346.
these progenitors represent subsets of CCSP- 10. Teisanu RM, Lagasse E, Whitesides JF, Stripp
expressing cells, and that these progenitor cell BR. Prospective isolation of bronchiolar stem cells
types have a non-uniform distribution throughout based upon immunophenotypic and autoÁuorescence
airways. Conducting airways progenitor cells can characteristics. Stem Cells 2009; 27:254-264. 11.
be functionally subdivided by their requirement for Teisanu RM, et al. Functional Analysis of Two
stromal cell interactions, their response to growth Distinct Bronchiolar Progenitors during Lung Injury
factors, and the morphology of clonally derived and Repair. Am J Respir Cell Mol Biol. 2010 (in
epithelial colonies. Ongoing studies deÀning Press).
molecular pathways that regulate renewal and
differentiation of these progenitor cell types will be
discussed. These Àndings provide new insights into Session M19: Chemoprevention: New
cellular mechanisms of epithelial maintenance and Approaches in High Risk Populations
remodeling, and provide a basis for development
of cell-based and either genetic or pharmacologic
therapies aimed at restoring the regenerative capacity
of injured airways. Supported by the NHLBI and
NASA. Selected literature: 1. Stripp BR, Reynolds Chemoprevention: New Approaches in High Risk Populations
SD. Maintenance and repair of the bronchiolar Wednesday, 6 July 2011 16:30-18:00
epithelium. Proc Am Thorac Soc 2008; 5:328-333.
2. Stripp BR. Hierarchical organization of lung M19.1 RISK MODELING: APPROACHES
progenitor cells: Is there an adult lung tissue stem TO POPULATIONS AT HIGH RISK FOR
cell? Proc Am Thorac Soc 2008; 5:695-698. 3. Evans DEVELOPING LUNG CANCER
MJ, Cabral-Anderson LJ, Freeman G. Role of the Margaret R. Spitz, Anthony M. D’Amelio, Carol J. Etzel
Clara cell in renewal of the bronchiolar epithelium. Epidemiology, M.D. Anderson Cancer Center/United
Lab Invest 1978; 38:648-653. 4. Hong KU, Reynolds States Of America
SD, Giangreco A, Hurley CM, Stripp BR. Clara
Abstract: Results from the National Lung Screening models have shown only modest improvements in
Trial showing a 20% reduction in lung cancer discrimination. We have added the top hits from
mortality in the screened arm have heightened four published genome wide association studies
awareness of, and the need for, reliable risk (including our own) and showed that addition of
prediction tools for estimating the probability of lung the genetic information improved the area under the
cancer. Such models have substantial public health curve statistic by 1%, with modest improvement
implications and value in clinical decision making. in both sensitivity (9%) and speciÀcity (6%). The
High-risk individuals could undergo a program of receiver operating characteristics (ROC) curve
screening surveillance that might not be appropriate may not be sensitive to differences in probabilities
for a lower risk population. Further, risk prediction between models and, therefore, may be insufÀcient
tools could be incorporated into the design of to assess the impact of adding new predictors. A very
smaller, more powerful, and “smarter” prevention large independent association of the new marker is
trials. The challenges, however, are substantive. Over required for a meaningful improvement in AUC,
80% of lung cancer cases occur in ever smokers, and a substantial gain in performance may not yield
but only an estimated 11% of female smokers and a substantial increase in AUC. Research is now
17% of male smokers will be diagnosed with lung in progress to determine the calibration (based on
cancer in their lifetimes. For expensive screening ten year and Àve year absolute risk calculations),
programs, it is necessary to identify the highest risk discriminatory power, and clinical utility of our
subgroups of current and former smokers that use model using prospective cohort data from the Dutch-
more than smoking phenotypes to deÀne high risk. Belgian randomized lung cancer screening trial,
We have constructed and internally validated clinical NELSON.
tools for lung cancer risk prediction for current, Keyword: risk models
former and never smokers, based on epidemiologic
and clinical data derived from a case control study
of 1851 non Hispanic white lung cancer patients Chemoprevention: New Approaches in High Risk Populations
and 2001 matched controls. Variables included were Wednesday, 6 July 2011 16:30-18:00
environmental tobacco smoke (for never and former
smokers only), family cancer history, dust exposure, M19.2 MOLECULAR PATHOLOGY OF
physician diagnosed emphysema, and smoking LUNG CANCER & INTERMEDIATE
history variables (packyears for current smokers MARKERS OF CARCINOGENESIS
and age stopped smoking for former smokers). All Ignacio Wistuba, Humam Kadara, Edward Kim,
have strong biologically plausible etiologic roles, Waun K. Hong
and are relatively easy to ascertain through patient Thoracic And Head & Neck Medical Oncology,
interview. The validated concordance statistics for University Of Texas, M.D. Anderson Cancer Center/
the former and current smoker models were modest United States Of America
(0.63, and 0.58, respectively), but slightly higher
compared to other cancer risk prediction models Abstract: Lung cancer continues to be the leading
that do not include co-morbid conditions. We have cause of cancer-related deaths worldwide with
adopted similar approaches to construct risk models over one million deaths each year. Lung cancer
for African Americans. Since the precision of these mortality is high in part because most cancers are
models is modest, we have also estimated the degree diagnosed after regional or distant spread of the
of improvement obtainable by adding functional disease had already occurred and due to the lack
assessment of DNA repair capacity, and have shown of reliable biomarkers for early detection and risk
that addition of biomarker assays signiÀcantly assessment. The identiÀcation of new effective
improved the sensitivity of the expanded models, early biomarkers will undoubtedly improve clinical
although these assays are technically not suitable management of lung cancer and is tightly linked
for wide scale application. The advent of genome- to better understanding of the molecular events
wide association studies to identify low-penetrance associated with the development and progression of
common susceptibility alleles heralds the possibility the disease. It has been suggested that histologically
of incorporating panels of gene variants into existing normal-appearing tissue adjacent to neoplastic
risk prediction models and of assessing improvement lesions display molecular abnormalities some of
in model performance. However, to date, the updated which are in common with those in the tumors.
This phenomenon, coined Àeld of cancerization, Chemoprevention: New Approaches in High Risk Populations
has been shown to be important in lung cancer. We Wednesday, 6 July 2011 16:30-18:00
have demonstrated than mutations in EGFR occur
in normal appearing bronchial epithelium adjacent M19.3 EXPERIMENTAL MODELS AND
to EGFR mutant lung adenocarcinomas in never HIGH THROUGHPUT SCREENING
smoker patients, and also occurred at a higher Yuhong Du1, Andrea Kasinski1, Shala Thomas1,
frequency at sites more proximal to the tumors Aiming Sun2, Andrew Gewirtz3, James Snyder2,
than at more distant regions. More recently, gene Dennis Liotta2, Fadlo R. Khuri4, Haian Fu1
1
methylation patterns, as well as global mRNA and Pharmacology, Emory University/United States
microRNA (miRNA) expression proÀles, have Of America, 2Chemistry, Emory University/United
been described in the normal-appearing bronchial States Of America, 3Pathology, Emory University/
epithelium of healthy smokers. Importantly, United States Of America, 4Hematology & Medical
modulation of global gene expression in the normal Oncology, Emory University-Winship Cancer
bronchial epithelium in healthy smokers is similar Institute/United States Of America
in the large and small airways, and the smoking-
induced alterations are mirrored in the epithelia of Abstract: Many chemical carcinogens, such as
the mainstem bronchus, buccal and nasal cavities. cigarette smoke, act as major risk factors for lung
Increasing our understanding of early phases in lung cancer in part through triggering inÁammation. It
cancer pathogenesis will aid in the identiÀcation is well established that the inÁammatory response
of early stage non-small cell lung cancer (NSCLC) in premalignant lesions is a major enabling
patients at higher risk for recurrence or second characteristic that helps incipient neoplasias acquire
primary tumor development. Recently, we have hallmark capabilities for cancer development, such
performed global gene expression analysis of as cell proliferation, survival, and angiogenesis.
the Àeld of cancerization in smoker patients with One major pathway that mediates the inÁammatory
early stages NSCLC to better understand lung response occurs through the action of the inhibitor
cancer pathogenesis and predict recurrence or of B kinase (IKK)-nuclear factor-B (NF-B) signaling
second primary tumor development. Our Àndings cascade. Thus, agents that attenuate IKK-NF-B
highlight expression signatures and activation of signaling would be expected to have potential
cancer-related pathways in a cancerization Àeld anti-inÁammatory effects and could be used for
that may drive lung cancer pathogenesis and be chemoprevention and chemotherapeutic studies in
associated with recurrence or second primary tumor lung cancer. In this study, we aimed to target the
development in NSCLC patients. We propose that NF-B signaling pathway using high throughput
the study of Àeld cancerization phenomenon using screening (HTS) and high content screening (HCS)
high-throughput molecular proÀling (protein, technologies. Initially, we speciÀcally examined
mRNA, miRNA and DNA) methodologies combined the efÀcacy of newly developed curcumin analogs
with coupled with functional pathway analysis and and demonstrated their superior activity over the
studies of in vitro and in vivo models will provide parental agent in a panel of lung cancer cell lines.
promising markers to improve risk assessment, new In particular, a synthetic monoketone compound,
targets for novel targeted chemopreventive agents, 3,5-bis(2-Áurobenzylidene)piperidin-4-one
and selecting NSCLC patients who may beneÀt (referred to as EF24), exhibited a potency that was
from chemopreventive interventions to prevent approximately 10 times higher than that of curcumin.
disease recurrence. Supported by DoD grants In order to investigate the mechanism of action
W81XWH-04-1-0142 and W81XWH-10-1-1007. of these analogs, we examined the effects of test
Keywords: Àeld cancerization, Preneoplasia, compounds on the localization of NF-B. NF-B is
molecular proÀling, smoker maintained in an inactive state in the cytoplasm by
the inhibitor of B (IB), which negates the nuclear
localization of NF-B. Phosphorylation of IB by
IKK, via the canonical NF-B pathway, results in
subsequent ubiquitination of IB and proteasomal
degradation. It is this degradation of IB that liberates
NF-B, allowing its localization to the nucleus and
the transcriptional activation of its target genes.
Importantly, aberrant localization and activation Chemoprevention: New Approaches in High Risk Populations
of NF-B contributes to deregulated growth and Wednesday, 6 July 2011 16:30-18:00
resistance to apoptosis. Based on this mechanism,
we used high content screening technology with M19.4 MOLECULAR MECHANISMS OF
an automated imaging system to monitor the effect CHEMOPREVENTIVE COMPOUNDS
of the curcumin analogs on the activation of NF- AND NOVEL APPROACHES
B. We found that EF24 rapidly blocks the nuclear (MOLECULAR IMAGING) TO ASSESS
translocation of NF-B, with an IC50 value of 1.3 M EFFICACY
compared to curcumin, which had an IC50 value of Fadlo R. Khuri1, Shi-Yong Sun2, Johann C. Brandes3,
13 M. Furthermore, EF24 effectively inhibited tumor Haian Fu2
1
necrosis factor (TNF)±-induced IB phosphorylation Hematology And Medical Oncology, Emory
and degradation, suggesting a role for this University/United States Of America, 2Emory
compound in targeting IKK. Indeed, EF24 directly University/United States Of America, 3Hematology
inhibited the catalytic activity of IKK in an in vitro- & Medical Oncology, Emory University-Winship
reconstituted system. Our study identiÀes IKK as a Cancer Institute/United States Of America
target of effective curcumin analogs and provides
a molecular explanation for the superior activity Abstract: Several decades of chemopreventive
of EF24 over curcumin. In order to discover new trials for lung cancer have failed to demonstrate
compounds that inhibit NF-B signaling pathways, meaningful beneÀt for patients using compound
we have designed a parallel HCS screening assay development largely based on epidemiologic data1.
with two distinct activators, TNF± and Áagella. These trials have included attempts at primary,
TNFï¡ activates IKK through the TNF receptor- secondary, and tertiary prevention of lung cancer.
mediated TRADD/FADD signaling complex while These trials focusing on primary prevention of
Áagella trigger IKK activation through the Toll-like lung cancer have attempted to reduce the impact
receptor 5-mediated pathway. Using this strategy, of tobacco consumption in lung cancer patients
we intend to identify three classes of compounds, and have included large trials using carotentoids,
(i) compounds that act on common pathways for retinoids, vitamin E, and other natural compounds,
TNF± and Áagella, (ii) compounds that are speciÀc which showed that continued exposure to tobacco
for blocking the TNF± pathway, and (iii) compounds smoke abrogates the anti-oxidant effects of most
that selectively block the TLR5 pathway. We have of these compounds2. Recent randomized trials
developed and optimized a HCS assay in a 384- that were initiated in patients at the highest risk for
well plate format with satisfactory performance development of lung cancer, namely patients who
parameters as measured by Z’ factor and S/N ratio. had already been treated for a previous primary lung
With this HCS system, we carried out a parallel or head and neck cancer were also unsuccessful.
screening with a small molecule chemical library These include trials of vitamin A and E derivatives3,
of 100,000 compounds. Progress from these studies as well as most recently a phase III trial that
will be presented. This presentation will focus on failed to show any beneÀt for selenomethionine
the use of state-of-the-art high throughput screening supplementation in patients with prior stage I lung
technologies for the discovery of anti-inÁammatory cancer4. However, there has been some evidence of
agents and for mechanism of action studies in an progress using targeted agents in speciÀc lung cancer
effort to develop the next generation of highly populations. Following on evidence from J.S. Lee
efÀcacious lung cancer chemoprevention agents. that indicated that retinoids could have efÀcacy in
Keywords: drug discovery, InÁammation, NF-kB, reversing premalignancy in former smokers5, several
high throughput screening (HTS) approaches attempting reversal of pre-malignancy
in former smokers have shown some efÀcacy. A
targeted approach using 9-cis-retinoic acid, a pan-
retinoid agonist, proved effective in upregulation of
RAR-ơ in pre-malignant lesions6. However, as we
and other have demonstrated, presence of RAR-ơ
in primary stage I lung cancers is associated with a
poor outcome, and correlates with over-expression
of COX-2 7,8. However, several approaches targeting
COX-2 have started to yield evidence of intriguing J Clin Oncol. 27(4):599-604, 2009. 3. Khuri F,
beneÀt. Kim et al randomized 182 patients to Van Zandwijk N. Molecular Carcinogenesis and
celecoxib or placebo for three months with half Chemoprevention of Lung Cancer. Principles and
the patients on each arm subsequently undergoing Practice of Lung Cancer. Pass HI, Carbone DP,
crossover. In this study, in which celecoxib was Johnson DH, Minna JD, Scagliotti GV, Turrisi AT,
originally dosed at 200 mg twice daily, evidence of eds, Lippincott Williams and Wilkins, Philadelphia,
efÀcacy was seen for the COX-2 inhibitor in former PA, 4th Edition, 275-283, 2010. 4. Karp DD, et
smokers9. In fact, reduction of Ki-67 expression al. A phase III, intergroup, randomized, double-
was seen in former smokers that was sustainable blind, chemoprevention trial of selenium (Se)
in those individuals who had six months of high supplementation in resected stage I non-small cell
dose celecoxib. Mao et al conducted a randomized, lung cancer (NSCLC). Proceedings of ASCO, Vol
double blind, placebo controlled study of 400 mg 28 (No 15S) abs CRA7004, 2010. 5. Lee JS, et al.
b.i.d. of celecoxib or placebo to high risk former Randomized placebo-controlled trial of isotretinoin
smokers10. This study showed that of the 137 in chemoprevention of bronchial squamous
patients, 101 completed both baseline and six month metaplasia, J. Clin Oncol, 12(5):937-45, 1994.
bronchoscopies and were evaluable for the primary 6. Kurie JM, et al. Treatment of former smokers
end point. A signiÀcant treatment effect was seen with 9-cis retinoic acid reverses loss of retinoic
in that celecoxib signiÀcantly decreased Ki-67 acid receptor-beta expression in the bronchial
by an average of 34%, versus placebo. Moreover, epithelium, Journal of the National Cancer Institute,
decreases in Ki-67 are associated with reduction 95(3):206-14, 2003. 7. Khuri, FR, et al. Retinoic
and/or resolution of lung nodules. The SPORE acid receptor (RAR-b) as a prognostic indicator in
trial of Iloprost also showed substantial evidence stage I non-small cell lung cancer. Journal of Clinical
of efÀcacy in pre-malignant lesions of former Oncology, 18(15): 2798-2804, 2000. 8. Khuri FR,
smokers, but not current smokers12. In order to et al. Cyclooxygenase-2 over-expression correlates
better hone our development of chemopreventive is a marker of poor prognosis in stage I non-
agents, it is important to study not only the success small cell lung cancer. Clinical Cancer Research,
of these trials through the appropriate intermediate 7(4): 861-867, 2001. 9. Kim ES, et al. Biological
biomarker, but to incorporate molecular imaging into activity of celecoxib in the bronchial epithelium
our therapeutic armamentarium. We have recently of current and former smokers. Cancer Prev Res,
conducted a trial of pre-operative everolimus in 3(2):148-59, 2010. 10. Mao JT, et al. Lung cancer
patients with resectable lung cancer that suggests chemoprevention with celecoxib in former-smokers,
that in former smokers, everolimus is highly Cancer Prevention Research, in press, 2011. 11.
effective in reducing metabolic uptake as assessed by Keith R Chemoprevention of lung cancer. Proc Am
FDG-PET in patients who take 10 mg of everolimus Thorac Soc, Vol 6:187-93, 2009. 12. Owonikoko
for three weeks prior to surgical resection of their TK, et al. Analysis of mTOR signaling pathway
non-small cell lung cancer12. This is consistent with biomarkers in non-small cell lung cancer patients
data from Dennis et al, which suggests that blockade treated with everolimus and docetaxel in a phase II
of the Akt/mTOR signaling axis leads to abrogation clinical trial. To be presented at the IASLC Meeting,
of oncogene addicted signaling pathways13. These Amsterdam, 2011. 13. West KA, et al. Rapid Akt
biopsy driven window of opportunity trials that activation by nicotine and a tobacco carcinogen
utilize surrogate biological markers and attempt to modulates the phenotype of normal human airway
correlate them with changes in metabolic imaging epithelial cells. J Clin Invest, 111(1):81-90, 2003.
will become increasingly important as we develop Keywords: chemoprevention, Lung cancer,
compounds that target speciÀc cell survival Biomarkers, retinoids
pathways, but require a more non-invasive approach.
References: 1. Amin AR, et al. Enhanced anti-tumor
activity by the combination of natural compounds,
(-)-epigallocatechin-3-gallate and luteolin: potential
role of p53. J Biol Chem, 285(45):34557-65, 2010. 2.
Papadimitrakopoulou VA, et al. Randomized trial of
13-cis retinoic acid compared with retinyl palmitate
with or without betacarotene in oral premalignancy.
Session M20: New Applications of NSCLC patients. PET imaging using [11C]docetaxel
Imaging Techniques and [11C]erlotinib provides information on the
biodistribution of these tracers in normal organs as
well as in tumor tissue. Tumor uptake of both tracers
is highly variable between patients and appears to
be associated with subsequent response to treatment
New Applications of Imaging Techniques Wednesday, 6 July 2011 with therapeutic doses of the corresponding drugs.
16:30-18:00 Importantly, PET microdosing can predict tumor
uptake of a therapeutic dose, which was shown for
M20.1 NEW TRACERS FOR RESPONSE [11C]docetaxel by performing a second [11C]docetaxel
EVALUATION IN NSCLC scan during a therapeutic infusion of docetaxel.
Astrid Van Der Veldt1, Mark Lubberink1, N. H. These Àndings indicate that PET microdosing may
Hendrikse1, Idris Bahce2, Albert D. Windhorst1, be of additional value in identifying NSCLC patients
Adriaan A. Lammertsma1, Egbert F. Smit2 most likely to beneÀt from a speciÀc drug. Next to
1
Nuclear Medicine And Pet Research, VU University quantiÀcation of drug uptake itself, more insight
Medical Center/Netherlands, 2Pulmonary Diseases, into factors that affect this uptake in tumor tissue is
VU University Medical Center/Netherlands warranted. [11C]erlotinib uptake is associated with
the mutational status of the epidermal growth factor
Abstract: In the treatment of non-small cell lung receptor (EGFR) in tumor tissue, whereas [11C]
cancer (NSCLC) patients, clinical failure of drugs docetaxel uptake is highly correlated with tumor
remains a major challenge, as patients are subjected perfusion. The latter indicates that administration of
to therapy-related toxicity without therapeutic drugs that change tumor perfusion may signiÀcantly
beneÀt. It is clear that there is a need for techniques affect delivery of speciÀc drugs such as docetaxel to
that can predict tumor response to speciÀc anticancer tumors, possibly affecting their efÀcacy. Indeed, this
drugs. Molecular imaging techniques, in particular hypothesis was conÀrmed by a rapid and signiÀcant
positron emission tomography (PET), hold promise decline in tumor perfusion and [11C]docetaxel uptake
for early prediction of tumor response in NSCLC in NSCLC tumors after a single dose of the anti-
patients. In clinical practice, PET is mainly used to angiogenic drug bevacizumab. In summary, these
image glucose metabolism and, more recently, DNA Àndings indicate that radiolabeled drugs may be
synthesis using 2v-[18F]Áuoro-2vdeoxy-D-glucose useful to predict response to anticancer drugs in
(FDG) and 3vdeoxy-3v-[18F]Áuorothymidine (FLT), individual NSCLC patients. Therefore, PET using
respectively. PET, however, can also be used to radiolabeled drugs may be an important technique
monitor pharmacokinetics and pharmacodynamics for optimizing drug scheduling in NSCLC patients
of any drug by radiolabeling with a short-lived and for personalized treatment planning.
positron emitting radionuclide such as carbon-11. Keywords: Non-small cell lung cancer, radiolabeled
As response to anticancer drugs is, at least in part, drugs, Positron Emission tomography
thought to depend on achieving sufÀcient drug
levels in tumor tissue, assessment of drug uptake
in tumors in vivo may be useful for understanding New Applications of Imaging Techniques Wednesday, 6 July 2011
treatment failure in patients. PET using microdoses 16:30-18:00
of radiolabeled anticancer drugs can quantify drug
uptake in tumors and may be valuable for predicting M20.2 FDG PET FOR RESPONSE
outcome prior to start of treatment and, as such, may MONITORING IN NSCLC
be an important tool for individualized treatment Wolfgang A. Weber
planning. Although the number of human studies is Department Of Nuclear Medicine,
still limited, there is an increasing interest in PET Universitätsklinikum Freiburg/Germany
studies using radiolabeled anticancer drugs, primary
because of the potential to predict rather than to Abstract: Measurements of tumor size on CT
monitor response to treatment. At our institute, currently represent the standard for assessing tumor
we have performed several clinical studies using response to therapy in patients with NSCLC. CT
radiolabeled drugs, including radiolabeled docetaxel has become an extremely fast and robust technique
([11C]docetaxel) and erlotinib ([11C]erlotinib), in that provides high resolution images of the primary
tumor, lymph node and distant metastases. Criteria been published 8 . Clinical results of FDG-PET
for assessing response on CT have been standardized for monitoring tumor response In the neoadjuvant
by the response evaluation criteria in solid tumors setting, several studies have correlated Àndings on
(RECIST). While clinical experience and meta- FDG-PET with histopathologic tumor response 9-14.
analyses of large clinical trials demonstrate that While these studies indicate that focal FDG uptake
tumor response according to RECIST is correlated correlates with residual viable tumor tissue on
with favorable outcome, the correlation is far from histopathology, data on the sensitivity and speciÀcity
perfect and several studies did not Ànd a close of FDG-PET in this setting vary widely. To a large
relationship between tumor shrinkage and patient extent this is explained by different deÀnition
outcome 1. CT cannot differentiate between tumor of &ldquoresidual viable tumor tissue&rdquo
and surrounding atelectasis, which can make and &ldquohistopathologic response&rdquo. A
size measurements inaccurate. The interobserver more meaningful comparison can be made for the
variability of assessment of tumor response in correlation between tumor response assessment
NSCLC by CT is signiÀcant 2. Furthermore, it on PET and survival. Here, almost all studies have
is generally not possible to differentiate viable reported a signiÀcant correlation between changes
tumor tissue from treatment induced Àbrosis. in metabolic activity and patient survival as recently
Finally, some target therapies appear to improve reviewed by Hicks 15. FDG-PET for monitoring of
survival without causing a rapid decrease in tumor palliative chemotherapy in advanced NSCLC has
size. Methodological considerations for response also been evaluated in three single center studies
16-18
assessment by FDG-PET A series of studies has . A signiÀcant correlation between metabolic
evaluated the use of PET with the glucose analogue changes after one or two cycles of chemotherapy and
Áuorodeoxyglucose (FDG-PET) for monitoring patient survival has been observed. Furthermore, the
chemo- and chemoradiotherapy in NSCLC. For studies indicate a gradual decrease in tumor FDG
staging of malignant tumors FDG-PET scans are uptake during chemotherapy 17. As a consequence
assessed visually, and focally increased FDG-uptake optimal threshold values for differentiation between
not explained by the normal biodistribution of responding and nonresponding tumors increase
FDG is considered to be suspicious for metastatic with time after start of chemotherapy. Preclinical
disease. In a similar way PET scans may also be studies19 and four clinical trials 20-23 indicate that
read after completion of chemo- or radiotherapy. tumors responding to EGFR kinase inhibitors
FDG uptake should have normalized at this time also show rapid changes in FDG uptake. Early
and focal FDG-uptake generally indicates residual identiÀcation of patients with nonresponding tumors
viable tumor tissue. Following radiotherapy, provides the opportunity to change treatment to
however, care must be taken not to confuse radiation second line regimens and may reduce the side effects
induced inÁammation with residual tumor tissue. and costs of ineffective therapies. Conclusions
This can usually be achieved by evaluating not only FDG-PET allows signiÀcantly more accurate
the intensity, but also the pattern of FDG uptake. assessment of tumor viability than CT. Furthermore,
Radiation induced inÁammation involves not only FDG-PET has been found to provide prognostic
the tumor tissue, but also the normal tissues in the information independent from tumor response on
radiation treatment Àeld 3. Quantitative assessment CT. Nevertheless, larger conÀrmatory studies in a
of tumor metabolism is generally necessary, when multi-center setting are needed in order to deÀne
FDG-PET scans are performed during treatment more exactly the prognostic value of FDG-PET in
in order to predict subsequent tumor response. At speciÀc clinical situations. Following evaluation
this time the metabolic activity of the tumor tissue in multicenter trials it is expected that monitoring
has decreased in responders, but generally there tumor response in non-small cell lung cancer
will be still considerable residual FDG-uptake. will be based on CT and PET as these modalities
A series of studies have now indicated that tumor are likely to provide complementary prognostic
FDG uptake can be measured with high test-retest information. Furthermore, in patients with locally
reproducibility 4-7. However, it is important to advanced disease, CT will provide exact anatomical
emphasize that quantitative analysis of FDG-PET localization of lesions on PET, which is required for
scans is only feasible when images are acquired determining tumor respectability after preoperative
according to a standardized protocol. International therapy. References 1. Birchard KR, et al: Cancer
guidelines for quantitative PET studies have recently 115:581-6, 200 2. Ford R, et al: Eur J Cancer 45:268-
74, 2009 3. Hicks RJ, et al: Int J Radiat Oncol Biol for enhancing glucose inÁux into cells. The glucose
Phys 60:412-8, 2004 4. Minn H, et al: Radiology transporters GLUT-1 and GLUT-3, subtypes with
196:167-73, 1995 5. Weber WA, et al: J Nucl Med a relatively high afÀnity for glucose, belong to the
40:1771-7, 1999 6. Nahmias C, et al: J Nucl Med sugar trans-porter family, which currently includes
49:1804-8, 2008 7. Krak NC, et al: Eur J Nucl 133 individual members. Increased concentrations
Med 32:294-301, 2005 8. Boellaard R, et al: Eur of the glucose phosphorylation enzyme,
J Nucl Med 37:181-200, 2010 9. Akhurst T, et al: hexokinase, with decreased rates of glucose-6-
Ann Thorac Surg 73:259-64, 2002 10. Ryu JS, et phophatase are considered to accelerate glucose
al: Lung Cancer 35:179-87., 2002 11. Port JL, et al: phosphorylation, which results in enhanced FDG
Ann Thorac Surg 77:254-9, 2004 12. Cerfolio RJ, et intracellular trapping. Upregulation of hexokinase
al: Ann Thorac Surg 78:1903-9, 2004 13. Hellwig and glucose transporters, especially GLUT-1, and
D, et al: J Thorac Cardiovasc Surg 128:892-9, 2004 downregulation of glucose-6-phosphatase are
14. Poettgen C, et al: Oncology 73:316-23, 2007 15. frequently associated with malignant transformation.
Hicks RJ: J Nucl Med 50 Suppl 1:31S-42S, 2009 16. Glucose transport activity can be regulated by
de Geus-Oei LF, et al: J Nucl Med 48:1592-8, 2007 alterations in the expression of GLUT transporters
17. Nahmias C, et al: J Nucl Med 48:744-51, 2007 and by post-translational mechanisms, including
18. Weber WA, et al: J Clin Oncol 21:2651-7., 2003 transporter translocation to plasma membranes.
19. Su H, et al: Clin Cancer Res 12:5659-67, 2006 It has been shown that squamous cell carcinomas
20. Aukema TS, et al: J Nucl Med 51:1344-8, 2010 demonstrate higher GLUT-1 expression, relative to
21. Mileshkin L, et al: Clin Cancer Res, epub ahead adenocarcinomas. One of the factors responsible
of print, 2011 22. Sunaga N, et al: Lung Cancer, for the regulation of GLUT1 in malignant cells
59:203-210, 2008 23. Zander T, et al: J Clin Oncol, is hypoxia-inducible-factor-1a (HIF-1a), which
epub ahead of print 2011 is upregulated under hypoxic conditions. The
Keywords: PET, FDG, NSCLC, Response increased level of lactate and acid produced by
the enhanced glycolysis will decrease intracellular
pH, which is potentially cytotoxic. To counteract
New Applications of Imaging Techniques Wednesday, 6 July 2011 this cytoplasmic acidiÀcation, cells can upregulate
16:30-18:00 monocarboxylate transporter 4 (MCT4), which is
composed of a catalytic unit (MCT) and an accessory
M20.3 BIOLOGICAL CORRELATES OF subunit (CD147) and transports lactate/H+ out of
FDG UPTAKE the cell. In squamous cell carcinomas, GLUT-1
Lioe-Fee De Geus-Oei, W.J.G. Oyen and MCT4 expression increase with increasing
Department Of Nuclear Medicine, Radboud distance from the vasculature, whereas upregulation
University Nijmegen Medical Centre/Netherlands of MCT4 is found at closer distance from vessels
in adenocarcinomas. Adenocarcinomas rely mainly
Abstract: The great advantage of on aerobic glycolysis for ATP production, whereas
18
F-Áuorodeoxyglucose positron emission the behavior of squamous cell carcinomas is more
tomography (FDG-PET) is that this technique physiologically, i.e. mitochondrial oxidation with
cannot only visualize but can also quantify anaerobic glycolysis where appropriate. High
glucose metabolism and thus is able to distinguish GLUT-1 plus high MCT4 expression determined
metabolically highly active from less active an aggressive tumor behavior in adenocarcinomas.
tumor tissues. It therefore offers an opportunity Moreover, the rate of FDG uptake in the primary
for noninvasive, in vivo tumor characterization. site of NSCLC has been correlated with tumor
As many factors can inÁuence the extent of FDG doubling time and proliferation rates which, in turn,
uptake, the underlying mechanisms for FDG are known to correlate with tumor aggressiveness.
accumulation in tumors, are still a matter of debate. Furthermore, apoptosis plays a central role in the
A variety of mechanisms have been proposed elimination of (the precursors of) tumor cells.
for accelerated glucose use in growing tumors Therapy resistance can be attributed, at least in
and in transformed and malignant cells: passive part, to a disabled apoptotic program. Furthermore,
diffusion, Na+-dependent glucose transport and via it was demonstrated that primary tumors showing
facilitative glucose transporters (GLUT). The latter high FDG uptake have the potential to be resistant
is considered to be the most important mechanism to therapy and to metastasize. Strong expression
of the cysteine protease caspase-3, which is a agents. These agents poses new demands on
key enzyme in apoptotic cell death, might be a imaging modalities, for which FDG-PET is ideally
signiÀcant factor to predict poor prognosis. Better suited, since metabolic changes precede changes in
understanding of a possible relationship between tumor volume. Previous studies have also shown
FDG uptake and apoptosis may provide insights into that EGFR mutations are predominantly found
sensitivity or resistance of tumor cells. Furthermore, in females, in never-smokers, in patients with
tumors that grow too rapidly or have a deÀcient adenocarcinoma, and in Asians. Altogether a very
vascular system are characterized by the formation new and interesting topic to be studied.
of necrosis. Necrosis reÁects cell death caused by Keywords: EGFR, FDG-PET, GLUT1, hexokinase
hypoxia. Hypoxia results in enhanced anaerobic
glycolysis and hence in increased FDG uptake.
Finally, the presence of inÁammatory cells, might New Applications of Imaging Techniques Wednesday, 6 July 2011
be confounding, since inÁammatory cells may have 16:30-18:00
a major impact on FDG uptake. At present it is still
not fully elucidated which of these factors contribute M20.4 DIFFERENTIATION OF
to the variable levels of FDG uptake in NSCLC or MALIGNANT FROM BENIGN LUNG
head- and neck cancers. Results from studies on LESIONS
other tumor types cannot be extrapolated to NSCLC Kyung Soo Lee
or head- and neck cancer, as different tumors have Radiology, Samsung Medical Center, Sungkyunkwan
different glucose-regulating mechanisms and enzyme University School Of Medicine/Korea
expression patterns in association with various
oncogenic alterations. FDG uptake also seems to Abstract: Morphologic Evaluation Small sized,
be a predictor of the presence of epidermal growth smooth, well-deÀned margins are suggestive of,
factor receptor (EGFR) mutations. The problem of but not diagnostic for, benignity and a lobulated
detecting in vivo EGFR with a noninvasive approach contour or an irregular or spiculated margin with
is one of the most challenging in the selection of distortion of adjacent vessels is typically associated
patients to receive EGFR inhibitors. It has been with malignancy. Diffuse, laminated, central nodular,
reported that EGFR mutation could predict favorable and popcorn-like calciÀcations within nodules
outcomes in tyrosine kinase inhibitors (TKI)-treated suggest benignity. On the other hand, eccentric
patients. This Ànding might justify the conÀrmation or stippled calciÀcations have been described in
of EGFR genotype prior to TKI treatment; however, malignant nodules. Fat or calciÀcation may be
in clinical practice, it is often difÀcult to obtain an observed in up to 50% of pulmonary hamartoma.
amount of tumor tissue sufÀcient for the genetic test In a multivariate analysis study, a lobulated
in patients with advanced cancer stages, for which margin, a spiculated margin, and the absence of a
FDG-PET could provide a solution. In previous satellite nodule are independently associated with a
studies it is suggested that low standardized uptake diagnosis of a malignant nodule with a higher odds
values (SUVs) in primary tumors harbor a higher ratio. The results of the Early Lung cancer Action
incidence of EGFR mutations, when compared Project (ELCAP) suggested that nodules with pure
with those with high SUVs. However, there are rare (nonsolid) or mixed (partially solid) ground-glass
molecular data to explain the association between opacity at thin-section CT are more likely to be
SUV and EGFR mutation. Although several studies malignant than are those with solid opacity. Mixed
have suggested that glucose uptake is related with ground-glass opacity, a subtype with ground-glass
EGFR expression its association with the EGFR opacity in the periphery and a high-attenuation zone
pathway in lung cancer is unknown. Studying the in the center, was seen much more often in malignant
association between FDG uptake and the presence lesion (41%) than in benign lesions (7%).
of EGFR mutations can be relevant in light of Growth Rate Assessment
treatment response monitoring. In contrast to It is difÀcult to reliably detect growth in small (<
traditional anticancer agents, the effects of tyrosine 1 cm) nodules. To overcome this limitation, it has
kinase inhibitors are cytostatic rather than cytotoxic. been proposed that the growth rate of small nodules
Therefore, determining treatment response based be assessed using serial volume measurements
on anatomical criteria alone (RECIST) probably rather than diameter. Volumetry for ground-glass
underestimates the therapeutic effect of these opacity or semisolid (solid nodule containing
ground-glass opacity component) nodules is more primary pulmonary malignancies, such as carcinoids,
difÀcult than that of purely solid nodules, because bronchioloalveolar carcinomas, adenocarcinoma
the nodules have lower nodule-to-lung parenchyma with predominantly bronchioloalveolar carcinoma
contrast ratio compared to that of solid nodules. component, and malignant SPNs of < 10 mm in
Hemodynamic Characteristics by Helical Dynamic diameter. FDG PET yields false-negative results
CT The evaluation of tumor vascularity with HDCT in about 5% of all T1 lung cancers, but in only 3%
has proved to be useful in the differentiation of of T1 lung cancers greater than 5 mm in diameter.
malignant and benign nodules. Various threshold The long-term survival of patients with a negative
attenuation values have been reported to be useful PET scan for lung cancer suggests that these tumors
for distinguishing malignant nodules from benign behave indolently. Diffusion-Weighted MR Imaging
nodules by HDCT. The threshold attenuation (DWI) Diffusion-weighted MR imaging is based
values refer to the cut-off HounsÀeld Units on single-shot echo-planar imaging. It allows to
(HUs) of increased attenuation following contrast measure microscopic water mobility (Brownian
injection for differentiating malignant nodules from motion). Decreased diffusion is seen in pathologic
benign nodules. Evaluation of SPNs by analyzing processes including malignant tumor (increased
combined wash-in and wash-out characteristics at cellularity, Àbrosis, shape of intercellular spaces,
dynamic CT allows more precise evaluations of etc). Thus, it provides functional information.
nodule hemodynamics. In addition, the efÀcacy By applying certain cut-off value of apparent
of tissue characterization has improved, and now diffusion coefÀcient (ADC), benign lesions can be
sensitivities and speciÀcities of more than 90% are differentiated from malignant ones. The ADC values
achieved using evaluations of wash-out patterns are smaller in small cell carcinoma than in non-small
in the delayed dynamic phase. Application of the cell carcinoma. Among non-small cell carcinomas,
dual energy (DE) technique provides a virtual poorly-differentiated adenocarcinoma or squamous
nonenhanced and an iodine-enhanced image from cell carcinoma has less ADC value than well-
a single scanning after iodine contrast material differentiated adenocarcinoma or adenocarcinoma
injection by material differentiation of iodine. With in situ. Characterization of Sub-centimeter Nodules
this technique, we are able to detect calciÀcation on Since the introduction of helical and multi-
a virtual nonenhanced image and directly measure detector row CT, the detection of small pulmonary
the iodine component on an iodine-enhanced nodules < 10 mm has become routine. However,
image. Thus, the technique prevents additional characterization of nodule < 10 mm in diameter is
nonenhanced scanning and the patient’s radiation a challenge to radiologists. Although nodules < 10
exposure can be reduced. Metabolic Characteristics mm in diameter have low chance of being malignant,
by 18F-Áuorodeoxyglucose (FDG) Positron the reported percentage of malignancy varies from
Emission Tomography (PET) Malignant cells have the series. Currently, serial volume measurements on
upregulated metabolisms and proliferate rapidly. nodules are regarded as most reliable technique for
Comparable enhancements of glucose and FDG small nodule characterization. Helical dynamic CT is
uptake in malignant cells have permitted malignancy another reliable modality for nodule characterization.
detected by PET, which is considered an accurate, However, thin-section (1.0-mm section thickness
noninvasive diagnostic test, with a sensitivity of or less) images with large coverage along z-axis
88-96% and a speciÀcity of 70-90% for malignant are required especially for nodule characterization
nodules. Integrated PET/CT provides more located in the lower lung zone, where respiratory
anatomic detail, and improved non-small cell lung excursion of the lungs is great. PET or PET/CT is
cancer staging accuracy versus PET alone or CT suboptimal for the characterization of sub-centimeter
alone. SPNs with increased FDG uptake should be nodules, because spatial resolution (currently 7
considered malignant, although false-positive results mm in maximum) is insufÀcient for detection of
can be obtained in patients with infectious and malignant sub-centimeter nodules. Therefore, it is
inÁammatory processes such as active tuberculosis, necessary to provide practical guidelines for the
histoplasmosis, and rheumatoid nodules. The high follow-up and management of indeterminate small
speciÀcity of FDG PET for the diagnosis of benign pulmonary nodules. Very small (3-5 mm) well-
lesions has important clinical utility. Lesions deÀned nodules (sometimes called ‘’ditzels’’) has
with low FDG uptake may be considered benign. been more encountered with the advent of multi-
However, false negative results may be seen in detector row CT. Treatment decisions regarding these
nodules vary depending on the patient’s age, risk and type B3 have common and recurrent copy
of malignancy, risk of developing granulomatous number losses and gains in several areas of the
disease. Regarding radiologists’ interpretation of genome. Gene expression arrays cluster thymomas
and management decision for these nodules, most according to WHO classiÀcation. A major limitation
radiologists recommended short-term follow-up, in these studies is the necessity to select areas in
with less aggressive recommendations in cases the tumor that have a signiÀcant epithelial tumoral
with a lower likelihood of malignancy and more component, and this leaves out a large proportion of
aggressive recommendations in cases with a higher thymomas that have large lymphocytic inÀltration
likelihood of malignancy. (WHO B1 and B2). We have recently started a
Keywords: Solitary pulmonary nodule, large effort of RNA sequencing, exome sequencing
Characterization, CT, PET, MRI and whole genome sequencing, and some of those
results will be presented at this meeting. Functional
studies in thymomas are severely hampered by the
Session M21: Thymoma very limited number of cell lines and the absence
of speciÀc tumor models for the disease. Efforts
Wednesday, 6 July 2011 should be made to develop tumor models that allow
investigation of this tumor in more detail in the
future.
Thymoma Wednesday, 6 July 2011 16:30-18:00 Keywords: Thymoma, biology, mediastinum,
genome
M21.1 BIOLOGY
Giuseppe Giaccone, Iacopo Petrini, Yisong Wang
Medical Oncology Branch, National Cancer Thymoma Wednesday, 6 July 2011 16:30-18:00
Institute/United States Of America
M21.3 STAGING SYSTEM
Abstract: The biology of thymic malignancies Kazuya Kondo
is poorly understood. Studies investigating one Department Of Oncological Medical Services,
or a small number of genes, that are involved Institute Of Health Biosciences, The University Of
in cancer development of other tumors, are Tokushima Graduate School/Japan
available, to date. These studies have established
EGFR and c-Kit mutations in a small subset of Abstract: The clinical staging system for thymoma
tumors. Clinical observations have conÀrmed that was Àrst introduced by Bergh and associates in
activating mutations in these genes are rare and 1978, later modiÀed by Wilkins and Castleman,
this is responsible for the lack of activity of EGFR and conÀrmed by Masaoka and associates in 1981.
TKIs such as geÀtinib and c-Kit inhibitors such as The Masaoka clinical staging classiÀcation is the
imatinib. Mutations in p53 and methylation of p16 most widely accepted nowadays. A modiÀcation
have also been described in a varying percentage of this classiÀcation was suggested by Koga et al
of tumors, as well as upregulation of anti-apoptotic in 1994. In France, multiple centers have adopted
genes. However, all these descriptive studies have the Groupe dEtudes des Tumeurs Thymiques
in common the relatively small number of samples (GETT) staging system, as described by the French
that were investigated and the limited insight on the Study Group on Thymic Tumours in 1991. In this
biology that they provide. Genome-wide studies have system, the predominant feature is the extent of
also been performed. Genetic alterations involving surgical resection. The clinical staging of patients
changes of large parts of chromosome 1 (1q copy should be determined before treatment to select the
number gains) and deletions of chromosome 6 have optimal approach. The TNM system classiÀcation
been established by traditional CGH over a decade and clinical staging system for thymic epithelial
ago. Use of array CGH has allowed us to narrow tumors have not been established yet. Until now,
down areas of the genome that may be important four TNM staging systems have been proposed:
for prognosis and potentially be involved in the Yamakawa and Masaoka in 1991 (Y-M system),
progression of the disease. Overall type A thymomas Tsuchiya et al. in National Cancer Center Hospital
according to the WHO classiÀcation, have very few of Japan in 1994 (NCCHJ system), the WHO
changes in copy number, whereas thymic carcinoma Consensus Committee in 2004 (WHO system) and
Bedini et al. in National Cancer Institute of Italy in between N factor and clinical staging system is
2005 (NCII system). The Masaoka classiÀcation is different. It is very important to determine how T, N
now the most widely accepted and is an excellent or M factors inÁuence prognosis of the patients with
predictor of the prognosis of thymoma. However, thymic epithelial tumors to establish a suitable TNM
several articles have pointed out problems and have system classiÀcation. The International Thymic
suggested that an update of the system is desirable. Malignancy Interest Group (ITMIG) is currently
These TNM systems for thymic epithelial tumors engaged in the development of a validated formal
revised Masaoka staging system. 1) The Masaoka stage classiÀcation system for thymic malignancies,
clinical staging system does not provide appreciable together with the IASLC and under the auspices
prognostic separation between stage I and II. of the UICC and AJCC in preparation for the next
NCCHJ system and NCII system combined stage I edition of the international tumor staging manuals
and stage II in the Masaoka system, reclassiÀed as in 2017. In order to collect reliable and large-
stage I. 2) Some deÀnitions in the Masaoka system scale clinicopathological and prognostic data of
are not clinically applicable because surgical or thymic epithelial tumors, ITMIG has chosen to
pathological assessment is required. In particular, the use the Masaoka-Koga stage classiÀcation system,
deÀnition of stage II is unclear. Some pathologists consistent with what has been adopted most broadly.
propose that microscopic invasion into the capsule In the Masaoka-Koga stage system, many nuances
in stage II should be replaced by microscopic have never been clearly deÀned and are often
transcapsular invasion. NCCHJ and WHO systems interpreted differently. The deÀnitions adopted
deÀned T2 thymoma as tumor invades pericapsular by ITMIG deÀned precisely what constituted
connective tissue. 3) As stage III thymoma is mediastinal pleural or pericardial involvement, and
highly heterogenous in terms of involved organs, required that macroscopic suspicion of involvement
classiÀcation should divide the subgroups according should be conÀrmed microscopically for pathologic
to the prognosis. Some studies reported that stage. ITMIG hopes that this standard will be
involvement of the great vessels is an independent adopted worldwide, as it will enhance collaboration
prognostic factor in patients with stage III thymoma. and deÀnition of a better classiÀcation system
Four TNM systems did not divide stage III in in the future. ITMIG DeÀnition of Details of the
Masaoka system into subclassiÀcations. Large-scale Masaoka-Koga Staging System I : Grossly and
clinicopathological and prognostic data of thymic microscopically completely encapsulated tumor II a:
epithelial tumors in stage III subgroups such as Microscopic transcapsular invasion IIb: Macroscopic
invasion to the pericardium, great vessels, lung, invasion into thymic or surrounding fatty tissue,
sternum, phrenic nerve, etc, are essential to classify or grossly adherent to but not breaking through
suitable groups. 4) Most of the reports about thymic mediastinal pleura or pericardium III: Macroscopic
epithelial tumors demonstrated that the completeness invasion into neighboring organ (i.e. pericardium,
of tumor resection is the most important predictor great vessel or lung) IV a: Pleural or pericardial
of survival not only in thymoma but also in thymic metastases IVb: Lymphogenous or hematogenous
carcinoma, although a value of so-called debulking metastasis
procedures is controversial. NCII system proposed Keywords: Thymoma, clinical staging system,
that the residual tumor is classiÀed by use of the R prognostic factors, Thymic Carcinoma
category. Although the clinical staging of patients
should be determined before treatment to select the
optimal approach, R category may be useful for Thymoma Wednesday, 6 July 2011 16:30-18:00
predicting the prognosis after surgery. 5) Although
the Masaoka clinical stage is an excellent predictor M21.4 CHEMOTHERAPY FOR THYMIC
of the prognosis of thymoma, it is not well suited MALIGNANCIES
for staging thymic carcinomas. Although the Patrick J. Loehrer Sr.
deÀnition of T, N and M factors is similar among Department Of Medicine, Indiana University Melvin
four TNM systems (N0: no lymph node metastasis And Bren Simon Cancer Center/United States Of
N1: metastasis to anterior mediastinal lymph nodes, America
N2: metastasis to intrathoracic lymph nodes except
anterior mediastinal lymph nodes, N3: metastasis Abstract: Thymomas and thymic carcinomas
to extrathoracic lymph nodes), the relationship are rare epithelial tumors, but represent the most
common tumors of the anterior mediastinum. Finally, another trial conducted by ECOG evaluated
Prospective studies on the treatment of thymic carboplatin plus paclitaxel in patients with advanced
epithelial tumors are limited due to the very low thymoma and thymic carcinoma resulted in an
incidence of these tumors. Up to one third of overall response rate of 34.8% and 28.6% in patients
patients with thymoma and the majority of patients with thymoma and thymic carcinoma respectively.
with thymic carcinoma will have locally advanced The median overall survival was 84.1 months for
or metastatic disease at presentation for which patients with advanced thymoma where as it was
chemotherapy should be considered a component of only 15.4 months in thymic carcinoma patients. In
the therapeutic armamentarium. Most combination sum, each of these non-anthracycline containing
regimens have been platin-based with cisplatin, regimens produced response rates which appear
doxorubicin and cyclophosphamide (PAC) with or inferior to previous reports with anthracycline–based
without other agents, cisplatin plus etoposide (PE), regimens. Collectively, trials conducted by the
or carboplatin plus paclitaxel as commonly used Eastern Cooperative Oncology Group and others
regimens. Anthracycline-based regimens are the have suggested that combinations which contain
standard of care based on various phase II clinical anthracyclines have produced higher objective
trials. Fornasiero and colleagues reported on 37 response rates (70-90%). The most active single
patients with stage III and IV thymoma who were agents in advanced thymic tumors appear to be
treated with cisplatin, doxorubicin, vincristine cisplatin, corticosteroids, doxorubicin, and alkylating
and cyclophosphamide (ADOC) combination agents. Clinical trials agents remains limited, but
chemotherapy. The overall response rate was 91.8% case reports and small series have suggested activity
(with 43% CR) but a median survival time of only with a broad range of agents, including: ifosfamide,
15 months. An intergroup trial in 29 thymoma and octreotide (with or w/o prednisone), pemetrexed,
one thymic carcinoma patients with metastatic or gemcitabine, soraÀnib(thymic carcinoma),
progressive locally advanced disease treated with Áuoropyrimidines and most recently, belinostat.
cisplatin, doxorubicin and cyclophosphamide(PAC) Trials with more targeted therapies with drugs
demonstrated an overall 50% response rate (10% such as geÀtinib, erlotinib, bevacizumab, imatinib
CR) and a median survival of 37.7 months (Loehrer have not demonstrated major clinical activity. This
et al). In another phase II study of multidisciplinary presentation will provide an overview of the past
approach with induction chemotherapy, followed clinical trials and discuss issues relevant to future
by surgical resection, radiation therapy and clinical and translational research.
consolidation chemotherapy for unresectable Keywords: Thymic Carcinoma, Chemotherapy,
thymomas, Kim and colleagues reported on 22 Thymoma
patients receiving induction chemotherapy with
PAC plus prednisone for three cycles. Induction
chemotherapy produced 14% complete responses
and 63% partial responses. Because thymic Session M23: Organisation of
cancers often occur in elderly patients, the use of Supportive and Palliative Care to Lung
anthracyclines may be limited in this population, Cancer
based on cardiac history and a possible need to use
radiotherapy. Therefore non-anthracycline regimens
may be preferable for this group of patients. The Wednesday, 6 July 2011
European Organization for Research and Treatment
of Cancer (EORTC) conducted a trial with 16 Organisation of Supportive and Palliative Care to Lung Cancer
patients with advanced or recurrent thymoma were Wednesday, 6 July 2011 16:30-18:00
treated with cisplatin and etoposide (PE) with
an overall RR of 56%. The Eastern Cooperative M23.1 NURSING SUPPORT
Oncology Group (ECOG), twenty patients with Liz Darlison
advanced thymoma and eight patients with thymic Mesothelioma UK, University Hospitals Of Leicester
carcinoma were treated with etoposide, ifosfamide NHS Trust/United Kingdom
and cisplatin (VIP). A RR of 35% and 25% (all
partial responses) was reported in patients with Abstract: This abstract highlights the broad
thymoma and thymic carcinoma respectively. range of Cancer Nurse Specialists (CNS’s)
currently practicing in England. Detail about based specialist palliative care and District Nurses
the role and function of CNS’s working in lung was one issue raised by the benchmarking exercise
cancer is explored and the beneÀts of the role are and following discussion this was developed into
demonstrated through an End of Life Care Project a project to be addressed by the Lung Cancer CNS
carried out by the Lung Cancer CNS team working team. The UHL Lung Cancer CNS’s team went on to
at the University Hospitals of Leicester NHS Trust complete a year long project looking at and reÀning
(UHL). A census of the English cancer specialist referral patterns to Community Palliative Care and
nurse workforce carried out in 20101 demonstrated District Nurses resulting in redesigned services that
there are nearly 2800 tumour speciÀc (breast, lung, avoid inappropriate referrals and maximise current
Urology etc) cancer nurse specialists in England. resources. References
The census describes 284 nurses as working in lung 1. National Cancer Action Team 2010 .Quality in
cancer which mirrors the National Lung Cancer Nursing. Clinical Nurse Specialists in Cancer Care;
Forum for Nurses2 membership of 280 members. The Provision, Proportion and Performance. A census
National Cancer Action Team describes the high- of the cancer specialist nurse workforce in England
level activities of Cancer CNS’s separating them into 2010.
four main functions3. 2. National Cancer Action Team 2010. Excellence in
1. Using and applying technical knowledge of cancer Cancer Care: The Contribution of the Clinical Nurse
and treatment to oversee and coordinate services, Specialist
personalise ‘the cancer pathway’ for individual 3. Department of Health, 2010. National Cancer
patients and to meet the complex information and Patient Experience Survey Programme – 2010 :
support needs of patients and their families National Survey Report.
2. Acting as the key accessible professional for the 4. Department of Health, 2008. End of Life Care
multidisciplinary team, undertaking proactive case Strategy.
management and using clinical acumen to reduce the Keyword: nursing
risk to patients from disease or treatments
3. Using empathy, knowledge and experience to
assess and alleviate the psychosocial suffering Organisation of Supportive and Palliative Care to Lung Cancer
of cancer including referring to other agencies or Wednesday, 6 July 2011 16:30-18:00
disciplines as appropriate
4. Using technical knowledge and insight from M23.2 HOSPITAL-BASED SUPPORT
patient experience to lead service redesign in order TEAMS
to implement improvements and make services Paul Glare
responsive to patient need Much has been written Medicine, Memorial Sloan-Kettering Cancer Center/
about the beneÀt to patients and carers of having United States Of America
access to a clinical nurse specialist, most recently in
the 2010 Cancer Patient Experience Survey Report4. Abstract: Lung cancer patients have many more
SpeciÀc questions regarding access to a CNS were needs than just treating their disease. They may have
included in the survey for the Àrst time and results pain or other physical symptoms such breathlessness.
clearly showed how much patients value access to a They may be anxious or depressed. If they have
CNS with responses reporting a better experience in advanced, incurable disease they will need to make
numerous areas. In 2008 the Department of Health an advanced care plan. Their families need support.
published the End of Life Care Strategy5 and in order To address all of these needs, comprehensive care
to embrace the actions and recommendations set out of lung cancer patients requires the pulmonologist,
in the strategy the UHL carried out a benchmarking surgeon and/or oncologist to develop and co-
exercise of current end of life care practice within the ordinate a care plan delivered by interdisciplinary
hospital. The benchmarking exercise which involved group. This may include referral to a palliative care
9 clinical directorates and palliative care services (PC) specialist. In 2011 most lung cancer care is
highlighted several examples of good practice ambulatory, and early involvement of specialist PC
however there were also inconsistencies across UHL in the outpatient setting has been shown to improve
suggesting uncertainty with some aspects of end of symptom control, quality of life and other outcomes.
life care. Inconsistencies and uncertainty about how With a few exceptions, most hospitalizations
best to communicate with and refer to primary care of patients with advanced lung cancer is for
complications of progressive disease or debilitation, education, pain management, psychosocial support,

or toxicity of palliative chemotherapy. These request consultation, other symptom management,
hospitalizations are typically short and focused on advanced care planning, (clarify code status identify
acute medical management. Most large US hospitals health care proxy, arrange family conference) and
(>50 beds) now have a PC program/support team, spiritual support. Further clinical investigations
but their role is not as well established as in the were occasionally recommended. In approximately
clinic. These programs may be effective, but the data one-third of consults, the patient’s/family’s PC
are difÀcult to synthesize because of variations in needs were deemed to be “simple”, i.e. manageable
the structure, role, scope and degree of integration. by the oncologists or hospitalists leading the GI
Usual “consult etiquette” leaves the decision to inpatient team, with only curbside advice from the
call a PC consult as the prerogative of the treating PC specialist. These oncologists and hospitalists
physician. However, the number of patients with PC develop substantial skills in handling simple PC
needs is much higher than the number of consults issues in hospitalized patients. There are various
called. A German study of hospital physicians found other short and long term outcomes of this project,
18% lung cancer patients had PC needs. A snapshot which are currently being analyzed. Patients
survey by nurses of PC needs in inpatients at were also asked to rate their symptoms using
Memorial Hospital (MH) revealed 58% patients with the condensed Memorial Symptom Assessment
metastatic lung cancer had poor performance status, Schedule at the time of screening and 4 days later,
life threatening complications, symptom control and to complete a simple satisfaction survey on
problems or end of life issues, but only 11% got PC their care, and the impact of the PPC consult; we
consults. The same applies to GI Oncology patients, are looking at the changes in symptoms scores
and a quality improvement project to improve between Day 0 and Day 4, and patient satisfaction
access to specialist PC for hospitalized GI Oncology with the PPC consult. We are also evaluating if PC
patients at MH was undertaken. The results should consultation impacted on length of stay, code status,
be directly applicable to hospitalized lung cancer ICU admissions, hospice enrollment, readmission,
patients. During this past winter (11/1/10-1/28/11), aggressiveness of treatment in the Ànal month of
the National Comprehensive Cancer Network’s life, or survival. This data is still being collated and
PC Guideline was implemented to screen 254 analyzed. In conclusion, hospitalized lung cancer
consecutive GI Oncology patients admitted to MH. patients have a high prevalence of PC needs. Many
Floor nurses did the screening and most rated it if not most hospitals now have palliative programs,
as simple, easy, quick (<5 minutes/patient) and and specialist advice is able to assist with these
helpful, and not a burden when added to their other patients’ complex needs. Given that the need is far
duties. A subset of 104 patients was also evaluated in excess of the available resources of specialist PC
by the Guideline’s referral criteria; 66 (58%) met services, the next challenge is to determine which
the criteria and a PC consult was requested if the patients should be seen by those services during
oncologist concurred. 38 consults were able be done. their hospitalization, what the services offer, and
28 consults were missed for various reasons (e.g. whether it adds value to the care already being
patient already seen emergently before screening; given. These issues will be discussed during the
patient not on Áoor during consult rounds; oncologist presentation. References 1. Temel JS, Greer JA,
pushback). More than 1/3 of patients got a consult. Muzikansky A, et al. Early PCfor patients with
While there was no exact target, but we did expect metastatic non-small-cell lung cancer. N Engl J
to do consultations in 50-75% but the number done Med 2010;363:733-42. 2. Virik K, Glare P. ProÀle
was still much higher than the usual level (10%). and evaluation of a palliative medicine consultation
The actual content of the consults was evaluated. service within a tertiary teaching hospital in Sydney,
The median number of PC problems per case was Australia. J Pain Symptom Manage 2002;23:17-
three. They included pain, non-pain symptoms, 25. 3. Vernooij-Dassen MJ, Groot MM, van den
psychosocial or spiritual problems, patient/family Berg J, et al. Consultation in palliative care: the
having trouble accepting options are limited, and relevance of clariÀcation of problems. Eur J Cancer
assisting with dispo planning. Recommendations 2007;43:316-22. 4. Casarett D, Pickard A, Bailey
made by the PC physician at consultation were FA, et al. Do palliative consultations improve patient
(in descending order of frequency): disposition outcomes? J Am Geriatr Soc 2008;56:593-9. 6.
planning/facilitate hospice transition, patient Glare P, Plakovic K, Griffo Y, et al. Fast-tracking
aplliative care consults: pilot implementation of was 86%. Median PFS was 13.9 and 10.5 months
National Comprehensive Cancer Network (NCCN) in the Àrst and second line settings respectively.
PC screening and referral guideline (Abstract for Common toxicities included diarrhea, rash and
Electronic Publication only: ID e19636). In: ASCO nail changes. Following on from these results, two
Annual Meeting. Chicago; 2011. phase 3 studies are underway evaluating afatinib
Keywords: palliative care, consultations, as Àrst line therapy in patients with stage 3B or 4
hospitalization, guidelines adenocarcinoma and activating EGFR mutations.
The Àrst is an open label study comparing afatinib
(40 mg daily) to chemotherapy with cisplatin and
Session M24: EGFR Resistance pemetrexed, with a primary endpoint of progression
free survival. This study completed accrual in early
Thursday, 7 July 2011 2011, and results are awaited. The other is a study
of similar design which is still accruing patients,
using cisplatin and gemcitabine as the chemotherapy
EGFR Resistance Thursday, 7 July 2011 10:30-12:00 comparator. Afatinib has been evaluated in a double
blind, placebo controlled phase 3 study in patients
M24.3 IRREVERSIBLE EGFR with stage 3B or 4 adenocarcinoma of the lung
INHIBITORS: CLINICAL DATA who had progressed following treatment with 1
Michael Boyer or 2 lines of chemotherapy (including a platinum)
Medical Oncology, Sydney Cancer Centre/Australia and at least 12 weeks of treatment with erlotinib
or geÀtinib. The primary endpoint of the study
Abstract: EGFR inhibitors, such as geÀtinib was OS, with PFS, response, quality of life and
and erlotinib, are used widely in the treatment of safety as secondary endpoints. 585 patients were
advanced non-small cell lung cancer (NSCLC) randomised to afatinib or placebo (2:1 in favour of
in both Àrst and subsequent lines of treatment. afatinib) between 5/2008 and 9/2009. Median OS
However, de-novo or acquired resistance limits the was similar in both arms (placebo 11.9 months,
efÀcacy of these agents. Irreversible inhibitors of afatinib 10.7 months, HR 1.07, p=0.74) despite
the EGFR have been developed in an attempt to a better RR (13% vs. 0.5%), and better PFS (3.3
limit the impact of resistance, especially that caused vs. 1.1 months) in the afatinib treated patients.
by the exon 20 T790M mutation. Clinical data are Unexpectedly, for a population that had received
available for several irreversible EGFR tyrosine 2 or 3 lines of treatment prior to study entry, 60
kinase inhibitors, including EKB 569, neratinib, to 70% of patients had chemotherapy subsequent
canertinib, afatinib, and PF299804. However, only to study treatment, and this may have confounded
afatinib and PF299804 are continuing to undergo the survival results. In a sub-group analysis, those
development in NSCLC and further discussion will patients whose tumors were likely to have had
be limited to these drugs. Afatinib (BIBW2992) is EGFR mutations based on clinical features (CR/
an irreversible inhibitor of both EGFR and Her2 PR and or duration of >48weeks with prior EGFR
tyrosine kinases. In a phase 2 study carried out TKI) seemed to derive more beneÀt from afatinib.
in Taiwan and the USA, afatinib was evaluated However, the results of EGFR mutation analysis
in patients whose tumors were known to have an will be required to understand these observations.
activating EGFR mutation, and who were either Ongoing studies with afatinib are evaluating its role
chemo-naÃ¯ve or had previously received one line in tumors with Her2 overexpression, and the beneÀt
of chemotherapy. The primary endpoint of this open of continuing afatinib beyond the time of objective
label, single arm study was response rate (RR), with progression, in combination with chemotherapy,
secondary endpoints that included progression free in patients who have had prior chemotherapy and
survival (PFS), overall survival (OS), safety, and EGFR TKIs. PF299804 is an irreversible inhibitor of
clinical beneÀt. Treatment was with afatinib 50 mg EGFR, Her2, and Her4, with clinical data available
daily, but a high rate of dose reductions for adverse in the 1st line, 2nd / 3rd line, and refractory (post
events resulted in this being reduced to 40 mg daily EGFR TKI) settings. In a phase 2 study untreated
for the Ànal 30 patients in the trial. 129 patients patients with advanced adenocarcinoma were
were accrued, 68 of whom were chemo-naive. The clinically selected (never or light ex smokers, Asian,
CR + PR rate was 61%, and the CR + PR +SD rate or non Asian but K-Ras wild type). 74 patients were
enrolled between 3/2009 and 5/2010 and treated Session M25: How Molecular Pathology
with PF299804 at 45 mg daily (later modiÀed to a May Affect Diagnosis and Treatment of
starting dose of 30 mg daily with dose escalation Lung Cancer
if tolerated). EGFR mutations occurred in 34 of
42 (81%) patients with available samples. Overall
RR was 42% in all patients and 55% in those with Thursday, 7 July 2011
known EGFR mutations. PFS data remain immature.
Common toxicities included rash, diarrhea, hand How Molecular Pathology May Affect Diagnosis and Treatment of
foot syndrome and stomatitis. PF299804 has also Lung Cancer Thursday, 7 July 2011 10:30-12:00
been compared to erlotinib in a randomized phase
2 study in patients who had received 1 or 2 lines M25.2 MI-RNA IN LUNG CANCER
of prior chemotherapy, but not otherwise selected. Pan Chyr Yang
The primary endpoint was PFS. 188 patients were Department Of Internal Medicine, National Taiwan
randomized between 10/2008 and 11/2009. Median University College Of Medicine/Taiwan
PFS was 12.4 months in the PF299804 arm and 8.3
months in the erlotinib arm (HR 0.68, p=0.019), Abstract: Lung cancer is the leading cause of cancer
while response rates were 17% and 4% in these arms mortality worldwide. Delayed diagnosis and poor
respectively. EGFR mutations were present in 20% treatment outcome are the unsolved obstacles for
in the PF299804 arm and 12% in the erlotinib arm. most physicians in treating the lung cancer patients.
Toxicities were similar to those observed in other More than 75% of lung cancer patients are stage III
PF299804 studies, though rash and diarrhea were and IV diseases at diagnosis. The overall treatment
more common than with erlotinib. Patient reported outcome of lung is poor and more than 30% of
outcomes indicate that these toxicities were tolerable patients with early stage non-small cell lung cancer
and improved over time. In the refractory setting, (NSCLC) will develop metastasis within 5 years
data are available from two phase 2 studies, one after curative surgery. Recent genetic epidemiology
performed in Korea, the other in the USA. Both and pharmacogenomic studies revealed that lung
included patients who had previously been treated cancer in different ethnic groups, particularly in
with at least one line of chemotherapy as well as East Asia, is a distinct disease entity and different
erlotinib or geÀtinib, and whose tumours were from the Caucasian population. NSCLCs in East
either K-Ras wild type or EGFR mutant. In the Asia have higher prevalence of female non-smoker
Korean study, amongst 43 patients a RR of 17% was lung adenocarcinoma (>50%) and EGFR mutations
observed, with median PFS of 15 weeks. In the US (40-50% in female non-smoker adenocarcinoma).
study, amongst 66 patients RR was 5%, with PFS of The rapid increase in non-smoker adenocarcinoma
11 and 19 weeks in the absence and presence of an both in men and women has become an emergent
EGFR mutation respectively. In both studies, patient health threat to East Asian population. There is an
reported outcomes indicate that adverse effects did urgent need to develop an effective strategy for
not have a major impact on patients, and that some identiÀcation of the high risk patients and detect
disease related symptoms may have improved with lung cancer in earlier stage. The current staging
treatment. A double blind phase 3 study (NCIC system for NSCLC is inadequate to predict outcome
BR26) comparing PF299804 to placebo in patients of treatment. To identify biomarker and develop an
who have progressed following 1 or 2 lines of outcome prediction model for personalized therapy
chemotherapy as well as erlotinib or geÀtinib is of lung cancer is the most important goal of cancer
currently accruing. genomics. The biomarker can be classiÀed into
Keywords: PF299804, Afatinib, Irreversible EGFR three types. The prognostic markers are biomarkers
TKI that can be used to estimate patients’ outcome
independent of therapeutic decision. The predictive
markers are biomarkers that can help to make
therapeutic decision for the patients. The diagnostic
biomarkers are biomarkers that can assist disease
diagnosis, disease subclassiÀcation and monitoring
of the therapeutic response for the patients. Recent
advances in lung cancer genomics have revealed
that more than 50% of driver mutations of lung miR-146b has been identiÀed as a predictor of
adenocarcinoma may be identiÀed, such as EGFR overall survival in SCC. High miR-146 expression
activating mutations, KRAS mutation, c-MET, correlated with a poor overall survival in SCC
RAF, EML4-ALK and others. Several of these patients. In summary, the current understanding of
mutations can be served as predictive markers to miRNAs involved in lung cancer progression has
predict favorable treatment response to speciÀc highlighted their potential to serve as biomarkers
targeted therapy, such as EGFR mutation for for lung cancer risk stratiÀcation and outcome
EGFR-TKIs (GeÀtnib, Erlotinib and Afatinib) and prediction. The miRNA biomarkers and signatures
EML4-ALK for Crizotinib. Currently, new strategies may need further validations by prospective study to
have been developed for individualized therapy of conÀrm their clinical applicability for personalized
lung cancer patients based on detection of genetic therapy of lung cancer patients.
alterations to predict the response to targeted therapy Keywords: Lung cancer, microRNA, biomarker
in different population. Biomarkers regarded as
diagnostic and prognostic factors for cancer has
been presented in many studies. However, there How Molecular Pathology May Affect Diagnosis and Treatment of
is no mature biomarker used in clinical practice Lung Cancer Thursday, 7 July 2011 10:30-12:00
for speciÀc prognostic stratiÀcation. MicroRNAs
(miRNAs) are a class of small non-protein-coding M25.3 PROTEOMICS IN LUNG CANCER
RNAs that are approximately 22 nucleotides in Eric B. Haura
size. The miRNAs may function as endogenous Thoracic Oncology, MofÀtt Cancer Center/United
siRNA and can negatively regulate gene expression States Of America
through post-transcriptional gene silencing. Each
miRNA may regulate hundreds of target mRNAs Abstract: Advances in mass spectrometry-based
and about 30% of protein coding genes are regulated proteomics now allows molecular snapshots of
by miRNA. The miRNAs can target multiple systems and networks formed by cancer genes.
genes and signaling pathways and are involved in Similarly, chemical proteomics can enable
diverse cellular functions, including development, mapping of drugs to targets in cancer cells. These
differentiation, metabolism, proliferation, apoptosis, approaches can enable unbiased and system wide
tumorigenesis and metastasis. Dysfunctions of views of cancer signaling networks and potential
miRNAs are frequently seen in malignancies, therapeutic insertion points. We have used afÀnity
including lung cancer. The miRNAs can serve as puriÀcation coupled with liquid chromatography
tumor suppressors or oncogenes in lung cancer. The - mass spectrometry (LC-MS/MS) to elucidate
most typical example is the miRNA let-7 family networks driven by oncogenic forms of the
which may function as tumor suppressors. The miR- epidermal growth factor receptor (EGFR) and
let-7 can negatively regulate expression of multiple translocation of echinoderm microtubule associated
oncogenes, including RAS, MYC, HMGA2, and protein like 4 – anaplastic lymphoma kinase
cell-cycle progression regulators, such as CDC25A, (EML4-ALK). Mutations in EGFR or EML4-ALK
CDK6, and cyclin D2. Reduced let-7 expression rearrangements deÀne two unique subsets of lung
in non-small cell lung cancer (NSCLC) patients cancer characterized by hypersensitivity to small
is correlated with poor prognosis. The miR-17- molecule tyrosine kinase inhibitors (TKI). Despite
92 cluster and miR-31 may serve as oncogenes in striking results with kinase inhibitors directed
lung cancer and can promote tumor growth and against these targets, not all patients respond, the
neoangiogenesis. The miRNA proÀle is also useful drugs are non-curative, and resistance remains a
for histological classiÀcation, risk stratiÀcation and consistent problem. We characterized signaling
outcome prediction. The miR-205 is a useful marker networks driven by EGFR mutations and EML4-
to differentiate squamous cell carcinoma (SCC) ALK using tandem afÀnity puriÀcation (TAP) and
from non-SCC NSCLCs. High miR-155 and low liquid chromatography-mass spectrometry (LC-MS/
miR-let7a-2 expression correlated with poor overall MS) to map protein-protein interactions and anti-
survival in lung adenocarcinoma patients. We also phosphotyrosine immunoprecipitation coupled with
identiÀed a Àve-miRNA signature (miR-137, miR- LC-MS/MS to map tyrosine phosphorylation. An
372, miR-182*, miR-221 and let-7a) that correlated ongoing functional analysis including siRNA and
with disease-free survival in NSCLC patients. The small inhibitor screen will functionally validate
these targets and examine combination effects clinic, where lung function tests were performed, and
with ALK inhibitors. This network approach has questionnaires concerning health, lifestyle, smoking
potential translational applications to identify novel habits and psychosocial consequences of screening
combination approaches to treatment of lung cancers were completed (1). CT scans were evaluated by 2
addicted to RTK and could be useful in patients with experienced radiologists (1) and volumetric analysis
acquired resistance to TKI. Updated work will be of detected nodules validated as in the NELSON
presented. trial (5). PET scans were used to supplement the
Keywords: systems biology, tyrosine kinase radiological assesment (6). Results: The DLCST
inhibitors, proteomics, Mass spectrometry showed that smoking habits during screening were
unaffected by CT screening pr se at 1 year follow-
up (2) and also after 5 annual screening rounds with
Session M26: Screening by Low Dose CT CT (to be published). In addition we have shown
that current smoking status has a major inÁuence on
Thursday, 7 July 2011 lung density assessed by CT, and that lung density
decreases after smoking cessation, presumably due
to a reduced inÁammatory reaction in the lung (3).
Screening by Low Dose CT Thursday, 7 July 2011 10:30-12:00 Contamination by off study CT scans in the control
group was low (0.04 %) (4). The detection of lung
M26.3 DANISH STUDY UPDATE cancers during the trial was: In the CT screening
Jesper H. Pedersen1, Asger Dirksen2 group a total of 68 lung cancers were diagnosed. At
1
Thoracic Surgery, Righospitalet (2152), University baseline the detection rate was 0.8% (1) , while the
Of Copenhagen/Denmark, 2Pulmonary Medicine Y, incidence rounds had a mean annual detection rate
Gentofte University Hospital/Denmark of 0.6% (chi-square-test; p=0.492). Three were small
cell lung cancers (SCLC) and 65 were non-small
Abstract: The Danish Lung Cancer Screening Trial cell lung cancers (NSCLC). Fifty-seven (84%) were
(DLCST) is a Àve-year prospective randomised early stage (I-IIIA NSCLC & limited stage SCLC)
controlled screening trial evaluating the effect of and thus potentially curable. Eleven (16%) were
annual CT screening for lung cancer. The overall diagnosed in late stage (IIIB-IV NSCLC & extensive
design and baseline results has been published in stage SCLC). One interval cancer was diagnosed
2009 (1). Methods: From October 2004 to March ten months after the 3rd incidence scan, in a patient
2006, 4,104 men and women were enrolled after with In the control group: Twenty-four participants
giving written informed consent. Recruitment was were diagnosed with lung cancer. Six had extensive
through advertisements in local and regional free stage SCLC and one limited stage. Ten (42%) were
of charge newspapers, stating the purpose, study in early stage, and 14 (58%) in late stage. One of
design, enrolment criteria and that the trial was these early stage lung cancers was in a participant
funded in full by a governmental grant. Recruitment who received a CT scan for screening purposes
criteria: Males (55 %) and females (45 %), aged 50 through his general practitioner (contamination).
to 70 years, who were current or former smokers A stage IA lung cancer was found and was treated
with at least 20 pack years of smoking history. by surgery. SigniÀcantly more lung cancers were
Former smokers should have quit for no more diagnosed in the screening group (chi-square-test:
than 10 years. Lung function was measured by 68 vs. 24 p<0.001) and more were low stage (chi-
spirometry and forced expiratory volume in Àrst square-test: 57 vs. 10; p<0.001). The number of
second (FEV1) had to be at least 30% of predicted. late stage lung cancers was the same in both groups
Exclusion criteria were body weight over 130 kg, (chi-square-test: 11 vs.14; p=0.640). The number
history of cancer diagnosis and treatment, lung of new lung cancers remained high during all four
tuberculosis, expected life expectancy less than ten incidence rounds in the screen group as compared
years, and chest CT received during the last year for to the control group: 11+13+12+15 vs. 4+6+7+6
any reason. Randomisation was to either a screening (p<0.001). A high proportion of the screen detected
group (n=2,052) or a control group (n=2,052). The lung cancers ( > 75 %) were treated by minimally
screening group received Àve annual low dose chest invasive surgery (VATS). DLCST is approved by
CT scans (one baseline scan and four incidence the Ethics Committee of Copenhagen County and
scans). All came for an annual visit to the screening the Danish Data Protection Agency, and registered
in Clinical Trials.gov Protocol Registration System launched to answer the question of the efÀcacy and
(identiÀcation no. NCT00496977). The collaboration cost-effectiveness of lung cancer screening in high
and contributions of the steering commitee of the risk subjects. One arm studies were not sufÀcient
DLCST is gratefully acknowledged. It members mainly because the overdiagnosis related to the
are : Zaigham Saghir, Asger Dirksen, Haseem possible detection of indolent lung cancers detected
Ashraf, Philip Tønnesen, Karen Bach, Hanne at screening by chest Rx in older randomised trials.
Hansen, Birgit Guldhammer Skov, Jann Mortensen, For this reason lung cancer screening randomised
Hanne Thorsen, John Brodersen, Martin Døssing, trials (RT) have been implemented in USA and in
Niels Seersholm, Klaus Fuglsang Kofoed, Paul Europe. Recently the NLST US study (about 50.000
Clementsen, Klaus Richter Larsen and Jesper Holst subjects) was early stopped after 8 years of follow up
Pedersen References: 1) Pedersen JH et al. The because an interim analysis showed a 20% mortality
Danish Lung Cancer CT Screening Trial – Overall reduction for the intervention arm. In Europe an
design and results of the Prevalence Round. J Thorac international collaboration between RTs was set
Oncol 2009; 4; 608-14 2) Ashraf H et al. Smoking up in Liverpool with the aim of pooling data from
habits were unaffected by CT screening at 1 year national studies. The whole screening cycle has
follow-up in the Danish Lung Cancer Screening been completed (baseline +3 screening rounds) and
Trial (DLCST). Thorax 2009; 64; 388-92 3) Ashraf results for the screened subjects are here reported.
H et al. Short term effect of changes in smoking MATERIALS AND METHODS The study was
behaviour on emphysema quantiÀcation by CT. carried out in three screening centres in Florence,
Thorax (2010). Doi:10.1136/thx.2009.132688 4) Pisa and Pistoia of the Tuscany Region (Italy) and
Saghir Z et al. Contamination during 4 years of supported by the Regional Health Public Authority.
annual CT screening in the Danish Lung Cancer and approved by the Local Ethic Committee of
Screening Trial (DLCST). Lung Cancer (2010), each participating institution. The Institute for
doi:10.1016/j.lungcan.2010.06.006 5) Ashraf H et Cancer Prevention and Research (ISPO) of Florence
al Lung nodule volumetry: segmentation algorithms was the coordinating centre. Subjects received a
within the same software package cannot be used letter and consented to randomized. Eligible were
interchangeably. Eur. Radiol 2010; 20, 1878-85 6) subjects aged between 55 and 69 years at the time
Ashraf H et al. Combined use of positron emission of enrolment with a smoking history of at least 20
tomography and volume doubling time in lung packs–year since the last 10 years . Subjects who
cancer screening with low-dose CT scanning. Thorax attended the baseline test (n=1406) were re-invited
(2010). Doi: 10.1136/thx.2010.136747 at subsequent 3 rounds. CT Scan had double reading
by radiologists and positive screening test for nodule
at baseline was considered a solid or part-solid non
Screening by Low Dose CT Thursday, 7 July 2011 10:30-12:00 calciÀc nodule (NCN) with mean diameter more than
5 mm. at baseline test (3 mm. at repeated screening
M26.4 THE ITALUNG RANDOMISED testThe protocol was basically similar to that of the
TRIAL: RESULTS OF THE SCREENING International-ELCAP Study. FDG-PET, FNA or
ROUNDS AND PERSPECTIVES 3-months follow up were suggested for assessment.
Eugenio Paci1, Laura Carrozzi2, Mario Mascalchi3, On case-by-case basis FBS was performed. All the
Fabio Falaschi4, Francesco Giusti1, Giulia Picozzi5, surgically removed lesions were evaluated according
Francesca M. Carozzi1, Andrea Lopes Pegna6 to the World Health Organization Criteria. A parallel
1
Epidemiology, Ispo/Italy, 2Dept Pneumology, Aou collection of sputum and blood was obtained by
Pisa/Italy, 3Dept Diagnostic Imaging, Aou Careggi/ the screening participants. RESULTS Results of
Italy, 4Dept Diagnostic Imaging, Aou Pisa/Italy, baseline and all the three annual repeat CT scans
5
Diagnostic Imaging Unit, Asl Pistoia/Italy, 6Dept will be reported. From 2004 to 2006, 1593 subjects
Pneumology, Aou Careggi/Italy were randomised as controls and 1613 enrolled
in the intervention arm. 1406 (87.2%) accepted to
Abstract: After the publication in 1999 of the be screened and underwent baseline CT scan. Out
results of the ELCAP study, one arm studies have of the screened at baseline (1,406), 97.8%, 96.7%
shown the good performance of low dose CT Scan and 97.2% were screened at the Àrst, second and
screening for the detection of early lung cancer cases third subsequent rounds, respectively for a total
and high survival rates. Randomised trials were compliance of 78.3%. 426 participants (30.3%) had
a NCN detected at baseline CT, and 619 (15.8%). 40 Statement 2005: priorities for the European Union/
primary lung cancers were detected in 38 participants United States Spiral Computed Tomography
(2.7%), 21 at the baseline screening (DR: 1.4%), and Collaborative Group. Thorac Oncol 2006; 1:497–
17 (DR:0.4%)at the subsequent screening rounds. 498. Lopes Pegna A, Picozzi G, Mascalchi M, et
The adenocarcinomas were the 48% at baseline, and al. Design, recruitment and baseline results of the
71% at repeated tests. 6 subjects were diagnosed ITALUNG trial for lung cancer screening with low-
after the follow-up CT Scan (29%) at baseline ; dose CT. Lung Cancer 2008; 64:34–40).
12 lung cancers were diagnosed after a follow-up Keywords: CT Lung cancer screening, randomised
at repeated tests (71%).6.4% of the subjects with trial
NCNs, had a FDG-PET; with a positive result in
29/90 subjects (32.2%) and the 22.2% of lung
cancers. In 34 subjects (2.4%) work-up was carried Screening by Low Dose CT Thursday, 7 July 2011 10:30-12:00
with 38 CT guided FNA; 24 FNA (24/34= 70.5%)
were positive for lung cancer and 2 for metastasis. M26.5 LUNG CANCER SCREENING BY
Pneumothorax occurred in 11/38 (30%) of the LOW DOSE CT (DISCUSSANT)
subjects, but only 2 cases needed thoracic drainage Stephen Lam1, Martin Tammemagi2, Anthony
. The combination of FNA and PET positive result Miller3, John Mayo4, Michael Johnston5, James
lead to a 88.2% of subjects preoperatively classiÀed Dickinson6, Huiming Yang7, Verna Mai8, William K.
as lung cancer. Surgery was the main therapy for Evans9
1
28/32 NSCLC and for 3/3 typical carcinoid and Integrative Oncology, BC Cancer Research Centre/
1/1 for mixed cancer NSCLC + SCLC; 6 cancer Canada, 2Department Of Community Health
were treated with adjuvant therapy. DISCUSSION Sciences, Brock University/Canada, 3Dalla Lana
Member of the group of RCT on going in Europe, School Of Public Health, University Of Toronto/
ITALUNG is a population-based trial randomising Canada, 4Department Of Advanced Cardiac
to 4 screening rounds versus usual care. The Imaging, Vancouver General Hospital/Canada,
5
randomised subjects of the intervention and Department Of Surgery, Queen Elizabeth II Health
control group were invited to a smoking cessation Sciences Ctr./Canada, 6Faculty Of Medicine,
counselling , if not ex smokers. In a recent meeting University Of Calgary/Canada, 7Populationa Dn
held in Pisa teh European Trialists, including the Public Health, Alberta Health Services/Canada,
8
ITALUNG, conÀrmed the opportunity of continuing Prevention And Cancer Control, Cancer Care
the RT. Most European trials are considering the Ontario/Canada, 9Juravinski Hospital And Cancer
usual care as the reference group. Furthermore Centre, Cancer Care Ontario/Canada
most of them were based on the invitation from
the population lists and not on volunteer subjects. Abstract: Lung cancer is the most common cause
Information of major side effects and estimates of of cancer death world-wide. Despite advances in
the possible excess of incidence/overdiagnosis for therapies, the outcome of patients with lung cancer
lung cancer related to screening is an important remains poor. In the last decade, the 5-year survival
result for the evaluation of the cost-effectiveness rate changed from 13.9% to 17.7% with a slightly
of any future service screening programmes. The better improvement in the one-year survival from
better identiÀcation of the high risk subjects and 36% to 43% (Lancet 2011;377:127-138). Roughly
possible integration of biomarkers in the detection 85-90% of lung cancers are attributable to smoking.
and followup of subjects will also be important Currently more than half the lung cancers diagnosed
for the future. For this reason the ITALUNG study in North America are diagnosed in former-smokers,
will continue the follow up of the subjects enrolled. and for this reason lung cancer is expected to
Essential references (Henschke CI, McCauley DI, remain a major public health concern for many
Yankelevitz DF, et al. Early Lung Cancer Action years to come. The recent Ànding by the National
Project: overall design and Àndings from baseline Lung Screening Trial (NLST) in the United States
screening. Lancet 1999; 354:99–105), Henschke that screening of high-risk smokers with low dose
CI, Yankelevitz DF, Libby DM, et al. Survival of computed tomography (LDCT) reduces lung cancer
patients with stage I lung cancer detected on CT mortality by 20% compared to screening with chest
screening. N Engl J Med 2006; 355:1763–1771. x-ray may represent a potential strategy that can
Field JK, Smith RA, Duffy SW, et al. The Liverpool signiÀcantly improve the outcome of patients with
lung cancer staging, resection techniques and treatment methods

NLST, NELSON-Danish and the ITALUNG are the and pathologists experienced with interpretation of
Àrst randomized trials using superior study designs small biopsy specimen need to be made available.
to evaluate the efÀcacy of CT screening to reduce The development of screening programs will need
lung cancer mortality. Simple case detection and to be accompanied by a parallel process of quality
demonstration of improvement of survival in single assurance including medical technologists, picture
arm studies are not equivalent to efÀcacy as some archiving and communications (PACS) specialists,
cancers may not be curable, nor have their natural radiologists, external evaluators and medical
history modiÀed by available treatment. Some physicists. Further developments in computer
cancers may never have become life-threatening aided diagnosis (CAD) technology should reduce
in the patient’s lifetime (over-diagnosis bias). The radiologist’s interpretive errors.
randomized controlled trial design with lung cancer Screening can be useful for those who are in the
mortality as the outcome avoids length, lead-time deÀned target group, but carry a risk of causing net
and overdiagnosis biases that invalidate study harm if performed on low risk individuals. More
designs dependent upon survival. Selection or accurate lung cancer risk prediction tools to identify
participation bias – i.e., the healthy volunteer effect, individuals at risk of lung cancer beyond age and
is still present in randomized controlled trials, so smoking history alone have been developed using
they may have better outcomes than can be achieved data from the Prostate Lung Colon and Ovarian
in the general population. Cancer Screening Trial (Tammemagi M. et al. J
Screening is a process, not a single event. It requires Natl Cancer Inst. Under review). The PLCO lung
the use of tests to detect unrecognized health risks or cancer prediction tool was applied to recruit high
diseases in order to permit timely intervention. For a risk current and former smokers between 50 to 74
screening program to demonstrate effectiveness at a years of age in the Pan-Canadian Early Detection of
population level, the screening tests must be applied Lung Cancer Study. Preliminary results suggest this
systematically on a large scale. They are used to prediction tool performs well allowing identiÀcation
distinguish apparently unaffected (undiagnosed) of subjects harboring a 3-year lung cancer risk of
people from those who may have a disease. A 2%. The incremental value of biomarkers such as
screening test is not intended to be diagnostic. The lung function to the prediction tool has also been
test results require conÀrmation through deÀnitive evaluated. Data from the British Columbia Lung
diagnostic tests, followed by treatment of conÀrmed Health Study and the Pan-Canadian Early Detection
cases. Screening can only be effective if effective of Lung Cancer Study suggest lung function (FEV1)
treatment is available for the disease revealed by adds signiÀcantly to lung cancer risk prediction and
screening. The potential beneÀts of screening must that there is a gender difference in lung cancer risk
be balanced against possible harms of screening and decline in lung function (Tammemagi M, Lam S,
tests, downstream investigations or therapeutic McWilliams A, et al. Incremental value of pulmonary
intervention for suspicious lesions that turn out to be function and sputum DNA image cytometry in lung
non-malignant, and these may be several times more cancer risk prediction. Cancer Prediction Research
frequent than the true cancers. 2011;4(4);1-11.).
Implementation of lung cancer screening at the Further research is required in a number of areas in
population level requires coordinated and specialized lung cancer screening including: features that best
professional expertise to ensure beneÀts of deÀne the screened population, discrimination of
screening are maximized while the potential risks benign versus malignant lung nodules, most efÀcient
are minimized. For example, population penetration follow-up diagnostic and treatment pathways and
strategies for large scale screening will have to be the optimal frequency and duration of screening.
developed; pulmonologists and thoracic surgeons Evidence based guidelines for treatment of small
experienced in management of lung nodules, lung cancers using sub-anatomic resection or
interventional pulmonologists skilled in diagnosis stereotactic body radiation versus conventional
of peripheral lung lesions and staging of lung anatomic resection need to be established. Wide-
cancer using endoscopic ultrasound; radiologists spread lung cancer screening programs might be
skilled in interpretation of lung cancer screening best introduced in stages to ensure that adequate
low dose CT scans, biopsy and localization of small infrastructures are available and that quality
lung nodules, thoracic surgeons knowledgeable in assurance and program performance can be
evaluated at least at a local level, before national targets that will allow patients to be enrolled on
implementation of a program is instituted. This will clinical trials that will conÀrm or deny the beneÀt of
allow efÀcient troubleshooting of problems before the new predicted therapies. An important example
they become widely implemented. The data collected of this is the results of the Lung Cancer Mutation
can then be used to model the effect of potential Consortium in deÀning actionable oncogene
strategies, to facilitate the development of guidelines mutations in 1,000 lung adenocarcinomas. Large
for the most effective program. A well designed Panel of Lung Cancer Cell Lines and Xenografts
screening program can also provide the opportunity with Clinical, Molecular, and Drug Response
for research such as on tobacco addiction and Phenotype Annotations: The development of a large
smoking cessation modiÀers as well as lung cancer panel of non-small cell (over 100) and small cell
risk reduction through the use of chemoprevention lung cancer (over 50) lines (NSCLC, SCLC) with
drug therapy or immunotherapy. clinical annotation and a large legacy database of
molecular analyses and drug response phenotypes
has been pivotal in preclinical development of new
Session M27: Based on Long therapeutic approaches. Currently several centers
Experience: What Brings the Future? are determining if molecular biomarkers (such as
mRNA or proteomics proÀles) of the tumor cell
lines associated with in vitro and in vivo (xenograft)
Thursday, 7 July 2011
drug response phenotypes are also predictive of drug
responses in patients. The recent addition of matched
Based on Long Experience: What Brings the Future? Thursday, 7 July pairs of tumor cell lines and immortalized normal
2011 10:30-12:00 lung epithelial cells from the same patients has
allowed comparisons of selective therapeutic toxicity
M27.1 MOLECULAR AND FUNCTIONAL for tumor over normal cells as well as providing
PORTRAITS OF NON-SMALL CELL for genome wide sequence analysis. Development
LUNG CANCER THAT PROVIDE of Immortalized Human Lung Bronchial and
ENROLLMENT BIOMARKERS FOR Small Airway Epithelial Cells (HBECs, HSAECs)
THERAPY SELECTION including Isogenic Derivatives with DeÀned
John D. Minna Oncogenic Changes: Cell biologic advances have
Hamon Center For Therapeutic Oncology Research, allowed the development of a large panel (over
University Of Texas Southwestern Medical Center/ 50) of immortalized lung epithelial cell lines from
United States Of America both the central (HBECs) and peripheral (HSAECs)
airways. These lung epithelial cell strains have many
Abstract: The Opportunity and the Challenge: properties of basal stem cells in the lung and can
Amazing advances on multiple fronts in molecular differentiate into lung epithelium under controlled
and cell biologic approaches and clinical trials conditions. They clone with high frequency, are
have provided an unprecedented opportunity to non-tumorigenic, can be genetically manipulated,
fundamentally alter our approach to classifying and their isogenic derivates (manipulated to have
and developing personalized treatments for lung deÀned oncogenic changes in oncogenes and tumor
cancer. Besides the recent striking examples of suppressor genes) permit detailed molecular and cell
targeted therapy in clinical trials that focus on biologic studies of much simpler oncogenotypes
deÀned oncogene mutations, these include genome than are found in full Áedged lung cancers. These
wide DNA sequence analyses, DNA copy number, studies have shown that over 5 such changes are
DNA methylation, mRNA expression, miRNA needed to develop full malignancy. IdentiÀcation
expression, proteomics, new cell biologic systems of Lung Cancer Stem Cells: Recent advances have
and understanding of cancer stem cells, and genome allowed the detection and characterization of lung
wide functional (siRNA, shRNA) analysis of lung cancer stem cells (CSCs) or “cancer initiating
cancer coupled with appropriate biostatistical and cells”. These studies have shown that NSCLCs that
bioinformatics approaches. These provide exciting are enriched in lung CSCs have worse prognosis,
new leads for new drug development. However, the that the molecular characteristics and identifying
Ànal output needs to be CLIA certiÀed laboratory markers of lung CSCs can vary depending on the
tests of patient’s tumors that identify “actionable” lung cancer oncogenotype, and the Notch pathway as
an attractive therapeutic target. Molecular Portraits need for multi-disciplinary and multi-institutional
(“Clades”) of Lung Cancer: The wealth of new require the developing, nurturing, and maintenance
genome wide molecular analyses of lung cancers and of effective collaborations. Grant Support: NCI
lung cancer cell lines has permitted lung cancer to SPORE in Lung Cancer (P50CA70907), NCI
be molecularly classiÀed into different “Portraits” or CTD2N (RC2CA148225), DOD “PROSPECT”,
“Clades”. NSCLCs can be divided into 5-10 different NASA NSCOR, and State of Texas CPRIT grants.
molecular groups and these have distinct clinical, Collaborators: I thank my long time colleague in
histological, oncogenotype, outcome and drug and this effort Dr. Adi Gazdar and my many current and
targeted therapy response phenotypes. The molecular former collaborators. References: Gazdar AF et al.
deÀnitions allow lung cancer cell lines, xenografts, Lung cancer cell lines: Useless artifacts or invaluable
and tumor specimens to be linked together and tools for medical science? Lung Cancer 68:309-18,
comparisons between different groups made. NCI 2010 Gazdar AF et al. Lung cancer cell lines as tools
Cancer Target Discovery and Development Network for biomedical discovery and research. J Natl Cancer
(CTD2N): The NCI’s new CTD2N has allowed the Inst 102:1310-21, 2010 Schreiber SL, et al: Towards
development of genome wide functional approaches patient-based cancer therapeutics. Nat Biotechnol
(knocking down one gene at a time with siRNAs, 28:904-6, 2010.
or shRNA library screening) combined with Keywords: Lung Cancer Lines, Lung Cancer
screening of large chemical libraries on the panel Xenografts, Molecular ProÀles, Molecular Biology
of characterized lung cancer lines. This approach
has identiÀed genetic targets (“knockdowns’) and
chemical compounds that are “monogenic lethals” Based on Long Experience: What Brings the Future? Thursday, 7 July
– that kill lung cancer by themselves but do not 2011 10:30-12:00
kill normal lung epithelial cells. In addition, these
lethals only kill certain lung cancers which can M27.2 PATHOLOGY
be mapped to the molecular portraits. Together, Adi F. Gazdar
these genome wide and chemical compound Hamon Center For Therapeutic Oncology Research,
reagents are permitting a totally new functional Pathology, University Of Texas Southwestern
classiÀcation of for identifying all of the “acquired Medical Center/United States Of America
vulnerabilities” lung cancer The relationship of
this sensitivity to the molecular portrait allows the Abstract: The past 40 years have witnessed major
molecular portrait to be an enrollment biomarker changes in our beliefs and practice of the pathology
for moving these new therapies into the clinic. of lung cancer. The major changes are summarized
Development of CLIA CertiÀed Tests: If these below. · The realization in the 1980s that small
new approaches are going to be moved to the cell lung cancer (SCLC) had different clinical and
clinic, the enrollment biomarkers need to have biological features from non-small cell lung cancer
tests developed that can be CLIA certiÀed and (NSCLC) and therapeutic responses to cytotoxic
also performed on small biopsy materials which is therapy. This led to the pathologic distinction of
often Àxed and archival as found in real life clinical lung cancers into SCLC and NSCLC types. · The
situations. Appropriate Biostatistical Analysis with realization that true non-invasive adenocarcinomas
Documentation of Analytic Methods: Recent events (formerly called brochioloalveolar carcinomas or
have demonstrated that the large molecular, genome BACs) had an excellent prognosis if small and
wide datasets needed for these approaches can be completely resected highlighted the importance of
subject to many errors in analyses. Thus, it is very precise identiÀcation of the presence and extent of
important to provide for independent veriÀcation of invasion (). · The WHO classiÀcation ()at the turn
Àndings and documentation such as that provided of the century was an important contribution in
by “SWEAVE.” Important Role of Patients and identifying the criteria for the major forms of lung
Advocates in the Process: An important new cancer and their subtyping. It was limited because
addition to the scientiÀc team has been the role of it was basically a “Pathology ClassiÀcation by
patients and patient advocates in the process. Need and for Pathologists”. Subtyping of tumors had
for International Collaboration and Consortium little or no clinical relevance. Diagnosis depended
Efforts: All of these new approaches by their on obtaining large tissue specimens such as
large scale, resource requirements, data sets, and resections. · We have a much deeper understanding
of the pathologic and molecular preneoplastic academic exercise by pathologists to a dynamic

and preinvasive changes that precede the onset of multidisciplinary approach that is clinically relevant.
invasive and metastatic carcinomas (). Because It will continue to evolve as our knowledge of
the peripheral lung cannot be serially biopsied, our the clinical and molecular basis of lung cancer
understanding of the multistage pathogenesis of increases. References: 1. Noguchi M. Stepwise
lung cancer has lagged behind that of squamous progression of pulmonary adenocarcinoma--clinical
tumors. However the onset of CT based screening and molecular implications. Cancer Metastasis
studies has greatly increased our knowledge of the Rev. 2010;29:15-21. 2. Brambilla E, Travis WD,
origins or peripheral adenocarcinomas. · During Colby TV, Corrin B, Shimosato Y. The new World
the past decade we have learnt that the clinical Health Organization classiÀcation of lung tumours.
responses and toxic effects to both conventional Eur Respir J. 2001;18:1059-68. 3. Brambilla E,
and cytotoxic therapy depend on accurate typing of Gazdar A. Pathogenesis of lung cancer signalling
NSCLC. The development of simple immunostains pathways: roadmap for therapies. Eur Respir J.
and mucin stains that can be used to subtype the 2009;33:1485-97. 4. Travis WD, Brambilla E,
majority of cases including cytological specimens Noguchi M, Nicholson AG, Geisinger KR, Yatabe
and small biopsies has greatly aided this task. This Y, et al. International association for the study of
also resulted in many fewer cases being given the lung cancer/american thoracic society/european
default terms “large cell carcinoma” or “NSCLC, respiratory society international multidisciplinary
NOS” in the absence of obvious differentiation classiÀcation of lung adenocarcinoma. J Thorac
along squamous or adenocarcinoma pathways. Oncol. 2011;6:244-85.
· The advent of targeted therapy, especially for Keyword: Pathology classiÀcation
speciÀc subgroups of adenocarcinoma, has stressed
the importance of NSCLC typing and subtyping.
The gradual realization that speciÀc molecular Based on Long Experience: What Brings the Future? Thursday, 7 July
abnormalities are associated with speciÀc subtypes 2011 10:30-12:00
of NSCLC has pointed out the importance of
accurate subtyping and the importance of reporting M27.3 RADIOTHERAPY
it, especially in clinical trials. · Pathologists play Andrew T. Turrisi
a crucial role in the management of clinical trials Radiation Oncology, Radiation Oncology Center,
by providing tissue repositories, performing Sinai Grace Hospital/United States Of America
prognostic and predictive tests, performing accurate
typing and subtping of lung cancers, etc. As the Abstract: Radiotherapy has been the most
amount of tissues available for these diagnostic advantaged modality in making progress over the
and clinically relevant tasks becomes smaller and past 40 years, as we use it by itself and as integrated
smaller, pathologists have learnt to do more with into combined modality management. The early
less. · There has been a gradual realization that years separated two key features: (SCLC) separate
pathology classiÀcations must be multidisciplinary from (NSCLC) and thoracic radiotherapy alone
In origin and serve the practice of clinical oncology. superior to surgery in small cell (Fox and Scadding)
Thus classiÀcations must be devised in close , and the role of thoracic radiotherapy dose in non-
collaboration with oncologists, pulmonologists, small cell seemed to have been established at 60Gy
surgeons, radiotherapists and radiologists. Input [radiotherapy was quickly pushed off center stage
from basic science studies including molecular by the use of even single agent chemotherapy]
biology is essential. The recent revised classiÀcation (Bergsagel). It took 20 years for radiotherapy’s
of pulmonary adenocarcinoma () is the “poster integral role in limited disease small cell, as thoracic
child” for such an approach. · Multidisciplinary radiotherapy (Pignon), and then 30 years to prove
studies with squamous cell carcinoma and SCLC beneÀt of prophylactic cranial irradiation (Auperin).
have lagged behind adenocarcinoma. However a Linear accelerators became standard, skin was
“Systems Genetics” (i.e. comprehensive molecular) spared, but normal tissue tolerance to acute and
study of squamous cell carcinomas may help late effects limited the dose of radiotherapy. In the
rectify the situation. SCLC largely remains the chest, 50% of treatment came from anterior beams
“forgotten disease”. In summary, pathology has the remainder from posterior beams. Dose was
greatly evolved during the last 40 years from an prescribed to the mid-plane depth, and that meant
tissue at entry and exit might receive 20% higher dose per week. Each may be use a fractional dose
dose. It was normal tissue tolerance rather than more than once daily. Hyperfractionation with
tumor control that limited dose. Modeling after small per fraction dose intends to decrease late
the successful wide-Àeld treatment of Hodgkin’s effects and improve long term toxicity. Accelerated
Disease and reasoning of predictable spread to treatment intends to defeat rapidly re-populating
regional nodes, targets often included nodes from cell populations that might double within 24 hours,
the supraclavicular fossa and thoracic inlet to the but at the price of acute toxicity. In lung cancer,
diaphragmatic hiatus, and both hilar zones. The there is no evidence supporting hyperfractionation,
spinal cord tolerance of 50 Gy, and esophageal but accelerated schemes have proven efÀcacy in
tolerance limited dose. RTOG 73-01 trial established NSCLC (CHART, Saunders) and SCLC (Intergroup,
60 Gy over 50 Gy and two schedules of 40 Gy as the Turrisi). Despite evidence, accelerated schemes
standard that frankly has endured until today.(Perez) are orphans: misunderstood and hard to adopt. The
The survival at 5 years was 5-10%, and local control future is indeed now. The Goldilocks paradigm of
was said to be about 50%. Biology was fueled wanting strategies to be not too big (Àeld size, dose,
by knowledge of oxygen effect, and interrupting toxicity) or too small (missing tumor because of
therapy (Split Course for 2-4 weeks) was common set up variation, motion, incorrect target), but just
as in one of the arms of RTOG 73-01. The trial was right allows for optimizing of radiotherapy with
under-powered for survival and the arms overlapped other modalities. Chemotherapy is solidly in place
each other. Chemotherapy was only used in SCLC for both small cell and non-small cell. However,
and never in NSCLC. Concurrent therapy was too molecular determinants may point to use of certain
toxic, and no one used doses higher than 60 Gy in agents (i.e,ERCC-1 +/- for cis-platinum; EGFR
NSCLC and 50 Gy in SCLC, and even that was codon mutations for cetuximab or geÀtinib/erlotinib).
eschewed due to esophageal toxicity: stricture. Today We are not yet clear about PET scan determinates
most agree that elective nodal irradiation adds little for “adaptive therapy” (more dose to persistently
beneÀt, but does increase toxicity. The Ann Arbor PET avid areas) or markers for hypoxia. Physics
dose escalation trial introduced this idea recognizing determinants for target expansion (GTV, CTV, PTV)
that dose escalation could not be achieved with and motion, as well as dose calculation methods
Hodgkin’s-like volumes (Hazuka, Hayman). While (equivalent path length, Monte Carlo) may be more
imperfect, the Yuan study adds substantial evidence or less important. New Technology and techniques
in support. Radiotherapy technology improved to apply very high doses to targets have produced
since 1970 when there were no computerized axial exciting results in Europe, Asia, and North America.
tomograms (CT’s). The CT revolutionized radiation The term Stereotaxy has been applied, and unique
oncologists’ ability to select patients, deÀne targets, machines (Cyberknife, Tomotherapy HiArt, ?
and ultimately formed the foundation of three- Proton beams) may be used to deliver gargantuan
dimensional treatment planning (3D-TP). These single or fractionated doses. Anatomic location may
systems were developed in university departments in mitigate toxicity (Fakiris). Total dose and schedule
the 80’s and 90’, and then developed commercially vary widely. If local control and survival at 3 years
in the late 1990’s, and almost instantly standard with very minimal toxicity and very high survival
by 2000. As collimator assemblies evolved from and local control are adequate evidence, we are
thick blocks of ballast to thin leaÁets with ever already there for medically inoperable cases, and
decreasing width and individual motors, the tools even sufÀcient background for prospective trials
for beam modulation that enables dose variation of peripheral lesions in otherwise operable cases.
across the Àelds. Intensity modulation and multiple It may even be possible to do this with ordinary
beams require much professional physics time linear accelerators and multiple beams, especially
and pre-treatment assurance that systems work with intermediate dose/fraction and up to 3 week
as planned. Dose described as energy absorbed, treatment – we are enamored of and swept away
needs to be thought about as dose per unit of time. by the technology, but the biology of these very
A standard scheme delivers 10 Gy/week. Using high doses/fraction can be mimicked by multiple
very small doses/fraction multiple times per day beams and real-time imaging on widely available
is called hyperfractionation, but generally does accelerators. It’s not magic. Minimizing the volume
not increase the dose per week by less than 20%. of normal tissue receiving these very high doses,
An accelerated scheme delivers more than 50% and tailoring dose per fraction to normal tissue to
more ordinary fractional doses accomplishes this resection of lung tissue for the sake of maintenance
feat without excess toxicity, technology, or cost. of patient’s QOL. Video Assisted Thoracoscopic
Protons produce beams with interesting physical Surgery (VATS) spread throughout the world during
characteristics. The prospect of neutron-like biologic the past two decades and, more recently, introduction
beams (virtually no repair; very little oxygen of the robotic surgery is underway. VATS and robotic
enhancement ratios) such a neon or carbon beams surgery are promising surgical technologies for the
require huge resources and trials to prove beneÀt. future, however, there are still many issues to be
Keyword: Radiotherapy; 40 year’s Progress; solved and further improvements to be made. The
Radiotherapy in the future desire of the people is to enjoy non-invasive, safer,
higher quality and, yet, cheaper medicine, which
obliges us to further our effort in developing more
Based on Long Experience: What Brings the Future? Thursday, 7 July adequate medicine including surgical procedures.
2011 10:30-12:00 In order to satisfy their demands and to achieve our
goal of eradication of lung cancer, we will have to
M27.4 SURGERY make efforts to Ànd the adequate medicine by means
Harubumi Kato of cytobilogical and cytochemical approaches in
Thoracic Surgery, Niizashiki Central General addition to our 40 years of experience.
Hospital/ Tokyo Medical University/ International Keywords: history, progresses in diagnosis and
University Of Health And Welfare/Japan therapy of lung cancer
Abstract: Conceptual preparation to form an

international organization for the study of lung Based on Long Experience: What Brings the Future? Thursday, 7 July
cancer started in as early as 1972 and, Ànally, in 2011 10:30-12:00
1974, the International Association for the Study of
Lung Cancer was formally founded. 40 years have M27.5 MANAGEMENT OF NON-SMALL
passed since then, and during these past four decades CELL LUNG CANCER: 40 YEARS
much progress has been made in many diagnostic EXPERIENCE
and therapeutic procedures on lung cancer. In the Lawrence H. Einhorn
meeting, these progresses including surgery as Medicine - Oncology, Indiana University/United
well as future direction of lung cancer medicine States Of America
will be presented. In the early 1970’s, therapeutic
results were quite poor due to most cases being Abstract: During the past 40 years, lung cancer
at their advanced stages. Surgery was almost the has been the number one cause of cancer-related
only way for the therapy of lung cancer in those mortality in the United States and most other
days. Since the pathogenesis of lung cancer was countries around the world. With vigorous efforts
not well-known at the time, there were no adequate from cancer agencies, committed governments,
diagnostic and therapeutic strategies. In 1960’s, the and the oncology community, the incidence of
sputum cytology, Àberoptic bronchoscopy, and trans- smoking, fortunately, has shown a downward
thoratic percutaneous needle biopsy were developed trend. For most patients with stage I, stage II,
for the diagnosis of lung cancer. The guideline for and selected patients with stage IIIA, the optimal
the pathological classiÀcation, staging, detection, treatment remains surgery. The use of stereotactic
diagnosis and therapy of lung cancer had further radiosurgery is a newer modality that is gaining
developed since then. Lung surgery of lung cancer prominence, but thus far, there are no randomized
started from pneumonectomy in 1950’s and shifted trials to prove non-inferiority with surgery. In the
to lobectomy with systemic dissection of mediastinal 1970s and 1980s, there was no evidence of beneÀt
lymph nodes in 1970’s. During 1970’s and 1980’s with adjuvant chemotherapy. In the 1990s, it was
surgeries were performed extensively. We spent demonstrated that post-op radiation therapy, with the
tremendous amount of time and exerted much of our possible exception of stage IIIA N2 disease, had no
efforts in the study of diagnostic pathology, staging, beneÀcial role. The IALT study, for the Àrst time,
therapeutic effect and prognosis from the resected demonstrated that there was a possibility to improve
specimens during those years. In 1990’s, surgical progression-free survival and overall survival in
procedure was gradually shifted to the limited selected patients with adjuvant cisplatin combination
chemotherapy. This is now the world standard line therapy only for patients with non-squamous,
for patients with stage IIA, IIB, and IIIA resected non-small cell lung cancer. Erlotinib was the Àrst
non-small cell lung cancer. Unanswered questions single agent molecular targeted agent to provide
include the number of courses of chemotherapy survival beneÀt. This is particularly pronounced
and whether the use of molecular targeted agents in the never smokers and especially those who
such as Bevacizumab could further improve results have the EGFR mutation at Exon-19 or Exon-21.
when added to a cisplatin doublet. Studies are With the advances in molecular understanding of
underway to utilize molecular discriminants rather this complicated disease and the desire to achieve
than just histopathologic classiÀcation to optimally personalized medicine, hopefully further improved
determine which patients should receive adjuvant therapies will be forthcoming. One of the most
chemotherapy and whether it should include dramatic of these is the demonstration of the 4 EML
cisplatin. In locally advanced inoperable disease, ALK mutation. Phase II results with crizotinib
radiotherapy alone had been the standard of care have been very impressive and phase III studies are
for several decades. However, in the 1980s, studies currently being conducted. This is also primarily in
were done demonstrating improved survival with non-smokers and only 4% of stage IV lung cancer
sequential chemoradiotherapy. The standard today patients harbor this mutation. Nevertheless, we
is concurrent chemoradiotherapy. Clinical trials are now unlocking the molecular mysteries of this
have looked at various forms of combinations of fascinating disease and are developing successful
chemotherapy and radiotherapy including a study therapies based not just upon histopathology, but the
looking at prophylactic cranial irradiation and also molecular determinants that drive the progression of
the question of chemotherapy being given before disease.
and/or after the concurrent chemoradiotherapy. In Keyword: Non-small cell lung cancer and
stage IV disease, cure is not the objective, but instead chemotherapy
palliation of symptoms and modest prolongation
of survival. Twenty-Àve years ago, there were
valid arguments as to whether cisplatin-based Based on Long Experience: What Brings the Future? Thursday, 7 July
chemotherapy, despite its minimal prolongation of 2011 10:30-12:00
survival, was producing more harm than beneÀt for
patients because of the severe chemotherapy-induced M27.6 PULMONOLOGY
nausea and vomiting. Perhaps one of the more subtle, Stephen Spiro
but deÀnite advances in the palliation of stage IV Respiratory Medicine, Royal Brompton Hospital/
lung cancer was the development of more effective United Kingdom
antiemetics to mitigate the chemotherapy-induced
nausea and vomiting. Platinum combination therapy Abstract: The place of the chest physician in the
is the standard Àrst-line therapy. Data from the management of lung cancer remains pivotal. Most
ECOG 4599 study demonstrated a further 2 month cases are initially referred to a chest physician who is
improvement in median survival time (10.3 vs. 12.3 responsible for the diagnosis,staging and explaining
months) by adding bevacizumab to carboplatin + possible treatment options. They should also be
paclitaxel. However, the AVAIL study of cisplatin expert in breaking bad news, and must remain
+ gemcitabine with or without bevacizumab failed the reference point for the patient throughout the
to conÀrm an improvement in overall survival. illness. Once treated, the patient should be referred
Further advances during the past decade have back to the chst physician for long term review of
included second, third, and even fourth-line therapy care pathways and to prevent confusion common
for patients with stage IV disease. Docetaxel was with multiple carers. Also, the complications of
compared to vinorelbine or ifosfamide or best the disease ( and of treatment) are often respiratory
supportive care and demonstrated improved survival and he is best positioned to deal with these. As
as second-line therapy. A non-inferiority study respiratory medicine deals with many other illnesses
compared pemetrexed to docetaxel with similar in addition to lung cancer,especially COPD, as well
results as far as response rate, progression-free as many with no serious organic illness, he is best
survival, and overall survival, but with more ease placed to give preventative advice. We are unique
of administration and less toxicity. Pemetrexate is amongst carers of lung cancer in this respect and
currently recommended as Àrst-line or subsequent- smoking cessation remains one of the most effective
means of reducing the prevalence of lung cancer. patients have signiÀcantly better survival than
Recent developments in practice enhance the role. those with distant metastases and they are now
Examples include the management of pulmonary classiÀed as T4 (Stage IIIB) (Rami-Porta, 2007).
nodules found on CT,reÀning endobronchial lymph The contralateral lung is a relatively uncommon
node mapping and biopsy which will become site for metastases, and autopsy studies have found
routine.The place of lung function testing around their presence in only 20- 22% of patients dying of
surgery and radical radiotherapy, must be optimised NSCLC. 5-year survival for patients who undergo
and it is the responsibility of the chest physician resection for bilateral synchronous lung cancers
to maintain these standards.The interested chest is 38-43% [Voltolini 2010, DeLeyn 2008], and
physician should have expert knowledge on is approximately 30% for patients who undergo
screening as thier population is often a high risk resection for a second nodule in an ipsilateral lobe.
one.Also, is predictive markers for diagnosis or Adrenal oligometastases Autopsy studies have
susceptibility become available, this is an area shown that the adrenal glands are a common site
outside the routine oncological practice. In an of metastatic involvement (involved in 18-42%
increasingly aging population the challenge to of patients dying with lung cancer). However,
assess and maintain Àtness despite increasing co- the incidence of solitary adrenal metastases is
morbidities is our remit. In future lung cancer may reported to be lower (2-4%) (Porte 2001). A recent
become a chronic disease with multiple treatment systematic review evaluated 10 studies with a total
regimes; then overall care of co-morbidities, quality of 114 patients and concluded that patients with
of life and Àtness will be as important as prevention. synchronous metastases had signiÀcantly shorter
Keywords: pulmonologist, overall care median survival than patients with metachronous
lesions (12 months vs. 31 months), however no
difference in 5-year survival was identiÀed (26%
Session M28: Oligometastatic Disease and 25%, respectively)(Tanvetyanon 2008). A large
multi-institution study (42 patients) from France,
Thursday, 7 July 2011 which was not included in the systematic review,
contradicts these results showing no difference in
outcome between synchronous and metachronous
Oligometastatic Disease Thursday, 7 July 2011 10:30-12:00 metastases (Porte 2001). In this study adrenalectomy
for solitary NSCLC metastases was associated
M28.2 ADRENAL, OTHER SITES with a median survival of only 11 months with
David Rice only 3 (7%) patients alive at 5 years. The role of
Thoracic And Cardiovascular Surgery, MD Anderson neoadjuvant or adjuvant systemic therapy in the
Cancer Center/United States Of America setting of adrenalectomy for oligometastatic NSLC
is unknown. A literature review of 18 cases from
Abstract: It can be difÀcult or even impossible to 1965 to 1999 suggested a possible survival beneÀt
differentiate an oligometastasis in the lung from a for adrenalectomy with systemic therapy, but the
second primary tumor. Factors such as radiographic numbers are really too small to draw any Àrm
appearance may help but even metastastic lesions conclusions (Abdel-Raheem 2002). In all of the
may appear spiculated. Molecular markers and above studies there is a large element of selection
tumor grade are frequently different among primary bias that confounds the results making it difÀcult to
tumors and metastatic lesions and so are not yet make at deÀnitive conclusions. Other extrathoracic
reliable tests to determine origin. Characteristics sites Surgical resection of extrathoracic non-cranial,
that suggest that a tumor is more likely to be a non-adrenal oligometastases is rare. Luketich
second primary, include contralateral location, reported on 14 patients who had metachronous
interval of greater than 2 years from the primary solitary NSCLC metastases to extrathoracic lymph
tumor and absence of metastatic nodes in the shared nodes (6), skeletal muscle (4), bone (3) and small
lymphatics, however none of these is conclusive bowel (1) (Luketich 1995). The median disease
(Martini and Melamad 1975). Though same- free interval before metastases was 19.5 months
histology nodules in a different ipsilateral lobe and 10-year survival was 86% in this highly select
were traditionally considered metastastic (M1), the patient population. Other publications have been
recent IASLC staging project showed that these mainly anecdotal reports of single cases. But what
is the denominator? Only one study has been adrenal metastases in non-small-cell lung cancer:
performed that prospectively evaluated surgical a systematic review and pooled analysis. J Clin
resection for patients with synchronous solitary Oncol. 2008 1;26(7):1142-7. Voltolini L, Rapicetta
metastases of NSCLC (Downey 2002). Though this C, Luzzi L, et al. Surgical treatment of synchronous
study included patients with oligometastases in a multiple lung cancer located in a different lobe or
variety of organs it is important because it provides lung: high survival in node-negative subgroup. Eur
us with a denominator, something missing in all J Cardiothorac Surg. 2010;37(5):1198-204. Rami-
other retrospective series reported to date. Downey Porta R, Ball D, Crowley J, et al. The IASLC Lung
et al conducted a phase II trial in 23 patients with Cancer Staging Project: proposals for the revision
solitary synchronous M1 NSCLC with or without N2 of the T descriptors in the forthcoming (seventh)
disease who received three cycles of chemotherapy, edition of the TNM classiÀcation for lung cancer.
followed by resection of all disease sites, and then International Staging Committee; Cancer Research
two additional cycles of chemotherapy. 14 (63%) and Biostatistics; Observers to the Committee;
patients had brain metastases and the other sites Participating Institutions. J Thorac Oncol.
of disease were adrenal (3), bone (3), spleen (1), 2007;2(7):593-602.
lung (1) and colon (1). 13 patients underwent R0 Keywords: Oligometastasis, NSCLC, Adrenal, Lung
resection, of which only 8 completed the prescribed cancer
preoperative chemotherapy. Nine patients either had
disease progression during induction treatment or
were found to be unresectable at surgery. Median Oligometastatic Disease Thursday, 7 July 2011 10:30-12:00
survival for the whole group (n=23) was 11 months
and only 2 patients survived 5 years or more. Less M28.4 PULMONARY METASTASECTOMY
than half (10/23) of the patients had resection of both FOR OLIGOMETASTASES IN NON-LUNG
the primary tumor and the solitary metastasis, which CANCER
would be similar to the patient populations described Tom Treasure
in most retrospective studies. This ‘favorable’ group Mathematics, Clinical Operational Research Unit
had a 5-year survival of 20%. Thus caution must UCL/United Kingdom
be used when applying the seemingly good results
of retrospective studies of oligometastasectomy to Abstract: Hellman and Weichselbaum in 1995
decision making in patient care. Conclusion Surgical proposed the existence of a clinical state of
resection of oligometastatic NSCLC, though feasible, oligometastases.(JCO 1995;13:8) The word gained
remains controversial and should probably be currency in deÀning patients with sufÀciently
performed only in highly selected patients and after few metastases to offer a reasonable prospect of
discussion in a multidisciplinary forum. References their eradication. Pulmonary metastasectomy was
Abdel-Raheem MM, Potti A, Becker WK, et al. already established as a commonplace practice
Am J Clin Oncol. 2002;25(1):81-3. De Leyn P, from the 1970s particularly for solitary metastases
Moons J, Vansteenkiste J, et al. Eur J Cardiothorac from colorectal cancer.(JRSM 2010;103:60) At the
Surg. 2008;34(6):1215-22. Downey RJ, Ng KK, end of the 1980s substantial series of pulmonary
Kris MG, et al. A phase II trial of chemotherapy metastasectomy operations for sarcoma were
and surgery for non-small cell lung cancer patients reported by Goldstraw(EJCTS 1989;3:105)
with a synchronous solitary metastasis. Lung and Pastorino(JSO 1989;40:275). The word
Cancer. 2002;38(2):193-7. Luketich JD, Martini N, oligometastasis had not yet been proposed.
Ginsberg RJ, et al.Successful treatment of solitary The descriptive utility of the term is evident but the
extracranial metastases from non-small cell lung implication that there is an entity distinguishable by
cancer. Ann Thorac Surg. 1995;60(6):1609-11. the “fewness” of metastases is not. It would require
Martini N, Melamed MR. J Thorac Cardiovasc Surg. demonstration of a bimodal distribution in metastatic
1975;70(4):606-12. Porte H, Siat J, Guibert B, et count. It is more likely that these are patients at one
al. Resection of adrenal metastases from non-small end of a continuous distribution of the number of
cell lung cancer: a multicenter study. Ann Thorac metastases. Nevertheless, number matters. Fewer and
Surg. 2001;71(3):981-5. Tanvetyanon T, Robinson particularly solitary pulmonary metastases have been
LA, Schell MJ, et al. Outcomes of adrenalectomy shown to be associated with longer survival after
for isolated synchronous versus metachronous pulmonary metastasectomy for all cancer types in the
International Registry of Lung Metastases.(JTCVS such as having few metastases, then the natural
1997;113:37) Early in the era of clinical acceptance survivors will be over represented in surgical follow
of metastasectomy Aberg asked whether the up studies. If the presumption is that less invasive
effect of metastasectomy was fact or Àction?(ATS means of ablation will replicate the claimed beneÀts
1980;30:378) He suggested that long survival might of surgery, but with less harm, then the therapists
be related to the selection of good prognosis patients should be reminded of this lack of proof. The best
rather than surgical eradication of disease. He argued way to resolve this uncertainty is with a randomised
that survival might be erroneously attributed to controlled trial. The PulMiCC trial (Pulmonary
surgery. Aberg’s hypothesis has not yet been refuted; Metastasectomy in Colorectal Cancer) is in essence
citation network analysis shows that his challenge a trial of surgical effectiveness in patients with
has largely been ignored(Fiorentino BJC 2011). The oligometastatic disease.(JTO 2010:5(S6):S203) The
commonest primary cancer site for which pulmonary number is not mandated by protocol; the design
metastasectomy is undertaken is colorectal cancer. allows teams to allocate patients to metastasectomy
There have been many follow up and observational when they believe there is uncertainty concerning
cohort studies with statistical analyses of the beneÀt. On current evidence and practice this might
inÁuence of the number of metastases on survival. include patients with 2-4 pulmonary metastases.
In the quantitative synthesis of 51 reports(JRSM However the number of metastases is only one of
2010;103:60) about 60% of 3504 patients had a the factors on which a clinical decision might be
solitary metastasis and that was more favourable based so solitary metastases, or 5+, are not excluded
than multiple metastases for survival as an outcome. if, taking other factors into account, the team
In an analysis from MSKCC(ATS 2009;87:1684) the conclude that there is uncertainty about the decision
favourable effect of having oligometastatic disease to perform metastasectomy or not for this patient.
was lost at four or more metastases. In the context It is only by such formal studies that we will bring
of colorectal cancer this might serve as an upper a better understanding to whether the “fewness” of
bound on the oligometastatic state in the process of metastases has a utility in planning management.
selecting patients for surgery or ablative therapies Keywords: Oligometastasis, Pulmonary
if we are to spare them unavailing interventions. metastasectomy
The reminder that interventions to remove or
ablate metastases might be followed by further
progression of cancer should prompt practitioners
to consider exactly what beneÀcial outcome they
are seeking to achieve in the management of so
called oligometastatic disease. The surgical literature
is dominated by studies in which the outcome
reported is survival, usually expressed as the
proportion alive at Àve years. Symptoms, before or
after metastasectomy, are very rarely mentioned.
It is generally assumed that in the natural history
of metastatic colorectal cancer survival to Àve
years is a rare occurrence: survival is attributed to
surgery in surgical reports. There are no controlled
studies so attempts have been made to approach the
question of effectiveness of metastasectomy by use
of mathematical modelling.(JTO 2010;5(S6):S200)
The Àrst notable Ànding, which contradicts the
assumption that all survival is attributable to
metastasectomy, is that in cancer registry data there
are 5-10% natural survivors amongst patients deÀned
as having metastatic disease on entry to the registry.
If only a minority are selected (and data indicate
that it is low single Àgure percentages) and that
they are selected on factors which are prognostic,
EDUCATIONAL SESSIONS an anti-mesothelin antibody and pseudomonas

exotoxin (SS1P) are being conducted. Two Phase I
studies showed SSP1 was relatively well tolerated
Session E01: Treatment of and resulted in some interesting clinical effects,
Mesothelioma including partial responses and stable disease.
A Phase II trial combining SS1P with standard
chemotherapy is ongoing at the NCI in the U.S.
Monday, 4 July 2011
A trial using a modiÀed listeria bacterial vector
encoding mesothelin was also conducted, however
Treatment of Mesothelioma Monday, 4 July 2011 10:30-12:00 preliminary results did not demonstrate generation
of impressive cellular immune responses. Our group
E01.1 IMMUNOLOGICAL TREATMENT at the University of Pennsylvania conducted a series
IN MPM of Phase 1 clinical trials of a replication-incompetent
Daniel H. Sterman1, James Stevenson2, Andrew R. adenoviral vector encoding HSVtk (Ad.HSVtk)
Haas3, Steven M. Albelda3 delivered intrapleurally (followed by Ganciclovir)
1
Medicine, University Of Pennsylvania/United States into 34 patients with pleural mesothelioma. Dose
Of America, 2Hematology/Oncology, Abramson limiting toxicity was not reached, side effects were
Cancer Center, University Of Pennsylvania/United minimal and gene transfer was conÀrmed in a
States Of America, 3University Of Pennsylvania dose-related fashion with clearly detectable gene
Medical Center/United States Of America transfer (evidenced by immunostaining) at tumor
surfaces and up to 30-50 cell layers deep. Anti-
Abstract: Malignant Mesothelioma has been a tumor antibodies and strong anti-adenoviral immune
target of immunotherapy for decades. Early studies responses, including high titers of neutralizing
used systemic and/or intrapleural cytokines delivery antibody and proliferative T-cell responses were
to initiate immune response. In the early 1990’s, generated, however, with no obvious adverse side
Boutin and colleagues showed signiÀcant clinical effects. Interestingly, a number of clinical responses
responses in early-stage mesothelioma to intrapleural were seen at the higher dose levels, including two
administration of interferon-gamma. Subcutaneous patients that remained alive (one without disease) for
interferon-alpha (a Type 1 interferon) demonstrated more than 10 years after vector instillation. Based
anti-tumor activity in clinical trials. Immunotherapy on a series of preclinical experiments, our group has
trials using IL-2 have also been conducted, either completed a series of Phase 1 dose escalation studies
as single agent intrapleural, or in combination evaluating the safety and feasibility of intrapleural
with multi-modality therapy. Vaccines have also interferon-beta gene transfer using an adenoviral
been studied in clinical trials. Approaches include vector (Ad.IFNb) in patients with malignant pleural
autologous tumor cells (with and without adjuvants mesothelioma (MM) and metastatic pleural effusions
such as GM-CSF) and a vaccine containing peptides (MPE). Ad.IFNb was administered through an
from the Wilms tumor-1 (WT-1) gene product with indwelling pleural catheter in doses ranging from 9
cellular and humoral immune responses induced, x 1011 to 3 x 1012 viral particles (vp). A total of 27
and notation of anecdotal clinical responses. More patients in 3 trials have been dosed since 2005 and
recently, a trial conducted in the Netherlands by include 17 with malignant mesotheliomas, 5 with
Hegmans et al. using tumor antigen-loaded dendritic advanced lung cancer, 3 with metastatic ovarian
cells has shown promise. Based on strong preclinical cancer, and 2 with metastatic breast cancer. In the
data, a clinical using an agonistic CD40 antibody Àrst trial, we used one dose of vector; later trials
to stimulate immune responses in combination used two doses spaced at 14 or 7 days apart.Subjects
with Gemcitabine chemotherapy was recently were evaluated for toxicity, gene transfer, humoral,
initiated at the Sir Charles Gairdiner Hospital in cellular, and cytokine-mediated immune responses,
Perth, Australia. The protein mesothelin, which and tumor responses via 18-Áuorodeoxyglucose
is highly upregulated on mesothelioma, has been (18FDG) positron-emission tomography (PET) scans
indentiÀed as a potentially good tumor antigen and and chest CT scans. Intrapleural Ad.INF-b was
thus a target for immunotherapy. Clinical trials generally well tolerated with transient lymphopenia
initiated at the NCI using a high afÀnity antibody the most common side effect. The presence of the
alone (MORAB-009) or a fusion protein between vector did not elicit a marked cellular inÀltrate in
the pleural space. Good gene transfer seen after the standard therapeutic armamentarium.
Àrst dose with high IFN beta levels measured in Keywords: immunotherapy, mesothelioma, Vaccine,
the pleural Áuid after vector installation. However, Cytokine
only very low gene transfer seen after a second
dose- with either 14 day and 7 day spacing. We
attribute this to rapid upregulation of neutralizing Treatment of Mesothelioma Monday, 4 July 2011 10:30-12:00
antibodies against adenovirus. Anti-tumor humoral
immune responses were seen almost all patients with E01.3 MPM GUIDELINES IN THE YEAR
reactions seen against known Meso tumor antigens 2011
(SV40 large T antigen and mesothelin) and against Arnaud Scherpereel
unknown proteins in cell lysates. Given the caveats Pulmonary And Thoracic Oncology, University Of
of Phase 1 trials (small numbers, different doses, Lille Hospital/France
heavily pretreated patients), we still saw clinical
responses (deÀned as prolonged stable disease, Abstract: Malignant pleural mesothelioma (MPM)
prolonged survival, partial or complete responses has become a serious issue because of its global
by modiÀed RESIST criteria, decreased metabolic poor prognosis and its growing incidence. This
tumor activity by PET scanning, or “mixed” incidence seems to have already reached a peak in
responses) in about 1/3 of the patients. We are some countries where asbestos was banned earlier
currently administering two doses of a similar Type than in most countries, taking account of the long
I interferon transgene - Intrapleural Ad.INF-alpha- latency of mesothelioma (about 40 years) after
2b - spaced only three days apart. This appears to asbestos exposure, its main tumorogenic factor.
be well tolerated. Based on strong preclinical data However, MPM incidence is expected to increase
supporting the combination of gene therapy and for at least the next ten years in several Western
chemotherapy, we have started a trial using Ad.INF countries, linked to a late ban of asbestos (for
instillation into the Àrst treatment cycle of Àrst line example, only in 2005 in the European Community).
(Cisplatin/Pemetrexed) or second line chemotherapy Moreover asbestos is still widely produced and
(Gemcitabine). We are also utilizing concomitant used in many emerging or developping countries,
COX-2 inhibition with Celecoxib to modulate suggesting the risk of a future worldwide epidemy
intratumoral immunosuppression, and to decrease of malignant mesothelioma in the next decades.
suppressor cell activity, as has been demonstrated In 2009, the European Respiratory Society (ERS)
by Hegmans, et al. Our groups is also generating and the European Society of Thoracic Surgeons
“designer chimeric T cells” in which a single chain (ESTS) experts proposed practical and up-to-dated
antibody fragment is linked to the transmembrane guidelines on management of MPM (Eur Respir J.
and cytoplasmic regions of the T-cell receptor. This 2010 35(3): 479-95. [Epub 2009 Aug 28]). Are these
artiÀcial T-cell receptor is then transduced into guidelines still relevant in 2011? To obtain an earlier
T-cells that are then reinfused. The T-cells are then and reliable diagnosis of MPM is a crucial issue. The
activated by cells expressing mesothelin. Preclinical experts recommended, except in case of preoperative
data show striking activity against mesothelin- contraindication or pleural symphysis, to perform
expressing tumors in mice. Mesotheliomas make thoracoscopy with multiple histological biopsies for
large amounts of the immunoinhibitory cytokine, the diagnosis of MPM. To date, the performances
transforming growth factor-beta (TGF-b). Preclinical of other diagnostic procedures, i.e. pleural cytology,
studies using TGF-b blockers have shown activity blind or even guided pleural biopsies, are still too
in mouse models of mesothelioma and a clinical low compared to thoracoscopy, the gold standard
trial using an anti- TGF-b antibody is ongoing at the for MPM diagnosis. Standard staining procedures
University of Pennsylvania and the University of in pathology are insufÀcient in 7-15% of cases.
Chicago. In summary, immunotherapies are being Therefore it is recommended that a diagnosis of
actively studied in mesothelioma and have shown MPM always be based on immunohistochemical
some promising results. Future trials are focusing examination. The International Mesothelioma
on combining these approaches with chemotherapy Panel also recommended to use two markers
and surgery. Given the relatively mild and non- with positive diagnostic value for mesothelioma
overlapping toxicities, we believe these, or other (anti-calretinin and anti-WT1 or anti-EMA, or
immunologic approaches will soon become part of for epithelioid mesothelioma, anti-CK5/6...) and
two markers with negative diagnostic value (anti- (EORTC 08031...) and studies raise the question
Ber-EP4, anti-TTF1...) to validate the diagnosis. of the feasibility and the value of EPP. Therefore
The staging of MPM is still a difÀcult issue in the several authors suggested that P/D could be a better
absence of a uniform, robust and validated staging surgical procedure as part of multimodal treatment.
system. A new staging system for MPM should be Due to the lack of strong evidence, it is not possible
proposed soon by experts from a joined IASLC- to recommend radiotherapy after EPP or P/D in
IMIG project. But to date, the ERS/ESTS experts routine, even using intensity-modulated radiotherapy
adviced to use of the most recent (1995) TNM (IMRT). Thus post-operative irradiation should only
based classiÀcation, and proposed a three steps pre- be proposed in clinical trials, in specialized centres
treatment assessment according to the therapeutic for MPM. Finally there are new exciting therapeutic
project of each patient. Performance status of the tools or strategies such as targeted therapies, gene or
patient and histopathological subtype of the tumor cell therapies but still under investigation in MPM
(the epithelioid subtype is considered of better patients. Some of these new agents such as pro-
prognosis than other MPM subtypes) are currently apoptotic drugs (histone deacetylase inhibitors...) or
the only prognostic factors of clinical importance anti-angiogenic tools will be detailed during this talk.
in the management of MPM in the general practice. In conclusion, guidelines on MPM management from
Other potential clinical or biological prognostic 2009 ERS/ESTS taskforce are still relevant in 2011.
parameters, suggested by the EORTC and the Because of still limited data available on the best
CALGB for instance, should be recorded at baseline combination treatment for MPM in 2011, it must be
and reported in clinical trials. Monitoring of patients emphasized that inclusion of MPM patients in Àrst
still relies mostly on clinical examination and chest and second-line clinical trials is highly encouraged,
CT-scan data, using modiÀed RECIST criteria. and that potential candidates for a multimodal
Based on recent but limited literature, PET-scan approach should be included in a prospective trial in
and potential soluble tumor markers such as blood specialized centres.
mesothelin (SMRP) seem promising in this goal Keywords: mesothelioma, guidelines, diagnosis,
but are not validated in routine. MPM exhibits treatment
a high resistance to standard chemotherapy and
only few patients are candidate for radical surgery.
ERS/ESTS guidelines on MPM treatment are still Session E02: Imaging for Radiotherapy
relevant in 2011. When a decision is made to treat Planning and Adaptive Planning
patients with chemotherapy, subjects in a good
performance status (PS > 60% on the Karnofsky
Monday, 4 July 2011
scale or < 3 on the ECOG scale) should be treated
with Àrst line combination chemotherapy consisting
of platinum and pemetrexed (or raltitrexed). Patients Imaging for Radiotherapy Planning and Adaptive Planning Monday,
demonstrating prolonged symptomatic and objective 4 July 2011 10:30-12:00
response with Àrst line chemotherapy may be
treated again with the same regimen (pemetrexed) E02.1 CURRENT ROLE OF 4D PET SCANS
in the event of recurrence. Alternatively, inclusion Wouter Van Elmpt, Michel Öllers, Philippe Lambin,
of the patients in Àrst and second-line clinical Dirk De Ruysscher
trials is highly encouraged. Radiotherapy and Department Of Radiation Oncology (MAASTRO),
surgery indications are limited and still highly Grow-School For Oncology And Developmental
discussed in MPM. In 2009, it was also stated that Biology, Maastricht University Medical Centre/
(a) radical surgery (extrapleural pneumonectomy Netherlands
or EPP) should be performed only in clinical trials,
in specialized centres, as a part of multimodal Abstract: FDG-PET/CT imaging is a major
treatment, and (b) pleurectomy/decortication (P/D) component in the staging of non-small cell lung
should not be proposed in a curative intent but cancer patients. It is an integral part for the optimal
can be considered in patients to obtain symptom deÀnition of target volumes as well.[1] Although
control, especially symptomatic patients with respiratory movements have been incorporated
entrapped lung syndrome who cannot beneÀt from in radiation planning by 4D-CT scans, the role of
chemical pleurodesis. However recent clinical trials respiratory correlated (or 4D) PET imaging is still
not implemented in routine clinical practice. For this phase, the corresponding phase of the CT
4D PET imaging typically uses a surrogate scan can be chosen on which the target and organs-
measurement of the patient’s respiratory cycle, e.g. at-risk delineations are performed. The advantage is
a pressure belt strapped around the thorax of the that the statistical accuracy is again comparable to
patient or imaging of a reÁective marker positioned the standard 3D PET but without motion-blurring.
on the patient’s chest. Afterwards the 4D PET scan In conclusion, compared to 4D CT imaging the
is reconstructed according to measured breathing counterpart for 4D PET has not been widely used
surrogate. A phase-based or an amplitude based in clinical practice. There is a potential for 4D
reconstruction algorithm might be used for this. PET also in the clinical routine. This may also be
The advantages of 4D PET imaging are numerous. In necessary in future where PET imaging will be more
principle a more accurate quantiÀcation of the tumor frequently used in (automatic) target deÀnition or
volume is possible because motion-blurring due to with the current trials focusing on boosting and dose-
respiration is removed. Small nodules might become painting an accurate (sub-)target volume deÀnition
detectable and accurate SUV quantiÀcation is more is mandatory. Using respiration-correlated PET
robust.[2] Removing respiratory blurring from the imaging removes one of the uncertainties in this
PET images decreases one of the components that tumor characterization procedure.
adds to the overall uncertainty of entire procedure.
Possible drawbacks that are currently hampering References:
further implementation are due to non-optimized 1. De Ruysscher D, Faivre-Finn C, Nestle U,
logistics and technical issues in the commercial Hurkmans CW, Le Péchoux C, Price A, Senan S.
systems. Attenuation correction of the individual “European Organisation for Research and Treatment
phases need a proper matching of the corresponding of Cancer recommendations for planning and
CT phase, this might cause problems if the CT is delivery of high-dose, high-precision radiotherapy
made using an amplitude binning algorithm and for lung cancer,” J Clin Oncol 28(36):5301-10
the PET is binned according to a phase-binning (2010).
type. Handling the large amount of data could be 2. García Vicente AM, Soriano Castrejón AM,
problematic and viewing stations might not be able Talavera Rubio MP, León Martín AA, Palomar
to show the 4D phases of a respiratory correlated Muñoz AM, Pilkington Woll JP, Poblete García
acquisition. Prolonged acquisition times are VM, “(18)F-FDG PET-CT respiratory gating
necessary to have enough statistical accuracy to yield in characterization of pulmonary lesions:
the same contrast-to-noise ratios as in conventional approximation towards clinical indications,”Ann
non-gated PET acquisitions. Nucl Med 24(3):207-214 (2010).
There are various solutions to incorporate tumor 3. Liu C, Alessio A, Pierce L, Thielemans K,
motion during the respiratory cycle in the image Wollenweber S, Ganin A, Kinahan P. “Quiescent
acquisition or reconstruction. A Àrst simple approach period respiratory gating for PET/CT,” Med Phys
might be to acquire a 3D PET image using multiple 37(9):5037-43 (2011).
breath holds, however given the condition of lung 4. van Elmpt W, Hamill J, Jones J, De Ruysscher D,
cancer patients this might not be a feasible approach Lambin P, Ollers M., “Optimal gating compared to
for the majority of the population. A somewhat 3D and 4D PET reconstruction for characterization
intermediate approach has been proposed by Liu of lung tumours,” Eur J Nucl Med Mol Imaging in
et al.[3] and van Elmpt et al.[4] that make use of press (2011).
the longer exhale phase in the breathing cycle to 5. Dawood M, Buther F, Jiang X, Schafers KP.
reconstruct a static PET image with only information “Respiratory motion correction in 3-D PET data with
acquired in this phase. Motion blurring is minimal advanced optical Áow algorithms,” IEEE Trans Med
and hence a non-blurred static 3D PET image is Imaging 27(8):1164-75 (2008).
acquired. Other techniques that are currently under
development are the use of non-rigid registration
models either directly implemented in the list-mode
PET reconstruction software or afterwards applied
to the reconstructed 4D PET images [5]. These
techniques allow the reconstruction of a single 3D
PET image at a reference phase that can be chosen.
Imaging for Radiotherapy Planning and Adaptive Planning Monday, motion, reducing the beneÀt of gating/tracking
4 July 2011 10:30-12:00 or potentially even reducing the overall accuracy.
Alternatively, intra-fraction imaging can be designed
E02.2 INTRAFRACTIONAL AND to monitor the mean (over the respiratory cycles)
ADAPTIVE CORRECTION STRATEGIES target position, trailing systematic changes to the
Jan Jakob Sonke position of the target. Such tumor trailing techniques
Radiology, NKI-AVL/Netherlands requires less complex systems with lower response
time and lower imaging frequencies with lower
Abstract: Radiation therapy of lung cancer is imaging dose. Adaptive radiotherapy (ART) typically
associated with complex geometrical uncertainties utilizes a feedback loop that operates at a time scale
such as respiratory induced motion, (differential) of days to weeks. Over this time period, patient
baseline shifts of primary tumor and involved lymph speciÀc variations and systematic discrepancies
nodes and anatomical changes due to treatment between planning and delivery are quantiÀed.
response. Consequently, the actually delivered dose Subsequently, a new treatment plan is designed
generally does not equal the planned dose (what that takes these patient speciÀc parameters into
you see is not what you get). In the absence of account. Because systematic errors have a factor of
correction strategies, generous safety margins are 4 larger impact on the delivered dose than random
required to account for these uncertainties which error, such adaptations based on information from
limit the potential of dose escalation to improve previous days remains effective. For stereotactic
treatment outcome. The current state of the art in body radiotherapy (SBRT), delivering a high
accurate treatment delivery of radiation therapy is therapeutic dose in only a small number of fractions,
IGRT (image guided radiotherapy), which is the the beneÀt of ART is expected to be limited. For
process of 1) acquiring an image of the patients conventional fractionated RT, ART has the potential
anatomy, generally in the treatment room with to account for shape changes, differential baseline
the patient in treatment position, 2) comparing shifts and even geometric and biological response.
the treatment position with planned position of Currently, necessary tools to implement ART are
the tumor, organs at risk or some surrogate and 3) not commercially available, hampering large scale
correcting the treatment position, generally with clinical implementation. Additionally, it has not been
a couch correction. Such correction strategies proven that adapting the treatment plan to treatment
are mostly limited to the management of inter- response (tumor regression and/or biological
fraction setup error and inter-fraction baseline response) is safe and effective. Such adaptations
shifts. Further improvements are expected from should therefore only be implemented in clinical
so-called imaging feedback-loops, e.g. utilizing trials.
information obtained from repetitive imaging that Keyword: imaging, adaptive radiotherapy,
are fed back to the delivery process. Such feedback intrafraction motion, respiration
loops can operate at a short time scale (seconds to
minutes) to manage intra-fractional variability, or
at a longer time scale (days to weeks) to manage Imaging for Radiotherapy Planning and Adaptive Planning Monday,
inter-fractional variability’s and progressive changes. 4 July 2011 10:30-12:00
Intra-fraction monitoring generally aims to quantify
respiratory induced motion and feeds this signal to E02.3 ADVANCES IN ON-BOARD IMAGE-
the delivery system to either gate the beam (only GUIDANCE
switch on the beam when the target is predicted to Matthias Guckenberger
be within a region of interest) or to track the target Department Of Radiation Oncology, University
(continuously steer the beam to the target). Due to Hospital Wuerzburg/Germany
the random nature of respiratory induced motion
during treatment delivery, the expected gain of Abstract: Traditionally, patient set-up in daily
such gating and tracking techniques are likely to be treatment was based on skin marks and portal
limited. Moreover, currently available techniques are imaging was performed for veriÀcation of patient
often based on an external surrogate of respiratory set-up. However, image quality, especially soft-tissue
motion. Various groups have demonstrated limited contrast, of these portal images was insufÀcient
correlation between external signals and internal for visualization of the pulmonary target itself: the
bony anatomy then served as a surrogate for the which can be detected with CBCT and can be used
target position. However, today it is well known to initiate an adaptation of radiotherapy (Fig. 1). Not
that substantial tumor motion independently from only changes of tumor but also of the normal tissue
the bony anatomy is observed in many patients. (atelectasis, pleural effusion) is regularly observed
This cannot be detected with portal images; if and such changes should trigger replanning if certain
not compensated by appropriate, rather large thresholds are exceeded. Such adaptive replanning
safety-margins, underdosage of the tumor with work-Áows, however, are still an area of active
decreased local tumor control is the consequence. research and further technologies like deformable
Since several years, image-guidance technology image registration are required for broad clinical
has become available for veriÀcation of the target implementation.
position prior to treatment. The most advanced Keywords: NSCLC, Onborad imaging, cone beam
and most frequently used technique is the so-call CT, adaptive radiotherapy
cone-beam CT (CBCT): this technology consists
of a kilo-voltage x-ray source integrated into the
linear accelerator with a digital Áatpanel for image Imaging for Radiotherapy Planning and Adaptive Planning Monday,
acquisition. The imaging is installed orthogonal to 4 July 2011 10:30-12:00
the therapeutic mega-voltage beam and allows for
acquisition of a volumetric image within a 180° E02.4 ROLE OF PET SCANS IN
gantry rotation. The image quality of this CBCT RADIOTHERAPY - PROGNOSIS AND
is sufÀcient for visualization of soft tissue tumors, TARGET DEFINITION
despite mediastinal structures cannot be fully Michael P. MacManus
segmented. The major advantage of this on-board Radiation Oncology, Peter MacCallum Cancer
design is the fact that imaging can be performed Centre/Australia
in treatment position without needing to move the
patient or the treatment couch, which could introduce Abstract: Introduction The advent of PET imaging,
secondary errors. Since recently, respiration and more recently of its technically superior
correlated CBCT is available for full integration of cousin PET/CT, has transformed the way radiation
breathing motion into the image-guidance work-Áow. oncologists approach lung cancer. After biopsy,
18
For hypo-fractionated stereotactic body radiotherapy, F-Áuorodeoxyglucose (FDG)-PET/CT is the most
veriÀcation of the target position prior to every signiÀcant single investigation for selecting patients
treatment fraction using CBCT is considered as for deÀnitive radiotherapy or chemoradiotherapy.
best practice: this compensates for both set-up PET/CT often contradicts conventional imaging (CI)
errors of the patient as well as base-line drifts of and has a much higher probability of reÁecting the
the pulmonary tumor within the lung. It needs to true extent of primary, nodal and metastatic disease
be considered that such base-lien drifts could cause than CI. Role of FDG-PET in Patient Selection for
the tumor to move closer to a critical organ-at-risk Radiotherapy: PET as a Pre-Treatment Prognostic
with the risk of increased toxicity if this image- Factor Stage is the most important prognostic factor
guided isocenter correction is performed. Depending in NSCLC. Numerous individual prospective studies
on immobilization, total treatment time and and several meta-analyses have proven the superior
fractionation, repeated imaging during the treatment accuracy of PET assisted mediastinal staging
fraction might be reasonable for intra-fractional compared to CT based staging. PET and PET/CT
target monitoring. It is essential that breathing are also superior for detecting distant metastasis.
induced motion of the target is fully integrated into In a prospective study of radiotherapy candidates,
the image-guidance work-Áow. In conventionally about one third of 153 cases were found to be
fractionated radiotherapy, image-guidance might me unsuitable for potentially curative therapy after PET,
more complicated. Motion or drifts of the primary either because of distant metastasis or extensive
tumor independently from the mediastinal / hilar mediastinal disease 1. PET stage was more predictive
nodes has been described. Such complex changes of of survival than CI stage. Similar results were
the shape of the target volume cannot be corrected reported by a Polish group in that only 75 of 100
via a single couch correction. Additionally, shrinkage radical radiotherapy patients with NSCLC actually
of the macroscopic tumor is frequently observed in went on to receive radical RT after PET/CT imaging
2
conventionally fractionated radio(chemo)therapy, . The standardized uptake value or SUV, may have
prognostic signiÀcance. Some reports indicate that an approach currently being investigated by De
as the SUV rises the prognosis worsens, but not all Ruysscher and colleagues. We are exploring PET
studies are in agreement and it is unclear to what imaging with both FDG and the proliferation marker
extent SUV is an independent prognostic factor 18F-3 -deoxy-3 -Áuoro-l-thymidine (FLT) to
because SUV is correlated with stage. Role of FDG- assess tumour response during therapy. Role of PET
PET for Radiotherapy Target DeÀnition in NSCLC Response assessment as a Prognostic Factor after
Because FDG-PET based imaging is the most Radiotherapy There is clear evidence that FDG-
accurate we have, it is logical to use this information PET imaging performed approximately 2 months
routinely in radiotherapy planning, employing it after completion of treatment provides powerful
as a “gold standard” in the absence of pathological prognostic information and is far superior to CT
5
staging. All published studies show a clinically . Metabolic response measured by FDG-PET is
signiÀcant impact of PET in radiotherapy planning. the most important single prognostic factor after
The magnitude of this effect differs between studies chemoradiation. Conclusion Molecular imaging with
reÁecting, varied sample sizes and radiotherapy FDG-PET/CT has rapidly become established as the
planning practices. In cases with atelactasis it is key imaging modality for lung cancer. It profoundly
often possible to spare collapsed lung and reduce affects patient selection and radiotherapy planning.
the target volume. In other cases, PET may caused Staging and restaging with PET also provides the
an increase in the target volume when small lymph most powerful pre- and post-treatment prognostic
nodes are found to be FDG positive. PET may based information available. The results of studies
planning may enable safe dose escalation 3. Only a currently in progress may eventually lead to dynamic
recent PET/CT scan should be used for radiotherapy changes in the delivery of radiotherapy during the
planning. In a prospective study we reported a treatment course. References 1. Mac Manus MP,
very rapid rate of disease progression between Hicks RJ, Ball DL, et al. F-18 Áuorodeoxyglucose
initial staging PET scans and radiotherapy planning positron emission tomography staging in radical
images performed a median of 3 weeks later. radiotherapy candidates with nonsmall cell lung
Approximately 39% of scans showed progressive carcinoma: powerful correlation with survival and
disease at locoregional or distant metastatic sites, high impact on treatment. Cancer 2001;92:886-95. 2.
which in 29% of cases caused a change from radical Kolodziejczyk M, Kepka L, Dziuk M, et al. Impact
to palliative therapy. An enormous advantage of of [(18)F]Fluorodeoxyglucose PET-CT Staging on
PET/CT is the reduced observer variability in tumour Treatment Planning in Radiotherapy Incorporating
contouring compared to CT alone. However, even Elective Nodal Irradiation for Non-Small-Cell Lung
using PET/CT images, there can be signiÀcant Cancer: A Prospective Study. Int J Radiat Oncol
variations between observers. Our centre employs Biol Phys. 3. De Ruysscher D, Wanders S, Minken
a visual contouring protocol to achieve a high level A, et al. Effects of radiotherapy planning with a
of reproducibility. Other centres use automated dedicated combined PET-CT-simulator of patients
approaches to tumour contouring, in which a with non-small cell lung cancer on dose limiting
software programme determines tumour margins. normal tissues and radiation dose-escalation: a
A wide range of automated methods is available planning study. Radiother Oncol 2005;77:5-10.
and all have their limitations 4. Automated methods 4. Nestle U, Kremp S, Schaefer-Schuler A, et al.
cannot entirely replace the human observer, but these Comparison of different methods for delineation
protocols can provide an excellent starting point for of 18F-FDG PET-positive tissue for target volume
subsequent human editing. Potential Role of PET deÀnition in radiotherapy of patients with non-
Response assessment as a Prognostic Factor during Small cell lung cancer. J Nucl Med 2005;46:1342-8.
Radiotherapy/Chemoradiation Tumor imaging during 5. Mac Manus MP HR, Matthews JP, McKenzie
therapy may allow for modiÀcation of the treatment A, Rischin D, Salminen EK, Ball DL. Positron
course in real time. Serial PET imaging during Emission Tomography is superior to CT scanning
a course of radiotherapy can provide prognostic for response-assessment after radical radiotherapy/
information and may also provide an opportunity chemoradiotherapy in patients with non-small cell
to target higher radiation doses to regions that lung cancer. J Clin Oncol 2003;21:1285-92.
are more resistant to therapy. Alternatively, the Keywords: Radiotherapy, PET, Chemotherapy,
baseline PET scan may be used to target regions of Prognosis
most intense tumour activity with boosting dose,
Session E03: Borderline Operable non-invasive cardiac testing treatments. If they

NSCLC need coronary intervention, lung resection should
be postponed at least for 6 weeks. If the condition
can be treated medically, treatment should be
Monday, 4 July 2011
instituted and evaluation should proceed with lung
function tests (6). 4.- Lung function Once the cardiac
Borderline Operable NSCLC Monday, 4 July 2011 10:30-12:00 evaluation is performed and the patient is found to
have low risk or can be medically treated, next step
E03.1 WHO IS A BORDERLINE is the evaluation of lung function. The recommended
OPERABLE PATIENT? Àrst step is forced expiratory volume in 1 second
Ramon Rami-Porta (FEV1) and diffusing capacity of the lung for carbon
Thoracic Surgery Service, Hospital Universitari monoxide (DLCO). If both are greater than 80%,
Mutua Terrassa/Spain lung resection, including pneumonectomy, can be
performed with acceptable risk. If either one is
Abstract: Introduction In selecting patients with below 80%, further tests are needed. In the latest
lung cancer for lung resection, two different concepts guidelines (6), the next test is the peak oxygen
have to be considered: operability and resectability. consumption (peak VO2). If it is greater than 75%
Operability is a patient’s condition that will enable or greater than 20 mL.kg-1.min-1, any type of lung
the patient to undergo the planned lung resection resection can be performed with an acceptable
or not. Resectability is a condition of the tumour risk. However, if it is less than 35% or less than
that indicates whether it can be completely resected 10 mL.kg-1.min-1, lobectomy and pneumonectomy
or not, providing the patient with a probability of are not recommended and other options should be
long-term survival (1). The assessment of all lung considered. For those patients whose peak VO2 is
cancer patients is recommended to be performed between 35 and 75% or 10-20 mL.kg-1.min-1, split
by a multidisciplinary team (MDT) of specialists function tests to calculate the predicted postoperative
from all the disciplines related to the case: imaging, FEV1 (ppo-FEV1) and DLCO (ppo-DLCO) are
pulmonology, oncology, pathology, nuclear indicated. If both are greater than 30%, resection
medicine, and thoracic surgery. The MDT will assess can be performed. If one is below 30%, further
the critical factors in each patient and will make the decisions are based on the ppo-VO2: if greater than
necessary diagnostic and therapeutic indications, 35% or greater than 10 mL.kg-1.min-1, resection can
after consideration of the patient’s performance be performed with acceptable risk; but if below 35%
status, comorbidity, and cardiac and lung condition or less than 10 mL.kg-1.min-1, then resection is not
(2). 2.- General condition The patient’s general recommended. 5.- The borderline operable patient
condition is commonly assessed by a comorbidity There are patients whose scores do not recommend
index (the Charlson index) and the performance resection, but resection could still be possible if
status index (Karnofsky or Zubrod). The Charlson the proper alternatives are considered. This is the
index considers the presence or absence of diabetes, borderline operable patient. Parenchyma-saving
renal failure, lung conditions, cardiovascular resections are acceptable alternatives to lobectomy
conditions, previously treated cancers (except and pneumonectomy. Sublobar resection, preferably
for squamous cell carcinoma of the skin), and segmentectomy, may be a good alternative to
alcoholism, among others (3). The Charlson index is lobectomy in patients with borderline pulmonary
predictive of survival both in patients with resected function tests, and sleeve lobectomy may be a good
and non-resected tumours (4, 5). The different alternative to pneumonectomy. Sublobar resections
performance status indexes describe the degree of are associated with higher local recurrence rates, but
activity of the patients and their general condition. long term survival is similar to that of lobectomies
3.- Cardiac function The European Society of (7). Sleeve lobectomies spare lung parenchyma and
Thoracic Surgeons (ESTS)/European Respiratory their oncological value is similar to larger resections
Society (ERS) guidelines for preoperative evaluation (8). In selected patients with heterogeneous
recommend that patients with cardiac conditions emphysema in upper lobes, an upper lobectomy
requiring medication, or with any newly suspected may even improve postoperative lung function
cardiac condition, or inability to climb two Áights (9). Minimally invasive techniques, such as video-
of stairs should have a cardiac consultation with assisted thoracoscopic lobectomy, segmentectomy
or wedge resection minimize the effect of the Borderline Operable NSCLC Monday, 4 July 2011 10:30-12:00
incisions on the chest wall mechanics, reducing
the postoperative loss of function. Another aspect E03.3 OUTCOME OF SBRT IN PATIENTS
to consider is the improvement of lung function by WITH POOR PULMONARY FUNCTION
pulmonary rehabilitation. This improvement may José Belderbos1, Matthias Guckenberger2, Alize
shift the patient’s condition from borderline operable Scheenstra1, Inga Grills3, Jan Jakob Sonke1
1
to operable. References: Department Of Radiation Oncology, The
1. Grupo Cooperativo Médico-Quirúrgico del Netherlands Cancer Institute - Antoni Van
Carcinoma Broncogénico del Hospital Universitario Leeuwenhoek Hospital/Netherlands, 2Department Of
12de Octubre de Madrid. Carcinoma Broncogénico, Radiation Oncology, University Hospital Wuerzburg/
2010 update: www.mbeneumologia.org/pautaCB. Germany, 3Radiation Oncology, William Beaumont
2. Ninane V, Le Pechoux C, Curran W et al. Critical Hospital/United States Of America
factors for patient management. Lung Cancer 2003;
42: s7-s8. Abstract: Stereotactic Body Radiotherapy (SBRT)
3. Charlson ME, Pompei P, Ales KL, Mackenzie CR. is characterized by one or a few fractions with a
A new method of classifying prognostic comorbidity high dose per fraction using high precision delivery
in longitudinal studies: development and validation. techniques. Because of the reported excellent local
J Chronic Dis 1987; 40: 373-383. control rates in the 90% range of SBRT in early
4. Moro_Sibilot D, Aubert A, Diab S et al. stage medically inoperable Non Small Cell Lung
Comorbidities and Charlson score in resected stage I Cancer (NSCLC) patients, SBRT is increasingly
nonsmall cell lung cancer. Eur Respir J 26: 480-486, used. To make a choice for a non-invasive treatment
2005. like SBRT over surgery is especially valid in
5. Do, SY, Bush DA, Slater JD. Comorbidity- elderly and frail patients. The most relevant acute
adjusted survival in early stage lung cancer and late toxicity of SBRT for patients with poor
patients treated with hypofractionated proton pulmonary function is radiation-induced lung
therapy. J Oncol, vol 2010, article ID 251208; doi: toxicity like radiation pneumonitis (RP), lung
10.1155/2010/251208 Àbrosis, or perfusion changes all resulting in
6. Brunelli A, Charloux A, Bolliger CT et al. ERS/ decreased pulmonary function (PF). To decide
ESTS clinical guidelines on Àtness for radical whether SBRT is a good treatment option in
therapy in lung cancer patients (surgery and chemo- patients with severe pulmonary co-morbidities it
radiotherapy). Eur Respir J 34: 17-41, 2009. is important to: 1) Measure changes in pulmonary
7. Lung Cancer Study Group (prepared by Ginsberg function tests after SBRT in patients with poor PF
RJ, Rubinstein LV). Randomized trial of lobectomy 2) Understand the pulmonary perfusion changes
versus limited resection for T1N0 non-small cell after SBRT 3) Test available models to estimate the
lung cancer. Ann Thorac Surg 1995; 60: 615-23. incidence of radiation pneumonitis after SBRT 1)
8. Stallard J, Loberg A, Dunning J, Dark J. Is Pulmonary function test changes after SBRT: In a
a sleeve lobectomy signiÀcantly better than a large international group of patients treated with lung
pneumonectomy? Interact J Cardiovasc Thorac Surg SBRT four-hundred eleven patients were treated
2010; 11: 660-666. using image guided radiotherapy for T1-T2N0M0
9. Kushibe K, Takahama M, Tojo T et al. Assessment NSCLC. The inÁuence of SBRT on pulmonary
of pulmonary function after lobectomy for lung outcome was presented by Guckenberger et al. at
cancer – upper lobectomy might have the same effect ASTRO 2010. The mostly medically inoperable
as lung volume reduction surgery. Eur J Cardiothorac patients with peripheral tumors were irradiated
Surg 2006; 29: 886-890. within Àve radiotherapy departments from 1998-
Keywords: Lung cancer, operability, perioperative 2009. Median age was 74 years. T1N0 tumors were
evaluation diagnosed in 68%, T2N0 in 30% and 1% with locally
recurrent lung cancers after surgery. The median
maximum tumor dimension was 2.4 cm (range
0.9-8.5 cm). Patients were treated with a variety
of prescription doses according to each institute’s
local protocol (median dose 54 Gy in 3 fractions,
median overall; treatment time 8 days). Median
pretreatment FEV1 was 1.4l (range 0.43 to 4.4l) incidence of radiation pneumonitis are clinically
median predicted DLCO was 53% (range 10-103%). available and can be used before the start of SBRT
Radiation induced pneumonitis grade II occurred treatment. It may therefore be concluded that a poor
in only 7% of all patients and was not increased in pretreatment pulmonary function alone should not
patients with lower pretreatment pulmonary function. be used to exclude medically inoperable patients
In multivariate analysis pretreatment DLCO was with early stage NSCLC, who are candidate for
correlated with decreased overall survival. It was SBRT, for this treatment. For patients with severe
concluded that a poor pulmonary function should pulmonary co-morbidities the advantage of SBRT
not be a contraindication for SBRT. 2) Post SBRT over surgery is the favorable decrease of pulmonary
pulmonary perfusion analysis : Forty-two inoperable function compared to limited resection (for example
patients with early stage NSCLC in the left or right anatomical segmentectomy).
upper lobe (median GTV=7.0cc) were irradiated Keywords: Poor Pulmonary Function, radiation
with SBRT and analyzed at the NKI-AVL. The pneumonitis, Non small cell lung cancer, SBRT
prescription dose was 54 Gy in 3 fractions and
median Mean Lung Dose of 7.9 Gy (range 3.4-16.6
Gy). Prior to treatment and 4 months post SBRT Session E04: Imaging Aspects of
a single photon emission computed tomography Staging in Lung Cancer
(SPECT) lung perfusion scan was acquired. The
scans were registered to the planning CT and the
Monday, 4 July 2011
corresponding planned dose distribution to obtain the
effect of the local dose with the relative reduction in
perfusion. The doses were converted to EQD2 with Imaging Aspects of Staging in Lung Cancer Monday, 4 July 2011
an Ơ/ơ ratio of 3 Gy. The well-perfused regions in 16:30-18:00
the lung were extracted and the local dose effect
relation for lung perfusion was found established (by E04.1 USE AND CHALLENGES FOR THE
Àtting a 3-parameter logistic model, maximal effect USE OF PET-CT IN NSCLC
a = 42.36%±1.0, the dose for which 50% of the Walter De Wever1, Johan Coolen1, Johny
effect was reached D50=46.36±0.5 and the steepness Verschakelen2
1
parameter k=1.5±0.08). In conclusion: a local dose Radiology, University Hospital Gasthuisberg/
response relation for reduction in lung perfusion four Belgium, 2University Hospitals Leuven/Belgium
months after SBRT treatment was established and
will be tested in a larger group of patients treated Abstract: Integrated Positron Emission Tomography
at different time points. 3) The Mean Lung Dose a / Computed Tomography (PET/CT), introduced in
commonly used model in conventionally fractionated clinical practice in 1998, is the combination of two
radiotherapy to estimate the incidence of RP was different examination techniques in one machine:
analyzed in a group of 187 NSCLC patients treated Computed Tomography (CT) giving anatomic
with SBRT (54 Gy in 3 fx) at the NKI-AVL (see information and Positron Emission Tomography
abstract by Scheenstra et al.). Median FU-time was (PET) giving metabolic information. PET/CT
17 months. The crude incidence of RP grade 2 was has two major advantages: 1/ CT can be used for
4.25%, no grade 3 RP was observed. All RP were attenuation correction and 2/ PET/CT improves
reported at 3-4 months after SBRT, except in one diagnostic accuracy when compared to CT and PET
patient that experienced RP 1 month after SBRT. alone. A rapidly expanding amount of literature
For lung SBRT the incidence of RP grade 2 was demonstrates the additional value of PET/CT in the
correlated with the Mean Lung Dose. Conclusions: diagnosis, staging, prognosis, treatment planning,
The reported incidence of radiation pneumonitis assessment of treatment response and diagnosis
grade 2 or higher was low after SBRT (7%) in 411 of recurrence of different tumor types. In general,
medically inoperable stage I lung cancer patients the additional information provided by PET/CT
treated with SBRT. A poor pretreatment pulmonary is 1) the detection of lesions initially not seen on
function was not associated with increased rates CT or PET alone, 2) a more precise localization
of toxicity in these patients . Analysis of perfusion of the lesion 3) a better delineation of the lesion
reduction in SBRT patients at four months revealed and its relationship with the surrounding structures
local perfusion changes. Models to predict the and 4) a better characterization of the lesion as
benign or malignant. CT increases the sensitivity of will be very unlikely to gain useful information
the PET/CT examination, but the most beneÀcial from PET for a lesion below 5 mm. A positive PET
effect of having the CT data is the increase of the in a small, intermediate risk lesion might push one
speciÀcity of the PET data. PET data also helps to toward biopsy or excision, though a negative PET
specify CT information. Sensitivity and speciÀcity in such a lesion must be considered to provide
of 18F-Fluorodeoxyglucose PET (18F-FDG PET) no information whatsoever. Highly differentiated
and 18F-Fluorodeoxyglucose PET/CT (18F-FDG tumors and certain tumor entities such as mucinous
PET/CT) for determining malignancy of solitary carcinomas may exhibit only insigniÀcant FDG-
pulmonary nodules are close to 95% and 80% uptake due to only modest hexokinase activities and
respectively. The limits of the PET-technology are may thus not be detected with FDG-PET/CT. Tracers
well known. False negative results are mainly due binding to speciÀc receptors or entering different
to certain histological types with low metabolic metabolic pathways can act as an alternative for
activity (such as bronchiolo-alveolar carcinoma imaging. Such tracers are e.g. 68Ga-DOTATOC for
and typical carcinoid), or small size (nodules less neuro-endocrine tumors, 18F-Flurorothymidine (FLT)
than 8 mm). False positives are mainly represented for proliferation imaging, 18F-Áuoromisonidazole
by granulomatous and infectious processes. 18FDG (FMISO) for hypoxia imaging. Thoracic
PET/CT is superior to CT alone, PET alone and radiotherapy with curative intent for NSCLC is
PET and CT images viewed side by side in tumor challenging. One distinct advantage of PET/CT in
staging of patients with NSCLC as shown in several radiotherapy planning is its potential to improve
studies (Lardinois 2003, Antoch 2003, Cerfolio tumor delineation, reducing intra-observer and inter-
2004, De Wever 2007). 18FDG PET/CT has a observer variability and making treatment volumes
pooled average of 82% for correct T-staging with more standard across individuals and institutions.
a 6% overstaging and 13% understaging. The most The high sensitivity and speciÀcity of PET/CT for
important advantage of 18FDG PET/CT is the fact mediastinal lymph node involvement and superior
that the FDG uptake can be located very accurately capacity to discriminate between tumor extent and
on the CT images. For T-staging this may be helpful atelectasis signiÀcantly alters the target volumes with
in the evaluation of tumor invasion in the chest wall a potential to either reduce dose to organs-at-risk
or mediastinum. Also delineation of the tumor from or deliver increased doses to the tumor and thereby
surrounding or retro-obstructive atelectasis may be improve outcomes (Gupta, 2010) In conclusion,
improved. Because of the metabolic information by providing both morphologic and metabolic
that is provided, PET can also often differentiate information, integrated PET/CT has achieved better
between a malignant and a benign pleural effusion. efÀcacy in staging lung cancer than CT alone or PET
For N-staging, it is shown that PET is better than alone and integrated PET/CT becomes now a Àrst-
CT to predict the benign or malignant character of line lung cancer imaging and staging technique.
the mediastinal and hilar lymph nodes but integrated
PET/CT further increases the speciÀcity to diagnose
these malignant lymph nodes because a more exact Imaging Aspects of Staging in Lung Cancer Monday, 4 July 2011
localization of the FDG hotspot becomes possible. 16:30-18:00
De Leyn (2006) showed that for mediastinal
restaging integrated PET/CT is the best imaging E04.3 EBUS AND EUS FOR N-STAGING IN
procedure to predict residual mediastinal lymph NSCLC
node metastasis. Integrated PET/CT increases the Kazuhiro Yasufuku
speciÀcity and accuracy in predicting residual Division Of Thoracic Surgery, Toronto General
lymph node metastasis. Integrated PET/CT is also Hospital/Canada
the best imaging tool to detect distant metastases
in expected sites as well as in unexpected sites. Abstract: Despite the advances in surgical treatment
The evaluation of small lesions, especially sub- and multimodality treatment, lung cancer is still
centimeter pulmonary nodules, is still difÀcult. The the leading cause of death from malignant disease
sensitivity for malignancy is lower in these smaller worldwide. Accurate staging of the disease is
lesions, while one would expect the speciÀcity important not only to determine the prognosis
to be higher. Given that the resolution of current but also to decide the most suitable treatment
generation PET scanners is only 5 to 6 mm, one plan. During the staging process of non-small cell
lung cancer (NSCLC), mediastinal lymph node (N1) lymph nodes. EUS-FNA has access to the
staging is one of the most important factors that inferior mediastinal lymph nodes not accessible
affect the patient outcome. Non-invasive staging by mediastinoscopy. EBUS-TBNA and/or EUS-
such as computed tomography (CT) and positron FNA have in fact replaced mediastinoscopy in
emission tomography (PET) indicate size and many patients with diffuse mediastinal adenopathy,
metabolic activity, respectively. However imaging where a simple tissue diagnosis is required to
alone is inaccurate and therefore tissue sampling determine treatment. It is still uncertain whether
is the preferred and most reliable. Surgical staging EBUS-TBNA and/or EUS/FNA will completely
by mediastinoscopy is still the gold standard for replace mediastinoscopy for precise mediastinal
mediastinal lymph node staging. However for lymph node staging of lung cancer. Endoscopic
some parts of the mediastinum not assessable by ultrasound, however, is less invasive, safer and
mediastinoscopy, video-assisted thoracoscopic more cost effective compared to mediastinoscopy.
surgery (VATS) is necessary. However, Endoscopic ultrasound offers the advantage of
surgical staging requires general anesthesia and obtaining a diagnosis as well as lymph node staging
complications cannot be ignored. Endoscopic simultaneously in an outpatient setting. Initial
ultrasound techniques provide a minimally invasive mediastinal lymph node staging by EBUS-TBNA/
alternative for surgical staging. The current available EUS-FNA will allow mediastinoscopy to be reserved
endoscopic ultrasound techniques for mediastinal for re-staging after induction treatment.
staging include transesophageal endoscopic Keywords: Lung cancer, Staging, EBUS, EUS
ultrasound guided Àne needle aspiration (EUS-FNA)
and endobronchial ultrasound guided transbronchial
needle aspiration (EBUS-TBNA). Both procedures Imaging Aspects of Staging in Lung Cancer Monday, 4 July 2011
can be performed in an outpatient setting under 16:30-18:00
local anesthesia. EUS-FNA is a sensitive and safe
method of evaluating the inferior mediastinal E04.4 CASE PRESENTATION: T2
nodes (stations 7, 8, and 9) and some parts of the ADENOCARCINOMA OF THE LEFT
anterior mediastinal nodes if the lymph nodes are UPPER LOBE WITH IPSILATERAL N1
accessible from the esophagus. However, in spite of LYMPH NODES THAT ARE POSITIVE ON
the strength of EUS-FNA for evaluating the inferior FDG PET
mediastinal nodes, its ability to evaluate lesions Daniela E. Oprea- Lager, Emile F. Comans
anterior to the trachea is limited. On the other hand, Nuclear Medicine & Pet Research, VU Medical
EBUS-TBNA is an accurate bronchoscopic method Center/Netherlands
for lymph node staging which has reach to the
paratracheal and subcarinal (stations 2R, 2L, 4R, Abstract: Appropriate tumor staging is essential for
4L, 7), as well as the N1 lymph nodes (stations 10, establishing the best treatment strategy and deÀning
11, 12). In experienced hands, EBUS can be used prognosis in lung cancer patients. Our case demonstrates
through the esophagus for a EUS-like approach to the role of imaging in the revised location of left hilar
the inferior mediastinal lymph nodes. Thus, EUS- lymph nodes (station 10 L) according to the newly
FNA and EBUS-TBNA are complementary methods proposed International Association for the Study of Lung
for lymph node staging in lung cancer and most of Cancer (IASLC) lymph node map and emphasizes the
the mediastinum and the hilum can be evaluated with importance of using clear anatomical deÀnitions for
these endoscopic procedures. Aortic nodes (stations delineating lymph node stations. A 58-year-old woman
5 and 6) are exceptions and must be evaluated by presented with a 20-pack-year smoking and a negative
surgical methods (anterior mediastinotomy, VATS, clinical history. She complained about fatigue, dyspnea
thoracotomy). Based on the current evidence, and left chest discomfort since 5 months. Subsequent
EBUS-TBNA and EUS-FNA presents a minimally physical examinations revealed no abnormalities,
invasive endoscopic procedure as an alternative to except rhonchi in the left upper portion of the chest
mediastinoscopy for mediastinal staging of NSCLC at pulmonary auscultation. The chest x-ray showed a
with discrete N2 or N3 lymph node enlargement, diffuse consolidation in the left upper lobe, adjacent
provided negative results are conÀrmed by surgical to mediastinum. A diagnostic contrast-enhanced
staging. EBUS-TBNA can access all lymph nodes computed tomography (CT) was performed under the
accessible by mediastinoscopy as well as hilar assumption of Nonsmall cell lung cancer (NSCLC).
The next imaging step used to establish the Tumor Imaging Aspects of Staging in Lung Cancer Monday, 4 July 2011
Node Metastasis (TNM) staging was a whole body 16:30-18:00
integrated positron emission tomography (PET)/ low
dose CT, according to the Dutch guidelines for NSCLC. E04.6 CASE PRESENTATION: T2
Both the diagnostic CT and the low dose CT in lung TUMOUR OF THE RIGHT MIDDLE
setting demonstrated the presence of a relative centrally LOBE WITH MEDIASTINAL
located left upper lobe tumor, with a lobulated aspect, LYMPHADENOPATHY IN A PATIENT
measuring 3.3 X 3.1 cm. Two ipsilateral enlarged lymph WITH AN IMPAIRED PULMONARY
nodes were seen lateral to the left pulmonary artery FUNCTION
and in the left hilar region. According to the previously Idris Bahce1, Katrien Grunberg2
1
used Mountain-Dressler map, these lymph nodes were Pulmonary Medicine, VU University Medical
localized subaortic, in the aortopulmonary window (N2 Centre/Netherlands, 2Pathology, VU University
disease). With reference to the new IASLC lymph node Medical Center/Netherlands
map, these nodes, having as upper border the lower
rim of the left pulmonary artery and as lower border Abstract: Purpose: This case presentation is
the left interlobar region, are deÀned as hilar nodes (N1 intended to enable participants and tumor board
disease). No other lesions suspicious for metastases members to discuss pre-treatment diagnostic and
were found within the scanned part of the body. The therapeutic strategies, using arguments based on
PET component also showed diffuse high FDG uptake clinical and radiological Àndings. Participants
in the left pulmonary mass in the two hilar lymph nodes prerequisite: During this presentation, participants
left, this being indicative for a T2a lung process with will be asked several questions. These are not
additional N1 lymph nodes metastases and no distant intended to test their knowledge, but to invite them
metastases. Based on imaging, the presented case aims to make clinical decisions on which interventions
to demonstrate the typical lymph node drainage of should follow, and to argue these choices.
tumors originating from the left upper lobe and to mark Knowledge on the management of lung cancer is
the difference between the subaortic nodes and left recommended. Case discussion: In this clinical
hilar nodes. Aspects related to the lymph node staging case, a 65-year-old patient who suffered from long
modalities in such patients and therapy management will standing cough was seen for haemoptysis. He
be discussed in detail. had a history of alcoholic liver disease, peripheral
Keywords: PET/ CT, Hilar lymph nodes, Subaortic vasculopathy and a moderately severe chronic
lymph nodes, Nonsmall lung cancer obstructive pulmonary disease (COPD). The chest
X-ray showed a mass in the right lung. The CT
scan revealed extensive bullous and centrilobular
Imaging Aspects of Staging in Lung Cancer Monday, 4 July 2011 emphysema, particularly in the upper lobes,
16:30-18:00 furthermore calciÀcations in the aorta, and enlarged
lymph nodes at several nodal stations (lymph node
E04.5 CASE PRESENTATION: SMALL T1 station 4 right, subcarinal and lymph node station
SUBPLEURAL LUNG LESION IN THE 10 right). A cavitating, partly necrotic and liquiÀed
RIGHT UPPER LOBE, INCIDENTALLY tumor was seen in the middle lobe, with involvement
FOUND of the thoracic pleura and the minor Àssure. The
Mark W. Onaitis accompanying positron emission tomography
Surgery, Duke University/United States Of America (PET) scan showed a weak Áuorodeoxyglucose
(FDG) uptake at the site of the enlarged lymph
Abstract: Modern imaging identiÀes many nodes, and intense FDG uptake in the tumor wall,
indeterminate lung nodules. Controversy exists as to while the necrotic center showed no uptake. As
appropriate radiologic work-up and potential surgical he was diagnosed with COPD, a spiroÁowmetry
treatment of patients with these abnormalities. We was performed, which showed moderate airway
will present pertinent clinical scenarios to stimulate obstruction. A Àrst dilemma is posed at this point,
discussion of diagnostic and therapeutic alternatives. as a choice must be made as to how to obtain
Thoracoscopic approaches to these patients may tissue samples from the tumor and the enlarged
optimize safe diagnosis and treatment. lymph nodes. Three options were considered:
Keywords: thoracoscopy, Lung nodule bronchoscopy, endobronchial ultrasonography
(EBUS) or mediastinoscopy. In the present case, differences in their investigation by pathologists,

bronchoscopy and EBUS were performed. Biopsies and treatment by oncologists has driven renewed
of the tumor showed non-small cell lung cancer; interest in this differential diagnosis. It is no longer
however Àne needle aspiration of lymph node station acceptable to amalgamate these different diseases in
4 and 7 using EBUS only revealed reactive lymphoid the increasingly meaningless category of ‘non-small
cells, no malignancy. This latter Ànding does not cell carcinoma’. Adenocarcinoma is an epithelial
exclude the presence of lymph node metastasis. malignant tumour characterised by combinations
Should an additional mediastinoscopy be performed of tumour showing glandular differentiation. A
to reach a more sensitive mediastinal staging? Or, squamous cell carcinoma is an epithelial malignancy
could a treatment decision be made with the current showing evidence of keratinisation, indicated
information, without full mediastinal staging? How by the presence of cellular keratinisation and/or
valuable is the PET scan at this point? The decision intercellular bridges. In some cases, the degree or
to perform full mediastinal staging poses a second extent of diagnostic differentiation may be limited
dilemma, as a choice has to be made on what should and such diagnostic areas may not be sampled during
be the next step: mediastinoscopy, surgery (video small biopsy diagnosis (see below). In the context of
assisted thoracic surgery (VATS) or thoracotomy?), surgically resected tumours, the distinction between
or something else. At this point the need for squamous cell and adenocarcinomas is generally
additional testing will also be discussed. This patient straightforward and has no bearing, currently, on
underwent a cyclo-ergometry, MRI brain, bone scan, the selection of patients for adjuvant therapy. In
and liver ultrasound. Eventually, he was treated with patients with advanced disease, however, given the
primary thoracotomy. An extrapleural bilobectomy differential efÀcacy or toxicity of several possible
was performed, which showed a 5.8 cm squamous treatments, an accurate and reliable distinction
cell carcinoma, resection margins were free of tumor. between squamous cell and adenocarcinoma is
There was pleural invasion (Pl1), no involvement in becoming essential, not only for the selection of
any of the 5 resected lymph nodes in stations nr 10, appropriate drugs but also for the most judicious
11, 4 right, and 7. pT2bN0Mx. The postoperative use of tissue and other laboratory resources in
course will only be discussed brieÁy, as this is not appropriate biomarker testing to assist with drug
within the scope of this presentation. Evaluation: selection. The diagnostic distinction between
Finally, the added value of the multidisciplinary squamous cell and adenocarcinoma in advanced
tumor board discussion will be evaluated. disease patients may be a challenge. These patients
Keywords: Imaging, clinical care generally do not have a surgically resected tumour
available for examination. Rather, the diagnosis
and subtyping of the lung tumour is based on small
Session E05: Diagnosis and Treatment diagnostic samples of cytological or histological
Decisions type. The WHO classiÀcation of lung cancers is
not fully applicable to such small samples. Several
deÀning diagnostic criteria cannot be applied to
Monday, 4 July 2011
small samples. Small samples may contain only
undifferentiated tumour cells, showing none of the
Diagnosis and Treatment Decisions Monday, 4 July 2011 16:30-18:00 diagnostic cytological features or tissue architecture
of the differentiated tumour components on which
E05.1 DISTINCTION BETWEEN the tumour subtype is predicated. Thus there is an
ADENOCARCINOMA AND SQUAMOUS inherent inaccuracy in subtyping non-small cell
CELL CARCINOMA (NSCLC)-type lung cancers in small samples. In a
Keith M. Kerr proportion of cases, the lack of any differentiated
Department Of Pathology, Aberdeen Royal cells or architecture necessitates the use of the
InÀrmary/United Kingdom term NSCLC-not otherwise speciÀed (NSCLC-
NOS). The proportion of cases, so diagnosed on
Abstract: Squamous cell and adenocarcinomas morphological grounds alone, will vary according
of lung show differences in their histological to the sample type (it tends to be higher in
appearances, usual clinical presentation, molecular cytological versus histological samples) and the
abnormalities and pathogenesis. The emerging bias / experience of the pathologist. NSCLC-NOS
rates of 20-25% for tissue biopsy samples are not best balance between sensitivity and speciÀcity
unreasonable. Assuming an unselected case cohort for each test stain. Some cases will not show a
representing the usual range of NSCLC types, it predictive immunophenotype. This is entirely to be
is essentially impossible to achieve NSCLC-NOS expected and so there will remain a small number
rates of under 10% in small sample diagnostis using of cases, typically 5-6% overall, which would
only morphological. Large cell and sarcomatoid remain NSCLC-NOS, after appropriate IHC. Still,
carcinomas account for around 10% of cases, a majority of these are differentiated tumours, just
cannot be correctly diagnosed in this context and poorly sampled. A range of more sophisticated
should always receive an NSCLC-NOS diagnosis. molecular proÀling techniques (gene expression
The majority of NSCLC-NOS small samples are, arrays, microRNA etc) have been proposed for
in fact, derived from differentiated tumours but distinguishing squamous cell from adenocarcinoma.
are undifferentiated due to sampling error. Most Readily diagnosable tumours of each type have their
NSCLC-NOS cases are actually adenocarcinomas. differential molecular proÀles determined, from
It is possible to reÀne the diagnosis of NSCLC-NOS ‘signatures’ are derived to discriminate between
cases using immunohistochemistry (IHC). A number these differentiated tumours. There are differences
of IHC markers are preferentially expressed in either in many aspects of the molecular landscape between
squamous cell or adenocarcinomas. Few of these squamous cell and adenocarcinomas. Even in
markers are unique to one particular tumour type; tumours easily classiÀed by standard histopathology,
none is a deÀning diagnostic criterion for a diagnosis none of these signatures is 100% successful and none
of either tumour type. The relevant literature is have been used to address the NSCLC-NOS issue.
extensive, often confusing, sometimes contradictory There is now a therapeutically-driven clinical need
and difÀcult to interpret due to different for accurate, consistent diagnosis of squamous cell
methodologies and presentation of results. For and adenocarcinomas in patients with advanced lung
squamous cell carcinoma the most important markers cancer. Even with the constraints of diagnosis on
currently used are p63, cytokeratin (CK) 5/6, high small tissue samples, the appropriate, appropriate use
molecular weight (HMW) CK (34betaE12) and of IHC can augment diagnosis of the traditionally
desmocollin-3 (DSC3). DSC3 is probably the most stained material to provide accurate classiÀcation of
speciÀc of these, HMWCK the least speciÀc and p63 squamous cell and adenocarcinomas. Only a small
and CK5/6 the most often used. For adenocarcinoma proportion of such cases should remain with a non-
TTF1, Napsin A and CK7, as well as a mucin stain, speciÀc diagnosis.
are the most important. Napsin A and mucin stains Keywords: squamous cell carcinoma, differential
are most speciÀc but lack sensitivity, CK7 has high diagnosis, immunohistochemistry, Adenocarcinoma
sensitivity but lacks speciÀcity. TTF1 is the best
compromise for a single marker. It is very important
to understand that these markers DO NOT conÀrm Diagnosis and Treatment Decisions Monday, 4 July 2011 16:30-18:00
or deÀne the tumour subtype. Their presence/absence
only supports one subtype rather than the other, E05.3 DISTINCTION BETWEEN SECOND
on a statistical basis – they help predict the likely PRIMARY AND METASTASES
subtype. Thus, when a subtype is predicted on the Sanja Dacic
basis of IHC, the correct diagnosis to be rendered is Department Of Pathology, University Of Pittsburgh
still NSCLC, with the appropriate caveat, ‘probably School Of Medicine/United States Of America
squamous’ or ‘probably adenocarcinoma’. The
predictive value of these tests tends to be around Abstract: The reported incidence of synchronous
80-85%. If these markers are to be used in this way, tumors of the lung ranges from 0.5 to 2%; however,
it is essential that the pathologist and laboratory the number of patients presenting with multiple
are aware of the detailed methods required for lung nodules has been increasing. This is most
reliable staining, have clearly deÀned criteria for likely a result of the development of higher-
what is considered a positive or predictive IHC resolution chest imaging techniques, more frequent
test and thus have validated the predictive power screening of smokers for lung cancer, and closer
of each test used. If this is not done, errors will follow up of patients with routine chest scans after
result. This approach can achieve very high Àgures initial surgical resection. The main issue regarding
of positive and negative predictive value, and the multiple lung tumors is to determine whether they
represent separate primary tumors or metastases. more comprehensive approaches analyzing a large
This determination has impact on tumor stage and number of single nucleotide polymorphic loci in
subsequent treatment and prognosis. Criteria to a single assay or large-scale DNA sequencing of
deÀne multiple primary lung tumors or metastases tumors were used. A comprehensive aCGH analysis
were initially published by Martini and Melamed followed by the analysis of multiple somatic
in 1975, and were recently updated by the AJCC. mutations of originally presumed cases of multiple
The proposed rather empirical criteria sound primary lung cancers based on Martini and Melamed
straight forward, but clinicopathologic distinction criteria, resulted in discrepant classiÀcation between
between the two groups is not always possible and molecular data and clinico-pathologic criteria in
it may not be genetically or prognostically valid. 18% of analyzed cases (Clin Cancer Res 2009;
Furthermore, molecular analysis of synchronous 15(16):5184). These data provided support evidence
tumor nodules that may distinguish a primary tumor for implementation of genomic analysis into clinical
from metastases was not incorporated into the practice which would be challenging due to e.g.
current classiÀcation criteria. Methods: PubMed requirement of a large amount of high quality
available peer-reviewed original articles and DNA, fresh frozen tissue and lack of standardized
experience of the author. Results: The diagnosis of software for array data analysis. A more practical
multiple primary lung carcinomas is easily made approach would be targeted mutational proÀling
when the morphology is different (e.g. squamous cell of DNA extracted from formalin-Àxed, parafÀn
carcinoma and adenocarcinoma). If the morphology embedded tissue. It was suggested that the strength
is the same, the distinction between two primary of the evidence from individual mutational matches
carcinomas or metastases can be very difÀcult. depends on the rarity of the mutation, e.g. speciÀc
Recently, several molecular approaches have KRAS or EGFR mutations (Clin Cancer Res 2009;
emerged including DNA microsatellite analysis, 15(16):5184; Chest 2010; 137(1);46; J Thorac Oncol
DNA sequencing for common somatic mutations, 2007;2(1);12; Cancer 1999;85:1734). A role of
aCHG , and gene expression analysis. A role of quantiÀcation of the relative amounts of morphologic
detailed histologic subtyping, particularly of lung subtypes in lung adenocarcinomas as proposed
adenocarcinomas, was also suggested. Studies by the recent IASLC/ERS/ATS classiÀcation of
using clonality assays used two approaches: a panel lung adenocarcinomas has been suggested as
of variable number of polymorphic microsatellite potentially useful in determining clonal relationship
markers and X-chromosome inactivation analysis. between the two or multiple tumor nodules (Chest
Tumors with largely concordant results were 2010; 137(1);46). However, the reproducibility
considered clonal in origin (metastases), and of histologic subtyping remains to be established.
those with discordant Àndings were considered Unlike mutational proÀling, a reliable histologic
to be independent primary tumors. The data subtyping cannot be performed on the cytology
from published reports indicate a highly variable specimens. Conclusions: Molecular approaches to
percentage of multifocal tumors identiÀed as classiÀcation of multiple lung tumors have not been
clonally related (up to 70%)(Am J Surg Pathol 2005; prospectively validated, and their performance in
29(7):897;Ann Diagn Pathol 2001;5(6):321; Clin routine clinical practice remain to be established.
Cancer Res 2000; 6(10):3994; J Natl Cancer Inst Aggressive surgical resection of multiple intralobar,
2009;101:560). It is difÀcult to determine the correct ipsilateral, or even bilateral multifocal nodules is
percentage because of the relatively small number a standard treatment in many centers. It is very
of analyzed cases, mixed analysis of synchronous unlikely that tumor tissue from multifocal nodules
and metachronous tumors, and use of different will be available for molecular analyses before
methods and interpretation criteria. However, all surgery. Therefore management decisions should be
reports agree that multifocal tumors may arise either made after careful clinicopathological evaluation by
as metastases from a single tumor or as independent a multidisciplinary team.
tumors resulting from Àeld cancerization. The main Keyword: synchronous tumors
shortcoming of earlier studies is a limited number
of genes analyzed, and data have to be interpreted
with caution since similar patterns of allelic losses
may be present throughout the respiratory epithelium
of smokers with or without lung cancer. Recently,
Diagnosis and Treatment Decisions Monday, 4 July 2011 16:30-18:00 Session E06: Quality Control and
Concentration of Care
E05.4 CYTOLOGICAL DIAGNOSIS OF
LUNG CANCER: OPPORTUNITIES AND
Monday, 4 July 2011
LIMITATIONS
Maureen Zakowski
Pathology, Memorial Sloan-Kettering Cancer Quality Control and Concentration of Care Monday, 4 July 2011
Center/United States Of America 16:30-18:00
Abstract: Cytology is often used in the diagnosis E06.2 EUROPE CONCENTRATION OF

of primary lung cancer. Conventional preparations CARE
such as sputum, bronchial brushes and washes as Walter Klepetko
well as Àne needle aspiration (FNA) biopsies are Division Of Thoracic Surgery, Medical University
excellent means of documenting the presence of Vienna/Austria
tumors. It has always been considered sufÀcient to
separate bronchogenic carcinoma into the two major Abstract: Surgical treatment of lung cancer within
categories of small cell carcinoma and non small Europe is performed under very variable conditions. In
cell carcinoma (NSCLC). In addition, little attention some countries thoracic surgery is exclusively provided
has been paid to separating adenocarcinoma into by specialised thoracic surgeons, whereas in others it
any speciÀc subtypes. In the era of targeted therapy is performed by cardiac or cardiothoracic surgeons, by
against lung cancer new, non chemotherapeutic general surgeons, or sometimes by vascular surgeons.
agents have emerged that successfully “target” However, the rapid increase in speciÀc knowledge
speciÀc types of lung cancer. The tyrosine kinase and skills and the increasing complexity of treatment
inhibitor (TKI) Tarceva appears particularly algorithms, demands for a higher specialisation and
useful against well differentiated adenocarcinoma, level of performance, which undoubtedly can only
especially when a bronchioloalveolar component be provided by physicians, concentrating on one core
is present. The presence of EGFR mutations speciality. Even further, some very complex surgical
underlies the response of adenocarcinoma to procedures, that nowadays have become available,
TKIs. This agent is ineffective in the treatment of are rare, and therefore should only be provided in
squamous cell carcinoma. Another agent, Avastin, centers of higher specialisation and concentration. The
a monoclonal antibody to VEG F, may be cause two relevant scientiÀc societies, the ESTS (European
lethal pulmonary hemorrhage on patients with Society of Thoracic Surgery) and the EACTS
squamous cell carcinoma of the lung. The speciÀc (European Association of Cardiothoracic Surgery),
features of adenocarcinoma and squamous cell which represent the Àeld of thoracic surgery within
carcinoma must be identiÀed in cytologic material europe, have therefore suggested a system of centers
and morphology suggestive of bronchioloalveolar of standard and of excellence (1) , which allows to
carcinoma (BAC) must be recognized in order to provide the necessary services ubiquitary and for all
help direct appropriate therapy. Since cytologic levels of complexity. In addition, requirements in terms
cell blocks can be used for the analysis of EGFR of stafÀng, ressources, spezial training etc. have been
mutations, it is becoming increasingly important to deÀned. To follow such suggestions, in order to offer
prepare and correctly diagnose cell block material. In patients the best possible care, should be in the interest
addition immunohistochemical stains such as TTF-1, of every physician. This would imply, that creation of
CK 7, CK 20, 34bE12, 4A4 and p63 can be applied such circumstances whereever they are not yet available
to cytologic material to aid in the correct diagnosis should be fostered, and that referral patterns should
of lung cancers. Limitations to the use of cytologic be adapted to the actual quality needs. In doing so,
material include small sample size, lack of pre even rare, but however very advanced, complex and
analytical standardization and inability to perform on ressource intensive procedures can be provided with
site assessment for sample adequacy. optimal quality. Ref: 1) Structure of General Thoracic
Keyword: cytology Surgery in Europe; W. Klepetko, A. Lerut, T. Aberg.
European Journal of Cardiothoracic Surgery 2002.
Keyword: thorax
Quality Control and Concentration of Care Monday, 4 July 2011 the study and practice of thoracic surgery and related
16:30-18:00 medical subjects. This involves the organization
of European Board Exams in Thoracic Surgery,
E06.4 THOUGHTS ON TRAINING organizing annual conferences, supporting scientiÀc
Dirk E. Van Raemdonck publications in thoracic surgery and facilitating
Thoracic Surgery, University Hospitals Leuven/ exchange of teachers and trainees in thoracic surgery.
Belgium In so doing the Charity will be able to provide advice
and support for European authorities on matters
Abstract: Every patient in need of medical concerning thoracic surgery, and coordinate the
help deserves the right to be treated according systematic collection of data on thoracic surgical
to the best practice of care. More speciÀcally, activity and outcome. Ultimately the Charity exists
patients needing a surgical intervention have to for the beneÀt of patients with thoracic surgical
be assured that the kind of surgical intervention diseases.” The Society has steadily grown in numbers
to which they have consented is appropriate and over the years crossing the barrier of 1000 members
results in an outcome acceptable by international in late 2009 and reaching 1200 members in 2011.
standards. In order to achieve this, young surgeons This makes ESTS now the largest society in Europe,
should receive the best training across different and probably also worldwide, dealing with general
institutions, both nationally and internationally thoracic surgery only. In order to improve the results
whenever possible and should be exposed to state and to diminish suffering for our patients, a society of
of the art education. Established surgeons and their this size is obliged to offer its members a platform to
institutions should be able to provide information share knowledge, to invest in education of its trainees,
regarding outcomes after surgical treatment based and to collect data for benchmarking and accreditation
upon validated data and risk-adjusted for case mix. of units across Europe. Over the recent years, several
It is likewise important that healthcare providers initiatives have been deployed to meet the educational
are reassured that their Ànancial support of surgical objectives stated in the constitution. This includes the
interventions is being used effectively, not only in installation of an European Conference on General
terms of outcome, but also in resource utilization. Thoracic Surgery (www.estsmeetings.org)a European
General Thoracic Surgery is one of the smaller School of Thoracic Surgery (www.estsschool.org)
specialty groups in medicine. It also has developed with both theoretical courses, held in Antalya, Turkey
differently throughout Europe. In some countries, and practical courses run at the Covidien animal
it is considered part of cardiothoracic surgery, in facilities in Elancourt, France, a Textbook on Thoracic
other countries it lies within the remit of general Surgery, and a European Thoracic database (www.
surgery, and in a few countries it is a recognized thoracicdata.org). The society has appointed four
specialty of its own. This diversity has certainly directors, each one responsible for the educational
contributed to the fact that Europe has lagged behind activities listed above. To evaluate the level of
in societal initiatives to help improving quality of training in Europe, the society is hosting during its
care compared to the USA. Also, the development annual meeting the European Board of Thoracic
of instruments, technology, and infrastructure and Cardiovascular Surgeons (www.ebtcs.org) that
necessary to compare outcome after general thoracic organizes the exams that lead to a European CertiÀcate
surgery was hindered compared to cardiac surgery, in Thoracic Surgery within the structure of UEMS
mainly because of limited resources and manpower (European Union of Medical Specialists; www.uems.
indispensable to succeed. The European Society of net ). This certiÀcate will facilitate recognition of
Thoracic Surgeons (www.ests.org) was established the speciality in Europe and exchange of thoracic
in Heidelberg on 18 November 1993 under the surgeons between different European countries. Based
visionary leadership of Ingolf Vogt-Moykopf - ESTS on data accrued in the thoracic surgery database
Àrst president. The history of the society has recently and published in the Annual Report (Silverbook),
been reviewed by Laureano Molins (Barcelona, bench marking between European institutions has
Spain) in his Presidential Address delivered to the now become possible and outcome indicators have
membership during the 17th European Conference already been proposed to measure quality of care
on General Thoracic Surgery in 2010 in Krakow, after major lung resection [3, 4]. This instrument will
Poland [1]. The ESTS in its constitution [2] deÀnes greatly facilitate the creation of a system that allows
its objectives as “the advancement of education by accreditation of thoracic surgical units across Europe.
The initiatives above will be discussed and illustrated limited uptake of the interventions, we have used
during the presentation. I am grateful for the support the MRC Framework for the Development of
received from numerous ofÀcers, councilors, regents, Complex Interventions to develop a novel supportive
ad hoc committee members, and individual members care intervention to manage the symptom cluster
over the years in establishing a professional society of breathlessness, cough and fatigue, which we
that cares about education of our trainee members to called a respiratory distress symptom cluster. We
guarantee the quality of care that is needed in treating initially identiÀed that there is such a cluster both
patients across all European thoracic surgery centers. with qualitative and quantitative work. Three
References [1] Molins L. ESTS Presidential Address; systematic reviews from our group have shown that,
an exciting journey through ESTS: from birth to while some interventions with promise do exist
adulthood. Eur J Cardiothorac Surg 2010;37:501- in relation to the management of breathlessness,
508. [2] The European Society of Thoracic Surgeons the evidence for cough management is minimal
constitution. http://www.ests.org/sections/information/ and based on data often from the 1970s or earlier.
constitution/index.html . We have worked with patients, carers and health
Date accessed 10 April 2010. [3] Brunelli A, Varela professionals to ‘model’ the intervention and explore
G, Van Schil P, Salati M, Novoa A, Hendriks JM, feasibility issues, acceptability and preference. In
Jimenez MF, Lauwers P, ESTS Audit and Clinical the Àrst study we explored these issues and usability
Excellence Committee. Multicentric analysis of of the interventions identiÀed in the systematic
performance after major lung resections by using reviews conducting interviews with 37 patients
the European Society Objective Score (ESOS). Eur with lung cancer and 23 of their caregivers. Very
J Cardiothorac Surg 2008;33:284-8. [4] Brunelli A, little symptom management was reported other than
Berrisford R, Rocco G, Varela G, European Society self-management attempts. Crucial issues identiÀed
of Thoracic Surgeons Database Committee. The included an intervention delivered at home (or close
European Thoracic Database project: composite to home), by a health professional, had a variety
performance score to measure quality of care after of components, led to immediate relief, with the
major lung resection. Eur J Cardiothorac Surg caregiver being involved, not in a group of other
2009;35:769-74. patients and being able to incorporate it in the
Keywords: Thoracic surgery, education, society, daily life. 5 focus groups with 34 specialist health
exams professionals identiÀed very similar attributes of
an intervention. Finally, a study of 88 patients with
lung cancer using a Discrete Choices Experiment
Session E07: Organising Lung Cancer (best-worst scaling method) also identiÀed that
Nursing location of delivery, and intervention delivered
by a health professional were crucial aspects to
consider. We have also developed and validated
Monday, 4 July 2011
a scale to assess cough in lung cancer with 135
patients, as there was no validated such scale for
Organising Lung Cancer Nursing Monday, 4 July 2011 16:30-18:00 our population. The novel intervention now offers
two face-to-face sessions one week apart teaching
E07.1 A COMPLEX INTERVENTION patients diaphragmatic breathing, cough suppression
FOR THE MANAGEMENT OF A exercises and acupressure to chest points, together
RESPITORY DISTRESS SYMPTOM with supplementary reading material on issues
CLUSTER (BREATHLESSNESS, COUGH suggested by the patients and carers (for home
& FATIGUE) IN PATIENTS WITH LUNG reading), followed by a phone call follow up two
CANCER weeks later and will be delivered considering the
Alex Molassiotis above aspects Àrst with a feasibility trial later on in
School Of Nursing, University Of Manchester/United the year, followed by a large trial.
Kingdom Keyword: lung cancer, breathlessness, cough,
fatigue, supportive care intervention
Abstract: As many supportive care trials in lung
cancer fail to complete due to high attrition, loss
to follow up, major recruitment problems, and
Organising Lung Cancer Nursing Monday, 4 July 2011 16:30-18:00 their family members during the palliative phase.
E07.2 ASPECTS OF (NURSING) CARE Methods

OF PATIENTS WITH A DIFFERENT Qualitative interviews were conducted as we looked
ETHNICAL BACKGROUND (FOR for the personal views of ‘very ill’ cancer patients
NETHERLANDS FOR INSTANCE with a Turkish or Moroccan background, their
TURKEY, MOROCCO) family members and their Dutch care providers.
Fuusje De Graaff Eighty-three people were interviewed, accounting
Mutant/Netherlands for a total of 33 cases. Six patients, Àve male and 25
female family members and 47 care providers were
Abstract: This conference aims to support and interviewed: 19 nurses, 17 general practitioners,
inform physicians, nurses and researchers regarding Àve medical specialists, four social workers and
current treatment approaches for individuals two pastoral workers. The interviews were analysed
with lung cancer, as well as on issues related to qualitatively.
prevention, early detection, imaging, staging and
palliative care. Palliative cancer care aims to improve Results
quality of life and ultimately quality of dying for A main Ànding concerns different views on ‘good
patients with an incurable disease. Prolonging life care’. According to Turkish and Moroccan families
is no longer an objective when death nears. The good care implied: maximum treatment and curative
question is, however, whether these perspectives on care until the end of their lives, never having
palliative care Àt with the perspectives of immigrant hope taken away, receiving devoted care from the
families with a Turkish or Moroccan background. families, avoiding shameful situations and dying
with a clear mind. Their views conÁict with those of
Background care professionals who emphasize the importance
Some years ago we investigated why patients with a of comfort care, quality of life and advance care
Turkish or Moroccan background in The Netherlands planning, also including discussing diagnosis and
make little use of home care even when the patients prognosis with the patient (De Graaff et al., 2010).
are terminally ill (De Graaff & Francke, 2003). Our
qualitative research among relatives of these patients Another important aspect is the language barrier.
identiÀed obstacles on various levels. Many elderly Turks or Moroccans don’t master the
1) The patient’s level: Lack of understanding of Dutch language. Although the Dutch government
illness and cause of death, Ànances interpreters, care professionals seldom use
2) The family’s level: Complexity of family formal interpreters, as they consider this a time-
structure, decision making patterns, values and consuming practice that requires planning and,
standards about care, moreover, one that most relatives did not appreciate.
3) The community level: Limited care for the Relatives often fear that the information provided
patient and family and signiÀcant pressure from the by the formal interpreter to their beloved sick one
community, would be too direct. But patients often appreciate
4) The organizational level: Limited information and the consultations with a formal interpreter and many
little or negative experience with home care. relatives indicate afterwards that care professionals
In a survey we also investigated the perspectives could help their families by freeing them from
and experiences of general practitioners and nurses overprotective relationships.
regarding the limited access and use of home care
of families with a Turkish or Moroccan background Another problematic aspect of the communication
(De Graaff & Francke, 2009). The study among GPs between care providers and patients with a Turkish
and home care nurses conÀrmed the Àndings derived or Moroccan background relates to the triadic
from the interviews with relatives. form of consultations. Consultations rarely take
Aim of the study place on a one-on-one basis, as a great deal of
The aim of a subsequent study to be presented at this communication occurs via relatives. This situation
conference was to gain insight into decision-making is generally regarded as normal by patients and
and communication among various health care family, but as troubling by the care providers, Many
professionals and Turkish or Moroccan patients and care professionals dislike the dependence on family
members acting as interpreters, and feel insecure qualitative study of cancer patients with a Turkish
because of the – to them – complex relations in or Moroccan background, their relatives and care
the family. They may be insufÀciently trained in providers. In: BMC Palliative Care, 9:19.
handling triadic communication. Keyword: palliative care; communication;
immigrants;
Finally, communication problems may be reinforced
because a large number of people are involved in
the decision-making process. Decisions on treatment Organising Lung Cancer Nursing Monday, 4 July 2011 16:30-18:00
and care frequently depend on preferences of many
relatives, whose arguments are often related to social E07.3 HOW ARE LUNG CANCER NURSES
and religious considerations. Dutch care providers ORGANIZED? (NETHERLANDS)
may feel helpless because they do not understand Albert Olijve
the relations within the family, nor the normative Lung, MCA/Netherlands
pressure in the migrant communities. Turkish and
Moroccan families experience a rather comparable Abstract: Since January Àrst 2007 a Special
vulnerability, not understanding the often Interest Group (SIG) Pulmonary Oncology was
fragmentised network of Dutch health care services. established in the Netherlands. This SIG is part of
In their despair they often go ‘shopping’ among the the formal organisational structure of the Dutch
many services in the Netherlands as well as in their Nursing Association (V & VN). It stimulates and
home country. This journey often enhances their supports the network of the nursing staff within the
losing of conÀdence in professional care and relying Pulmonary Oncology Care. The SIG has a permanent
on their own community and religious traditions. function and is accessible trough out the country.
The motivion to start the SIG Pulmonary Oncology
Conclusion is the increasing amount of lung cancer patients in
Physicians and nurses working with incurable ill the Netherlands. In 2009 the breakup of new cases of
patients may beneÀt from greater awareness of lung cancer was 6867 men and 4118 woman ( Source
some speciÀc aspects of care of patients with a NKR ) The death rate among patients of lung cancer,
different ethnical background. They have to be during a period of one year, is just about as high
trained in dealing with conÁicting views on ‘good as new cases being discovered. In 2010 6500 men
care’, in working with a formal interpreter and in and 3600 women died of the disease.(Source CBS)
handling triadic conversations. Besides this, more Unfortunately the medical treatment is still restricted
communication among care providers can result in in comparison with other tumour types. The nursing
considerable beneÀt for the quality of palliative care staff are getting more involved with these type of
of patients with a different ethnical background. patients. They combine their recourses in the SIG to
improve their quality of care to these patients. The
References objectives of the SIG are; Ø Support the mission
De Graaff FM, Francke AL. and goals of the V & VN oncology Ø Support and
2003 Home care for terminally ill Turks and promote the network for the nursing staff specialized
Moroccans and their families in the Netherlands: in Pulmonary Oncology Ø Function as a platform
carers’ experiences and factors inÁuencing ease of between the nursing staff with the specialization
access and use of services. In: International Journal in pulmonary Oncology Ø IdentiÀes and examines
of Nursing Studies, 2003 (40), 797-805. speciÀc questions raised within Pulmonary
Oncology, like the development and implementation
De Graaff FM, Francke AL. of guidelines. Ø Gathers knowledge and experiences
2009 Barriers to home care for terminally ill Turkish and makes sure of distribution by doing professional
and Moroccan migrants, perceived by GPs and development and education Ø Expresses a point of
nurses: a survey. In: BMC Palliative Care jan 2009, view in connection with new developments within
26;8(1):3. this Àeld The SIG has a core of nine representatives.
All members of the V & VN Oncology, active
De Graaff FM, Francke AL, Van den Muijsenbergh within the Pulmonary Oncology, will be able to join
METC, Van der Geest S. the SIG. The members of the V&VN are the most
2010 ‘Palliative care’: a contradiction in terms? A important target of the SIG. The SIG communicates
with its members regarding new developments in this Organising Lung Cancer Nursing Monday, 4 July 2011 16:30-18:00
Àeld and is a source of information for the members
concerned with Pulmonary Oncology. Another target E07.5 HOW ARE LUNG CANCER NURSES
group are the professional society of the nursing and ORGANIZED? (AUSTRALIA)
medical staff. They can join the group discussions Mary Duffy
and the developing of new guidelines and standards. Lung Service, Peter MacCallum Cancer Centre/
Australia
Organising Lung Cancer Nursing Monday, 4 July 2011 16:30-18:00 Abstract: Lung cancer remains the leading cause
of cancer deaths world wide and in Australia. There
E07.4 HOW ARE LUNG CANCER NURSES were 9,703 new cases and 7,626 deaths from lung
ORGANIZED? (UK) cancer reported in Australia in 2007, accounting for
John McPhelim one in Àve (19%) of deaths due to cancer nationally
Cancer Division, Hairmyres Hospital/United (The Australian Institute of Health and Welfare,
Kingdom 2010). The Australian government introduced the
National Health and Medical Research Council
Abstract: Lung Cancer Nursing is a relatively new (NHMRC) clinical practice guidelines for the
sub-specialisation in the management of patients prevention, diagnosis and management of lung
with lung cancer. The UK has been at the forefront cancer in 2004. The NHMRC guidelines suggest
of developing this specialist nursing role. The optimal care for people with lung cancer is
National Lung Cancer Forum for Nurses has been in achieved through care delivery by multidisciplinary
existence for 14 years it has led in the development teams (MDT). Importantly these guidelines also
of nursing roles, innovations in clinical practice, acknowledge the contribution of lung cancer nurses
promoting education and learning, it has undertaken in care delivery. Individual lung cancer patients also
many audit and research projects and is regarded advocated for specialist lung cancer nurse roles.
in the UK as the professional body representing Lung cancer nurses are an integral part of effective
lung cancer nurses. The forum has representation MDT’s as they have more contact with patients, in
on nationally recognised organisations, including, terms of time, than any other team member As such
The British Thoracic Society, BTOG, The National they are well positioned to provide continuity of
Intitute for Clinical Excellence and many other care across the lung cancer journey. Specialist Lung
strategic organisations. This presentation will Cancer nurse roles were Àrst appointed in Australia
focus on how the clinical role of the lung cancer in 2002. The Àrst meeting of lung cancer nurses
nurse has developed in the last 14 years, as a key occurred at the inaugural Australian Lung Cancer
individual in the lung cancer multidisciplinary team, Conference (ALCC) in 2006. At that time it was
demonstrating quality improvements in service, agreed the New Zealand lung cancer nurses would
diversity within the role in terms of service delivery, join the Australian group. Since then the number
it will examine the quality impact of the role on of lung cancer nurses has increased nationwide.
patient outcomes and the signiÀcant impact it has In addition these nurses identiÀed the need for a
had on patient’s experience of care. The presentation national professional lung cancer nurses group.
will in addition look to the future, and examine how Over a period of two years with the assistance of
the lung cancer specialist nurse role may develop in the Australian Lung Foundation (ALF) the Australia
the years to come and how the role will continue to and New Zealand Lung Cancer Nurses Forum
be a positive contributor to the care of patient with (ANZ-LCNF) evolved. Terms of Reference for the
lung cancer. forum were established which include a statement
Keyword: nursing, development, support, of purpose, objectives, general principles and an
innovation organisational structure in the form of a Steering
Committee. The ANZ-LCNF consists of a group of
passionate nurses with a common focus of improving
patient care, health care delivery and outcomes for
patients, their families and carers with a particular
emphasis on the importance of supportive care. The
forum is a special interest group with professional
afÀliations and collaborative links with the ALF and for networking among nurse lung cancer specialists.
the Cancer Nurses Society of Australia (CNSA). This role is rapidly evolving and will be critical to
These links are reÁected in the logo of the forum. lung cancer patient care as treatment for lung cancer
The ANZ-LCNF was ofÀcially launched in October becomes more individualized and complicated in the
2011 at the 3rd Australian Lung Cancer Conference. near future.
The steering committee have established a strategic Keyword: Oncology Nursing Society, Lung Cancer
plan and goals for the next 12 months. This paper Nurse Navigators
will share the process involved in establishing the
forum, key relationships which include patient
advocacy groups. Achievements in increasing the Organising Lung Cancer Nursing Monday, 4 July 2011 16:30-18:00
awareness of lung cancer nationally will also be
highlighted. E07.7 HOW CAN/SHOULD LUNG
Keywords: lung cancer nurses, australian context CANCER NURSES PLAY A ROLE WITHIN
THE IASLC?
Liz Darlison
Organising Lung Cancer Nursing Monday, 4 July 2011 16:30-18:00 Respiratory, University Hospitals Of Leicester/
United Kingdom
E07.6 HOW ARE LUNG CANCER NURSES
ORGANIZED? (USA) Abstract: The concept of developing an
Patricia Palmer international network for nurses working in lung
Patient Care Services, University Of California cancer originated after many discussions and visits
Davis Health System/United States Of America between nurses and Countries. These conversations
converted into action and it was decided to hold a
Abstract: The Oncology Nursing Society (ONS) nurse networking lunch at the 13th World Conference
is the organizing body for oncology nurses in the on Lung Cancer in San Francisco in 2009. This
United States. Founded in 1975 it now boosts meeting was an opened discussion, with fellow
membership of more than 37,000 registered nurses nurses, and conÀrmed that there was a need for
and other healthcare professionals dedicated to an international nurses group. This meeting was
excellence in patient care, research, administration, supported by IASLC and interest was overwhelming
and education in the Àeld of oncology. More than with approximately 60 international nurses
220 local chapters provide a network for education attending from many countries including USA,
and peer support at the local level. In addition, 27 UK, Australia, Europe, Canada and Asia. From
special interest groups (SIGS) facilitate national this meeting the International Thoracic Oncology
networking of members in subspecialty areas. Nurses Nurses Forum (ITONF) was established and will
who care for lung cancer patients belong to ONS ofÀcially be launched at the 14th WCLC in July 2011
nationally, locally and are involved in the Thoracic in Amsterdam UK. This session will provide an
Cancer Focus Group and the newly formed Nurse opportunity to discuss how the ITONF can establish
Navigator SIG as well as other SIG’s organized a working relationship with the IASLC.
by ONS. The mission of the ONS is to promote Keyword: International Nursing in Lung Cancer
excellence in oncology nursing and quality cancer
care. The core work of ONS includes; publishing
peer-reviewed literature, publishing guidelines and
standards, providing accredited nursing education,
advocating for the oncology nursing profession
and quality cancer care, serving as a community,
fostering networking, establishing priorities for
oncology nursing research and preparing oncology
nursing leaders. The ONS Foundation has provided
more than $22 million in funding for research,
education, leadership, career development and public
education since 1982. The recent advent of Lung
Cancer Nurse Navigators has provided a new avenue
Session E08: Biology of Radiotherapy - Biology of Radiotherapy - An Update Monday, 4 July 2011 16:30-
An Update 18:00
E08.3 TARGETING GALECTIN-1 IN NON-

Monday, 4 July 2011
SMALL CELL LUNG CANCERS
Quynh Thu Le
Biology of Radiotherapy - An Update Monday, 4 July 2011 16:30- Radiation Oncology, Stanford University/United
18:00 States Of America
E08.1 CANCER STEM CELLS AND Abstract: Non-small cell lung cancer (NSCLC) is
RADIORESISTANCE a highly lethal disease. Despite dose escalation with
Maximilian Diehn conformal radiotherapy (RT) in combination with
Radiation Oncology And Institute For Stem Cell modern chemotherapy, there is still a signiÀcantly high
Biology & Regenerative Medicine, Stanford rate of intrathoracic failure and poor overall survival
University & Cancer Center/United States Of in patients with locally advanced disease. A novel
America approach is needed to improve RT and chemotherapy
effectiveness in these tumors. We have previously
Abstract: The cancer stem cell hypothesis posits demonstrated that hypoxia does exist in NSCLC though
that tumors are maintained by a subpopulation of to a lesser extent than head and neck cancer. Using
cancer cells called cancer stem cells (CSCs) or proteomic analysis, we identiÀed Galectin-1 (Gal-1) as
tumor initiating cells. CSCs can divide to give rise a hypoxia-regulated protein at the level of secretion in
to more CSCs and to other cancer cells that are not several cancer cell types, including NSCLC. Galectin-1
able to form tumors upon in vivo transplantation (Gal-1) is a secreted carbohydrate binding lectin that is
(called non-tumorigenic cancer cells). The well known for its role in modulating T-cell homeostasis.
existence of a subpopulation of putative CSCs More recently, it has been shown to play a major role
has been documented in a large variety of human in cancer progression. It is expressed in many cancers,
tumors, including lung cancers. Furthermore, including NSCLC, where increased Gal-1 expression
accumulating evidence indicates that CSCs are is closely associated with larger tumors, more nodal
often relatively resistant to standard treatments metastasis and lower overall survival. In human head
such as chemotherapy or radiotherapy. Multiple and neck cancer, expression of Galectin-1 was inversely
CSC resistance mechanisms have been identiÀed related to intratumoral T-cell level and correlated
and these appear to be both tumor type and patient with prognosis. Mechanistically, Gal-1 has been
speciÀc. Targeting of CSCs, either directly or implicated in several pathologic processes including
through sensitizers to standard therapies is an tumor proliferation, adhesion, migration, angiogenesis
active area of investigation. The development of and enhancing T-cell apoptosis, which can, in turn,
CSC-targeted therapies will likely be complicated can confer tumor immunity. In addition to hypoxia,
by the risk of normal stem cell toxicity as well as Gal-1 secretion was also enhanced by RT, raising the
the acquisition of treatment resistance. Successful hypothesis that it may counteract RT effectiveness in
targeting of CSCs in the clinic holds the promise of cancers. Applying a combination of down-regulating
signiÀcantly improving patient outcomes. Gal-1 in a non-NSCLC cell line and knocking-out the
Keywords: Tumor inititiating cells, Cancer stem gene in host mice, we show that tumor-derived Gal-1 is
cells, Radioresistance more important than host-derived Gal-1 in promoting
tumor growth and spontaneous metastasis. Further
mechanistic studies suggested that Gal-1 mediated its
tumor promoting function by enhancing intratumoral
T-cell death while protecting hypoxic tumor cells from
apoptosis. Clonogenic studies also showed that Gal-1
down regulation increased radiation sensitivity in these
cells, especially under hypoxia. Based on these data, it
is logical to evaluate Gal-1 as a new target in NSCLC in
combination with radiation and chemotherapy.
Keyword: radiation, galectin-1, hypoxia
Biology of Radiotherapy - An Update Monday, 4 July 2011 16:30- after large doses per fraction may be greater than
18:00 presently recognized due competing risks of death
in patients who are frequently elderly or with co-
E08.4 SBRT FOR CENTRAL LUNG morbidities (ie a large proportion of patients may not
TUMORS: RADIOBIOLOGICAL live long enough to exhibit potential late toxicity),
MODELING AND EMERGING CLINICAL the challenges in assigning attribution (eg sudden
DATA death – was it unrelated to SBRT or due to a SBRT-
Andrea Bezjak related catastrophic event such as ruptured vessel)
Radiation Oncology, Princess Margaret Hospital - and the difÀculties in recognizing milder forms of
University Of Toronto/Canada toxicity (eg grade 2 toxicity). Further challenges in
creating the most accurate dose-volume-outcome
Abstract: Advances in image guidance, and the data include knowing how best to evaluate the
ability to treat well identiÀed targets with high importance of volume in different serial organs
precision and very tight margins through SBRT (eg is Dmax important? Dose to a small volume
techniques have led to wide-spread use of very of the entire organ? Dose to the ipsilateral wall of
large doses per fraction, with curative intent. The that organ?), how best to determine the actual dose
effect of these high ablative doses on normal tissues received (ie to include setup and intrafraction motion
remains a concern. In the case of peripheral lung data and organ deformation, and calculate the dose
tumors, technical advances, small volumes treated accumulated, rather than simply dose planned)
and absence of critical structures results in a low and how to account for intra-individual patient
rate of signiÀcant normal tissue toxicity. However, differences (whether due to comorbidity, eg small
delivery of highly hypofractionated SBRT schedules vessel disease, concomitant medications (steroids,
may lead to potentially very signiÀcant and even antioxidants), dietary factors or unknown genetic
fatal toxicity when lung tumors are located more or humoral modiÀers of normal tissue response to
centrally. Organs at risk (OARs) include trachea, injury). Given these challenges, it is not likely that
central bronchial tree, esophagus, great vessels, any of the models will be sufÀciently validated any
heart, brachial plexus and less commonly spinal time soon. Thus, we need to proceed carefully with
cord, phrenic or recurrent laryngeal nerves. Being SBRT of centrally located tumors, and monitor and
able to accurately estimate the risk of RT damage to report toxicities to provide optimal treatments to our
these OARs would greatly facilitate the achievement patients. The approach taken in different center with
of optimal therapeutic ration of risk vs beneÀt. respect to fractionation and planning of centrally
Radiobiological modeling has long been used to located tumors will be reviewed, including the
predict the risk of normal tissue complications, and planning approach and doses used in the RTOG 0813
to compare different fractionation schedules, using phase I/II seamless study of SBRT for early stage
concepts of BED (Biologically effective dose) and centrally located NSCLC in medically inoperable
EQD2 (eguivalent dose at 2 Gy/fraction) [Fowler patients (www. rtog.org) References: Fowler JF and
and Dale]. However, it is far from clear whether Dale RG. When is a “BED” not a “BED”? – when it
the existing models apply to these very large doses is an EQD2: in regard to Buyyounouski et al. (Int J
per fraction [Borst]. Proposed improvements to the Radiat Oncol Biol Phys 2010; 76: 1297-1304). Int J
linear-quadratic (LQ) model include the modiÀed Radiat Oncol Biol Phys 2010; 78(2): 640-641. Borst
LQ (MLQ) [Guerrero and Li], the lethal –potentially GR, Sonke JJ, Belderbos JS et al. Normal tissue
lethal (LPL) model, multitarget model, and the complication probability after hypofractionation
universal survival curve [Park]. One of the great increased due to the high dose per fraction or the
challenges is the paucity of clinical data to validate high total Biological Equivalent Dose? Radiother
these models. Although data comparing the different Oncol 2010; 94(3): 388. Guerrero M and Li XA.
radiobiological models exists regarding lung toxicity Extending the linear-quadratic model for large
post SBRT [Wennberg, Borst], lung, often the dose- fraction doses pertinent to stereotactic radiotherapy.
limiting organ in thoracic RT, is not the main OAR Phys Med Biol 2004; 49(20): 4825-4835. Park C,
of concern in SBRT situations, particularly not in Papiez L, Zhang S et al. Universal survival curve
cases of centrally located tumors. Animal models and single fraction equivalent dose: useful tools in
offer some ability to test these models, but data understanding potency of ablative radiotherapy. Int
is far from deÀnitive to guide practice. Toxicity J Radiat Oncol Biol Phys 2008; 70(3): 847-852.
Wennberg BM, Baumann P, Gagliardi G et al. NTCP Assessment and Measurement of Outcomes in Supportive Care
modeling of lung toxicity after SBRT comparing Wednesday, 6 July 2011 10:30-12:00
the universal survival curve and the linear quadratic
model for fractionation correction. Acta Oncologica, E09.3 QUALITY OF PALLIATIVE CARE
2011 (Epub ahead of print) Borst GR, Ishikawa SERVICES
M, Nukamp J et al. Radiation pneumonitis after Kris C.P. Vissers1, Yvonne Engels1, Jeroen
hypofractionated radiotherapy: evaluation of the Hasselaar1, Karen Van Beek2, Kathrin Woitha1,
LQ(L) model and different dose parameters. Int J Ahmed Nisar3, Xavier Gomez-Batiste4, Birgit
Radiat Oncol Biol Phys 2010; 77(5): 1596-1603. Jaspers5, Leppert Wojciech6, Johan Menten7, Sam
Ahmedzai3, Jean-Marc Mollard8
1
Anesthesiology, Pain And Palliative Medicine,
Session E09: Assessment and Radboud University Medical Centre/Netherlands,
Measurement of Outcomes in 2
Radiation Oncology And Palliative Care, University
Supportive Care Hospitals Leuven/Belgium, 3University Of ShefÀeld/
United Kingdom, 4Institut Catala D’oncologia/Spain,
5
University Bonn/Germany, 6Poznan University Of
Wednesday, 6 July 2011 Medical Sciences/Poland, 7University Hospitals
Leuven/Belgium, 8Association Ensemble Soigner Et
Assessment and Measurement of Outcomes in Supportive Care Accompagner à Paris/France
Wednesday, 6 July 2011 10:30-12:00
Abstract: The WHO deÀnition of palliative care
E09.2 PSYCHOLOGICAL DISTRESS launched in 2002 broadens the target population
Mari Lloyd-Williams to all patients with an incurable disease. Moreover
Blank, Hospital/United Kingdom palliative care should be applicable early in the
course of the illness. For politicians, caregivers
Abstract: It is acknowledged that depression is and policy makers it is important to Ànd tools to
present in upwards of 20% of patients with advanced measure the quality of the organization of palliative
cancer, that it is seldom assessed, diagnosed or care. For this purpose consensus was sought on
treated. This presentation will overview some of quality indicators, which are ‘explicitly deÀned
the outcome tools currently available together with and measurable items referring to the outcomes,
their strengths and weaknesses and present data from processes or structure of care’ A systematic review
a very recently completed study of a longitudinal on quality indicators for palliative care showed that
study of depression in over 600 palliative care clinical indicators are widely overrepresented over
patients. This study was carried out to determine indicators that assess organizational issues. During
the natural history and determinants of depression workshops it was agreed that the organization of
in this population and to look at what factors may palliative care can be deÀned as follows: “systems
predict or prevent depression in the last months of (structures and processes) meant to enable the
life. The presentation will include a brief overview of delivery of good quality palliative care. The quality
challenges of conducting a large multicentre study in of the organization of palliative care could be
palliative care patients in addition to suggestions for assessed in a framework with the domains of: 1
possible interventions which may be delivered within DeÀnition of palliative care service; 2 Access to
this population and further research that is required. palliative care (a. access and availability, b. out of
Keywords: Psychological Distress, palliative care, hours care, c. continuity of care); 3. Infrastructure;
depression 4. Assessment tools; 5 Personnel (a. staff, b.
education and training for staff/volunteers, c.
support systems, d. organization of care, e. sharing
information); 6. Documentation of clinical data (a.
clinical record, b. timely documentation); 7. Quality
and safety ( a. quality policies, b. adverse events,
c. complaints procedures); 8. Reporting clinical
activity of palliative care services; 9. Regional,
national and international aspects of palliative care
(a. national policy, b. guidelines, c. health/insurance for specialized training for professionals working
program, d. networks); 10. Research (a. local level, in palliative care were considered important.
b. national level) and 11 Education. Transmural On regional and national level the recognition,
multidisciplinary teams of caregivers were invited awareness and support of palliative medicine as
to participate in the generation of a consensus on the illustrated by associations, policies networks and
usefulness and clarity of the proposed indicators. regulations regarding the availability of palliative
After two rounds of consultation using a modiÀed care improve the quality. These indicators can be
Rand Delphi method in the top 10 indicators with a Àrst step towards improving the quality of the
the highest median rating, there are 3 indicators organization of palliative care in Europe and should
relative to education, 2 are personnel related, be further implemented. Per researched European
2 deal with the accessibility, 1 is infrastructure country, different types of indicators are valued as
related and two others are in the domain of national relevant for quality of palliative care. This implies
indicators. Most retained indicators concerned the that besides the international set of indicators, the
quality of the organization of settings that provide larger national sets are important to assess and
palliative care. On a broader level the following improve the quality of palliative care in a speciÀc
indicators were considered important: recognition country. These indicators can be used in tools for
of palliative medicine and palliative care nursing as cross-country comparisons, and are a Àrst step
specialty, the existence of a national health policy in improving the quality of the organization of
regarding palliative care, a national palliative palliative care in Europe.
care association, the collaboration in palliative Keywords: palliative care, quality indicators
care networks and national regulations regarding
availability of palliative care, stafÀng, beds and
geographical contribution across the country. Assessment and Measurement of Outcomes in Supportive Care
The availability of national guidelines regarding Wednesday, 6 July 2011 10:30-12:00
pan and symptom control, palliative sedation and
advanced care planning are considered important E09.4 PALLIATIVE SEDATION IN THE
in the improvement of the quality of palliative care. NETHERLANDS IN GUIDELINES AND
No single indicator from the domain “Quality and PRACTICE
safety” was considered essential for the quality Bregje Onwuteaka-Philipsen
of the organization of palliative care. It is judged VU MC, Emgo Institute For Health & Care, VU MC,
important to have a home support team as well as Emgo Institute For Health & Care/Netherlands
hospice beds. Access to palliative care facilities
and the possibility to consult or be visited by the Abstract: In the last phase of life patients frequency
caregiver 24 hours a day, and timely transfer of the have burdensome symptoms such as dyspnea,
patient and the clinical information are important agitation, pain and anxiety. Alleviation of these
quality indicators. There was consensus on the need symptoms is a central goal of medical care in these
for a multidisciplinary team and appropriate training patients. If symptoms are refractory, sedatives can
for staff and volunteers. Validated instruments to be used to render patients unconscious and thus
assess pain and other symptoms should be in place. oblivious to their symptoms. This palliative sedation
A structured clinical record adds to the quality. It can be deÀned as the deliberate lowering of the
was agreed that the use of a database for recording patient’s level of consciousness in the last stages of
clinical activity is important, but no consensus on life. It can be temporary or intermittent, but the focus
its content was reached. Also on local level the of this presentation will be on continuous sedation
availability of a research program and the structural until the moment of death. In 2001 a European
governmental funding are judged important quality study on end-of-life decision-making in 6 countries
indicators The infrastructure should allow privacy revealed that continuous sedation until death
of patients and families, including the possibility to occurred in all countries studied albeit in somewhat
die in a single bedroom, facilities for relatives to stay different percentages of all deaths: Denmark 2.5%,
overnight, the ability of a private place for saying Sweden 3.2%, Switzerland 4.8%, the Netherlands
good-bye to the deceased and no restrictions of 5.7%, Belgium 8.2%, and Italy 8.5%. In the
visiting hours. Standardized learning objectives for Netherlands, where euthanasia (ending the patient’s
basic and continuing training, as well as a program life by a physician on explicit request of the patient
using drugs) is allowed under strict conditions, the Session E10: Concurrent CT-RT for LA-
presentation of the incidence of continuous sedation NSCLC - Managing Toxicity and Follow-
gave rise to a discussion on whether palliative Up
sedation was normal medical practice or euthanasia
in disguise. Also the national ofÀce of the public
prosecution wondered whether some cases of Wednesday, 6 July 2011
palliative sedation should be judged judicially as
cases of euthanasia. These discussions prompted Concurrent CT-RT for LA-NSCLC - Managing Toxicity and Follow-Up
the Royal Dutch Medical Association to develop Wednesday, 6 July 2011 10:30-12:00
a national guideline for palliative sedation. The
guideline includes, among others, information on E10.2 PREDICTORS AND MANAGEMENT
indications and preconditions for palliative sedation, OF LATE RADIATION INJURY TO THE
the decision-making, requirements for good medical CHEST WALL AND BRONCHUS
practice, and the distinction between palliative Lawrence B. Marks, Eda Yirmibesoglu
sedation and euthanasia. An important precondition Radiation Oncology, University Of North Carolina
for palliative sedation in the Netherlands is that the At Chapel Hill/United States Of America
patient’s death is expected within one or two weeks.
On the basis of available evidence the guideline- Abstract: Radiation therapy (RT)-induced injury to
committee assumed that if the life expectancy the chest wall and bronchial structures is relatively
of the patient exceeded this period, stopping the uncommon with conventional radiation techniques.
administration of Áuids would hasten the time of With the more-recent adoption of hypo-fractionated
death. Palliative sedation should not shorten life, approaches, this is becoming a more relevant clinical
while euthanasia usually does. Regarding decision challenge. We herein review the incidence of, and
making the general rule is that the decision of associated dosimetric predictors for, these toxicities.
starting palliative sedation is based on consent of the Chest wall: A variety of studies have related the
patient or his representative. This involves timely incidence of chest wall pain and/or rib fracture,
and open communication with all persons involved. to dosimetric parameters with stereotactic body
Regarding good practice the drugs used are an radiation therapy (SBRT). The following metrics
important topic as in 2001 36% of cases of palliative have been implicated as being reasonable predictors
sedation physicians indicated to use morphine as of the risk of injury: Dmax for chest wall and rib;
drug, while benzodiazepines are considered the chest wall volume receiving 15, 20, 30, 40, 50 and
appropriate drugs. In this presentation, besides 60Gy; dose for 2cc of rib. In particular, the SBRT
giving information on the guideline for palliative data from Cleveland concluded that the absolute
sedation, data will be presented on the incidence risk is approximately 6%, 9%, 19%, 35%, 55%,
and characteristics of palliative sedation in the and 74% when the volume chest call receiving
Netherlands before and after the implementation of 30Gy exceeds 10, 20, 40, 60, 80, and 100cm3,
the guideline for palliative sedation. Furthermore, respectively (1). In two separate analyses, from
cases of palliative sedation and euthanasia will the University of Colorado and Indiana, a median
be compared on patient characteristics, reasons effective concentration (EC50) dose response model
for opting for this decision, characteristics of has been used to relate dose/volume parameters
the decision-making, drugs used and estimated of the rib and the chest wall to incidence of chest
shortening of life. wall toxicities (pain and/or fracture) (2, 3). The
Keywords: palliative sedation, palliative care, end of data from both analyses well demonstrate increased
life care, end of life decision-making risk with dose/volume parameters. The Colorado
analysis suggests that EC50 model for the chest
wall volume receiving 30Gy correlated best for
the severe chest wall toxicity. They reported that
the chest wall volume receiving 30Gy in three to
Àve fractions should be limited to <30cm3 (2). The
Indiana analysis suggests that the risk of any grade
rib fracture or chest wall pain increased at Dmax
doses of >50Gy. They reported that in order to limit
the risk of clinically relevant chest wall toxicity (broadly to include a variety of bronchial injuries)
to <30%, the EC50 model would limit the volume in 44/226 patients (19.5%) following HDR to total
of chest wall receiving 15Gy to 240cc, 20Gy to dose 24-35Gy in 4-6 fractions. The mean time of
130cc, 30 Gy to 40 cc, and the volume of chest wall onset was 10 months. Bronchial stenosis occurred
receiving 40 Gy to 15 cc (3). The total radiation in 21/226 (9.5%), bronchial wall necrosis in 7
dose prescribed in these studies typically was patients (3.5%), and hemoptysis in 15 patients
approximately 20-60Gy in 2-5 fractions. A Swedish (6.6%) (9). More recently, there is increasing data
study, suggests the strongest association between using hypo-fractionated SBRT. Timmerman et al.
risk of rib fracture and DVH parameters lay in the reported increased risks for pulmonary injury for
small-volume/high-dose region. They concluded centrally-placed lesions following delivery of 60-
that for the volume of 2cm3 of a rib, the doses giving 66Gy in three fractions. There, the incidence of
rise to 50% and 5% probability of rib fracture were experiencing severe toxicity was 11 fold increased
found to be 49.8 and 27.2Gy, respectively, for total with perihilar/central tumors compared to more
dose 60Gy in 3 fractions (4). Bronchial injury: peripheral locations (10). Management: Chest wall
Injury is unusual with conventionally fractionated pain and rib fracture typcially occur within a median
external beam radiation (EBRT) to doses less than time to onset of greater than 6 months after SBRT.
approximately 75Gy. Bronchial injury, typically Conservative measures are typically used to treat
stenosis, has been reported in a series of patients chest wall pain and rib fractures; e.g. pain medicine,
treated with brachytherapy, high dose external high non-steroidals (oral anti inÁammatory medication,
beam conventionally fractionated therapy (e.g. gabapentin, or narcotics), and immobilization.
1.6 BID to 74-86 Gy), and with hypo-fractionated The typical course in these patients is for gradual
SBRT. For implants, the risk appears to be >10% improvement in chest wall pain was 4.7 months
following delivery of high dose rate (HDR) 22.5- (range, 0.67-10.5) (2). Bronchial injury typically
30Gy in 3 fractions. Speiser and Spartling described occurs with a mean of 16-19 weeks for grade 1-2
a large series of 342 patients for bronchial toxicity. toxicities, 43-55 weeks for grade 3-4 toxicities (6).
They suggest risk of development of bronchitis or For bronchial injury, there are limited treatments.
stenosis is correlated with more prolonged survival Medical treatment has consisted of systemic
and is increased in patients receiving concurrent steroid (dexamethasone, prednisone) and inhalation
EBRT and HDR endobronchial treatment. They steroid therapy. For grade 3-4 toxicities, multiple
reported grade 4 stenosis in 12/342 patients (3.5%) debridements via bronchoscope, vascular balloon
overall, but 6/68 patients (9%) patients who were dilatation and silicone tracheobronchial stent can
treated to 60Gy EBRT plus 22.5-30Gy HDR RT be considered. There’s limited literature on this.
(5, 6). A French study suggests the risk of radiation References: 1. Stephans KL. IJROBP. 2011 [Epub
bronchitis, (broadly deÀned an any symptomatic ahead of print] 2. Dunlap NE. IJROBP. 2010; 76
event including swelling, stenosis and ever death (3): 796-801 3. Andolino DL. IJROBP. 2011 [Epub
from Àbrinous debris) is especially high for ahead of print] 4. Pettersson N. RO. 2009; 91 (3):
tumors located in the trachea or main stem bronchi 360-8 5. Speiser BL. IJROBP. 1993; 25 (4): 579-
compared to located in distal bronchi (18.5% vs. 87 6. Speiser BL. IJROBP. 1993; 25 (4): 589-97 7.
2%). Among factors, median radiation dose, the Hennequin C. IJROBP. 1998 Aug 1;42(1):21-7. 8.
mean volume of the 100% isodose, treatment Miller KL. IJROBP. 2005; 61 (1): 64-9 9. Guilcher
with two catheters and a higher Karnofsky score MA. IJROBP. 2011; 79 (4): 1112-6 10. Timmerman
(due perhaps to increased longevity and this more R. JCO. 2006; 24 (30): 4833-9 Supported in part by
time at risk for injury) seems to inÁuence the a grant from Turkish Society of Radiation Oncology
risk of bronchial injury (7). For approximately- (EY) and NIH grant R01-CA69579 (LBM)
conventionally fractionated external beam radiation, Keywords: chest wall toxicity, Radition therapy,
at about 1.6-2Gy per fraction, the incidence of Lung cancer, Bronchial injury
bronchial stenosis appears to increase markedly at
doses beyond 80Gy. In one study with the largest
number of patients with EBRT, albeit limited, the
apparent risk of bronchial stenosis was 4%, 5% and
25% following 74, 80 and 86 Gy, respectively (8). A
recent French study reported “radiation bronchitis”
Session E11: Surgery After Induction chemotherapy offers an attractive option to improve
Therapy IIIA prognosis of patients with stage IIIa NSCLC. Up
to now no improvement of prognosis could be
demonstrated by the combination of neoadjuvant
chemo- and radiotherapy. For the future the
identiÀcation of patients who might beneÀt from
Surgery After Induction Therapy IIIA Wednesday, 6 July 2011 10:30- induction treatment and who will be candidates
12:00 for surgery will be of importance. Standardized
assessment of pathological mediastinal clearing
E11.1 CHEMOTHERAPY AS INDUCTION might be one of the most important instruments for
IS ENOUGH this issue. Literature: - Rosell R et al, N Engl J Med
Martin Reck 1994; 330: 153-8 - Roth JA et al, J Natl Cancer Inst
Department Of Thoracic Oncology, Hospital 1994; 86: 673-80 - Westeel V et al, J Clin Oncol
Grosshansdorf/Germany 2010; 28: Abstract 7003 - Eberhardt W et al, J Clin
Oncol 1999; 17: 622-34 - Thomas M et al, J Clin
Abstract: In locally advanced non-small cell lung Oncol 1999; 17: 1185-93 - Thomas M et al, Lancet
cancer (NSCLC) with mediastinal lymph node Oncology 2008; 6: 636-648
involvement most patients will suffer from local Keywords: locally advanced NSCLC, Neadjuvant
or distant relapse shortly after primary resection. chemotherapy, Mediastinal Clearing, Mediastinal
Induction treatment with neoadjuvant chemo- or Downstaging
chemoradiotherapy might improve prognosis by
treatment of circulating tumor cells and sterilization
of mediastinal lymph nodes. Early randomized Surgery After Induction Therapy IIIA Wednesday, 6 July 2011 10:30-
trials reported a signiÀcant improvement of survival 12:00
for the combination of chemotherapy and surgery
in stage IIIa/IIIb patients with NSCLC. However E11.2 CHEMOTHERAPY AS
based on the small number of patients the validity INDUCTION IS BETTER, OR, TO PUT IT
of the results remains questionable. A consistent APPROPRIATELY, MORE PROMISING
survival and signiÀcant disease free survival Hideo Kunitoh
beneÀt was seen in a randomized French phase III Blank, Mitsui Memorial Hospital/Japan
trial which investigated the role of neoadjuvant
chemotherapy in stage I-IIIa patients with NSCLC. Abstract: Almost all agree that “N2 disease” of
EfÀcacy data of non randomized phase II trials NSCLC is a heterogeneous group. There are many
suggest that combination of neoadjuvant chemo- and poorly deÀned subgroups, such as clinical N2,
radiotherapy might increase efÀcacy of induction bulky N2, minimal N2, resectable and unresectable
treatment with response rates between 59-69% and N2, “marginally resectable” or even “technically
4 year survival rates of more than 25% in selected resectable” N2, with signiÀcant overlapping among
patients. Therefore a randomized phase III trial was them. Patients with pathological N2 status after
performed comparing induction chemotherapy with curative surgery seem to beneÀt most from adjuvant
induction chemotherapy in 558 patients with stage chemotherapy (Douillard et al). On the other hand,
IIIa/b NSCLC. Despite improvement of mediastinal many doubt the role of surgery itself in ANY N2
downstaging and pathological response in the diseases conÀrmed preoperatively. What makes the
chemoradiotherapy arm no signiÀcant prolongation matter even more complicated is that there seems to
of progression free survival (primary endpoint) be little consensus as to how far to perform nodal
or overall survival (secondary endpoint) could be staging procedure before surgery. CT scans, PET
achieved in all eligible as well as in all operated scans, mediastinoscope, transbronchial aspiration
patients by the combination of induction chemo- and endobronchial- or transesophageal- ultrasound-
and radiotherapy. Furthermore treatment-related guided needle aspiration. It is very difÀcult but
mortality was higher in the combination arm in critically important, therefore, to make a valid
patients who were treated with pneumonectomia. clinical question before trying to answer it.
In addition more side effects were observed in Theoretical advantage of chemoradiotherapy as
the interventional arm. In summary neoadjuvant induction
Adding radiotherapy to chemotherapy before Better local control might be achieved by

surgery could contribute to better local control. intensifying induction chemotherapy, instead
This strategy has been established in management of adding radiotherapy to it. Bevacizumab was
of the “marginally resectable” superior sulcus shown to enhance the response rates and prolong
tumor. Intensifying local therapy could, at least the PFS of platinum-based chemotherapy, and
theoretically, also prevent tumor dissemination at the induction chemotherapy plus bevacizumab is being
time of surgical manipulation. investigated. Preliminary data report feasibility of
Theoretical disadvantage of chemoradiotherapy the strategy.
as induction Discussion
Surgery itself gets technically more difÀcult, and risk According to the EBM principle, the question
of bronchial stump insufÀciency would be increased. “induction chemotherapy or chemoradiotherapy”
Tumor location, such as lower lobes, might make the before surgery makes no sense, because induction
radiation Àeld too large. therapy itself has not shown to be standard
What currently available data show and suggest for N2 NSCLC. Many claim that preoperative
There are many phase II reports of induction documentation of N2 contraindicates surgical
chemotherapy and chemoradiotherapy followed by intervention. Patients with minimal N2 disease
surgery in patients with N2 or selected N3 NSCLC, would probably beneÀt from curative resection and
and comparison of efÀcacy is impossible. Overall, systemic chemotherapy, given post-operatively
surgical morbidity or mortality is increased with or pre-operatively. Standardization of procedures
induction chemoradiotherapy, although some claim for N2 diagnosis and sub-classiÀcation of this
the risk could be minimized by stump coverage. heterogeneous population is necessary.
Induction chemotherapy and surgical resection So far, induction therapy was not yet shown to
was compared to sequential chemoradiotherapy improve the “oncological” resectability of N2
in patients with “unresectable” N2 disease who NSCLC, unlike the case in superior sulcus tumor
responded to chemotherapy by an EORTC trial (Van (Rusch et al, Kunitoh et al). The strategy is still
Meerbeeck et al), with no beneÀt in the surgical arm. evolving, and the question should be, “which is more
It implies unresectable disease remains unresectable promising” for future research.
even after response to chemotherapy. On the other Induction chemotherapy seems to be as effective
hand, both adjuvant and induction chemotherapy as adjuvant chemotherapy, and it has several
were shown to beneÀt patients, including those with advantages, such as better tolerance and wider
pathological N2 diseases, who underwent curative applicability. Technical advance will make it possible
resection, implying chemotherapy and surgery do to analyze molecular markers, currently available
work in “resectable” diseases. only after tumor resection, from biopsy or even
Induction chemoradiotherapy was compared to cytology specimens in the near future, paving the
deÀnitive chemoradiotherapy alone and by a US way to “customized” induction therapy.
intergroup trial (Albain et al), and it was also Induction chemoradiotherapy has not only
compared to induction chemotherapy and post- disadvantage in terms of surgical morbidity/
surgical radiation by a German trial (Thomas et al), mortality, but also limitation in applicability from
both in patients with “technically resectable” N2 anatomical tumor location. This is not the case with
diseases. the superior sulcus tumor, always located at the
The Intergroup trial showed improvement of PFS but apex, for which induction chemoradiotherapy got a
not OS by surgical resection. Right pneumonectomy success. Improvement of chemotherapy, such as in
was associated with unacceptably high surgical combination with target-based drugs, could avert this
mortality. In the German trial, the results were problem.
similar in both treatment arms; some patients in the Conclusion
chemo-surgery arm experienced fatal complication at Neither pre-operative chemotherapy nor
the time of post-surgical irradiation. chemoradiotherapy was shown to be standard in the
Taken together, although chemotherapy does management of N2 NSCLC. Induction chemotherapy
seem to beneÀt patients with resectable NSCLC seems to be more promising for future research.
patients, chemoradiotherapy and surgery was not References
demonstrated to be better than anything else even in Albain KS et al. Lancet 9687: 378-386, 2009
selected, potentially resectable N2 diseases. Andre F et al. J Clin Oncol 18: 2981-2989, 2000
Farray D et al. J Clin Oncol 23: 3257-3269, 2005 criteria. The revised RECIST criteria specify that
Depierre A et al. J Clin Oncol 20: 247-253, 2002 lymph nodes with a short axis<10 mm are considered
Douillard J-Y et al. J Thorac Oncol 5: 220-228, 2010 to be non-pathological. However, this cut-off size
Kunitoh H et al. J Clin Oncol 26: 644-649, 2008 may be problematic, since micrometastases might
Kunitoh H, Suzuki K. Br J Cancer 96: 1498-1503, be overlooked, and enlarged lymph nodes can occur
2007 due to inÁammation. To resolve these problems,
Rusch VW et al. J Clin Oncol 25: 313-318, 2007 qualitative evaluation such as pathological diagnosis
Thomas M et al. Lancet Oncol 9: 636-648, 2008 is required. Although the optimal management
van Meerbeeck JP et al. J Natl Cancer Inst 99: 442- of these patients is unclear, a common practice
450, 2007 has become to consider preoperative therapy
Keywords: N2, Induction Chemotherapy, induction and possible surgery. Which patients are most
chemoradiotherapy, Surgery appropriate to select for this approach is also
unclear, but it is clear that a major prognostic factor
is whether induction therapy achieves clearance of
Surgery After Induction Therapy IIIA Wednesday, 6 July 2011 10:30- N2, 3 node involvements. This observation is based
12:00 on the stage as determined after resection and raises
the question of how well preoperative restaging
E11.3 RESTAGING AFTER INDUCTION: tests can predict the pathologic stage and thus serve
IS IT NEEDED? to select patients for resection. Many physicians
Felix J.F. Herth have, in fact, adopted the management strategy
Dept. Of Pneumology And Respiratory Medicine, for stage IIIa(N2) NSCLC of induction treatment,
Thoraxklinik, University Of Heidelberg/Germany followed by resection of patients believed to have
been downstaged. This approach is taken despite the
Abstract: In the past two decades, a large number fact that most of the questions remain unanswered.
of trials investigated the impact of postoperative Whether surgical resection adds further beneÀt
(adjuvant) chemotherapy on survival after lung over chemoradiotherapy is controversial. Should
resection for non-small cell lung cancer. A smaller patients with a good response to chemoradiotherapy
number of trials have been conducted to evaluate undergo surgery because of a good response or not
the impact of neoadjuvant chemotherapy before undergo surgery because of a good response (or
lung resection, and four metaanalyses reported should resection be avoided in those with a poor
pooled hazard ratios in favor of chemotherapy. As no response or actually be pursued provided there is no
published trial has directly compared the outcome of disease progression)2? Finally, whether restaging
preoperative versus postoperative chemotherapy, the tests accurately predict the Ànal pathologic stage and
current surge of information leaves physicians and which restaging test is best are unclear. The most
surgeons alike wondering if there are any differences widely used method of selecting patients for surgery
in survival regarding the timing for administration. is the radiographic response by CT to induction
Many physicians have adopted the treatment strategy therapy. This occurs despite the fact that virtually
of induction therapy followed by resection of those every study that has analyzed this has found little,
patients thought to be downstaged. However, many if any, correlation between the response by CT and
aspects of this are unclear, including whether the pathologic Àndings after resection. This review also
strategy itself is beneÀcial, what induction treatment conÀrms that a normal-appearing mediastinum after
should be given, or how patients should be selected induction therapy carries a 30% FN rate and an
for this approach. Perhaps most surprising is how abnormal mediastinum a 30% FP rate. Therefore, use
convinced many are that the criteria for selection of CT alone to either select patients for or exclude
of patients for subsequent resection are well them from surgery is not justiÀed, at least not if
established. It is often forgotten that downstaged the goal is to only resect those patients who are
patients have been identiÀed after resection. Use of downstaged. Furthermore, a complete response by
downstaging to select patients for surgery requires a CT cannot be used to justify avoidance of resection
reliable method of identifying them before resection. because of a 50% FN rate. Although a radiographic
Malignant lymph nodes are common targets for the response makes the patient and the physicians
evaluation of cancer therapeutics. CT is used for feel good, it provides little information about the
assessment of malignant lymph nodes by RECIST presence of absence of viable tumor. PET imaging
is also commonly used to predict downstaging, Session E12: Smoking Cessation & Lung
although it is well recognized that RT can cause Cancer Stigma
Áuorodeoxyglucose uptake due to inÁammation.
Although PET performs somewhat better than CT,
approximately one fourth of patients with a negative
(“cleared”) mediastinum by PET still have pN2
involvement and approximately one third of those Smoking Cessation & Lung Cancer Stigma Wednesday, 6 July 2011
with persistent PET uptake in the mediastinum do 16:30-18:00
not. Surprisingly, whether RT was given has no
impact on these results. Indeed, no patient subsets E12.1 GENETIC CONTRIBUTIONS TO
could be identiÀed in whom restaging PET is NICOTINE DEPENDENCE AND LUNG
reliable. Finally, a complete response by PET in CANCER
all sites cannot justify omitting resection: one third Laura J. Bierut
of such patients still have viable tumor. Perhaps Psychiatry, Washington University School Of
more sophisticated assessments such as the percent Medicine/United States Of America
change in PET activity can be used. However, it
must be emphasized that such assessments require Abstract: Genetic studies in human population
great attention to detail to ensure consistency in samples have identiÀed associations between
the measurements. Remediastinoscopy has been smoking behavior and lung cancer to single
shown to be feasible and safe in experienced hands, nucleotide polymorphisms (SNPs) in the cholinergic
but few institutions are comfortable with this nicotinic receptor subunit (CHRN) genes. By far
technique. Because the results are disappointing, the most statistically signiÀcant Àndings are in
it is unlikely this will change. EBUS or EUS and the CHRNA5-CHRNA3-CHRNB4 gene cluster
needle aspiration are gradually becoming more on chromosome 15q25. Once an association is
widely available. The results seem to be slightly found, the next step is to understand the underlying
better than for remediastinoscopy, but the number of biology that leads to illness. One proposed
studies is limited, and it remains to be seen whether biologic mechanism involves the CHRNA5 SNP
these will hold up as the procedure is practiced more rs16969968, which causes an amino acid change
widely (outside of the pioneering centers and in less in the a5 nicotinic receptor protein. In vitro studies
well-selected patients). Primary mediastinoscopy demonstrate that this variant alters receptor function.
performs fairly well, consistent with the performance A second biologic mechanism, tagged by rs588765,
of primary mediastinoscopy in general (especially marks varying levels of mRNA of CHRNA5 in
the more thorough variations such as videoassisted human brain and lung tissue. By synthesizing the
mediastinal lymphadenectomy). However, this evidence from multiple studies, we demonstrate
requires avoidance of mediastinoscopy in the initial statistically independent associations of rs16969968
staging. Often little thought is given to the eventual and rs588765 with smoking quantity (mutually
treatment strategy at the time that patients are Àrst adjusted p-values: rs16969968 p value <10-35 and
evaluated and staged. Although these methods of rs588765 p value <10-8). We also observed similar
restaging are commonly used to select or exclude patterns of association with lung cancer. Studies in
patients from surgery, the data show them to be quite other populations such as African-Americans and
unreliable. In particular, mediastinal downstaging by Asians further reÀne the association evidence in the
CT, PET, or remediastinoscopy carry a FN rate of 20 CHRNA5-CHRNA3-CHRNB4 gene cluster. These
to 30%. EUS and EBUS may perform slightly better, multi-faceted human genetics approaches provide
but data are limited. Primary mediastinoscopy seems new insights about the role of cholinergic nicotinic
to be the most reliable method of assessment. Ideally, receptor genes in smoking behavior and point to
initial invasive staging of the mediastinum should be potential biological mechanisms.
done by a needle-based technique, so that primary Keywords: tobacco, Smoking, behavior, genetics
mediastinoscopy can be used for restaging.
Keywords: Lung cancer, Stage IIIb, downstaging,
Restaging
Smoking Cessation & Lung Cancer Stigma Wednesday, 6 July 2011 include reduction in treatment efÀcacy, increased
16:30-18:00 side effects and complications, increase in recurrence
and second primary tumors, poorer overall survival,
E12.2 SMOKING CESSATION AS A PART and decreased quality of life. A speciÀc review of
OF LUNG CANCER TREATMENT these Àndings, as they pertain to lung cancer, will be
Ellen R. Gritz presented, as well as recent Àndings about nicotine
Behavioral Science, University Of Texas MD and cancer. Smoking cessation interventions can be
Anderson Cancer Center/United States Of America successfully offered to patients undergoing medical
treatment for lung cancer or afterwards. Success
Abstract: Globally, in 2008, lung cancer was the rates appear to be higher when treatments are offered
leading site in cancer incidence (1,095,200 cases) closer to diagnosis. The highest quit rates are found
and mortality (951,000 deaths) in males; in women, in patients with smoking-related cancers, but relapse
it was the fourth highest site in incidence (513,600 can be substantial, even after a year of abstinence.
cases) and second highest in mortality (427,400 There are few randomized controlled trials of
deaths) (Jemal et al, 2011). In the United States, smoking cessation interventions for cancer patients,
approximately 116,750 men and 105,770 women and there are challenging methodological issues,
were diagnosed with lung cancer in 2010, and which will be reviewed. The USPHS Guideline
approximately 86,220 men and 71,080 women died for the treatment of tobacco use and dependence
of their disease (American Cancer Society, 2010). (Fiore et al, USDHHS, 2009) presents the evidence
The vast majority of those diagnosed with lung base for smoking cessation treatments. Tailoring of
cancer in the U.S. smoked during their lifetimes (85- interventions needs to occur for patients with cancer,
90%), although half or less were current smokers at involving education regarding the link between
the time of diagnosis. An ever-expanding literature cancer and smoking (and continued smoking),
documents the adverse effects of continuing to physical limitations imposed by disease and
smoke after cancer diagnosis. Yet, a surprisingly high treatment, medical contraindications to certain types
percent of patients with chronic diseases, including of pharmacologic treatment, psychological issues
lung cancer, continue to smoke after diagnosis. The such as negative affect (anxiety and depression),
National Cancer Institute deÀnes a cancer survivor stress, guilt, and co-morbid alcohol/substance use.
as “….anyone who has been diagnosed with cancer MD Anderson Cancer Center has created a model
from the time of diagnosis through the balance of his Tobacco Treatment Program that incorporates all of
or her life.” NHIS data show that over 15% of adult these elements and is available at no cost to every
cancer survivors were smokers in 2008. In two age MD Anderson patient who smokes, their spouse/
groups, about the same percent of cancer survivors partner, and to all employees. Consistent with the
smoked compared to the remaining US population: mission of cancer prevention and tobacco control,
for ages 45-64, 23.6% vs 22.3%; for ages 65+, 8.6% the program was developed and initiated in 2006
vs 9.4%. However, among the youngest cancer and continues through the present (Blalock et al,
survivors, ages 18-44, smoking rates are double in in press; Karam-Hage et al, 2011). This clinical
cancer survivors vs the remaining population, 40.4% service offers in-person and/or telephone behavioral
vs 24.6%. This is an appalling statistic that calls counseling, based on motivational interviewing
for dramatic attention, education and intervention. and social cognitive problem-solving strategies,
According to 2006 NHIS data (MMWR, 2007), prescription medication and nicotine replacement,
among chronic disease populations, 36.9% of those an initial comprehensive assessment and treatment
with any smoking-related chronic disease smoke, plan followed by six to eight counseling sessions
compared to 19.3% of those without a chronic over 12-16 weeks, and long-term assessments at
disease. Among all smoking-related cancers (except six and 12 months. The program is staffed by a
lung cancer), 38.8% of survivors smoke, and 20.9% multidisciplinary team (psychologists, psychiatrist,
of lung cancer survivors smoke. Astoundingly, 30% social workers, RN and PA), who maintain contact
of CVD survivors smoke and 49.1% of emphysema with the oncology care providers. New patient totals
survivors. The adverse effects of smoking after a reach almost 600/year, with a total of almost 24,000
diagnosis of cancer have been well-documented for appointments since the program’s inception. Overall,
surgery and radiation treatment, with some reports patients smoked an average of 16 cigarettes/day for
for chemotherapy, as well. These adverse effects 32 years; 13% reported a form of hazardous drinking
behavior; and over 48% met criteria for one or more Early work by Chapple et al. found that whether lung
co-morbid psychiatric diagnoses. At the one year cancer patients smoked or not, they felt stigmatized
follow-up, 30%-50% were abstinent (7 day point because their disease is so strongly associated with
prevalence), which compares favorably to highly smoking. Stigma in lung cancer is based on the
motivated populations of healthy smokers treated belief that one caused their own cancer. Lung cancer
with pharmacotherapy. Among those who did not is associated with short survival times and patients
quit entirely, smoking rates were cut by half (Karam- with lung cancer can receive stronger messages of
Hage et al, 2011). This program sets a standard for doom from family care givers and clinicians. These
healthcare settings, in terms of serving a cancer messages of doom contribute to self-attribution, a
patient population during and following treatment. strong predictor of distress. Stigma is correlated
Keywords: Cessation, lung, Cancer, Smoking with higher levels of guilt, shame, anxiety, and
depression and is linked to delayed diagnosis and
poor compliance with medical treatments. Evidence
Smoking Cessation & Lung Cancer Stigma Wednesday, 6 July 2011 suggests that increases in psychological morbidity
16:30-18:00 have a negative impact on treatment effectiveness
and quality of life (QOL). Until we developed the
E12.4 LUNG CANCER STIGMA AND Lung Cancer Stigma Scale, no valid and reliable
SYMPTOM BURDEN measure of stigma existed for use with lung cancer
Janine K. Cataldo patients. Therefore, no studies had examined the
Physiological Nursing, UCSF/United States Of severity of Lung Cancer Stigma (LCS) and its
America relationship with physical and psychosocial symptom
burden and QOL. In our previous work with lung
Abstract: Lung cancer is the leading cause of cancer cancer patients, strong associations were found
deaths in the United States. Compared to patients between LCS and depression (r= .68, p < .0001) and
with other types of cancer, lung cancer patients QOL (r=-.65, p < .0001). No signiÀcant differences
experience the greatest amount of psychological were found in demographic characteristics or
distress. Perceived stigma is deÀned as a personal study variables between ever smokers and never
experience characterized by exclusion, rejection, smokers. A simultaneous multiple regression with
blame or devaluation that result from anticipation 5 independent variables revealed an overall model
of an adverse judgment. This judgment is based on that explained 62.5% of the total variance of QOL
an enduring feature of identity conferred by a health (F5,168 = 56.015, P < .001). Lung cancer patients
problem, the judgment is medically unwarranted, experience greater symptom severity throughout
and may adversely affect health status. Stigma has their illness trajectory. The most common physical
been extensively studied in HIV/AIDS, mental symptoms include: dyspnea, fatigue, insomnia,
illness, epilepsy and physical disability, but not lung and pain. Very little research exist on factors that
cancer. The effects of perceived stigma, depend on contribute to increased symptom severity. Compared
whether or not patients themselves or others hold to other types of cancer, lung cancer patients
them responsible for the disease and whether the experience the greatest amount of psychological
disease leads to serious disability, disÀgurement, distress and are at higher risk for psychosocial
lack of control, or disruption of social interactions. problems during and after treatment. Studies have
Perceived stigma is associated with an increase in shown that one out of four persons with lung
the stress associated with illness and contributes cancer experience periods of depression or other
to psychological, physical and social morbidity. psychosocial problems during their treatment. Higher
Stigma in people with HIV is associated with QOL scores are associated with increased survival in
poor physical and mental health outcomes, limited lung cancer patients. Lung cancer survivors do not
sources of social support, concealment of disease experience the same level of QOL as other cancer
after prognosis, poor treatment adherence, increased survivors. Montazeri found that pre-diagnosis rating
disability, and diminished quality of life (QOL). of QOL was the most signiÀcant predictor of the
Lung cancer can conjure a similar attribution of length of survival even after adjusting for known
blame as that found with HIV, because HIV is often prognostic factors. Lung cancer patients experience
associated with homosexuality and IV drug use and greater symptom severity throughout their illness
lung cancer is associated with smoking cigarettes. trajectory. The most common physical symptoms
include: dyspnea, fatigue, insomnia, and pain. Very Session E13: TNM 7th Edition - What
little research exist on factors that contribute to Should Doctors Do?
increased symptom severity. Compared to other
types of cancer, lung cancer patients experience
the greatest amount of psychological distress and
are at higher risk for psychosocial problems during
and after treatment. Studies have shown that one TNM 7th Edition - What Should Doctors Do? Wednesday, 6 July 2011
out of four persons with lung cancer experience 16:30-18:00
periods of depression or other psychosocial problems
during their treatment. Very little research exist E13.1 ADEQUATE PN STAGING:
on factors that contribute to increased symptom WHAT SHOULD THE SURGEON DO?
severity. The purpose of this study was to explore SAMPLING, RADICAL DISSECTION,
the severity of LCS and its relationship with the SYSTEMATIC NODAL DISSECTION OR
severity of physical symptoms (i.e., appetite, cough, LOBE-SPECIFIC NODAL DISSECTION?
dyspnea, hemoptysis, pain. sleep), psycho-social Mark S. Allen
symptoms (self-esteem, anxiety, depression), and Surgery, Mayo Clinic/United States Of America
QOL. In a sample of 185 lung cancer patients, the
speciÀc aims were to: 1. Explore the relationships Abstract: Since the initial successful pneumonectomy
between LCS and the severity of physical symptoms; by Evarts A. Graham in 1933 and the subsequent
2. Explore the relationships between LCS and discovery that lobectomy was an acceptable resection
severity of psycho-social symptoms (i.e., self- to cure lung cancer, it has been unclear what is the best
esteem, anxiety, and depression); 3. Explore the method to deal with the lymph nodes that drain the
relationships between LCS and QOL; and 4. Identify area of cancer. Memorial Sloan Kettering described
the contributions of physical and psycho-social that patients who underwent a mediastinal lymph node
symptom severity and LCS to QOL. Methods: Lung dissection had a prolonged survival. Surprisingly, this
cancer patients were recruited from online lung assertion was not scientiÀcally tested, until 20 years
cancer support communities. IRB approved consent later, but only then with several retrospective studies.
forms and instruments were available on line. Data These include studies by Naruke, Izbicki, and Keller.
was collected on RedCap. Results: LCS had mild to In 1999 the late Robert Ginsberg was able to convince
strong associations with all physical symptoms and the American College of Surgeons Oncology Group
ranged from .26 to .46 (p< .001); LCS had moderate (ACOSOG) to perform a large randomized trial
to strong associations with all psycho-social comparing mediastinal lymph node sampling (MLNS)
symptoms from .41 to .55 (p<.001); A simultaneous to a complete mediastinal lymph node dissection
multiple regression with 4 independent variables (MLND) in patients with early stage lung cancer. The
(gender, age, depression, and LCS) revealed an study took about 12 years to complete and was able
overall model that explained 54.5% of the total to analyze 1,111 randomized patients. The Àndings
variance of QOL (F4,144 = 41.91, P < .001), stigma showed no difference in long-term survival between
uniquely explained 5% of the total variance of QOL MLNS and MLND. Only 4% of the patients that
after controlling for age, education, and depression initially had a MLNS were found to have a positive
(p<.001). A simultaneous multiple regression with mediastinal lymph node on MLND. The study also
4 independent variables revealed an overall model showed that there was no increase in the complication
that explained 36.4% of the total variance in total rate with MLND vs. MLNS; therefore, doing a LMND
lung cancer symptoms (F4,144 = 19.46, P < .001); seems to have very little downside except extending
stigma uniquely explained 6% of the total variance the operation about 15 to 20 minutes. However, since
of lung cancer symptoms, after controlling for age, the trial only studied patients with early stage cancer,
education, and depression (p<.001) . Conclusion: it is difÀcult to extrapolate the results to patients with
LCS is a strong predictor of psychosocial and stage II or stage IIIA cancers. The question of what
physical symptoms and QOL among lung cancer to do with the mediastinal lymph nodes during a
patients. pulmonary resection for lung cancer can be answered
with some scientiÀc evidence using the Z0030 study.
All patients should have a complete evaluation of the
mediastinum preoperatively with history and physical
(looking for evidence of hoarseness, cervical lymph and mediastinal lymph nodes are idenitiÀed by
nodes, decreased breath sounds from a paralyzed surgeons. Pathologists are required to identify
diaphragm, and enlarged neck veins from an obstructed hilar and intrapulmonary lymph nodes which are
central vein), computed tomography (CT), and found in the resected lung. On gross dissection
proton emission tomography (PET). When indicated of the resected lung, they should be careful not to
a mediastinoscopy, mediastinotomy or endoscopic fail to make a tissue block to examine these lymph
bronchoscopic ultrasound (EBUS) should be used nodes. SpeciÀcally, pulmonary hilar lymph nodes
to obtain pathological tissue to examine for further which are directly invaded by a main tumor should
deÀnition of the status of the mediastinal lymph nodes. be counted as pN1, though they may be easily
Once the chest is open all patients should have at least overlooked and scored as pN0 by a careless gross
a sampling of the hilar and mediastinal lymph nodes examination. A single, well-preserved HE-stained
and any enlarged or abnormal appearing lymph nodes tissue section from a maximal cut surface of each
should be removed. During the resection intralobar node can provide adequate and sufÀcient histologic
lymph nodes should be taken as part of the resection. evaluation of lymph node involvement. Clinical
For stage II cancers there is less scientiÀc information signiÀcance of minute metastasis are still under
on which to base a recommendation. Clearly, anyone investigation, and detailed modiÀcation of practical
with a stage II based on a positive intralobar lymph staging requires more evidence before clinical
node should undergo a complete mediastinal lymph introduction. For that purpose, metastatic tumors
node dissection since this would seem logical since the of 0.2 mm to 2 mm in actual size found in lymph
cancer has already shown its capability for spread to nodes are deÀned as micrometastasis. They should
lymph nodes, and to not examine the mediastinal lymph be described differently from those of ordinary
nodes would make logical sense since the lymph node size, such like pN1(mi), pN2(mi). Sentinel lymph
dissection does not increase the complication rate. For nodes could be identiÀed during surgery, separate
stage IIIa cancers patients deÀnitely need a complete description such like pN0(sn), pN1(sn), for example,
mediastinal lymph node dissection. For patients that is recommended. Evaluation and description of
are undergoing a resection after adjuvant chemotherapy isolated tumor cells (ITC), less than 0.2 mm by
and/or radiation therapy, the mediastinal lymph node deÀnition, found in regional lymph nodes is another
status is a key prognostic indicator, so removal for issue to be discussed. Immunohistochemistry, as
pathologic examination is indicated. For patients that well as some molecular tests such as PCR, is now
are discovered to have a positive mediastinal lymph in our hands of routine laboratorial work. However,
node at the time of sampling, it would seem wise to it should be mentioned that the results of these tests
remove the rest of the lymph nodes to be sure there is should be interpreted very carefully, and hopefully in
not residual cancer left behind and to completely stage conjuction with conventional histologic evaluation of
the mediastinum. the same lymph nodes. IdentiÀcation and description
Keyword: Lymph nodes of minimal, often morphologically invisible tumor
cells would be interpreted as a separate, and an
important effort devoted to establish the future
TNM 7th Edition - What Should Doctors Do? Wednesday, 6 July 2011 staging system, but does not necessarily mean a
16:30-18:00 precise staging in today’s clinical practice in the Àeld
of primary lung cancer.
E13.2 ADEQUATE PN STAGING: Keywords: lymph node metastasis, micrometastasis,
WHAT SHOULD THE PATHOLOGIST isolated tumor cells, immunohistochemistry
DO? NUMBER OF SECTIONS,
IMMUNOHISTO, MOLECULAR
MARKERS, PCR?
Yoshihiro Matsuno
Department Of Surgical Pathology, Hokkaido
University Hospital/Japan
Abstract: Pathologic staging should be performed

based on a standard procedure. Exact location
(ie, numbering) of dissected pulmonary hilar
TNM 7th Edition - What Should Doctors Do? Wednesday, 6 July 2011 more than 2 nodules or disease in other locations
16:30-18:00 despite the TNM 7th edition classiÀcation as M1a
disease. The Ànal change in the TNM 7th edition with
E13.3 WHICH CATEGORIES ARE surgical implications is the downstaging of T4N0-1
AMENABLE FOR SURGERY AFTER patients from Stage IIIB (unresectable) to Stage IIIA
DOWNSTAGING? where surgery can play a role. The T4N0-1 subset
Stephen G. Swisher was identiÀed early on as a group within TNM 6th
Thoracic And Cardiovascular Surgery, MD Anderson edition Stage IIIB locally advanced NSCLC that
Cancer Center/United States Of America has a favorable prognosis. SWOG 8805 treated 116
Stage IIIA/B NSCLC with concurrent cis/etop and
Abstract: Recently a new staging classiÀcation 45 gy of RT if patients did not progress they received
(TNM 7th edition) has been put forward that surgery. The T4N0-1 subset was identiÀed early on
reclassiÀes several groups of patients. The major as a favorable subset within TNM 6th edition Stage
changes in the TNM 7th edition staging system IIIB with a median survival of 32 months versus
include further subdivision of the T category by 12 months. Additionally, Grillo and colleague have
size (T1a (2 cm); T1b (>2-3 cm); T2a (>3-5cm); demonstrated that T4 tumors involving the carina can
T2b (>5-7 cm), T3 (>7 cm)). From the treating be resected with good long-term survival provided
physician’s perspective one important change of the N2 nodes are not involved. Our institution has
this size subclassiÀcation is that larger tumors are also found similar results with the resection of
now T3 (>7 cm) and T3N1M0 patients are now superior sulcus tumors invading the spine (T4N0-1)
reclassiÀed as IIIA (formerly IIB) in the TNM 7th provided the N2 nodes are not involved. In summary
edition. Since stage IIIA patients are often treated by then the shift in stage groupings of T4N0-1 tumors
oncologists without surgery (chemoradiation alone), from Stage IIIB to IIIA in the TNM 7th edition does
it is important to recognize that these T3N1 patients indeed appear to reÁect the good outcome of T4N0/1
may need to be separated from other TNM 7th edition tumors and puts them in a category where surgery
IIIA patients and treated with surgery instead of can often help control local disease and potentially
deÀnitive chemoradiation. Another major change improve long-term survival.
in the TNM 7th edition staging system with surgical Keywords: TNM 7th edition, NSCLC, Surgery
implications is that patients with two separate
nodules in the same lobe have been downstaged from
T4 to T3 while those with two separate nodules in TNM 7th Edition - What Should Doctors Do? Wednesday, 6 July 2011
different lobes have been downstaged from M1 to 16:30-18:00
T4. This revision reÁects the good overall survival of
patients with synchronous lung cancers treated with E13.4 UPSTAGES GROUPS: EVIDENCE
surgical resection and highlights the need of surgeons FOR ADJUVANT THERAPY
to target these patients for surgical therapy. Patients Jean Yves Douillard
with two separate nodules in different lungs are still Medical Oncology, ICO R Gauducheau/France
classiÀed as M1 disease (M1a) but it is important to
recognize that this may be due to a limitation of the Abstract: The TNM classiÀcation is an important
databases utilized for the TNM 7th edition staging tool for clinical practice. It allows to deÀne disease
system rather than a true biologic difference. The extension, to group such extension into stages and
databases used for the TNM 7th edition were not able to provide a prognostic value in term of relapse rate
to separate patients two nodules in different lungs risk and overall survival. It is also used to decide on
from patients with multiple (>2) nodules in different therapeutic strategies accordingly. It applies to a vast
lungs. The good outcome of 2 synchronous lung majority of cancers and is internationally deÀned
cancers in separate lungs may therefore have been and recognized under the auspices of International
missed because this favorable subset could not be Union Against Cancer (UICC) and the American
separated from patients who had clearly metastatic Joint Committee on Cancer (AJCC). In 2007 the
disease (multiple (>2) nodules in different lungs). International Association for the Study of Lung
It is therefore important to recognize that patients Cancer (IASLC) published its proposal for a revision
with two nodules in different lungs should still be of the TNM stage grouping and the edition of the 7th
considered for surgical resection if they do not have version of the TNM classiÀcation. Version 6th was
introduced in 2002 and actually did not suggest any adjuvant chemotherapy. It would however difÀcult
changes to the 5th edition from 1997. Since, clinical to Àt these data into the TNM 7th In the JBR10
stages have improved with better imaging including trial, the effect of adjuvant Vinorelbine-Cisplatin
the routine use of CT scan, In addition the set of was evaluated in stages pIB/II and showed overall
data used to propose the 7th edition included a total a signiÀcant beneÀt. However, subgroup analysis
of more than 67 000 cases of Non-Small Cell Lung showed that former TNM 6th stage pIB did not
Cancer (NSCLC) carefully selected by experts of beneÀt from adjuvant treatment and the overall
the working group, internationally from a total of 46 beneÀt was driven by the stage pII. Here again, stage
sources in 19 countries and a period ranging from pIB were T2N0M0 in TNM 6th and would now be
1990 to 2000. This was a more exhaustive analysis staged IB, IIA or IIB. A pooled exploratory analysis
than the database used for the 5th classiÀcation (5319 of JBR10 and CALGB has been presented evaluating
cases from a single institution and a period starting the effect of adjuvant chemotherapy according to T
in 1975). . The major modiÀcations implemented size in N0 cases reclassiÀed according to TNM 7th
in the TNM 7th edition essentially amend the T and . A total of 461 cases were included in this analysis.
the M parameters of the TNM. Accordingly, stage The Hazard Ratios (HR) of adjuvant chemotherapy
grouping has been modiÀed: -Small T2 tumours (>3 vs. surgery alone showed an increased reduction
and <5cm) T2a. T2a N1 M0 are down staged from in the risk of death and relapse with increasing T
stage IIB to IIA -Large T2 tumours (>5 and <7cm) size and a clear cut difference between pT2a and
become T2b, >7cm become T3 and are upstaged : pT2b/pT3. This data with the limitation of the
T2b N0 M0 are moved from stage IB to IIA, T3 N0 methodology and rather small sample size conÀrm
M0 from IB to IIB, T3 N1 M0 from stage IIB to the retrospective analysis of the impact of T size in
IIIA -Nodules in the same lobe become T3 and are CALGB. In other adjuvant trials including IALT,
down staged from IIIB to IIB if N0 and stage IIIA ANITA and BLT tumour size was not reported in
if N1or N2. -Nodules in another ipsilateral lobe are the study data collection and such analysis cannot
now T4 and down stage from former stage IV to be done retrospectively. In the ANITA trial, impact
IIIA if N0 or N1, stage IIIB if N2 or N3 -T4 tumours of adjuvant chemotherapy on survival has been
with other features are down staged from IIIB to reported according to pN stage. The TNM 7th is
IIIA if N0 or N1. -Tumours associated with pleural/ not modiÀed in term of pN stage and these data
pericardial nodules/effusion are upstaged from IIIB might be used to decide on adjuvant chemotherapy.
to IV. They also provide a more accurate Àgure in Based on what has been published retrospectively,
term of relapse rate and survival. Comparison of the T size matters. According to the present knowledge,
5-year survival rate according to the pTNM stages adjuvant chemotherapy should be offered to all
between the TNM 6th and 7th version on the data patients with pN1/pN2 disease. In patients with
base shows the following outcome (6th/7th): -Stage pN0 disease, according to the JBR10/CALGB
IA: 73/73% -Stage IB: 54/58% -Stage IIA: 48/46% retrospective pooled analysis, chemotherapy should
-Stage IIB: 38/36% -Stage IIIA: 25/24% -Stage IIIB: be discussed in patients with TNM 7th pT2b and
19/9% -Stage IV: 21/13% Most of these survival data above. Patients with smaller T2 tumours (T2a) and
on pTNM stages for resectable NSCLC have been N0 disease should be discussed individually and take
observed for surgery alone More recently another into account other prognostic factors. Should the 7th
single institution retrospective study reported the TNM classiÀcation modify treatment algorithms in
Local /Regional Recurrence (LLR) rate comparing term of adjuvant chemotherapy for resected NSCLC?
the 6th and 7th TNM used. % LLR % Metastasis First, the revision of the TNM for lung cancer did
-Stage IA: 16/16 16/16 -Stage IB: 26/23 36/28 -Stage not aim at providing information on the superiority
IIA: 43/37 64/56 -Stage IIB: 35/39 49/53 -Stage of a given treatment approach; second, change in
IIIA 40/30 85/65 The impact of the use of TNM 7th treatment algorithm based on the new TNM staging
on the indication of adjuvant chemotherapy is more should be evaluated in clinical trials. However, a
difÀcult to predict. For the former stage IB, in the recently published survey in the Thoracic Oncology
CALGB 9633 trial, tumours classiÀed as IB were community has shown that for “stage shifters”
pT2 N0 M0, T2 in the former TNM 6th . Overall this treatment strategy would be modiÀed based on the
study showed no beneÀt of Paclitaxel-Carboplatin new staging classiÀcation.
in the adjuvant setting. An exploratory analysis of Keyword: TNM VII, Upstages Groups, Adjuvant
the subset of tumours > 4cm showed a beneÀt from chemotherapy
Session E14: Lung Cancer Nursing Lung Cancer Nursing During and After Treatment Wednesday, 6 July
During and After Treatment 2011 16:30-18:00
E14.3 NURSING ASPECTS OF

TREATMENT WITH (EGFR) TKI:
IMMEDIATE TOXICITY
Lung Cancer Nursing During and After Treatment Wednesday, 6 July Suzan Ras - Van Spijk
2011 16:30-18:00 Daniël Den Hoed Clinic- Outpatient Care, Erasmus
MC/Netherlands
E14.2 NURSING ASPECTS OF
TREATMENT WITH (EGFR) TKI: Abstract: Patients with NSCLC can be treated
TOXICITY IN PATIENTS TREATED FOR with an EGFR-TKI inhibitor. Erlotinib is indicated
6 MONTHS for the treatment of patients with locally advanced
Atie W. Van Wijk, Annemarie Becker, Egbert F. or metastatic NSCLC after failure of at least one
Smit, Pieter E. Postmus prior chemotherapy regimen. GeÀtinib is indicated
Pulmonary Diseases, Vrije Universiteit Medical as the treatment for patients with locally advanced
Centre/Netherlands or metastatic NSCLC with an active EGFR-TKI
mutation. Treatment with EGFR-TKI inhibitors may
Abstract: 1. Background: Currently the inhibitor of cause side effects. Adverse reactions that may occur
the epidermal growth factor receptor (EGFR) tyrosine within two months are:
kinase erlotinib is widely used for the treatment of - Rash
non small cell lung cancer. Especially in patients - Diarrhea
with a mutation or deletion in the epidermal growth - Nail abnormalities
factor receptor gene. As these patients may beneÀt 45-100% of patients will experience a
most from the treatment, they may receive the drug papolupustulaire eruption. These side effects have
for a long period of time. 2. Methods: In our hospital a major impact on the quality of life. For the rating
we have reviewed the side effects of twenty-two of this skin disorder the NCI CTCEA list is used
patients receiving erlotinib for over six months. Male/ to score the different stages of disorder. These side
female: 3/19, EGFR deletion/mutation/unknown: effects may have an undulating course. It may be
15/5/2. All patients suffered from side effects, such more or less severe during the treatment. Dutch
as: diarrhea, folliculitis, paronchia, hair loss and Dermatologists have developed a treatment for every
hair changes, chronic cough and fatigue. Main side stage of the skin disorder and nail abnormalities.
effects were scored 1 and 2 common toxicity criteria The oncology nurse plays a important role in
(CTC). As we did not have much experience with coaching the patient and it’s relatives. She discusses
patients using erlotinib for months or even years, the preventive measurements that may affect the
we had to explore ways to treat side effects in a way patient. She is the Àrst point of contact for the patient
patients could continue therapy without too much if side effects occur. The sooner the patient reported
distress. 3. Results: in the presentation nursing care of side effects, the faster the treatment can be started.
these side effects and suggestions to support patients Of great importance is that the treatment with an
handling the side effects will be highlighted. Some EGFR-TKI inhibitor will not be interrupted when
case histories from patients with prolonged erlotinib side effects do show up.
treatment will be shown. 4. Conclusion: suffering
the side effects of EGFR inhibitors can be hard for Preventive measures against the skin disorder:
patients with non small cell lung cancer. New methods - Avoid direct sunlight
of treating the effects have to be investigated and - Use a moisturizing cream
described in medical/nursing literature. The use of - Protect the skin
specialist health care professionals is necessary to help Preventive measures against nail abnormalities:
patients in continuing the therapy, especially where - Wear gloves when doing housework
they beneÀt from this targeted therapy. The specialist - Do not wear tight Àtting footwear
nurse can play an important role in this process. - Cut the nails straight across
Keyword: Erlotinib, Long term side effects, nursing care - Daily inspect of the nails
Besides that, the oncology nurse also supervises in clinical trials were not included for the sake
the intake of medication. An important role of the of interference. A questionnaire was set up by
oncology nurse is the psychosocial coaching of the respiratory oncologists, a psychologist, and data
patient in respect to the disease and observe if any monitors working in our Respiratory Oncology unit.
adverse reaction occurs. They were submitted to patients by a co-worker not
involved in any treatment decision. It was explained
to the patients that we were questioning hypothetical
Lung Cancer Nursing During and After Treatment Wednesday, 6 July scenarios. It had to be completed at the start, after
2011 16:30-18:00 two and four cycles of chemotherapy, respectively.
Ten questions covered the topic of MT. Nine of
E14.4 MAINTENANCE THERAPY: HOW the ten questions could simply be answered by
DOES MY PATIENT FEEL ABOUT IT? “yes”, “no” or “don’t know”. One item addressed
Lies Peeters1, Beatrijs Anrys1, Anne Sibille1, Johan side-effects and this one used a 4 point Likert scale
Vansteenkiste2 format. A Àrst question asked whether patients would
1
Respiratory Oncology, University Hospital Leuven/ like to start with MT immediately after completing
Belgium, 2Respiratory Oncology Unit, University their 1st line treatment instead of a treatment-free
Hospital Leuven/Belgium period with careful follow-up. If not, a reason was
asked for and the questionnaire ended. If they would
Abstract: Non-small cell lung cancer (NSCLC) consider MT, further questions were asked about the
accounts for 80 to 85% of all types of lung expected beneÀt to consider MT, speciÀcally with
malignancies. First line chemotherapy for advanced regards to a certain expected mean survival beneÀt
stages of NSCLC is well-established and consists (1 year, 6, 3 and 1 months); or in the absence of
of 4 to 6 cycles of a platinum-doublet. Second line expected mean survival beneÀt to symptom relief or
treatment is classically started at disease progression. to radiological tumour stabilization. The next group
However, over the last years, a new concept has of questions was related to the maintenance drug
emerged: maintenance therapy (MT). This includes itself: would patients consider MT if administration
continuation of a given drug or consolidation of the drug was oral and daily; or if it was three-
with/switch to another drug directly after 1st line weekly and intravenously. The last question dealt
treatment. Both chemotherapeutic and biological with the acceptance of possible side effects. Each
agents can be used. Published phase III randomised of those (nausea, fatigue, diarrhoea, skin rash) had
studies have demonstrated progression-free survival to be graded on the Likert scale as none, mild,
(PFS) and overall survival (OS) beneÀts for MT moderate, severe. Recruitment was ongoing at the
with pemetrexed [1] or with erlotinib [2] after four time of submission of this abstract, and our Àrst data
cycles of a non-pemetrexed containing platinum- will be presented at the meeting. REFERENCES
doublet chemotherapy. Yet, pros and cons of this 1. Ciuleanu T, Brodowicz T, Zielinski C, et al.:
strategy remain in place. One major limitation Maintenance pemetrexed plus best supportive care
in the interpretation of the phase III trials is that versus placebo plus best supportive care for non-
the majority of the patients in the control arm small-cell lung cancer: a randomised, double-blind,
never received appropriate 2nd line therapy at the phase 3 study. Lancet 374, 1432-1440 (2009). 2.
time of progression. Therefore, it remains unclear Cappuzzo F, Ciuleanu T, Stelmakh L, et al.: Erlotinib
whether MT is really better than appropriate 2nd as maintenance treatment in advanced non-small-cell
line treatment at the time of disease progression. lung cancer: a multicentre, randomised, placebo-
Furthermore, issues with costs, quality of life and controlled phase 3 study. Lancet Oncol 11, 521-529
toxicity can be raised. Therefore, the preference of (2010).
patients well informed about pros and cons of MT
also has to be taken into account. We present our
preliminary results of a survey conducted on this
topic. The objectives were to evaluate the patients’
attitude towards MT in advanced NSCLC. Patients
were included if they were diagnosed with stage IV
NSCLC (any histology) and were planned to start
1st line doublet chemotherapy. Patients participating
Lung Cancer Nursing During and After Treatment Wednesday, 6 July in grade 2 in 96 patients
2011 16:30-18:00 t Nausea: EfÀcacy of aprepitant 125 mg once weekly
and metoclopramide 10 mg twice daily in 20 patients
E14.5 STRUCTURAL MANAGEMENT OF versus granisetron 1 mg once daily in 12 patients
PAITIENTS TREATED WITH CHEMO- t Cetuximab-induced dermatitis: EfÀcacy of
RADIOTHERAPY prophylactic minocycline 100mg once daily
Wilma Uyterlinde and elidel on demand in 16 patients versus no
Thoracic Oncology, NKI/AVL/Netherlands prophylaxis in cetuximab induced acneiform rash in
12 patients
Abstract: Many of the currently used supportive t Weightloss: feasibility en efÀcacy of initiating tube
care protocols are not evidence based but are feeding by the nutricionist in weight loss > 1 kg a
empiral. Often, suboptimal care is the result. week in 50 patients versus tube feeding according to
Adequate supportive care is a necessity for the the opinion of the phycisian
fulÀllment of treatment and reasonable tolerance of t Pain: efÀcacy of additional gabapantin and
toxicity. It is of importance to gain knowledge on the amitryptiline 75 mg once daily in 15 patients with
clinical characteristics and the relations with acute pleural pain or pain due to plexus brachialis ingrowth
toxicity and outcomes in patients with non-small t Nefrotoxicity: efÀcacy and contra indications
cell lung cancer treated with chemo radiotherapy. in standard hydration with 1000 ml saline before
Based on short-term interventions in small cohorts chemotherapy in 30 patients versus no hydration in
of patients the standardized supportive care program 30 patients
was optimized and improved guidelines were t Literature studies were performed on all topics and
developed. Concurrent chemo radiotherapy (CCRT) discussed in a multidisciplinary fashion with clinical
is the treatment of choice for locally advanced experts prior to the initiation of the interventional
irresectable or inoperable non-small cell lung cancer. trials.
Since 1990 daily dose cisplatin (6 mg/m2 for 24 Statistics: The Statistic Package for Social Sciences
days), is administered concurrently with accelerated (SPSS) version 18 was used for data entry.
high dose radiotherapy. The increase in survival Correlation and regression tests were performed for
(resp. 6% and 11% at 3 years) for concurrent versus the analysis
sequential chemo radiotherapy, or radiotherapy alone Results: Two hundred and thirty-seven patients were
is due to improved local control of the disease(1-3). treated concurrently in 2008, 2009 and 2010 in the NKI-
Side effect, however, are signiÀcant for the patient. AVL The prescription of oral magnesiumhydroxide
Patients and methods Patients Patients treated aluminum in grade 1 hypomagnesaemia resulted in less
concurrently with daily low dose cisplatin and grade 2 toxicity. Intravenous suppletion of magnesium
radiotherapy in 2008, 2009, 2010 in the Netherlands sulphate doesn’t increase the plasma magnesium
Cancer Institute Antoni van Leeuwenhoek Hospital nor reduces the duration of the hypomagnesaemia.
(NKI-AVL). Chemoradiotherapy Daily cisplatin Aprepitant and metoclopramide increases grade 2
6 mg/m2 (maximum 12 mg) followed by 2, 75 nausea and vomiting and are therefore not superior to
Gy on 24 consecutive working days. Because of granisetron in daily chemo radiotherapy Prophylactic
involvement in a randomized clinical trial, some minocycline reduces severe cetuximab induced skin
patients received cetuximab 250 mg/m2 weekly, toxicity and is superior to minocycline on demand Tube
aften an oading dose of 400 mg/m2 one week prior feeding according to guidelines is feasible and reduces
to the start of CRT Methods From January 2008 to the incidence of severe weight loss Hydration before
2010 several prospective small-cohort intervention chemotherapy stabilizes the glomerular Àltration rate
trials were initiated because of the side-effects/ and reduces forced endings of treatment. No increase in
complications of the CRT exempliÀed by the cardiac failure was observed Conclusions Small pilot
following studies are shown to be feasible and increase the toxicity
t Hypomagnesemia: EfÀcacy of oral tolerance in patients leading to therapy compliance
magnesiumhydroxide/aluminum400/200 mg 4 times and fulÀllment of treatment Intervention trials in small
daily in grade 1 (0.50-0.60 mmol/l) and 2 grams of cohorts of uniformly treated patients are an effective way
intravenous magnesiumsulphate in grade 2 (0.20- to improve supportive care in a short period of time.
0.50 mmol/l) hypomagnesaemia in 124 patients Keywords: chemo radiotherapy, supportive care
versus 1-4 grams of intravenous magnesiumsulphate
Session E15: Pain Management a mean number of four episodes per day (range
1-14) [4], whilst Portenoy and Hagen reported
Thursday, 7 July 2011 a median duration of 30 min (range 1-240) [5].
Management A task group on breakthrough cancer
pain of the Science Committee of the Association
Pain Management Thursday, 7 July 2011 10:30-12:00 for Palliative Medicine of Great Britain and Ireland
(APM) recommended that the management of
E15.3 FAST-ACTING OPIOIDS FOR breakthrough pain should be individualised, and
BREAKTHROUGH PAIN MANAGEMENT that consideration should be given to treatment of
Andrew Davies the underlying cause of the pain and to avoidance /
Palliative Care, St. Luke’s Cancer Centre/United treatment of the precipitating factors of the pain [1].
Kingdom Other treatment strategies that should be considered
include modiÀcation of the background analgesic
Abstract: Breakthrough pain has been deÀned as regimen / “around the clock medication”, use of non-
“a transient exacerbation of pain that occurs either pharmacological methods, and use of interventional
spontaneously, or in relation to a speciÀc predictable techniques [1]. However, the cornerstone of the
or unpredictable trigger, despite relatively stable management of breakthrough pain episodes is
and adequately controlled background pain” [1]. the use of so-called “rescue medication”. Rescue
Unfortunately, there is a lack of consistency in medication is taken as required, rather than on a
the use of the term breakthrough pain in clinical regular basis: in the case of spontaneous pain or
practice, and also within the medical literature. non-volitional incident pain the treatment should be
Indeed, the term is widely (mistakenly) used to taken at the onset of the breakthrough pain; in the
describe similar exacerbations of pain in patients case of volitional incident pain or procedural pain
with poorly controlled background pain. Clinical the treatment should be taken before the relevant
features Breakthrough cancer pain is a common precipitant of the pain [1]. In most cases the most
problem in patients with cancer, with an estimated appropriate rescue medication will be an opioid
prevalence of 40-80% amongst patients with cancer analgesic, rather than a non-opioid or an adjuvant
pain [2]. Breakthrough pain is not a single entity, analgesic. Traditionally, the most common form
but a spectrum of very different entities. Thus, of rescue medication has been the oral “normal-
breakthrough pain may be related to a number of release” (“immediate-release”) formulations of
different causes (cancer-related, treatment-related, morphine and other relevant opioid analgesics.
concomitant illness) and different pathophysiologies However, the pharmacokinetic / pharmacodynamic
(nociceptive, neuropathic, mixed) [3]. Breakthrough proÀles of oral opioids do not tend to mirror the
pain is usually classiÀed into one of two categories temporal characteristics of most breakthrough pain
[3]: § Spontaneous pain (“idiopathic pain”) – the episodes [3]. Thus, the slow onset of action (onset
episodes are not related to an identiÀable precipitant, of analgesia: 20-30 min; peak analgesia: 60-90 min)
and so are unpredictable in nature. § Incident pain results in delayed / ineffective analgesia, whilst
(“precipitated pain”) – the episodes are related to the prolonged duration of effect (3-6 hr) results in
an identiÀable precipitant, and so are somewhat ongoing adverse effects. In other words, oral opioids
predictable in nature. Incident pain is usually sub- are not the optimal rescue medication for most
classiÀed into one of three categories: 1.Volitional breakthrough pain episodes. The parenteral routes
incident pain - is brought on by a voluntary act of administration (intravenous, subcutaneous) are
(e.g. walking). 2.Non-volitional incident pain - is often used to manage breakthrough pain episodes
brought on by an involuntary act (e.g. coughing). in the secondary care setting. However, their use
3.Procedural pain - is related to a therapeutic in the primary care setting is somewhat limited by
intervention (e.g. wound dressing). The clinical practical considerations. The oral transmucosal
features of breakthrough pain vary from individual routes of administration (buccal, sublingual) have
to individual, and may vary within an individual increasingly been utilised in the management of
over time [3]. Nevertheless, breakthrough pain is breakthrough pain episodes, and there are currently
often reported to be frequent in occurrence, acute in three products available commercially (i.e. Actiq®,
onset, short in duration, and moderate-to-severe in Abstral®, Effentora®) with a number of other
intensity [3]. For example, Zeppetella et al reported products in development. Other transmucosal
routes of administration (nasal, pulmonary) Session E16: Radiotherapy Issues in

have also been utilised in the management of Small Cell Lung Cancer
breakthrough pain episodes, and there is currently
two intranasal products available commercially
(i.e. Instanyl®, PecFent®) with again a number of
other products in development. These alternative
routes of administration offer signiÀcant advantages Radiotherapy Issues in Small Cell Lung Cancer Thursday, 7 July 2011
in terms of onset of action over the oral route of 10:30-12:00
administration. The decision to use a speciÀc opioid
preparation should be based on a combination E16.1 ROLE OF RADIOTHERAPY IN
of the pain characteristics (onset, duration), ES-SCLC
the product characteristics (pharmacokinetics, Ben Slotman
pharmacodynamics), the patient’s previous response Radiation Oncology, VU University Medical Center/
to opioids (efÀcacy, tolerability), and particularly the Netherlands
patient’s preference for an individual preparation.
Indeed, it is extremely unlikely that any one opioid Abstract: Small cell lung cancer (SCLC) comprises
preparation will be suitable for all patients with 10-15% of all lung tumors. Haematogenous
breakthrough pain. It should be noted that some metastases are present at diagnosis in about
patients experience opioid-insensitive breakthrough two thirds of patients (ES; extensive stage).
pain, or ultra short duration breakthrough pain Chemotherapy is crucial in the treatment of SCLC,
(that is not amenable to any rescue medication). but improvements in survival for patients with
References [1]. Davies AN, Dickman A, Reid C, SCLC have in the last two decades mainly been
Stevens A-M, Zeppetella G. The management of achieved by the use of radiotherapy. Based on the
cancer-related breakthrough pain: recommendations effects of radiotherapy in patients with limited stage
of a task group of the Science Committee of the (LS) SCLC, key developments in radiotherapy
Association for Palliative Medicine of Great for patients with ES-SCLC will be presented. In
Britain and Ireland. Eur J Pain 2009; 13: 331-8. [2]. addition, the rationale behind ongoing studies on the
Mercadante S, Radbruch L, Caraceni A, Cherny N, use of radiotherapy in ES-SCLC will be addressed.
Kaasa S, Nauck F, et al. Episodic (breakthrough) Various studies have established the role of thoracic
pain. Consensus conference of an Expert Working radiotherapy (TRT) and prophylactic cranial
Group of the European Association for Palliative irradiation (PCI) in patients with LS-SCLC. Both
Care. Cancer 2002; 94: 832-9. [3]. Davies A. TRT and PCI not only improve control of disease
Cancer-related breakthrough pain. Oxford, Oxford in the thorax and brain, but also lead to improved
University Press; 2006. p. 1-11. [4]. Zeppetella survival. Because the risk of brain metastases is
G, O’Doherty CA, Collins S. Prevalence and even higher in patients with ES- than in those with
characteristics of breakthrough pain in cancer LS-SCLC, the EORTC performed a study on the
patients admitted to a hospice. J Pain Symptom use of PCI in patients with ES-SCLC [Slotman et
Manage 2000; 20: 87-92. [5]. Portenoy RK, Hagen al., N Engl J Med 2007,357,664-72]. Patients who
NA. Breakthrough pain: deÀnition, prevalence and had responded to chemotherapy were randomized
characteristics. Pain 1990; 41: 273-81. to PCI or no further therapy. Brain imaging was
Keywords: Breakthrough pain, Incident pain, not required on a routine basis, but performed
Cancer pain when signs and/or symptoms suggestive for brain
metastases were present. In this study, the use of PCI
resulted in a reduction of the risk of symptomatic
brain metastases at 1 year of 40.4% in the control
arm to 14.6% in the patients who received PCI.
Moreover, the study showed a signiÀcant beneÀt of
PCI for failure-free and overall survival. Survival at
1 year after randomization, which was on average
4 months after diagnosis, was 27.1% for the PCI
group, compared to 13.3% for patients in the control
arm. In this study, most patients received a PCI
scheme of 20 Gy in 5 fractions. The treatment was Radiotherapy Issues in Small Cell Lung Cancer Thursday, 7 July 2011
well tolerated, with very few patients experiencing 10:30-12:00
grade 3 or higher acute and/or late toxicity. Although
acute side effects negatively inÁuenced some quality E16.2 WHAT IS THE OPTIMAL
of life scales immediately after treatment, no overall RADIOTHERAPY DOSE AND TARGET
effect of global quality of life up to 9 months was VOLUME IN LD-SCLC
detected. Thoracic radiotherapy has traditionally Jeffrey Bogart
been reserved in ES-SCLC patients for palliative Radiation Oncology, Suny Upstate Medical
indications. The apparent lack of interest in TRT University/United States Of America
in these patients is probably related to the systemic
nature of the disease and the rapid progression in Abstract: Several variables regarding the treatment
many patients. Only one study investigated the use of limited stage small cell lung cancer, including
of TRT in ES patients in detail [Jeremic et al., J Clin radiotherapy dose, fractionation , timing, and
Oncol 1999,17,2092-9]. Patients with a complete treatment volume, have not been well deÀned even
response after three cycles of chemotherapy at though randomized clinical trials assessing these
distant sites and a partial or complete response in variables have been completed. Radiotherapy
the thorax, were randomized to either chemotherapy treatment guidelines vary greatly in modern
alone or radiotherapy (54 Gy in 36 fractions over prospective studies in part because it is not clear
18 days) given concurrently with carboplatin and whether the results of past trials translate to current
etoposide. The use of TRT in these selected patients therapy. The development of advanced radiation
resulted in a signiÀcant improvement of survival treatment techniques such as conformal radiotherapy
(median survival 17 versus 11 months. Survival at and image guided radiotherapy have resulted in
3 and 5 years was 22% and 9% for the TRT group a natural evolution in the treatment approach for
and 13% and 4% for the chemotherapy-only group, small cell cell lung cancer. For example, delivery
respectively. This single-center study has not yet of high doses of conventionally fractionated
been reproduced and did not lead to the routine use radiotherapy to a restricted target volume has
of TRT in ES-SCLC. Two studies on the role of become common clinical practice in both community
thoracic radiotherapy in ES SCLC have recently and academic centers despite the absence of level
been initiated. The Dutch Lung Cancer Study Group 1 evidence. Ongoing randomized trial in North
has activated an international randomized controlled America and Europe are assessing the role of high
trial of TRT versus observation for patients with dose fractionated radiotherapy in comparison with
ED-SCLC who have responded to chemotherapy. accelerated hyper-fractionated radiotherapy,though
The trial is open since 2009 [CREST-trial in the results are not likely to be available for several years.
Netherlands, Belgium, Germany and Norway; REST- This review will describe the available prospective
trial in the United Kingdom). Patients with ES-SCLC data that may help guide decisions for choosing a
who responded to chemotherapy with a WHO score radiotherapy regimen in patients with limited stage
of 0–2 are randomized to PCI plus TRT (30 Gy in small cell lung cancer who are not able to enroll on
10 fractions) or PCI only. The primary endpoint of prospective studies.
this study is overall survival. The RTOG has also Keywords: small cell, accelerated hyperfractionated
initiated a phase II trial on the role of consolidation radiotherapy, randomized trial
extracranial radiotherapy. In the experimental arm
of this trial, radiotherapy to the thorax and residual
extracranial metastatic sites is given alongside PCI
after a response to systemic chemotherapy [RTOG
0937]. Patients with up to three extrathoracic
metastatic sites can be included. The total dose of
45 Gy in 15 fractions. The results of these studies on
TRT are expected in about three years.
Keywords: thoracic radiotherapy, PCI, Small cell
lung cancer, extensive stage
Radiotherapy Issues in Small Cell Lung Cancer Thursday, 7 July 2011 Recently, targeted agents such as anti-angiogenic
10:30-12:00 agents, mTOR inhibitors and Bcl-2 inhibitors
have been studied either in combination with
E16.3 CHEMOTHERAPY FIRST LINE chemotherapy or alone without much success6,7.
AND AT RECURRENCE Topotecan, a topoisomerase inhibitor is the only
Suresh Ramalingam proven agent in patients that relapsed following
Hematology And Medical Oncology, Winship Cancer platinum-based chemotherapy, though its efÀcacy
Institute Of Emory University/United States Of is restricted to patients with chemotherapy-
America sensitive disease8. In a phase III study, topotecan
was associated with a higher symptom control rate
Abstract: Small cell lung cancer (SCLC) has compared to the combination of cyclophosphamide,
reduced in incidence over the past three decades and doxorubicin and vincristine. An oral formulation
now accounts for approximately 15% of all cases of of topotecan has been compared to intravenous
lung cancer1. It is characterized by the diagnosis at formulation and has demonstrated comparable
an advanced stage in majority of the patients and the efÀcacy and safety proÀle, making this another
presence of symptomatic disease. SCLC is usually option for patients with sensitive relapse. Amrubicin,
divided into limited stage disease or extensive stage an anthracycline derivative, has demonstrated
disease for the purposes of treatment and prognosis. promising response rates in phase II studies for
The new staging system for lung cancer (7th Edition relapsed/recurrent SCLC. This is now being
of the AJCC) developed by the IASLC Staging evaluated in a phase III study for second line therapy
Project, has recommended the use of the TNM of SCLC 9.
method for SCLC2. This system provides for better Ongoing studies are evaluating newer classes of
categorization of patients and deÀnition of prognosis. molecularly targeted agents such as the Hedgehog
Systemic chemotherapy is the mainstay of treatment inhibitors and the IGF-1R pathway inhibitors. A
for SCLC. For patients with advanced stage greater understanding mediators of resistance and
disease, the combination of a platinum compound sensitivity to platinum is also necessary to improve
and etoposide is the recommended regimen in the the efÀcacy of combination chemotherapy for SCLC.
United States. In the Japanese patient population, References
the combination of cisplatin and irinotecan has 1. Govindan R, Page N, Morgensztern D, et al:
demonstrated superior survival compared to cisplatin Changing epidemiology of small-cell lung cancer
and etoposide and has therefore become a commonly in the United States over the last 30 years: analysis
used regimen3. However, the cisplatin-irinotecan of the surveillance, epidemiologic, and end results
regimen was not superior to cisplatin-etoposide in database. J Clin Oncol 24:4539-44, 2006
two large randomized studies conducted outside 2. Shepherd FA, Crowley J, Van Houtte P, et al:
Japan4,5. Pharmacogenomic variations could have The International Association for the Study of
contributed to the conÁicting results across these Lung Cancer lung cancer staging project: proposals
studies. Present evidence supports the use of 4 regarding the clinical staging of small cell lung
cycles of chemotherapy, which is associated with a cancer in the forthcoming (seventh) edition of the
median survival of approximately 8 to 12 months. tumor, node, metastasis classiÀcation for lung cancer.
Approximately two-thirds of the patients beneÀt J Thorac Oncol 2:1067-77, 2007
from combination chemotherapy, and are referred to 3. Noda K, Nishiwaki Y, Kawahara M, et al:
as the ‘sensitive’ population. The remainder of the Irinotecan plus cisplatin compared with etoposide
patients either develop disease progression either plus cisplatin for extensive small-cell lung cancer. N
or within 90 days of completion of chemotherapy Engl J Med 346:85-91, 2002
(refractory population). 4. Hanna N, Bunn PA, Jr., Langer C, et al:
Since the adoption of platinum-based chemotherapy Randomized phase III trial comparing irinotecan/
as the cornerstone of treatment of small cell lung cisplatin with etoposide/cisplatin in patients with
cancer in the 1980s, very little progress has been previously untreated extensive-stage disease small-
achieved in the realm of systemic therapy. Various cell lung cancer. J Clin Oncol 24:2038-43, 2006
approaches including dose-intense chemotherapy, 5. Lara PN, Jr., Natale R, Crowley J, et al: Phase III
high-dose chemotherapy and alternating regimens trial of irinotecan/cisplatin compared with etoposide/
have all failed to improve survival in SCLC. cisplatin in extensive-stage small-cell lung cancer:
clinical and pharmacogenomic results from SWOG 1998; Slotman 2007]. No dose-effect relationship
S0124. J Clin Oncol 27:2530-5, 2009 for PCI was demonstrated in LD SCLC patients
6. Pandya KJ, Dahlberg S, Hidalgo M, et al: A so that the recommended dose is 25 Gy in 10
randomized, phase II trial of two dose levels of fractions. In NSCLC, it reduces the incidence
temsirolimus (CCI-779) in patients with extensive- of BM but individual trials could not show any
stage small-cell lung cancer who have responding or impact on survival and trials are still ongoing
stable disease after induction chemotherapy: a trial of [Gore 2010]. However, some clinicians may be
the Eastern Cooperative Oncology Group (E1500). J reluctant to propose it to patients because of its
Thorac Oncol 2:1036-41, 2007 potential neurotoxicity. Retrospective studies have
7. Rudin CM, Salgia R, Wang X, et al: Randomized reported neurological and intellectual impairment
phase II Study of carboplatin and etoposide with or abnormalities on brain computed tomography
or without the bcl-2 antisense oligonucleotide (CT) scan potentially related to PCI. Acute toxicity
oblimersen for extensive-stage small-cell lung is generally manageable and consists mostly in
cancer: CALGB 30103. J Clin Oncol 26:870-6, 2008 alopecia, headache, fatigue, nausea, and vomiting.
8. von Pawel J, Schiller JH, Shepherd FA, et al: Long-term sequelae such as severe memory loss,
Topotecan versus cyclophosphamide, doxorubicin, intellectual impairment or even dementia and
and vincristine for the treatment of recurrent small- ataxia have been reported in retrospective studies
cell lung cancer. J Clin Oncol 17:658-67, 1999 and attributed to PCI. However, most of these
9. Onoda S, Masuda N, Seto T, et al: Phase II trial studies are small, very heterogeneous and with no
of amrubicin for treatment of refractory or relapsed baseline evaluations. Evaluating PCI neurological
small-cell lung cancer: Thoracic Oncology Research toxicity is difÀcult because the related symptoms
Group Study 0301. J Clin Oncol 24:5448-53, 2006 can be caused by many different factors. It is well
Keywords: SCLC, Chemotherapy, Cisplatin, known that treatment modalities such as PCI dose
Topotecan and fractionation scheme (fraction size 3 Gy), or
the use of concurrent chemotherapy (ccCT) may
contribute to neurotoxicity. Some studies have also
Radiotherapy Issues in Small Cell Lung Cancer Thursday, 7 July 2011 suggested that neuropsychological impairment
10:30-12:00 could be attributable to cancer itself or pre-PCI
treatment, as baseline evaluation was impaired
E16.4 POTENTIAL TOXICITY before PCI in several studies both retrospective
OF PROPHYLACTIC CRANIAL and prospective. Age, effects of chronic cigarette
IRRADIATION abuse, paraneoplastic syndromes, and undiagnosed
Cecile Le Pechoux micrometastases may also contribute to neurotoxicity
Radiation Oncology, Institut Gustave Roussy/France or partly explain neurological symptoms.
Furthermore, patients may have symptoms of
Abstract: Whatever the stage and treatment, brain depression or anxiety that may interfere with
failures have become a major concern in lung neuropsychological evaluations. Neuropsychological
cancer. As survival is poor after development of assessment of long term toxicity is thus difÀcult
brain metastases in spite of speciÀc treatment, in lung cancer. The best evaluation of PCI toxicity
prophylactic cranial irradiation (PCI) has been comes from long-term follow-up of randomized
developed. PCI has been evaluated in randomized studies using validated questionnaires for QoL,
trials in both small cell (SCLC) and non-small cell general health status, and neurological functions.
(NSCLC) lung cancers to reduce the incidence of Two large prospective trials evaluating PCI in SCLC
brain metastases and possibly increase survival. It did not show any signiÀcant decline in neurological
is well established PCI reduces signiÀcantly the functions in the PCI group as compared to the
BM rate in both limited disease (LD) and extensive control group, with a follow-up not exceeding
disease (ED) SCLC and in non-metastatic NSCLC. 30 months [Arriagada, 1995; Gregor,1997]. A
Considering SCLC, PCI signiÀcantly improves third trial comprised a prospective neurocognitive
overall survival in LD (from 15 to 20% at 3 years) evaluation of all patients randomly assigned to
and ED (from 13% to 27% at one year) in patients receive irradiation and concomitant chemotherapy
who respond to Àrst-line treatment; thus it has now with or without warfarin [Ahles 1998]. Even if trial
become part of the standard treatment [Auperin, did not address directly PCI, the authors concluded
that the combination of chemotherapy and PCI Abstract: Background and purpose Thymic
had a negative impact on cognitive functioning, epithelial tumors are categorized into thymomas and
conÀrming that chemotherapy and PCI should not thymic carcinomas including thymic neuroendocrine
be administered concomitantly. In a more recent trial tumors. The main strategy of treatment for thymic
where all patients had PCI but at 2 different doses, epithelial tumors is supposed to be surgery. These
very few patients had severe deterioration of neuro- neoplasms are well-known for variability in the
psychological and cognitive functions and some histological appearance. Characteristics of thymoma
items seemed to worsen with age such as memory in microscopic appearance is the organotypic
and brain imaging abnormalities [Le Pechoux, 2009]. nature suggesting the thymic origin, which is
Concerning PCI in extensive stage SCLC, the results absent in thymic carcinomas. Nearly 70% of
showed a negative but limited impact of PCI, with a thymomas appear as Masaoka stage I or II diseases
signiÀcantly decreased QoL in terms of functioning while thymic carcinomas usually in advanced
scales among PCI patients at 6 weeks, which tended stages at the time of diagnosis. Finally, tumor
to be not signiÀcant at 3 months and afterwards. death occurs even after 10 years after resection in
Ways to possibly reduce the risk of neurocognitive thymoma patients while all the tumor deaths were
decline after whole brain irradiation are being seen within 5 years after resection according to
explored and will be developed: combination with our experiences. Thus, thymomas are generally
neuroprotective drugs such, and new approaches indolent and biologically different from thymic
using intensity modulated radiotherapy to spare carcinomas. These neoplasms are also heterogeneous
the hippocampus. They are being evaluated in the biological function. Our previous studies
in BM treatment and they could eventually be have revealed that most of thymomas possess
explored in the future for PCI. At present based CD4+CD8+ double positive T cells, which are
on randomized trials, neurocognitive functions exclusively present in the thymic cortex, suggesting
seem to be equivalent or moderately altered after that thymomas have immunological function
PCI as opposed to no PCI. PCI is now part of the similar to the thymic cortical epithelium, while
standard treatment in SCLC patients and should thymic carcinomas do not. Consistently with this
continue to be investigated in NSCLC patients with function, thymomas, but not thymic carcinomas,
locally advanced disease. PCI, if prescribed, should are frequently associated with autoimmune
always be performed in absence of concomitant CT. diseases represented by myasthenia gravis. Based
PCI should be reconsidered if long-term survival on the above heterogeneity of thymic epithelial
increased dramatically or if neurotoxicity appeared tumors, thymoma and thymic carcinoma should
more frequent and more severe. Such risk has to be be discussed separately. Masaoka stage reÁects the
put into balance with the beneÀt of PCI in terms of survival of thymoma patients, and patients with
BM incidence and survival. stage I or II diseases have good prognosis while
Keywords: prophylactic cranial irradiation, non- those with stage III or IV diseases have more
small cellung cancer, Small cell lung cancer, multi- chances of tumor deaths. Here, the implication of
modality treatment surgical treatment for advanced thymomas, but
not thymic carcinomas, was exclusively focused,
and the implication of surgery for thymomas with
Session E17: Advanced Thymoma stage III or IV diseases was examined to gain some
insight into the treatment strategy for this entity of
Thursday, 7 July 2011 neoplasm. Patients Outcome was reviewed based
on 121 patients with advanced stage (stage III or
IV) thymoma who underwent surgical resection at
Advanced Thymoma Thursday, 7 July 2011 10:30-12:00 Osaka University Hospital and the afÀliated hospitals
were examined. The number of patients with stage
E17.1 SURGICAL TREATMENT FOR III, IVA, and IVB were 87, 21 and 13, respectively.
THYMOMA WITH ADVANCED STAGES Results In Masaoka stage III patients, completeness
Meinoshin Okumura, Yoshihisa Kadota of resection and the involved organ are signiÀcant
Department Of General Thoracic Surgery, Osaka prognostic factors in stage III disease. The disease-
University Graduate School Of Medicine/Japan speciÀc 10-year survival rates were 91% and 53%
in patients undergoing complete resection and
subtotal resection, respectively. Disease-speciÀc 10- more efÀcient treatment strategy for thymomas with
year survival rates were 72% and 92% in patients distant metastasis.
with and without involvement of the great vessels, Keywords: Thymoma, Surgery, Induction
respectively. Complete resection was not achieved Chemotherapy
in 30% of the patients with involvement of the great
vessel. In patients without involvement of the great
vessels, Disease-speciÀc 10-year survival rates were Advanced Thymoma Thursday, 7 July 2011 10:30-12:00
93% and 83% in patients with involvement of the
pericardium alone and the lung, respectively. Tumor E17.2 INDUCTION THERAPY FOR
recurrence after complete resection was observed in LOCALLY ADVANCED THYMOMA
6%, 21% and 52% in patients with involvement of Gregory J. Riely1, James Huang2
1
the pericardium alone, the lung but not great vessel, Medicine, Memorial Sloan-Kettering Cancer
and the great vessel, respectively. Tumor recurrence Center/United States Of America, 2Memorial Sloan-
was observed mainly in the pleural cavity when Kettering Cancer Center/United States Of America
the lung was involved. On the other hand, distant
metastasis frequently occurred when great vessel was Abstract: Although rare, thymomas are the most
involved. Finally, WHO histological classiÀcation common tumors of the mediastinum and often
also reÁected the outcome of surgical treatment present with either localized or locally advanced
for stage III thymoma. Survival was signiÀcantly disease. Overall outcomes for patients with thymoma
better in the group of type A, AB, and B1 than in have been consistently shown to correspond to
the group of type B2 and B3. In Masaoka stage tumor stage and the completeness of surgical
IVA patients, all the patients had plural metastases, resection.1-3 With the clear prognostic beneÀt of
and only one patient had additional dissemination complete surgical resection in patients with locally
inside the pericardium. Direct invasion to the advanced thymoma, a number of investigators
pericardium, lung, and great vessel were also present have explored the role of pre-operative therapy for
in 10, 21, and 6 patients, respectively. Extrapleural optimal management of locally advanced thymoma.
pneumonectomy was not performed, and metastatic At least 4 groups have reported prospective clinical
lesions in the pleural cavity were resected with trials exploring multimodality therapy for locally
the surrounding pleura. The disease-speciÀc 10- advanced thymoma.4-7 Berruti et al conducted a
year survival rate was 67% in patients undergoing prospective clinical trial of cisplatin, doxorubicin,
macroscopically complete resection. On the other vincristine, and cyclophosphamide in patients
hand, the disease-speciÀc 10-year survival rate was with stage III and IVa thymoma. They observed
31% when there was a residual tumor. In Masaoka that Àve of six patients had a partial response and
stage IVB patients, lymph nodal involvement and then went on to surgery. Despite this high response
hemotogenous metastasis were seen in 8 and 5 rate, only one patient achieved a complete surgical
patients, respectively. The disease-speciÀc 5-year resection, the goal of such induction therapy.
survival rate was 33% in stage IVB disease. There Patients treated by Kim et al, were patients with
were no 5-year survivors in patients with distant locally advanced thymoma who received induction
metastasis while 2 patients with nodal metastasis cisplatin, doxorubicin, cyclophosphamide, and
survived over 5 years. Conclusion Long term prednisone, followed by surgery, radiation, and
survival of more than 10 years can be obtained by consolidation chemotherapy. Seventeen of 22
surgery even in patients with the advanced stage, patients had a response with chemotherapy. Six of
and therefore, surgical resection seems to be the 16 patients had greater than 80% tumor necrosis at
treatment of choice when complete resection is the time of surgical resection. Kunitoh et al gave
achieved. Multimodality treatment in combination weekly dose dense chemotherapy followed by
with surgical resection is highly recommended when surgery for patients with locally advanced thymoma,
the great vessel is involved. Surgical resection seems leading to a 62% response rate and 14% complete
to have some impact on survival even when the pathologic response rate.7 These trials emphasize that
tumor is associated with pleural or nodal metastatic prospective phase 2 trials for patients with locally
lesions. On the other hand, stage IVB thymoma with advanced thymoma are feasible. More recently,
distant metastasis has more chances of tumor death, investigators have attempted to incorporate radiation
and further experiences are required to develop or targeted therapies into induction therapy regimens.
Radiation therapy is a common component of post- tumor biology and predict response to the therapies
operative therapy for patients with locally advanced that are currently being evaluated. References: 1.
thymoma. The use of radiation was retrospectively Blumberg D, Port JL, Weksler B, et al. Thymoma: a
reviewed by Wright et al, and was associated with multivariate analysis of factors predicting survival.
a 40% rate of >90% tumor necrosis after combined Ann Thorac Surg 1995;60:908-913; discussion 914.
cisplatin, etoposide, and radiation therapy for 2. Masaoka A, Monden Y, Nakahara K, et al. Follow-
patients with locally advanced thymoma.8 Korst up study of thymomas with special reference to
and colleagues are prospectively evaluating this their clinical stages. Cancer 1981;48:2485-2492. 3.
approach in a phase 2 trial of cisplatin, etoposide, Wright CD, Wain JC, Wong DR, et al. Predictors of
and concurrent radiotherapy for patients with locally recurrence in thymic tumors: importance of invasion,
advanced thymoma [NCT00387868]. The primary World Health Organization histology, and size. J
endpoint of this clinical trial is complete pathologic Thorac Cardiovasc Surg 2005;130:1413-1421. 4.
response. Expression of epidermal growth factor Berruti A, Borasio P, Roncari A, et al. Neoadjuvant
receptor (EGFR) protein in a high percentage of chemotherapy with adriamycin, cisplatin, vincristine
thymomas suggests that incorporating anti-EGFR and cyclophosphamide (ADOC) in invasive
therapy may be of some beneÀt.9 Cetuximab is a thymomas: results in six patients. Ann Oncol
monoclonal antibody directed against EGFR that is 1993;4:429-431. 5. Kim ES, Putnam JB, Komaki R,
used for patients with colorectal cancer, squamous et al. Phase II study of a multidisciplinary approach
cell cancer of the head and neck and non-small with induction chemotherapy, followed by surgical
cell lung cancer. The use of cetuximab is further resection, radiation therapy, and consolidation
strengthened by two separate reports documenting chemotherapy for unresectable malignant thymomas:
clinical responses to cetuximab in patients with Ànal report. Lung Cancer 2004;44:369-379. 6.
advanced thymoma support the concept that EGFR Macchiarini P, Chella A, Ducci F, et al. Neoadjuvant
inhibition is a promising therapeutic avenue.10, 11 chemotherapy, surgery, and postoperative radiation
To explore the incorporation of cetuximab into a therapy for invasive thymoma. Cancer 1991;68:706-
preoperative chemotherapy regimen, there is an 713. 7. Kunitoh H, Tamura T, Shibata T, et al. A
ongoing phase 2 clinical trial of cetuximab with phase II trial of dose-dense chemotherapy, followed
cisplatin, doxorubicin, and cyclophosphamide by surgical resection and/or thoracic radiotherapy,
in patients with locally advanced thymoma in locally advanced thymoma: report of a Japan
[NCT01025089]. The primary endpoint is pathologic Clinical Oncology Group trial (JCOG 9606). Br
complete response rate. To prospectively evaluate J Cancer 2010. 8. Wright CD, Choi NC, Wain
the role of cetuximab alone in these patients with JC, et al. Induction chemoradiotherapy followed
locally advanced thymoma, patients receive an by resection for locally advanced Masaoka stage
initial four weeks of cetuximab prior to beginning III and IVA thymic tumors. Ann Thorac Surg
chemotherapy combined with cetuximab. CT scans 2008;85:385-389. 9. Henley JD, Koukoulis GK,
will assess response to cetuximab by itself as well Loehrer PJ, Sr. Epidermal growth factor receptor
as to cetuximab in combination with chemotherapy. expression in invasive thymoma. J Cancer Res
All patients will undergo surgical resection with a Clin Oncol 2002;128:167-170. 10. Farina G,
goal of complete resection. Additional exploratory Garassino MC, Gambacorta M, et al. Response of
endpoints include evaluating the role of PET scan thymoma to cetuximab. Lancet Oncol 2007;8:449-
for identiÀcation of sites of disease and predicting 450. 11. Palmieri G, Marino M, Salvatore M, et
response to therapy and outcomes, pathologic al. Cetuximab is an active treatment of metastatic
predictors of response to chemotherapy as well and chemorefractory thymoma. Front Biosci
as cetuximab. Given the importance of complete 2007;12:757-761.
resection in the optimal management of thymoma, Keyword: cetuximab
ongoing studies hope to deÀne the most active
combinations of therapy for further validation in
clinical trials. Prospective clinical trials are the
model for how we should proceed for evaluating
therapy for locally advanced thymomas. Induction
therapy studies provide a unique opportunity for
evaluating tissue biomarkers to better understand
Advanced Thymoma Thursday, 7 July 2011 10:30-12:00 recurrence wsa 8% in patients who were observed
vs. 0% in the radiotherapy group (p=0.15). Their
E17.3 ADJUVANT RADIOTHERAPY FOR conclusion was that the rates of recurrence after
THYMOMA complete resection of stage II thymoma were low
Ramesh Rengan and no beneÀt was observed to postoperative RT in
Department Of Radiation Oncology, Hospital Of Stage II thymoma as a group; however, a higher-
The University Of Pennsylvania/United States Of risk subset of these patients may beneÀt from
America adjuvant therapy. Although some studies showed
no beneÀt from adjuvant radiation therapy, the
Abstract: The overall incidence of thymoma recurrence rates of completely resected invasive
in the United States is 0.15 cases per 100,000, thymoma may approach 30%. A SEER study of 901
based on data from the National Cancer Institute patients showed 10% absolute improvement in 5
Surveillance, Epidemiology and End Results year overall survival, but interestingly no statistical
(SEER) Program. Thymomas are the most common difference in cause speciÀc survival in patients
anterior mediastinal neoplasm in adults and the with stage II-III disease. In a study by Monden and
most common tumor of the thymus gland. There colleagues, patients with resected stage II thymoma
are two accepted systems for clinical staging of the had recurrence rates of 8% and 29%, respectively,
tumor: the 1994 modiÀed anatomic Masaoka staging with and without adjuvant radiation therapy. Locally
system and the surgical resection-based GETT Advanced Thymoma and Unresectable Disease
staging system. The best predictors of recurrence of For patients with stage III/IV disease, the evidence
thymoma are the Masaoka stage, the World Health supporting the use of postoperative radiation therapy
Organization (WHO) histologic classiÀcation, and is more robust. Urgesi and colleagues reported no
the extent of surgical resection. Surgery remains in-Àeld recurrences in a study of 33 patients with
the cornerstone of treatment and its completeness completely resected stage III thymoma treated with
is related to the patient’s outcome. A complete postoperative irradiation. Curran and associates
resection is the most important prognostic marker for reported a 53% 5-year actuarial mediastinal relapse
disease free survival. Chemotherapy is only used in rate with stage II and III patients after surgery
unresectable or metastatic thymomas. Although the alone, compared with 0% after total resection and
role of adjuvant irradiation for invasive thymomas irradiation and 21% after subtotal resection or biopsy
has never been tested in a prospective, randomized and irradiation. Similarly, in a study of 70 patients
fashion, there is general agreement that radiation with Masaoka stage III/IV thymoma, the relapse
therapy is an effective adjuvant therapy for invasive rate for patients receiving postoperative radiation
thymomas, and most retrospective studies have therapy was reduced from 50% to 20%, and most
reported improvements in local tumor control and disease (80%) recurred outside of the irradiated Àeld.
survival after adjuvant irradiation. However, patients Primary radiation therapy alone as the deÀnitive
with encapsulated, noninvasive stage I thymoma treatment has been advocated in nonsurgical
do not require postoperative radiation therapy candidates or patients with unresectable advanced
after complete resection because the recurrence disease. In a study of 31 patients with unresectable
rate is approximately 0%to 2%. For patients with stage III or IV disease, Àve-year survival rates of
Masaoka stage II disease, there is controversy about 53% to 87% and 10-year survival rates of 44%
whether postoperative radiation therapy should be were reported for patients receiving radiation alone
used for completely resected invasive thymomas. after biopsy or incomplete resection. Techniques of
A meta-analysis of 22 studies with 592 patients Irradiation High-energy (>4-MV) x-rays usually are
with completely resected stage II or III thymoma preferred for irradiation. A CT scan is indispensable
found no reduction in recurrence after adjuvant for adequate treatment planning. Clips placed at the
radiotherapy. Berman and colleagues reported a time of surgery denoting the extent of resection in
single institution retrospective cohort comparison of completely resected tumors or outlining regions of
74 stage II thymoma patients after complete surgical residual disease are useful in guiding postoperative
resection. Patients who were felt to be at high risk irradiation. The planning target volume (PTV)
for local recurrence by the operating surgeon and the should include the gross tumor volume (GTV)
thoracic oncology team were referred for adjuvant and the thymus, if any, and tumor bed with a 1.5-
radiotherapy. In this series, the rate of locoregional to 2.0-cm margin. Use of a 4-D breathing scan,
if available, should be used to determine tumor

motion. Depending on histology and surgical
Àndings, areas of suspicious subclinical disease
and regional lymphatics are commonly included.
However, treatment of the entire mediastinal and
supraclavicular nodal basin prophylactically is not
advised because of the low incidence of lymph node
involvementand a higher normal tissue complication
rate when large target volumes are used. A SEER
database analysis of 1334 patients from 1973-2005
by Fernandes and colleagues found no increase in
long term cardiac mortality and rate of secondary
malignancies for patients treated with radiotherapy
compared with patients treated with surgery alone.
Conventional port arrangements may include a
single anterior port, two opposed anteroposterior
ports (weighted 2:1 or 3:2), wedged-pair techniques,
and other multiple-Àeld arrangements. Given the
advanced technical capabilities available, three-
dimensional (3D) conformal therapy or intensity
modulated radiation therapy (IMRT) should be
considered to provide dose homogeneity and allow
better sparing of adjacent normal critical structures.
Postoperative doses of 45 to 55 Gy given by
conventional fractionation have been used effectively
in most cases. The dose to the spinal cord should
be limited to 45 Gy using oblique mediastinal Àelds
or IMRT. For patients with gross residual disease
after resection or unresectable disease, doses of 60
Gy or more probably are required, but higher doses
correlate with higher risks of complications. This
presentation will center on the clinical outcome
data on adjuvant radiotherapy for thymoma and the
impact of modern radiotherapeutic techniques on
treating this disease.
Keywords: Radiotherapy, Thymoma
MEET THE EXPERT SESSIONS occult SCLC. Different antibodies involved in

SCLC leads to different paraneoplastic syndromes,
although for most disorders of the central nervous
Session MTE01: Small Cell Lung Cancer, system (CNS) the clinical syndrome is not speciÀc
Para Neoplastic Syndromes enough to exclude speciÀc antigens. Lambert-Eaton
myasthenic syndrome (LEMS) is caused by anti-
VGCC antibodies, that show reactivity with the
Monday, 4 July 2011
presynaptic neuromuscular junction. LEMS affects
about 3% of patients with SCLC. Encephalitis may
Small Cell Lung Cancer, Para Neoplastic Syndromes Monday, 4 July be caused by anti-Hu, anti-CV2, anti-amphiphysin,
2011 07:00-08:00 anti-Ri, anti-GAD, anti-GABAơ-R or anti-AMPA-R
antibodies. Patients with cerebellar degeneration
MTE01.1 SMALL CELL LUNG CANCER, might have anti-Hu, anti-CV2, anti-GAD antibodies,
PARA NEOPLASTIC SYNDROMES while sensory neuropathy can be caused by anti-
Harry J.M. Groen1, Maarten J. Titulaer2 Hu and anti-CV2 antibodies. Antiretinal antibodies
1
Pulmonary Diseases, University Medical Center can be found in patients with cancer related
Groningen/Netherlands, 2Department Of Neurology, retinopathy. As the clinical symptoms can be subtle
University Medical Center Leiden/Netherlands and symptoms can be disguised by other features
of the cancer and chemotherapy, it is important
Abstract: About 15% of patients with all cancer to consider PNS and know their clinical picture.
have one or more symptomatic neurologic Important for diagnostics are the antibodies in the
complications during the course of their disease. serum or cerebrospinal Áuid of SCLC patients
Neurologic disorders may occur, when small- that react with both the nervous system and the
cell lung cancer (SCLC) is already widespread. underlying cancer. For most PNS of the CNS,
Brain metastases are the most prominent cause. MRI is not reliable to diagnose the disease. In the
Paraneoplastic syndromes are a smaller part of peripheral nerve system, electrophysiological studies
the neurological spectrum of SCLC. However, in in patients with SCLC disclose delayed conduction
these cases neurologic symptoms are often the Àrst velocities (in neuropathies) or abnormalities with
evidence of SCLC. Paraneoplastic syndromes refer repetitive nerve stimulation (in LEMS). The most
to a constellation of signs and symptoms coming important part of the treatment is chemotherapy to
from damage to organs that are remote from the site treat SCLC. Secondly, immunosuppression might be
of the cancer or its metastases. Examples include necessary to treat or at least stop progression of the
hyponatriemia due to the syndrome of inappropriate neurological symptoms as swift treatment improves
antidiuretic hormone secretion, cancer cachexia, outcome. The Lambert–Eaton myasthenic syndrome
hypercalcemia, usually observed in non-small recovers once the tumor has responded, because the
cell lung cancer but also in SCLC, and Cushing’s damage to the neuromuscular junction is reversible.
syndrome. Paraneoplastic neurological syndromes Disorders involving the central nervous system were
(PNS) occur because the tumor secretes substances thought to respond poorly, stabilize to the best or
that mimic hormones or ion channels or that interfere respond not at all until recently. Encephalomyelitis
with circulating proteins. Most or all paraneoplastic or paraneoplastic cerebellar degeneration, associated
neurologic disorders are immune-mediated. The with SCLC and for example those with anti-Hu, is
symptoms of the PNS, caused by SCLC, usually thought to be mediated by T cells. These syndromes
begin before SCLC itself has become symptomatic. are usually associated with neuronal loss, and
PNS is sometimes occult, sometimes disabling because they evolve slowly and chemotherapy is
and occasionally lethal. Patients are usually Àrst often delayed, the neurons die, making recovery
aware of the neurologic symptoms that brings impossible. Immunosuppressant drugs such as
them to the medical specialist. A chest X-ray may cyclosporin, tacrolimus, sirolimus or mycophenolate
raise suspicion of lung cancer. A work-up with mofetil may be tried, but no evidence exist. Recently,
FDG-PET/CT, bronchoscopy, transthoracic lung new antibodies against membrane receptors were
biopsy, EUS-FNA and/or EBUS-FNA may lead found to cause limbic encephalitis in SCLC patients,
to the diagnosis of SCLC. Whole-body FDG-PET i.e. GABAơ receptor antibodies and AMPA receptor
may be the best screening method for locating the antibodies. Like in LEMS, they disrupt an ion
channel, thereby disrupting neuronal function, but events occur, leading to the formation of a tumor. It
the damage can be reversible. Nevertheless, the has been postulated that mesothelioma may derive
quicker treatment is started, the better. Besides from either the surface lining cells or an until now
chemotherapy, these might contain steroids, undeÀned submesothelial stem cell. The carcinogenic
intravenous immunoglobulins, plasma exchange or activity of asbestos may be mediated via a genotoxic
even rituximab or cyclophosphamide. Summarizing, initiation process or by an epigenetic mechanism.
recognizing PNS is important as SCLC might be Asbestos Àbres induce mostly DNA breaks linked
treated earlier in disease course, improving outcome. to the presence of Àbre-associated iron and reactive
Early treatment of the PNS ameliorates the outcome oxygen species generation. The consequence, at
of the neurological symptoms, improving quality of least in vitro, of this overall low but persistent
life. DNA damage in non-neoplastic cells is senescence.
Keyword: SCLC, Paraneoplastic The latter is a state of stable cell cycle arrest with
active metabolism secreting mitogenic factors.
Therefore, low level of persistent DNA damage
Session MTE02: Treatment of in mesothelial cells will lead mostly to epigenetic
Mesothelioma - New Pathways effects mediated via senescent cells that are not
efÀciently cleared by the immune system. During
mesothelial regeneration primitive mesenchymal
Monday, 4 July 2011
cells underlying a wounded area of mesothelium
proliferate, migrate and transdifferentiate into
Treatment of Mesothelioma - New Pathways Monday, 4 July 2011 surface mesothelial cells to restore the mesothelial
07:00-08:00 surface. Wound healing occurs also through the
recruitment of distant mesothelial cells, which
MTE02.1 TREATMENT OF move to the site of the injury. During this process
MESOTHELIOMA - NEW PATHWAYS the mesothelial cell assume a more mesenchymal
Emanuela Felley-Bosco phenotype. Transdifferentiation of mesothelium
Zurich University Hospital, Laboratory Of might be inÁuenced by microenvironment cues
Molecular Oncology/Switzerland from for example macrophage which secrete factors
stimulating mesothelial proliferation such as FGF2.
Abstract: The mechanism of development of Asbestos Àbres can induce transdifferentiation in
malignant pleural mesothelioma after exposure tracheal epithelia but in mesothelium the issue is
to asbestos Àbres is not well understood but few more difÀcult to address since mesothelium is an
hypotheses can be proposed based on experimental epithelium derived from splanchnic mesoderm,
data and observation of clinical samples. Inhaled which maintains mesenchymal characteristics such
asbestos Àbres pass the alveolar barrier and reach as vimentin expression. WT1 transcription factor is
the lung interstitium. During this process they expressed at the time of switch from mesenchymal
transiently activate signalling pathway such as to epithelial cells (MET) in precursors during
Nalp3 inÁammasome in alveolar and/or interstitial embryogenesis. Continuous WT1 expression is
macrophages by “frustrated phagocytosis”; in conserved in mesothelium through adult life and is
addition they activate the transcription factor NF- maintained in mesothelioma. However, it decreases
kB in lung epithelial cells and the overall outcome during epithelial to mesenchymal transition (EMT)
is the release of pro-inÁammatory cytokines. Then occurring in sarcomatoid mesothelioma. Although
Àbres accumulate in the pleural space, particularly during cancer evolution mesothelium undergoes
at the site of pleural Áuid drainage. The latter phenotypic changes, no data are yet available
occurs through the lymphatic stomata in parietal directly related to asbestos exposure. In MexTag
pleura which is in agreement with the concept mice in which the SV40 T antigen (Tag) is under the
that mesothelioma origins primarily from the control of mesothelin promoter and which develop
parietal pleura. Following persistent exposure to MPM tumors upon exposure to asbestos Àbres, Tag
asbestos Àbres or mesothelium injury tissue repair is not detected in the unexposed mice indicating that
is stimulated. Chronic tissue repair activates stem asbestos Àbres stimulate undifferentiated precursor
cell signalling pathways to regenerate the tissue but, cells not yet expressing mesothelin. Persistent
because of persistent system stimulation, oncogenic stimulation of repair leads to oncogenic events
occurring within the components responsible for ubiquitin ligase CRL4 and through that controls a
homeostasis. Activated stem cell signalling has subset of Hippo pathway target genes. This recent
already been suggested in MPM by the presence observation is consistent with previous evidence of
of an 11-gene signature, correlated with a stem- NF2 signaling-dependent activation of the Hippo
cell-like expression proÀle, which is associated pathway. The latter is an essential regulator of cell
with a poor prognosis in patients with MPM. Not proliferation during development and tumorigenesis.
much is known about stem cell signalling in MPM. Key components of the Hippo pathway include two
Wnt signalling is activated and Notch1 has been kinases: Mst and Lats. The sequential activation
found to control PTEN expression. Methylation of of these kinases leads to phosphorylation of the
promoters of BMP3b and BMP6, which are members transcription factor YAP. When Hippo signalling is
of the TGF-ß superfamily and critical mediators of attenuated, e.g. when NF2 signaling is disrupted,
early embryonic patterning, has been observed. In YAP phosphorylation is reduced resulting in its
a case of biphasic malignant mesothelioma with nuclear localization and regulation of target genes.
osseous and cartilaginous differentiation expression This “Meet the expert” session will illustrate how
of BMP2 has been observed. Nothing is known this knowledge may have clinical utility.
about sonic hedgehog signalling, but since stem Keywords: mesothelioma, NF2 signalling, Hippo
signalling pathways are interconnected it is likely signalling, Pi3kinase signalling
that this signalling is also deregulated. Overall, the
little information already available suggests that
stem cell signalling has a role in tumor progression. Session MTE03: Adenocarcinoma
Knowledge about common alterations observed in Classification Update
MPM, conÀrms that alteration in NF2 signalling,
which is responsible for homeostasis in tissue repair
Monday, 4 July 2011
and stem cell signalling, is the ideal target for an
oncogenic event to occur during the development
of MPM. Indeed, the two most abundant alterations Adenocarcinoma Classification Update Monday, 4 July 2011 07:00-
in MPM concern CDKN2A and NF2. Mutations in 08:00
NF2 gene have been found in 40% of mesothelioma.
In MPM tumors with no detectable genetic MTE03.2 ADENOCARCINOMA
alterations of NF2, its activity is downregulated CLASSIFICATION UPDATE -
by phosphorylation, which depending on the PATHOLOGY AND RADIOLOGY
phosphorylated amino acid, leads to functional Kavita Garg
inactivation or AKT-dependent degradation. Radiology, University Of Colorado/United States Of
Expression levels of the CPI-17, which inhibits the America
phosphatase reactivating NF2, were signiÀcantly
higher in 17% of MPM with no detectable NF2 Abstract: There is a widely divergent clinical,
mutations. On the other hand PTEN immunostaining radiologic, molecular and pathologic spectrum within
was absent in over 60% of MPM patients and lung adenocarcinoma. Despite remarkable advances
correlated with worst outcome. Experimental animal in understanding of this tumor in the past decade;
models indicate that disruption of the NF2 signalling there remains a need for a universally accepted
pathway, together with a deÀciency in CDKN2A, criteria for adenocarcinoma subtypes, in particular
is essential for mesothelioma development in a bronchioloalveolar carcinoma (BAC). The use of the
“permissive” (CDKN2A deÀcient) background. It term BAC encompasses a broad spectrum of tumors
has been proposed that genes which are inactivated ranging from solitary small peripheral lung tumors
in a given tumor type and directly regulate tumor with a 100% 5-year survival to widespread advanced
growth by either inhibiting growth or promoting disease with a 10% 3-5 year survivals, with widely
death are “gatekeeper” genes. NF2 does correspond varying use of terminology even after publication of
to this deÀnition and should be considered a the 1999 and 2004 WHO ClassiÀcation. There are
“gatekeeper” in mesothelioma. A role of NF2 in also clinical, radiologic, immunohistochemical, and
tissue repair is supported by the observation that molecular differences that are distinguishable among
the active form of NF2 suppresses tumorigenesis by the subsets of mucinous and non-mucinous types
migrating into the nucleus where it inhibits the E3 of BAC. As a result there is confusion in various
terminologies that are used for lung adenocarcinoma Session MTE04: Molecular Markers in
in literature and studies are difÀcult to compare. A Lung Cancer
new classiÀcation is needed to help use standardized
terminology which is clinically more relevant with
Monday, 4 July 2011
better multidisciplinary correlations. That would
allow more uniform criteria to evaluate patient
therapy and to help predict outcome in clinical Molecular Markers in Lung Cancer Monday, 4 July 2011 07:00-08:00
trials. The widespread availability of MDCT
and abundance of new information obtained MTE04.1 MOLECULAR MARKERS IN
especially from low-dose CT lung cancer screening LUNG CANCER
programs, have increased our understanding of the Luis M. Montuenga
management and types of small peripheral lung Biomarkers Lab. Oncology Division, Center For
nodules encountered in daily clinical practice, in Applied Medical Research. University Of Navarra/
particular, the importance and prevalence of subsolid Spain
pulmonary nodules. Subsolid nodules include both
pure ground glass nodules (GGN) and part-solid Abstract: Advances in molecular and cellular
nodules. GGNs are deÀned as focal nodular areas biology have accelerated our knowledge of lung
of increased lung attenuation through which normal cancer biology and new data are constantly being
parenchymal structures such as airways, vessels, and generated to understand its hallmarks. During
interlobular septa can be deÀned. Subsolid nodules the last decade, we have built a comprehensive
are now known to frequently represent the histologic catalogue of lung cancer associated molecular
spectrum of peripheral adenocarcinomas. In the alterations, including driver mutations; genomic
new proposed multidisciplinary classiÀcation, these abnormalities; copy number variations; gene,
lesions include premalignant atypical adenomatous protein and microRNA expression proÀles; as well
hyperplasia (AAH), carcinoma in-situ or as epigenetic changes. In the next future, whole
bronchiolalveolar carcinoma (AIS/BAC), minimally genome deep sequencing will provide even more
invasive (MIA) and invasive adenocarcinoma. Thin thorough and complete views of the detailed genetic
section CT has emerged as a new biomarker for traits of lung tumors. Moreover, the multistep
lung adenocarcinoma subtypes. GGN correlates molecular changes involved in the carcinogenic
with lepidic growth and better clinical outcome process of the different histological types of lung
than part-solid or solid nodules. Pure GGNs are cancers are also being unveiled. Some of these
typically FDG-PET negative. Key messages from molecular changes have been proposed as potential
radiology lecture are: 1) The term BAC is confusing biomarkers. This presentation will summarize
and it should no longer be used in reference to information concerning the search for biomarker
adenocarcinoma manifesting as GGNs or ground candidates, particularly in the early stages of lung
glass opacities. The new terms proposed for the cancer. The main non-invasive sources of biomarkers
adenocarcinoma subtypes that cause this pattern are for lung cancer are blood, sputum, bronchioalveolar
AIS/MIA and lepidic predominant adenocarcinoma. lavage, and exhaled breath. Molecular markers
2) Mucinous adenocarcinoma (previously called for lung cancer may be used in the following
BAC) is usually a solid tumor (not GGO). It may Àve clinically relevant scenarios: a) Lung cancer
also present as multilobar and multifocal areas risk associated SNPs may help to improve risk
of consolidation. 3) Multiple lesions – careful stratiÀcation models, currently based on exposure
description of each lesions is desirable because and clinical factors. b) Recent data suggest that low
multiple synchronous/metachronous primaries are dose CT-based screening is a promising strategy to
not uncommon. Change in size and attenuationof improve early detection at the population level. The
each lesion assists in management. potential role of biomarkers for early diagnostics as
adjuncts to imaging-based techniques is currently
being explored. Molecular markers, such as DNA
concentration or microRNA analysis in the plasma
of high risk individuals have been analyzed. c) If
programs of lung cancer screening are implemented,
the relative proportion of early stage tumors that
may be diagnosed in the future will increase. For unforeseen avenues in the Àeld, such as new
most early stage tumors, surgical resection is the proteomics approaches or the search for biomarkers
therapeutic option of choice. However, disease in the exhaled breath.
relapse rates are as high as 30% even among stage Keywords: Early Detection, Prognostic and
I patients. This has driven the interest in identifying predictive markers, Biomarkers, Molecular
additional molecular prognostic markers that may carcinogenesis
add to the TNM staging system and other risk factors
such as poor differentiation, vascular invasion,
wedge resection, etc. A large number of reports Session MTE05: Integral Approach
on prognostic individual or multiplexed molecular Nodal/Mediastinal Disease PET/EBUS/
markers, as well as gene expression signatures with EUS
prognostic value in lung cancer have been published.
The lack of translation of most of the reported
prognostic markers to the clinical setting is mainly Monday, 4 July 2011
due to problems related to lack of standardization
of methodology and thus the proposed REMARK Integral Approach Nodal/Mediastinal Disease PET/EBUS/EUS Monday,
criteria for reporting on prognostic markers. d) 4 July 2011 07:00-08:00
Another important unmet medical need, for which
molecular markers can play a helpful role, is the MTE05.1 INTEGRAL APPROACH
improvement of the existing decision criteria for NODAL/MEDIASTINAL DISEASE PET/
selecting patients for adjuvant treatment in early EBUS/EUS
NSCLC. Predictive molecular markers are currently Tawimas Shaipanich
being explored in clinical trials in the adjuvant Respirology, British Columbia Cancer Agency/
setting. A number of markers have been explored Canada
to predict sensitivity to chemotherapeutic drugs
in the adjuvant context. e) Markers for molecular Abstract: Lung cancer is one of the leading
targeted treatment selection, such as EGFR gene causes of cancer death. Non small cell lung cancer
alterations or EML4-ALK fusion gene, are mainly (NSCLC) accounts for the majority of lung cancer
being studied for late non-surgical stages of the cases. Survival prediction and therapeutic options
disease. All the aforementioned areas of clinical rely heavily on meticulous and accurate staging.
management will beneÀt from the increasing efforts Imaging studies such as CT scan and Positron
in our Àeld to develop sensitive and speciÀc, non- emission tomography (PET) scan have been used
invasive, robust, reproducible and cost-effective in mediastinal staging and to identify metastasis.
biomarkers. An emerging issue in the area of Mediastinoscopy has been considered a gold
NSCLC molecular markers is the pressing need standard procedure to obtain pathological sample
for more complete information on the different for conÀrmation of mediastinal nodal metastasis.
biological proÀles of lung squamous cell carcinoma With the advanced technology of Endobronchial
(SCC) and adenocarcinoma (AC). In the past, SCC Ultrasound (EBUS) and Endoscopic Ultrasound
and AC have been considered as a single entity in (EUS), mediastinal lymph node and hilar lymph
the clinical practice. There is increasing evidence node can be sampled in much less invasive fashion
that these two histologically distinct tumors are with safety. Positron emission tomography with
notably different in their carcinogenic process, 18F-Áuorodeoxyglucose (FDG) has also been widely
biology, genetic alterations, etc. and, thus, may differ used in cancer staging, especially in lung cancer. It
in their sensitivity to conventional or molecular has been shown to increase accuracy in lung cancer
targeted therapies. One of the most important staging. However, the utility of PET scan has been
bottlenecks in the development of clinically useful challenged due to its limitation in smaller lymph
molecular markers is the challenging need for node and speciÀcity. The sensitivity, speciÀcity
rigorous validation steps. There are some multi- and positive predictive value of PET scan were
institutional efforts to expedite the validation process reported ranging from 70% to 88%, 59.8 to 92% and
of lung cancer biomarkers. Finally, there are new 37.5% to 90% respectively4,11,12. However, false
technological developments in the search of lung negative PET scan can be found in smaller node
cancer biomarkers, which may open previously (less than 7mm), carcinoid, and bronchoalveolar
cell carcinoma16. Moreover, known causes of EBUS and EUS have become more commonly
false-positive PET results are inÁammation and performed procedures in many medical centers
infection (tuberculosis, histoplasmosis, sarcoidosis). and both procedures can be performed safely in
Therefore, cytologic or histologic conÀrmation may one setting14. EBUS/EUS may be superior to PET
be necessary particularly in the case of positive scan in mediastinal staging, however, PET scan
mediastinal node. Other advantage of PET scan is is less invasive and can identify extra thoracic
that it can detect unexpected distance metastasis metastasis. To achieve the excellent staging result,
up to 15%15. Cervical mediastinoscopy has been trained and highly skilled interventionists are
considered as gold standard in mediastinal staging. required in EBUS and EUS. In specialized centers,
However, it requires general anesthesia and EBUS/EUS can achieve excellent result in thoracic
hospitalization. In addition, the number of lymph lymph node sampling and may eventually replace
nodes that mediastinoscopy can access are limited mediastinoscopy in the future. Until this can be
particularly in the hilar regions. The sensitivity effectively reproduced in all centers, combined
and speciÀcity of cervical mediastinoscopy have multi-modality approach including CT scan, PET
been reported ranging from 44% to 92% and scan, EBUS/EUS and medistinoscopy are the
100%9. The complication rate of Mediastinoscopy current approaches to achieve improved accuracy
although is not common but had been reported to be of mediastinal staging in NSCLC13. Reference 1
approximately 2.5%, which includes paresis of the Yasufuku K, Nakajima T, Motoori K, et al. Chest
left laryngeal recurrent nerve, hemorrhage, injury to 2006; 130:710–718 2 Bauwens O, Dusart M,
the azygos vein, perforation of the esophagus, and Pierard P, et al. Lung Cancer 2008; 61:356–361) 3
mediastinitis10. Endobronchial ultrasound guided Wallace MB, Pascual JM, Raimondo M, Woodward
transbronchial needle aspiration (EBUS-TBNA) TA, McComb BL, Crook JE, Johnson MM, Al-
and Endoscopic ultrasound guided needle aspiration Haddad MA, Gross SA, Pungpapong S, Hardee
(EUS) have been used in mediastinal lymph node JN, Odell JA. JAMA. 2008 Feb 6;299(5):540-6.
staging in lung cancer. These procedures can be 4 Hwangbo B, Kim SK, Lee HS, Lee HS, Kim
performed in an outpatient setting under local MS, Lee JM, Kim HY, Lee GK, Nam BH, Zo JI.
anesthesia with conscious sedation. Comparing Chest. 2009 May;135(5):1280-7 5 De Leyn P,
to mediastinoscopy which has limited access Lardinois D, Van Schil PE, et al. Eur J Cardiothorac
mainly to central lymph node (station 1, 2, 4, and Surg. 2007; 32(1):1-8. 6 Detterbeck FC, Jantz
7), EBUS enables access to hilar lymph nodes MA,Wallace M, Vansteenkiste J, Silvestri GA. Chest.
(Station 10, 11, and 12) and mediastinal lymph 2007;132(3)(suppl):202S-220S. 7 Kernstine KH,
node (station 2, 4, and 7). Most of hilar, mediastinal Stanford W, Mullan BF, et al. Ann Thorac Surg.
lymph nodes and left adrenal gland metastasis can 1999;68:1022–1028. 8 Kramer. Ann Surg 2003;238:
be accessed by combined EUS and EBUS. With 180–188 9 Takeshi Arita. Chest 1996;110;1004-
real-time ultrasound guided, adequate lymph node 1008 10 Porte H, Roumilhac D, Eraldi L, et al.
sampling can be obtained via 21 or 22 gauge needle Eur J Cardiothorac Surg. 1998;13:196–199. 11
in lymph node as small as 5mm4. Several studies Dwamena BA, Sonnad SS, Angobaldo JO, et al.
have reported high sensitivity (92.3-95%), high Radiology. 1999;213:530–536. 12 Hellwig D, Ukena
positive predictive value (100%) and high negative D, Paulsen F, et al. Pneumologie. 2001;55:367–377.
predictive value (93-97%) of EBUS-TBNA and 13 Annema JT, van Meerbeeck JP, Rintoul RC, et
EUS1,2,3,4. When compare to PET/ CT-PET scan, al. JAMA. 2010;304(20):2245-2252. 14 Herth FJ,
the sensitivity and negative predictive value of Krasnik M, Kahn N, Eberhardt R, Ernst A. Chest.
EBUS-TBNA are also superior (70% vs 90% and 2010 Oct;138(4):790-4. 15 Pieterman RM, Van
85.2% vs 96.7%, respectively)4. As compared to Putten JWG, Meuzelaar JJ, et al. N Engl J Med.
surgical staging or mediastinoscopy considered the 2000;343:254–261. 16 Gupta NC, Tamim WJ,
gold standard according to guideline5,6, EBUS and Graeber GM, et al. Chest. 2001;120:521–527.
EUS have higher sensitivity, accuracy and safety in Keywords: PET scan, EBUS, Mediastinal staging,
mediastinal staging of non small cell lung cancer. EBUS, Mediastinal staging
Summary Accurate mediastinal staging in NSCLC
can avoid unnecessary thoracotomy. EBUS has
higher sensitivity, speciÀcity and negative predictive
value as compared to CT scan and PET scan4.
Session MTE06: New Technology in evolves so fast that it would not be feasible to
Radiotherapy - We Do not Need Phase III perform an RCT for each new version of, say, MRI
Trials scanning or software. It is also difÀcult to envision
RCTs in some speciÀc areas such as the clinical
impact of Quality Assurance (QA) programs. But
Monday, 4 July 2011 also in these cases, the question remains whether the
effort and cost of new technologies or intensiÀed QA
New Technology in Radiotherapy - We Do not Need Phase III Trials improves clinical outcomes in reasonable relation to
Monday, 4 July 2011 07:00-08:00 increased costs. Another problem is that treatments
validated in an RCT are seen as “proven forever”
MTE06.1 NEW TECHNOLOGY IN despite other advances in management or diagnosis
RADIOTHERAPY - WE DO NOT NEED or new insights into the etiology, for example human
PHASE III TRIALS - PRO papillomavirus (HPV) associated oropharyngeal
Dirk De Ruysscher cancer. Likewise, improvements in diagnostic
Department Of Radiation Oncology (MAASTRO), sensitivity may affect the validity of evidence from
Grow, Maastricht University Medical Centre/ older RCTs. If treatment A+B that improves survival
Netherlands over A alone in patients with enlarged mediastinal
lymph nodes on a chest X-ray, it may not necessarily
Abstract: The case for randomized controls in be superior to A alone in the era of routine CT
clinical trials Since the 1950s, randomized controlled imaging when small but enlarged lymph nodes can
trials (RCTs) have become the gold standard for easily be detected. Nevertheless, in the absence of
comparative effectiveness research of medical new evidence from a phase III trial, A+B will still be
interventions. Indeed, treatment guidelines often seen to be the standard therapy. Recently, the concept
rank evidence of clinical beneÀt using a hierarchy of personalized therapy has put the RCT under
with evidence from RCTs at the highest level, more pressure, as large trials with wide inclusion
Level I. Many regulatory authorities require Level and minimal exclusion criteria are increasingly seen
I evidence from RCTs for registration of a new as not the way to go. Moreover, the Áurry of novel
drug in a given indication or for reimbursement molecular targeted therapeutic agents, that are under
of the associated costs. As a result, when Level pre-clinical development, is confronting the medical
I evidence is not available, the treatment is often research community with the problem of prioritizing
viewed as being “unproven”. Ideally, every new important research questions that should lead to
diagnostic or interventional procedure should be the successful completion of randomized phase III
tested in RCTs before becoming standard care studies, with signiÀcant Ànancial consequences.
to avoid ineffective or harmful treatments. The Given all theoretical permutations, the consequence
reason is that even treatments supported by a clear of a too rigid, though scientiÀcally justiÀable,
biological rationale and strong pre-clinical data may conviction that the comparative effectiveness of
not produce a therapeutic gain; examples include novel interventions should be demonstrated in an
the detrimental effect of erythropoietin when used RCT before they can be regarded “evidence based”
together with radiotherapy for head and neck cancer would be centuries of phase III trials against a
or class 1c antiarrhythmic agents in myocardial background of almost unchanging daily patient
infarction patients. The unexpected result of these care. On the other hand, lowering the bar for the
studies provides a strong argument in favour of evidence needed for approval of new treatments
randomization. The limitations to the randomized comes with a risk of accepting expensive but
trial paradigm Despite the wide acceptance of the potentially ineffective or even harmful therapies.
randomized trial as the only method for avoiding This is the challenge: how can we build a reasonable
bias, many advances in medicine have never been level of evidence without the ideal requirement
tested in phase III trials. This is particular so when of randomized allocation to alternative treatment
the advances are in technological rather than options? We need to develop criteria for when a high
pharmaceutical, such as higher resolution imaging level of “evidence” without RCTs can be reached,
techniques, CT-based radiotherapy planning or the also when differences between treatment effects are
introduction of mega-voltage radiation in cancer not huge. Clearly, we need to reÀne our strategies for
therapy. One problem with technology is that it minimizing and detecting selection biases and for
prospectively assessing the effect on new therapies through dose escalation and/or hypofractionation
on clinical outcome. This is no simple task and has made possible by greater treatment precision and
not been accomplished convincingly in the past. We consequent improvement in the therapeutic ratio. The
hypothesize that in situations where phase III trials endpoints of interest may be biological (survival,
are not feasible, a level of evidence, level M, can local control, toxicity or quality of life) or they may
be reached in situations where 1) a mathematical be economic (cost beneÀt, cost utility). In the case
model is available that can predict outcome with an of these endpoints, conÀrmation of the superiority of
accuracy that is known and sufÀcient for the clinical the new over the old requires randomised phase III
question; 2) the limits of validity for application of trials, since it cannot be assumed that the outcomes
the model (e.g. the speciÀc characteristics of the will inevitably favour the experimental arm. For
patient population) are known and 3) the model example, a meta-analysis of 57 randomised trials
has been externally validated in prospective studies conducted by the RTOG revealed that innovative
indicating a non-signiÀcant statistical difference treatments were as likely as standard treatments to
from the predicted outcome. Level M may even be successful (odds ratio for survival: 1.01, P=0.5).
be placed in the hierarchy of levels evidence and On the other hand, treatment related mortality
if the modelling is sufÀciently well supported by was worse on the experimental arms (OR: 1.76,
observations, level M evidence may build at least P=0.008).1 It is important to distinguish the “direct
some conÀdence that an observed improved outcome effect” technologies from the “indirect”. The former
relates to a speciÀc intervention. require direct comparison of the technology for
Keywords: Radiotherapy, evidence based medicine, example IMRT versus 3D conformal. Although the
trial methodology dose distributions achieved with IMRT may appear
superior, there has been unanticipated normal tissue
injury in organs receiving low doses. Examples
New Technology in Radiotherapy - We Do not Need Phase III Trials are the deaths due to pneumonitis which were
Monday, 4 July 2011 07:00-08:00 observed following IMRT for mesothelioma2 and
helical Tomotherapy for lung cancer.3 Although
MTE06.2 NEW TECHNOLOGY IN these toxicities were observed in single arm studies,
RADIOTHERAPY - WE DO NOT NEED had they been less frequent, the impact of these
PHASE III TRIALS - CON iatrogenic deaths on outcome may only have
David Ball been detected otherwise by randomisation. The
Radiation Oncology, Peter MacCallum Cancer proponents of proton beam therapy have argued that
Centre/Australia the beam’s physical characteristics are by themselves
Abstract: The computer revolution has led to sufÀcient to establish therapeutic superiority over
an avalanche of technological innovation in x-rays, and that randomised trials are unnecessary to
radiotherapy treatment planning and delivery over demonstrate the obvious.4 It is possible that protons
the last decade. Some of these developments, are more effective for treating lung cancer (but we
such as computerised treatment planning and don’t know since they have not been compared), but
patient management systems, have led to greater given the cost of protons they would need to be very
efÀciencies. Others have resulted in improved much more effective than x-rays to provide a cost
accuracy of treatment planning and delivery, for beneÀt. There is no other way of demonstrating this
example 4D CT and in-room image guidance. The other than by unbiased randomisation with proper
beneÀts whether in terms of time saved or improved costings. The “indirect effect” technologies (such
ability to detect the gross tumour volume seem as hypofractionated stereotactic body radiotherapy
self evident, and it would be hard to persuade an - SBRT) can be thought of as applications of new
ethics committee that a randomised trial should technology (or combinations of technologies) to
be performed to conÀrm the usefulness of the deliver unconventional treatment schedules which
“efÀciency and accuracy” technologies, although it may have greater biological effect than conventional
is likely that all could be tested using randomised treatment. Here the primary comparison should not
trial methodology. New technology may also affect be between the various technologies that can be used
patient outcomes either directly through a potentially to deliver SBRT, but between novel and standard
greater cytotoxic effect or superior dose distribution, treatment schedules. Nevertheless there is a risk
for example hadron therapy or IMRT; or indirectly that the high levels of local control observed with
hypofractionated SBRT may be mistakenly attributed one to three brain metastases: phase III results of
to the technology rather than the treatment schedule, the RTOG 9508 randomised trial. Lancet. 2004;
especially within the lay community. Marketing 363:1665-72. 6. Timmerman R et al Stereotactic
claims of the superiority of one technology over Body Radiation Therapy for Inoperable Early Stage
another in terms of improved local control should Lung Cancer. JAMA. 2010; 303:1070-6.
be viewed with scepticism in the absence of a direct Keywords: Lung cancer, radiotherapy technology
randomised comparison. The observation that
outcomes were the same in patients whose brain
metastases were treated stereotactically by either Session MTE07: Non-Small Cell Lung
a linac or a Gamma Knife in a non-randomised Cancer with Synchronous Brain
comparison5 make it unlikely there would be Metastases: When is Aggressive
any enthusiasm for undertaking a phase III trial. Treatment Justified?
Finally a word of caution regarding the high dose
hypofractionated schedules in popular use for the
treatment of stage I lung cancer. The rates of local Monday, 4 July 2011
control are much higher than observed in historical
controls treated with conventional fractionation. But
because there has been no randomised comparison, Non-Small Cell Lung Cancer with Synchronous Brain Metastases:
we do not know if the better local control translates When is Aggressive Treatment Justified? Monday, 4 July 2011 07:00-
into an improvement in survival. The local control 08:00
in the phase 2 study RTOG 0236 of SBRT in early
stage lung cancer was an impressive at 90% at 3 MTE07.1 NON-SMALL CELL LUNG
years but survival was only 56%.6 Further, nine CANCER WITH SYNCHRONOUS BRAIN
of 55 patients (16%) died of unknown causes. Is METASTASES: WHEN IS AGGRESSIVE
this an excess number of deaths, possibly due to TREATMENT JUSTIFIED?
undetected treatment related toxicity? Only by Frank J. Lagerwaard
randomisation can we answer this question. In Radiation Oncology, VU University Medical Center/
summary, computer driven technological advances Netherlands
have improved efÀciency and treatment accuracy
in lung cancer radiotherapy, and we do not need Abstract: Brain metastases (BM) develop in
randomised trials to conÀrm these beneÀts. But when 30%-50% of patients with non-small cell lung
it is claimed that treatment outcomes are improved cancer (NSCLC), conferring a poor prognosis
by some inherent property of the technology, then and quality of life. Approximately 30% of these
those claims should be tested scientiÀcally by patients present with signs and symptoms from
randomised studies as is the case for any other new BM prior to the diagnosis of lung cancer. Although
therapeutic intervention, especially if the toxicity a few publications suggest a worse outcome for
and monetary costs are likely to be high. References: a synchronous presentation of BM and NSCLC,
1. Soares HP et al Evaluation of new treatments in most series have failed to show different outcomes
radiation oncology: are they better than standard for patients with a synchronous or metachronous
treatments? JAMA. 2005; 293:970-8. 2. Allen AM presentation of BM. Traditionally, in line with the
et al. Fatal pneumonitis associated with intensity- concept of short-term palliation for metastatic lung
modulated radiation therapy for mesothelioma. cancer, treatment has been directed toward the BM
Int J Radiat Oncol Biol Phys. 2006; 65:640-5. 3. only, generally consisting of a short course of whole
Song CH et al, Treatment-related Pneumonitis and brain radiotherapy (WBRT). However, randomized
Acute Esophagitis in Non-small-cell Lung Cancer studies have demonstrated improved survival for
Patients Treated with Chemotherapy and Helical patients presenting with a limited number of BM
Tomotherapy. Int J Radiat Oncol Biol Phys. 2010; who are treated with either surgical resection or
78:651-8. 4. Goitein M, Cox JD. Should Randomized stereotactic radiosurgery (SRS). Growing data that
Clinical Trials Be Required for Proton Radiotherapy? suggest that long-term survival can be achieved in
J Clin Oncol. 2008; 26:175-6. 5. Andrews DW et a subset of patients with aggressively treated BM
al. Whole brain radiation therapy with or without have raised the issue of how to treat the primary site
stereotactic radiosurgery boost for patients with in NSCLC. Magilligan et al. reported the Àrst study
of a substantial number of patients undergoing a for their BMs [Lind 2010]. It would appear that
combined resection of the primary lung tumor and a aggressive thoracic (or cranial) treatment may not
synchronous single BM. Long-term survival of 21% be justiÀed in these patients. All of the above data
at 5 years and 15% at 10 years could be obtained concern patients who are able to undergo surgery or
with this approach in their cohort of 41 selected radiosurgery for their BM, and most of these reports
patients. Other authors have reported similar long- involve patients with a single BM. Around 50% of
term survival rates in selected patients treated with NSCLC patients with synchronous BM present with
neurosurgery and lung surgery, with 5-year survivals multiple BM, or large size lesions not amenable to
ranging from 7% to 21% [Billing 2001; Bonnette (radio)surgery, and will be ineligible for aggressive
2001; Downey 2002; Hu 2006]. More recently, cranial treatment. The prognosis for these patients,
other authors have published similar outcomes for which WBRT remains the only available option
after SRS for the BM and surgery for the lung is very poor with a median survival ranging from 3-6
tumor [Yang 2008; Flannery 2008]. The majority months and approximately half of patients dying as
of these published studies were either restricted a result of neurological progression. In conclusion,
to, or reported signiÀcantly better outcome in, the optimal treatment approach of the primary tumor
patients with thoracic stage I-II disease, i.e. without in patients with synchronous brain metastases from
mediastinal involvement or extracranial metastases NSCLC remains to be deÀned. The limited, and
other than the BM [Billings 2001; Granone 2001, non-randomized data in the literature support radical
Louie 2009]. In the study by Billings et al., the thoracic treatments in patients younger than 65 years
5-year overall survival was 35% for patients with with a good performance status, who are eligible to
N0 disease, in contrast to 0% in patients with N1 or undergo SRS or surgical resection of synchronous
N2 lymph node disease. Thus, negative lymph nodes BM from NSCLC, even when stage III thoracic
status appears to be a signiÀcant prognosticator, disease is present. Patients with other synchronous
even in the presence of a single aggressively treated (extracranial) metastases may not beneÀt from
BM. Based on the above data in several studies, it aggressive treatment of the primary tumor (or BM).
can be concluded that combined cranial and thoracic Whether chemotherapy may be beneÀcial in a select
surgery or radiosurgery should be regarded as the group of patients after WBRT for synchronous BM
standard of care for Àt patients with thoracic Stage needs further investigation.
I-II and synchronous BM from NSCLC. The vast Keywords: brain metastases, thoracic treatment,
majority of patients with synchronous BM, however, synchronous, Radiosurgery
consists of patients with more advanced thoracic
stages. Patients with stage III NSCLC encompass
a very heterogeneous group with regard to primary Session MTE08: Surgery for
tumor volume and extent of nodal involvement. Mesothelioma Pleurectomy - EPP
However, keeping in mind the small number of
patients in reported subgroups, some data suggest
Monday, 4 July 2011
that selected patients with 18FDG-PET conÀrmed
thoracic stage III NSCLC who have their BM treated
aggressively may beneÀt from subsequent radical Surgery for Mesothelioma Pleurectomy - EPP Monday, 4 July 2011
thoracic treatment [Lind 2010]. Prospective clinical 07:00-08:00
data are required to conÀrm the validity of this
approach, which has become routine clinical practice MTE08.1 SURGERY FOR
in several centers. Whether thoracic treatment for MESOTHELIOMA PLEURECTOMY - EPP
Stage III patients with synchronous BM should Brian Mccaughan
involve chemotherapy, high-dose radiotherapy, or Cardiothoracic Surgery, Royal Prince Alfred
sequential or concurrent chemo-radiotherapy is Hospital/Australia
largely unknown, although it seems intuitive to use
a similar approach as for Stage III disease without Abstract: Malignant pleural mesothelioma is not
BM in Àt and relatively young patients. Patients with one disease entity, and therefore not surprisingly
stage IV thoracic disease (ie, with other synchronous there is not only one appropriate management
extracranial metastases) have a limited overall modality or treatment regimen for all patients. Those
survival, whether treated aggressively or palliatively clinicians who have been involved in the care of a
signiÀcant number of patients with mesothelioma this procedure back in 1991, in the Medical Journal
over many years have seen the full spectrum of this of Australia There was only one post-operative death
disease. We all remember the occasional patient with and one patient developed an empyema preventing
histologically proven mesothelioma who survived effective pleurodesis . The others all had an effective
beyond ten years without any active anticancer life long pleurodesis. Their survival ranged from 3
treatment but with effective early control of the to 54 months with a median survival of 16 months.
recurrent malignant pleural effusion. At the other end 3) Surgery also has a role in selected patients in
of the spectrum are those all too frequent patients an attempt to achieve maximal cytoreduction and
who have the “bushÀre” form of mesothelioma , therefore hopefully lead to a longer survival and
where no matter what cancer treatment modality is most importantly longer symptom free survival.
instituted, their disease progresses rapidly and death There has been a Áurry of activity in the last few
soon follows. These patients are often best served years comparing and contrasting two quite different
by minimal intervention other than symptom control procedures in this regard, in patients whose
and effective palliative care. Between these two performance status and extent of disease warrants an
extremes lie the majority of patients who contrary aggressive surgical approach, with or without neo-
to popular myth do not all die within twelve months adjuvant chemotherapy and/or adjuvant radiotherapy
and a median survival of only a few months. This and chemotherapy. Extrapleural pneumonectomy
large group of patients have the potential to beneÀt involves en bloc resection of the parietal pleura,
from conventional oncological interventions – lung, ipsilateral hemi-diaphragm and pericardium.
chemotherapy, surgery, radiotherapy – in various It is clearly a major procedure and not surprisingly
forms and combinations. Surgery is a cornerstone in varying surgical outcomes between institutions,
the management of patients with malignant plural with 30 day mortality rates ranging from 2.2 to
mesothelioma: 1) In some patients surgery may 11.8% in some published series. There is also a
simply provide for a deÀnitive tissue diagnosis signiÀcant difference in median survival between
after often multiple attempts at thoracocentsis and/ different centres but in several large centres a
or closed pleural biopsy in patients with recurring median survival now exceeds 20 months and most
pleural effusions and/or pleural thickening. In this importantly there is a signiÀcant tail in the long term
day and age such surgery takes the form of a “key survival beyond Àve years The role of neoadjuvant
hole” thoracoscopic procedure with three elements chemotherapy prior to extrapleural pneumonectomy
to that procedure: i) Identifying appropriate areas and adjuvant radiotherapy following extrapleural
for biopsy and taking adequately deep specimens pneumonectomy appears to improve survival,
to establish accurately the diagnosis ii) Assessing albeit in non randomised series. In those patients
the extent of malignancy such that should it prove completing all components of such a trimodality
to be mesothelioma, it’s suitability or otherwise for treatment regimen a 2 year survival of 60%, has
extensive surgery(discussed below) iii) Effective talc been reported, a Àgure not achieved in any previous
pleurodesis provided the underlying lung is capable signiÀcant series. The use of effective neoadjuvant
of reexpansion. 2) Surgery is used in many patients chemotherapy has two other beneÀcial effects: i)
with malignant pleural mesothelioma for symptom Firstly it assists in identifying those patients with
control. Effective palliation of symptoms is critical rampant disease who should not proceed to radical
in all patients with malignant pleural mesothelioma surgery. ii) It provides a period of accustomisation
and probably the most important is the control for the patient and family to the implications of the
of recurring pleural effusions. In many patients diagnosis before any radical surgery is performed.
thoracoscopic pleurodesis leads to effective control I Ànd both these issues of signiÀcant import in
of the pleural space and is the procedure of Àrst the appropriate selection of patients for radical
choice. However, in some of these patients, the bulk cytoreductive surgery with its attendant risks. The
of the tumour and the resulting large Áuid volume other cytoreductive surgery available, as mentioned
produced and/or the failure of the underlying lung to earlier, is pleurectomy and decortication with
re expand to facilitate pleurodesis and obliteration preservation of the underlying lung, followed in
of that pleural space, necessitates thoracotomy, some centres by adjuvant radiotherapy. There is little
pleurectomy and pulmonary decortication for control doubt that this operation carries a lower mortality
of the pleural Áuid. Prior to the reintroduction of risk (especially in Centres with a high operative
thoracoscopy we reported our Àrst 50 patients with mortality for extrapleural pneumonectomy) and
it does lead to effective palliation of symptoms. . completeness of resection with added therapeutic
Recent large series have also conÀrmed our much beneÀt. 2. Pleurectomy/decortication: parietal and
earlier Àndings with respect to median survival in visceral pleurectomy to remove all gross Tumor
the range of 12-20 months. A large multi institutional WITHOUT diaphragm or pericardial resection.
non randomised retrospective study comparing 3. Partial pleurectomy: partial removal of parietal
extrapleural pneumonectomy and pleurectomy/ and/or visceral pleura for diagnostic OR palliative
decortication reported an operative mortality of 7% purposes but leaving gross tumor behind. We prefer
for pleuropneumonectomy and 4 % for pleurectomy/ the term “Lung sparing total pleurectomy” to deÀne
decortication with an median survival of 16 months a procedure which mimics EPP in all but resection
for pleurectomy/decortication and 12 months for of the lung parenchyma. Staging Extrapleural nodal
extrapleural pneumonectomy. The authors of that involvement is associated with reduced survival.
paper however acknowledged that the choice of Preoperative staging is important to allow the patient
procedure for individual patients was multifactorial to make a fully informed decision about potentially
and stress that they were not able to advocate one morbid treatment. Both cervical mediastinoscopy
procedure over the other. Conclusion Based on a and EBUS have been used to assess nodal spread
25 years evolving experience of over 650 patients and whilst some nodes lie outside the scope of these
our current recommendation for the management methods ( mammary, diaphragmatic ) they can give
of patient with suspected malignant pleural a representative sample. Laparoscopy is suggested
mesothelioma follows the algorithm that will be by some to exclude occult peritoneal disease. There
shown. are deÀciencies in the current IMIG TNM staging
Keyword: Surgery for Mesothelioma system which have been recognised by the IASLC
who have embarked on a new staging project. We
have noted that the pathological IMIG stage was
Surgery for Mesothelioma Pleurectomy - EPP Monday, 4 July 2011 associated with DFI and overall survival; however,
07:00-08:00 preoperative IMIG stage was less useful. Further
improvements in pathological N stage and clinical
MTE08.2 SURGERY FOR T stage are expected. Case selection Selection
MESOTHELIOMA PLEURECTOMY - EPP criteria for EPP include ppoFEV1>50% predicted
David Waller and no evidence of pulmonary hypertension or right
Thoracic Surgery, GlenÀeld Hospital, University ventricular dysfunction. PD can be performed in
Hospitals Of Leicester/United Kingdom more elderly patients with poorer lung function and
in general has similar selection criteria to lobectomy
Abstract: The Àrst major report of extrapleural for NSCLC. Radical surgery is not feasible in T4
pneumonectomy (EPP) was produced from the tumours with myocardial or vertebral invasion
North East of England by Butchart in 1976 and was although local aortic resection can be undertaken.
promoted by Sugarbaker from the North East of The choice between EPP and PD is the subject of
America in 1991. Rusch in 1993 described ‘radical intense debate. Some argue that in stage III disease
pleurectomy/decortication’ or PD . The goal of MCR cannot be achieved by PD due to local
cytoreductive surgery should be the removal of invasion and involvement of the Àssures. Others
all visible or palpable tumor, or a macroscopic report favourable results for PD in stages I and II.
complete resection (MCR). The majority of surgeons In the presence of extrapleural nodal disease there
believe that EPP rather than PD is most capable appears to be no survival advantage of EPP over
of providing MCR . The IASLC Mesothelioma PD. Indeed in a large retrospective review Flores
Domain and the IMIG have therefore recommended found that a hazard ratio of 1.4 for extrapleural
the following terminology to be used in the pneumonectomy (P < .001) controlling for stage,
forthcoming Mesothelioma Staging Project: 1. histology, gender, and multimodality therapy. In the
Extended (or radical) pleurectomy/decortication: absence of clear survival beneÀt it seems illogical to
parietal and visceral pleurectomy to remove all use the treatment with the highest mortality in cases
gross tumor WITH resection of the diaphragm with the poorest prognosis and we advocate the use
and / or pericardium. The IASLC Mesothelioma of PD in bulky disease. The use of EPP should be
Domain prefers use of the term ‘extended’ rather conÀned to the early stages of disease where long
than ‘radical’ in this instance as the latter implies a term survival is possible. Video presentations will
address practical tips on how to avoid technical Cardiovasc Surg. 1991 Jul;102(1):10-4 Rusch V,
complications of patch dehiscence, bronchopleural J Clin Oncol. 1994 Jun;12(6):1156-63 Rusch VW.
Àstula and mediastinal shift. The median sternotomy Chest. 1995 Oct;108(4):1122-8 Flores RM, J Thorac
approach for EPP will be demonstrated together Cardiovasc Surg. 2008 Mar;135(3):620-6 Sugarbaker
with exposure of visceral pleurectomy in order to DJ, Eur J Cardiothorac Surg. 2011 Feb 8. Weder W,
achieve MCR in PD. Results In recent systematic Ann Oncol. 2007 Jul;18(7):1196-202 Rice DC, Ann
reviews operative mortality was found to be 7% for Thorac Surg. 2007 Nov;84(5):1685-92 Van Schil PE,
EPP and 4% for PD . EPP perioperative morbidity Eur Respir J. 2010 Dec;36(6):1362-9 Treasure T,
was 37% including atrial Àbrillation, empyema and Waller D,.J Thorac Oncol. 2009 Oct;4(10):1254-8
supraventricular arrhythmias. PD was complicated Keywords: mesothelioma, Surgery
by prolonged air-leak and postoperative empyema
in 9.8% and 4% of patients respectively . Important
prognostic factors include histological cell type and Session MTE09: Sleeve Resections
extrapleural nodal metastases. Favourable factors
are epithelioid histology and IMIG stage. Median Monday, 4 July 2011
survival ranges from 21 months in stage I to 12
months in stage IV. IMIG stage I has signiÀcantly
better prognosis than stages III and IV; N0 disease Sleeve Resections Monday, 4 July 2011 07:00-08:00
has better prognosis than both N1 and N2.There
appears to be no signiÀcant survival difference MTE09.1 SLEEVE RESECTIONS
between EPP and PD in stages II to IV. Only in Erino Rendina
stage I disease is there any beneÀt for EPP over Thoracic Surgery, University Of Rome “La
PD ( median survival 40 vs 23 months).Long term Sapienza” – Sant’Andrea Hospital/Italy
postoperative survival has been reported with up to
18% 3 year survival seen in younger females with Abstract: The indication for a sleeve resection is
epithelioid MPM and normal blood count . Long well established: a tumor arising at the origin of a
term survival from radical surgery is improved by lobar bronchus but not inÀltrating as far as to require
the use of additional systemic chemotherapy. The pneumonectomy. In addition, a sleeve resection may
use of preoperative chemotherapy is feasible and be indicated when N1 nodes inÀltrate the bronchus
does not increase perioperative morbidity. There from the outside, as is often the case in the left upper
remains debate whether postoperative chemotherapy lobe tumors requiring a combined reconstruction of the
is preferable. Some have used intraoperative, bronchus and the pulmonary artery. From a functional
intracavitary chemotherapy to improve local point of view, sleeve lobectomy is strictly indicated in
control and with similar intention intracavitary patients who cannot withstand pneumonectomy, but
photodynamic therapy and radical postoperative recent experiences have shown that the advantages of
hemithorax irradiation have been employed. sparing lung parenchyma are evident also in patients
However, compliance with radical trimodality without cardio-pulmonary impairment. Oncologically,
therapy is limited. Future directions The feasibility the primary goal is in every case the complete resection
of assessing radical surgery in a randomised of the tumor with free resection margins. When
controlled trial has been established by the MARS analyzing survival data reported in literature in the
group.Whether it is more practical to assess PD last years, most of the studies show similar or better
rather than EPP in such a trial remains to be studied. results for parenchymal sparing resections (including
Certainly with the changing epidemiology in the pulmonary artery reconstructions) if compared with
Western World there is an increasing incidence pneumonectomy. Moreover, in the analysis of 5-year
in the elderly exposed in construction during survival according to stage and nodal status, sleeve
1960s/70s. Hence the typical patient is less likely lobectomy results in higher survival rates for stages
to be Àt for EPP and more for PD. The epidemic I, II and III (Deslauriers ’04, Kim ’05, Ludwig ‘05),
of mesothelioma is moving eastwards across although the survival advantage in stage III appears
the globe and lessons learned today will be of to be limited and the beneÀt is not always conÀrmed
clinical importance around the World for the rest for stage III-N2 patients. Therefore the role of
of this century. References Butchart EG, Thorax. parenchymal sparing operations in patients with N2
1976 Feb;31(1):15-24. Sugarbaker DJ, J Thorac disease still remains not completely deÀned (Fadel’02,
Yildizeli ‘07). These results justify the increasing late phase clinical trials to establish efÀcacy and
use of parenchymal sparing procedures for lung safety. Phase III randomized placebo controlled
cancer also in patients with good cardio-pulmonary with cancer incidence endpoints remain the “gold
function, as observed in the last years. Postoperative standard” in determining if an interventional
morbidity and mortality data reveal overall better strategy is truly effective. However, the lengthy
results for patients undergoing sleeve lobectomy with time and intensive resources requried to perform
respect to pneumonectomy. Looking at literature data, phase III trials mandate that ther be a high level
when morbidity is evaluated according to the type of evidence indicating potential efÀcacy prior to
of complication, pneumonectomy patients appear to such studies. The history of cancer prevention
experience a higher rate of cardiac complications, while trials includes multiple examples of unintended
sleeve lobectomy patients show increased pulmonary harms from the tested agents (e.g., beta carotene
and airway complications incidence. The preservation increased rather than decreased the risk of lung
of lung parenchyma has been indicated by some cancer; rofecoxib and celecoxib were associated
authors as the possible cause of a theoretical increased with cardiovascular risks despite reducing colorectal
risk for locoregional recurrence after sleeve lobectomy. polyp recurrence). Therefore, phase II randomized
However, although in some experiences (Fadel’02) placebo controlled trials have a critical role in the
an higher local recurrence rate is reported for sleeve drug development process to help prioritize agents
resection with advanced nodal status (N2), the few for subsequent phase III testing. A number of agents
studies (Fadel’02, Terzi’02, Kim’05) analysing risk have been tested to date in the phase II setting for
factors for recurrence, show that the tumor stage and lung cancer prevention, including inhaled steroids,
the nodal status are the only negative predictive factors, cyclooxygenase inhibitors, lipoxygenase inhibitors,
rather than the type of operation performed. A number retinoids, and a prostacyclin analogue. It has
of studies indicate that lung parenchyma sparing become clear from these studies that several major
improves postoperative quality of life determining challenges exist. As multiple molecular pathways of
a greater cardio-pulmonary reserve, less pulmonary carcinogenesis are being identiÀed, intensive eforts
edema and less right ventricular dysfunction due to a are underway to identify the targets for intervention
lower pulmonary vascular resistance (Terzi’02, Martin- that could be expected to cover the majority of the
Ucar’02). high risk population. Risk assessment models to
Keyword: Sleeve resections identify the highest risk smokers who would be
expected to beneÀt the most from interventions and
whose inclusion in clinical trials would allow for
Session MTE10: Chemoprevention: smaller and shorter trials are under development.
Randomized Studies & What Have We The need for homogeneous populations in clinical
Learned trials (for instance, separating current versus former
smokers) is particularly important. Increasing
experience with trial endpoints is helping to identify
Tuesday, 5 July 2011 preliminary efÀcacy of agents targeting the central
lung (e.g., bronchial dysplasia) versus the peripheral
Chemoprevention: Randomized Studies & What Have We Learned lung (e.g., CT-identiÀed non-solid nodules). The
Tuesday, 5 July 2011 07:00-08:00 new generation of clinical trials is incorporating
high-throughput analyses that will provide abundant
MTE10.1 CHEMOPREVENTION: information on the impact of the interventions on
RANDOMIZED STUDIES & WHAT HAVE the molecular pathways of carcinogenesis. In this
WE LEARNED session, speciÀc lung chemoprevention trials, the
Waun K. Hong lessons learned, and pathways forward will be
Thoracic And Head & Neck Medical Oncology, discussed.
University Of Texas M.D. Anderson Cancer Center/ Keywords: chemoprevention, Clinical Trials
United States Of America
Abstract: The development of agents to prevent

lung cancer requries an iterative process of target
identiÀcation, preclinical testing, and early and
Session MTE11: Critical Perspective on new drugs for lung cancer are typically trialled in
the Treament of Stage IV Disease, Cost- advanced disease after established therapies have
Effectiveness Analysis New Drugs failed, the clinical beneÀt is often modest. CEAs
done in this setting are likely to be unattractive. For
example, the median survival beneÀt of erlotinib is
Tuesday, 5 July 2011 only 1.2 months in metastatic NSCLC. The ICER
of $Cdn 95,868/LYG led to a protracted delay in
Critical Perspective on the Treament of Stage IV Disease, Cost- the drug’s approval in Canada. Similarly, the high
Effectiveness Analysis New Drugs Tuesday, 5 July 2011 07:00-08:00 cost of bevacizumab led Roche not to Àle for a lung
indication in the UK after its breast cancer indication
MTE11.1 CRITICAL PERSPECTIVE ON was rejected on the basis of cost-effectiveness. The
THE TREATMENT OF STAGE IV NON- high cost of drugs and the economic recession have
SMALL CELL LUNG CANCER: COST resulted in some governments, such as Greece and
ANALYSIS OF NEW DRUGS. Spain mandating drug price reductions of up to 23%
William K. Evans on brand name drugs. Legislation in Germany will
Administration, Juravinski Cancer Centre/Canada allow healthcare plans to negotiate a discounted
price of up to 16% for products after their Àrst
Abstract: The global economic burden of year on the market. To avoid price controls, some
lung cancer is large and increasing. As a result, pharmaceutical companies have implemented
economic analyses (EA) are increasingly expected price caps and patient assistance programs. For
by governments prior to drug approval, as they example, Astra Zeneca Àxed the UK price of
provide an estimate of the drug’s beneÀt against geÀtinib at £12,200, irrespective of the duration of
the cost to achieve the beneÀt. Cost-effectiveness treatment and there will be no charge for patients
analysis (CEA) is the most common form of EA treated for less than three months. Risk sharing
and provides the incremental cost of the new drug partnerships between the pharmaceutical industry
compared to standard therapy over the incremental and national healthcare systems have occasionally
beneÀt measured in life-years gained (LYG). The been negotiated (multiple myeloma in UK) but this
incremental cost per case (ICER) can then be used is a new area for governments and industry. A key
by decision makers to determine if a new drug to success of such agreements will be a workable
represents good value for money. An ICER less than process for collecting effectiveness data after the
$50,000 per LYG has been commonly accepted as drug is marketed. Another strategy that ensures
“cost-effective” but there is not a strong rationale for appropriate treatment while containing costs is the
this number. A CEA does not take into account the use of biomarkers for patient selection. The selection
morbidity of the disease and its treatment, whereas of patients for treatment with erlotinib based on
a cost-utility analysis (CUA) does. The quality clinical factors and molecular markers can reduce
adjusted life year (QALY) incorporates morbidity cost while ensuring that those who can beneÀt
into a single measure (i.e. the quantity of life gained receive the appropriate drug (1). Similarly, tumour
by treatment is weighted by the quality of that life). markers can be used to select patients for geÀtinib
The QOL is approximated by a utility which is a (EGFR mutated tumours) (2) or for crizotinib (ALK
measure of preference for a given health state on gene) (3). These strategies are largely irrelevant in
a scale from 0 (equivalent to death) to 1 which is those countries with low per capita GDP where new
perfect health. CAUs are the preferred analysis for drugs for stage IV NSCLC are beyond the Ànancial
cancer drug approval. Although many of the drugs means of the majority of patients. One suggested
used to treat lung cancer have become generic strategy is to use pharmacoeconomic modeling
and are relatively inexpensive, newer drug entries techniques along with the value-based threshold
to the market, such as pemetrexed and molecular proposed by the WHO to estimate a value-based
targeted therapies such as erlotinib, geftinib and drug price (4). The threshold proposed by WHO is
bevacizumab are expensive; some CEAs will be a dollar value less than three times the per capita
presented. However, it is readily apparent that the GDP of the country. This strategy would make
CE or CU ratio is frequently much higher than drugs for lung cancer available to those in need
generally accepted and has led to delayed entry into in developing countries. However, it may not be
some markets or outright rejection by funders. As economically viable for the manufacturer as the
cost of drug production might exceed the threshold Abstract: Several factors have hampered the
in some poorer countries. The manufacturer might development of effective chemotherapy regimens
also be placed at risk as drug supplied to poor for malignant mesothelioma (MM). Because it is
countries might be exported to wealthier nations by uncommon, clinical trials are small and accrual can
an intermediary for the intention of proÀt making. be challenging. MM is heterogeneous, with many
In conclusion, the high cost of anticancer drugs prognostic factors, and 3 pathologic subtypes that
for lung and other cancers is increasingly limiting yield very different outcomes. MM is also difÀcult
patient access in many parts of the world. A new to accurately measure, and staging is unreliable.
paradigm needs to be developed in collaboration Despite these challenges, there has been modest,
with key stakeholders. It is essential that any new but genuine recent progress in systemic treatment
system reward drug innovation so that new drugs of this disease. Several drugs have been shown to
continue to be developed, while enhancing global improve survival and quality of life, and many novel
patient access. The use of pharmacoeconomic agents are being evaluated. The most active drugs
modeling techniques in combination with value are the antifolates. The pemetrexed/cisplatin regimen
thresholds based on the wealth of a nation is an was FDA and EMEA approved for MM based on a
approach meriting further consideration so that lung single-blind, placebo-controlled, phase III trial which
cancer patients worldwide can beneÀt from modern randomized 456 patients to cisplatin with or without
advances. References: 1. Bradbury PA, Seymour L, pemetrexed. The combination yielded a superior
Ng R et al. An economic analysis of the National overall survival (12.1 vs. 9.3 months, p=0.020), time
Cancer Institute Canada Clinical Trials Group BR 21 to progression (5.7 vs. 3.9 months, p=0.001), and
randomized trial of erlotinib versus best supportive response rate (41% vs. 17%, p<0.001) than cisplatin
care after cisplatin-based chemotherapy for advanced alone. Pemetrexed treatment also improved global
non-small cell lung cancer. J Thorac Oncol 2007;2 quality-of-life and pulmonary function. Similar
(suppl 4): 707. 2. Sordella R, Bell DW, Haber DA, results were achieved in a phase III trial of raltitrexed
Settleman J. GeÀtinib-sensitizing EGFR mutations plus cisplatin vs. cisplatin (median OS 11.4 vs. 8.8
in lung cancer activate anti-apoptotic pathway. months, p=0.048). Cisplatin can be poorly tolerated
Science 2004 Aug 30; 305 (5687): 1163-7. 3. Kwak in older patients; fortunately carboplatin achieves
E, Bang Y-J, Camidge R et al. Anaplastic lymphoma similar outcomes. The International Expanded
kinase inhibition in non-small cell lung cancer. N Access Program demonstrated comparable activity
Engl J Med 2010; 363; 1693-1703. 4. Dranitsaris G, for cis- and carboplatin in terms of response
Truter I, Lubbe MS, Amir W, Evans W. Advances in (26.3% vs. 21.7%), time to progression (7.0 vs. 6.9
cancer therapeutics and patient access to new drugs. months) and 1-year survival (63% vs. 64%). Similar
Pharmacoeconomics 2010. results were observed in two large phase II trials of
Keywords: New Drugs, Advanced NSCLC, Cost pemetrexed/carboplatin. The role of maintenance
pemetrexed in MM is uncertain. In a non-
randomized Dutch trial, maintenance pemetrexed
Session MTE12: Chemotherapy of was well-tolerated and responses occurred after 6
Malignant Mesothelioma cycles. A CALGB study that randomizes patients
to best supportive care or pemetrexed maintenance
after 4 cycles of platinum/pemetrexed should
clarify the role of maintenance in this disease.
In a retrospective analysis of 60 MM patients
Chemotherapy of Malignant Mesothelioma Tuesday, 5 July 2011 who received a pemetrexed-containing regimen,
07:00-08:00 low TS protein levels by immunohistochemistry
were predictive of improved survival (HR 2.05).
MTE12.2 CHEMOTHERAPY OF Prospective studies are required to conÀrm this
MALIGNANT MESOTHELIOMA observation. Gemcitabine has minimal single-
Hedy Lee Kindler1, Sjaak Burgers2 agent activity, but is quite active when given with a
1
Section Of Hematology/Oncology, University platinum. Response rates vary widely between trials,
Of Chicago/United States Of America, 2Thoracic however. Interestingly, a retrospective Canadian
Oncology, Netherlands Cancer Institute/Netherlands series reported no difference in overall survival
in patients who received a platinum with either
pemetrexed or gemcitabine. The encouraging activity treated patients who are randomized to vorinostat or
of vinorelbine (response rate 24%, median OS 10.6 placebo. The results of this trial should be reported
months in a phase II trial) led to its inclusion in the at this meeting. Many other novel agents are being
409 patient phase III MS01 trial, which compared evaluated, including drugs which target mesotheliin
active supportive care vs. vinorelbine or mitomycin/ (MORAb-009, SS1P), IGF-1R (IMC-A12, OSI-906),
vinblastine/cisplatin (MVP). Due to poor accrual, tumor vasculature (NGR-hTNF), TGF-B (GC1008),
the 2 chemotherapy arms were pooled in the Ànal G2 checkpoint (CBP-501), mTor (everolimus), and
analysis; there was a small, non-signiÀcant survival proteasomes (bortezomib). In summary, there has
advantage with chemotherapy. A trend towards a been modest, but genuine recent progress in systemic
2-month improvement in survival over supportive therapy for MM patients. Active drugs, including
care was observed for vinorelbine (HR 0.80, pemetrexed/cisplatin, certainly improve survival
p=0.08) but not for MVP (HR 0.99, p=0.95). The and quality of life. Yet many issues still need to
role of second-line chemotherapy in MM is not be clariÀed to optimize treatment. Key questions
well deÀned. In a 161 patient retrospective analysis, include the role of maintenance, the optimal second-
second-line treatment yielded a median PFS of 5.7 line treatment, the appropriate chemotherapy for
months and a response or stable disease in 56% elderly and frail patients, the timing of initial
of patients. In an observational study in patients therapy, and the role of biomarkers in patient
who had responding or stable disease lasting >3 selection. As we learn more about the biology of
months after Àrst-line pemetrexed, re-treatment with this complex disease, many novel agents are being
pemetrexed produced a 19% response rate, though investigated, offering hope for the future.
only patients with durable disease control for >12 Keywords: mesothelioma, Chemotherapy
months had a survival beneÀt. The only completed,
exclusively second-line randomized phase III trial
in MM compared pemetrexed to best supportive Session MTE13: Pathology for Non
care in 223 pemetrexed-naïve patients. Pemetrexed Pathologists
improved PFS (3.6 vs. 1.5 mo, p=0.0148) and time
to initiation of subsequent chemotherapy (15.7 vs.
4.3 months, p<0.0001), but not overall survival,
likely due to crossover. In the absence of randomized
data, vinorelbine has become a reference second- Pathology for Non Pathologists Tuesday, 5 July 2011 07:00-08:00
line regimen, based on a 63 patient single-arm,
phase II trial, which reported a 16% response rate MTE13.1 PATHOLOGY FOR NON
and a median overall survival of 9.6 months in PATHOLOGISTS
previously-treated patients. Unfortunately, many Kirk D. Jones
novel drugs that appeared promising in preclinical Pathology, University Of California, San Francisco/
models have demonstrated limited activity in United States Of America
MM patients, including several EGFR and PDGF
inhibitors. VEGF inhibitors such as thalidomide, Abstract: There are several common problems
vatalanib, sorafenib, sunitinib, axitinib, and cediranib which confront the pulmonary pathologist. In this
have modest activity in single arm phase II studies. session, we will discuss many of the usual problems
A randomized phase II trial of gemcitabine/ confronted by the pulmonary surgical pathologist.
cisplatin plus bevacizumab or placebo reported no Using a case-based approach, the issues covered
difference in progression-free or overall survival. In will include: Differentiation of adenocarcinoma
contrast, the randomized phase II/III MAPS study, from squamous cell carcinoma: Histology-directed
which evaluates the addition of bevacizumab to therapies have made the classiÀcation of non-small
pemetrexed/cisplatin, has met its phase II endpoint; cell carcinoma more prominent. Several methods
the phase III trial is ongoing. A phase I trial of the including immunohistochemical panels have been
histone deacetylase inhibitor vorinostat reported proposed with some success in the separation of
2 partial responses in 13 MM patients, a median these lesions. Neuroendocrine tumors and the
TTP of 3 months, and symptom improvement. This approach on small biopsy specimens: Often on
Ànding led to the largest trial ever performed in this small biopsies, a neuroendocrine lesion will be
disease, a global phase III study in 660 previously- crushed and difÀcult to interpret. Several recent
reviews show that a panel of stains that include a Session MTE14: Pre-Neoplastic Disease
proliferation marker and marker of neuroendocrine
differentiation may help in these diagnoses. Mucinous Tuesday, 5 July 2011
adenocarcinomas and tumors with lepidic growth:
The recently published criteria for adenocarcinoma
give more importance to the diagnosis of tumors Pre-Neoplastic Disease Tuesday, 5 July 2011 07:00-08:00
with surface alveolar growth. Diagnosis of invasion
versus in situ tumor may be difÀcult. Criteria for MTE14.1 PRE-NEOPLASTIC DISEASE
invasion are not well established, and a variety Sylvie Lantuejoul
of strategies have been proposed. Staging issues Pathology, University Hospital/France
in lung cancer: The current AJCC/UICC/IASLC
lung cancer staging system has been in use for two Abstract: Lung cancer is a major cause of mortality
years. Some typical issues of staging include pleural worldwide, more than 70% of NSCLC patients
invasion, tumor size, and multiple tumor nodules. presenting unresectable advanced diseases at the
Biomarker analysis: Personalized therapy in patients time of diagnosis. Improving the survival rate of
with speciÀc mutations including EGFR and EML4/ patients requires understanding of molecular events
ALK have required careful handling and triage of leading to lung cancer, in order to identify genetic
biopsy specimens. 1: Travis WD, et al. International markers implicated in tumoral progression, to
association for the study of lung cancer/american improve earlier detection of lung cancer, particularly
thoracic society/european respiratory society in high-risk patients, and to develop novel targeted
international multidisciplinary classiÀcation of lung therapeutic strategies including chemoprevention.
adenocarcinoma. J Thorac Oncol. 2011 Feb;6(2):244- Histology of Preinvasive Lesions
85. PubMed PMID: 21252716. 2: Yoshizawa A, et al. Three pulmonary preneoplastic lesions have been
Impact of proposed IASLC/ATS/ERS classiÀcation recognised in the recent WHO classiÀcation (2004):
of lung adenocarcinoma: prognostic subgroups and squamous bronchial dysplasia and carcinoma in situ
implications for further revision of staging based on (CIS), preceding bronchial squamous cell carcinoma
analysis of 514 stage I cases. Mod Pathol. 2011 Jan and basaloid carcinoma, atypical adenomatous
21. [Epub ahead of print] PubMed PMID: 21252858. hyperplasia (AAH) preceeding adenocarcinoma
3: Butnor KJ. Avoiding underdiagnosis, overdiagnosis, in situ and invasive adenocarcinoma, and diffuse
and misdiagnosis of lung carcinoma. Arch Pathol idiopathic pulmonary neuroendocrine cell
Lab Med. 2008 Jul;132(7):1118-32. Review. PubMed hyperplasia (DIPNECH), a proposal precursor of
PMID: 18605766. 4: Pelosi G, et al. Typical and carcinoid tumours. Of note, no SCLC precursor has
atypical pulmonary carcinoid tumor overdiagnosed as been identiÀed to date. Squamous cell preneoplasia
small-cell carcinoma on biopsy specimens: a major Morphological changes of the bronchial mucosae
pitfall in the management of lung cancer patients. include hyperplasia, squamous metaplasia,
Am J Surg Pathol. 2005 Feb;29(2):179-87. PubMed dysplasia of various degrees (mild, moderate
PMID: 15644774. 5: Pirker R, et al. Consensus for and severe) and in situ carcinoma. Bronchial
EGFR mutation testing in non-small cell lung cancer: hyperplasia and squamous metaplasia represent
results from a European workshop. J Thorac Oncol. common reactive changes and are not considered
2010 Oct;5(10):1706-13. PubMed PMID: 20871269. as preneoplastic conditions. Conversely, dysplasia
6: Loo PS, et al. Subtyping of undifferentiated non- are true preneoplastic lesions, mild dysplasia being
small cell carcinomas in bronchial biopsy specimens. considered as a low- grade lesion, whereas moderate
J Thorac Oncol. 2010 Apr;5(4):442-7. PubMed and severe dysplasia, and in situ carcinoma are
PMID: 20195168. 7: Nicholson AG, et al. ReÀning high- grade preneoplastic conditions, at signiÀcant
the diagnosis and EGFR status of non-small cell lung risk for cancer development. Their distinction is
carcinoma in biopsy and cytologic material, using a based on morphological criteria well described in
panel of mucin staining, TTF-1, cytokeratin 5/6, and the WHO classiÀcation, and despite controversies,
P63, and EGFR mutation analysis. J Thorac Oncol. this grading scheme has reached an acceptable level
2010 Apr; 5(4): 436-41. PubMed PMID: 20068475. of inter-observers and intra-observers variation.
Keywords: pathology, lung, Neuroendocrine, AutoÁuorescence bronchoscopy (AFB) is a sensitive
Staging method for detecting them, and a synchronous CIS
can be detected in 15% of patients with a known
lung cancer, and among patients with a previous to proto-oncogenes activation, (2) inactivation
squamous cell carcinoma, one third developed of tumour suppressor pathways (3) resistance
a high-grade bronchial dysplasia. Atypical to apoptosis, (4) DNA repair alteration and
Adenomatous Hyperplasia Although the cell of immortalisation, (5) angiogenesis, and (6) cellular
origin for most adenocarcinomas, such as mucinous migration. The sequence of molecular abnormalities
adenocarcinoma, remains unknown, peripheral- type during bronchial and bronchioloalveolar
adenocarcinomas arise from Clara cells or type II carcinogenesis will be detailed during the
pneumonocytes can be preceded by adenocarcinoma presentation, but in summary, the working model
in situ AIS (former bronchioloalvaleoar carcinoma, of bronchial carcinogenesis includes allelic loss at
according to the IASLC/ATS/ERS international multiple tumour suppressor genes loci in normal
multidisciplinary classiÀcation of adenocarcinoma bearing bronchial epithelium of smokers, followed
in 2011) and AAH. AAH is single or multiple, by telomere attrition in squamous metaplasia,
usually less than 5 mm, located at the periphery of and than by telomerase reactivation, p53 and
respiratory bronchioles, and composed of moderately p16 inactivation, and cyclin D1 overexpression
atypical cells lining ialveoli and separated by gaps. among others occurring in bronchial dysplasia. In
AIS is characterized by a growth without gaps of contrast, genesis of adenocarcinoma arising from
neoplastic cells along preexisting alveolar structures, the peripheral bronchiolo-alveolar epithelium
and with no evidence of stroma, vascular and pleural involves separate pathways, depending mainly on
invasion. AAH are observed in up to 40% in patients the smoking status of the patients and the origin of
with adenocarcinoma, but in less than 4% in patients the adenocarcinoma. The Àrst one, preferentially
without cancer. These lesions are pure ground observed in non- smoker females of Asian origin,
glass opacities on CT , but even when multiple, implies mutations and/or ampliÀcation of EGFR
do not inÁuence the prognosis of patients with gene, this genetic abnormality, which occurs since
adenocarcinoma. Diffuse interstitial neuroendocrine the AAH stage (50%), being sufÀcient for malignant
cell hyperplasia (DIPNECH) DIPNECH has been transformation and progression, but inactivated by
associated with a higher rate of carcinoid tumours tyrosine kinase inhibitors (geÀtinib and erlotinib).
of the lung, and represent their putative precursors. This pathway is mainly available for TTF1 positive
DIPNECH is a generalised proliferation of scattered adenocarcinoma of terminal respiratory unit origin.
single cells, small nodules (neuroendocrine bodies), Another pathway, most frequently observed in
or linear proliferation of neuroendocrine cells in smokers, requires K-ras mutations; they are mutually
the bronchial and bronchiolar epithelium. There exclusive with EGFR ones, and occur in TTF1
is no molecular or genetic marker to distinguish negative adenocarcinoma, sometimes of mucinous
DIPNECH from reactive neuroendocrine subtype. They are observed in 15 to 40% of AAH.
proliferation, but allelic imbalance at 11q13, where p53 and p16 inactivation, mainly via 9p21 loss, can
the tumour suppressor gene MEN1 is located are be found in both pathways and represent late events.
observed in 0 to 50% of typical carcinoids and 50 In 2007, another pathway has been discovered in
to 70% of atypical carcinoids, and DIPNECH is 3-7% of adenocarcinoma, involving EML4-ALK
recognised as a rare component of patients with fusion gene at 2p; it leads to a permanent ALK
MEN type 1 syndrome. activation and predominates in younger no or light
Genetic and Molecular Pathology of Preneoplasia smokers,with TTF1 positive solid or papillary
Concomitant to morphological changes from adenocarcinoma, often with goblet cells. These
normal epithelium to preneoplastic to neoplastic adenocarcinoma present a high response rate to an
lesions, genetic alterations occur at the genomic ALK inhibitor, the crizotinib.
level, leading to initiation, development and Conclusion
maintenance of lung cancer; these alterations The incidence and mortality associated with lung
are mutations, deletions, microRNAs, epigenetic cancers have not been signiÀcantly modiÀed, despite
modiÀcations or polysomy, and affect the entire the introduction of new drugs. This highlights the
bronchial tree, exposed to carcinogen exposure importance of the characterisation of the molecular
(“Àeld cancerisation”). Genomic instability and determinants of lung cancer and the targeted
accumulation of several key step events favour development of chemopreventive agents for the
cellular growth or survival; these events are (1) treatment of pulmonary preneoplasia.
activation of growth-signaling pathways related
Session MTE16: Radiation Pulmonary 1

Department Of Medicine (Cancer Research), West
Toxicity: Prediction and Prevention German Tumor Center, University Hospital Essen/
Germany, 2Department Of Radiotherapy, West
German Cancer Center, University Hospital Essen/
Germany
Radiation Pulmonary Toxicity: Prediction and Prevention Tuesday, 5 Abstract: Stage III non-small-cell lung cancer
July 2011 07:00-08:00 represents a rather heterogeneous group of patients.
The patient population should at the moment best
MTE16.1 RADIATION PULMONARY be described by a) the current IASLC staging
TOXICITY: PREDICTION AND classiÀcation b) by the Robinson classiÀcation
PREVENTION for IIIA(N2) and c) by the comorbidity proÀle
Laurie E. Gaspar where pulmonary function tests are of descisive
Department Of Radiation Oncology, University Of importance. Radiotherapy as a single modality does
Colorado Denver/United States Of America no longer represent the optimum treatment for the
majority of stage III patients. Several prospective
Abstract: Radiation or treatment-related randomized trials have conÀrmed that concurrent
pulmonary toxicity is an unfortunate relatively- chemoradiation is superior to radiotherapy alone as
common consequence of deÀnitive radiation well as sequential application of both modalities.
or chemoradiation. The learning objectives of Methods: We have analyzed the current literature
this session are to: a) Review the patient factors on the choice of chemotherapy, the radiotherapy
associated with pulmonary toxicity b) Describe scheme and the observed toxicities based on its
the radiation dosimetric factors associated with impact on the combined modality treatment strategy.
pulmonary toxicity c) Discuss current strategies to Preferably randomized trials were included into this
predict and limit normal tissue injury in the treatment analyses but also signiÀcant phase-II trials were
of lung cancer Clinical cases will be utilized to added. Results: a) chemotherapy: cisplatinum-based
increase discussion regarding patient selection and concurrent treatment is the treatment of choice.
radiation dose/technique decisions. Carboplatin as a single agent has no evidence-based
Keywords: pulmonary toxicity, radiation treatment proven activity as chemoradiation agent. When
overlooking the whole literature, cisplatin plus
etoposide or cisplatin plus vinca alkaloid are the
Session MTE17: Combined Modality currently most used combinations for concurrent
Treament, Espsecially Concomitatnt chemoradiotherapy protocols (Albain et al, Lancet
Chemoradiation: Which Chemotherapy? 2009, Curran et al, Proc ASCO 2005). The largest
Which Radiotherapy Fractionation populations have been published for cisplatin and
etoposide. Recently, cisplatin in combination with
Scheme? Toxicities?
vinorelbin has been established as an easy and
safe alternative (Vokes et al, J Clin Oncol 2002,
Tuesday, 5 July 2011 Zatloukal, Lung Cancer 2004.). Carboplatin-based
protocols (mainly carboplatin and paclitaxel) -
typically used in North America - have failed with
Combined Modality Treament, Espsecially Concomitatnt rather negative survival outcomes within a large
Chemoradiation: Which Chemotherapy? Which Radiotherapy Cooperative trial (Vokes et al, Proc ASCO 2006).
Fractionation Scheme? Toxicities? Tuesday, 5 July 2011 07:00-08:00 Innovative approaches include addition of cetuximab
within ongoing clinical trials as a further radiation
MTE17.1 COMBINED MODALITY sensitizer but results have to be awaited prior to
TREATMENT, ESPECIALLY further evaluation. Strategies to give one or two
CONCOMITANT CHEMORADIATION: cycles of chemotherapy either as induction treatment
WHICH CHEMOTHERAPY? WHICH prior to deÀnitive chemoradiation or as consolidation
RADIOTHERAPY FRACTIONATION treatment after the concurrent chemotherapy
SCHEME? TOXICITIES? protocol are added by several centers to address
Wilfried Eberhardt1, Martin Stuschke2 the high systemic risks of patients. The reference
data for consolidation are two cycles of cisplatin cisplatinum-based chemotherapy (Flentje et al,
and etoposide in the Intergroup trial (Albain et al, personal communication) or investigate new
Lancet 2009). The reference data for induction are cisplatinum combinations in full doses (cisplatin and
either two cycles of cisplatin and vinorelbine (Vokes pemetrexed). Age is not per se a treatment limitation.
et al, J Clin Oncol 2002) or three cycles of cisplatin However, comorbidity proÀles have to be carefully
and paclitaxel (Fournel et al, Proc ASCO 2007). checked when deciding onto an intensive concurrent
Consolidation with single agent docetaxel cannot chemoradiotherapy protocol in patients older than 75
be recommmended based on major toxicity issues years. Future research will also have to investigate
with increased infections and pneumonitis rates measures to reduce the high brain-metastasis rate
(Hanna et al, J Clin Oncol, 2008). Currently, a large observed within the Àrst two to three years following
prospectively randomized Phase-III trial is looking deÀnitive chemoradiotherapy in these stage III
at the combination of cisplatin and pemetrexed given NSCLC patient populations.
in full doses concurrently to 66 Gy radiotherapy Keywords: Lung cancer, Stage III,
versus standard concurrent chemoradiation based chemoradiotherapy
on cisplatin and etoposide. Results are awaited to be
reported within the upcoming years. b) conventional
fractionation of radiotherapy in 1,8 to 2.0 Gy single Combined Modality Treament, Espsecially Concomitatnt
fractions up to doses of between 66 and 74 Gy is Chemoradiation: Which Chemotherapy? Which Radiotherapy
currently the most active approach for concurrent Fractionation Scheme? Toxicities? Tuesday, 5 July 2011 07:00-08:00
chemoradiotherapy protocols. The majority of
studies has been published with cumulative doses MTE17.2 COMBINED MODALITY
of 63 to 66 Gy. Currently, based on improvements TREATMENT, ESPECIALLY
in treatment planning and PET/CT based guidance CONCOMITANT CHEMORADIATION:
of treatment Àelds doses up to 74 Gy have become WHICH CHEMOTHERAPY? WHICH
a possible treatment intensiÀcation in experienced RADIOTHERAPY FRACTIONATION
centers (Salama et al, Int J Radiat Oncol Biol Phys SCHEME? TOXICITIES?
2011). Hyperfractionated accelerated protocols - Martin Stuschke
although proven as effective measures for treatment Department Of Radiotherapy, West German Cancer
intensiÀcation - have not entered clinical practice Center, University Hospital Essen/Germany
outside induction protocols prior to surgery or within
speciÀc clinical trials c) Toxicity remains an issue Abstract: Simultaneous radiochemotherapy is
for all chemoradiation protocols with pulmonary evidence based standard treatment for clinical stage
toxicity being the dose limiting one. Other important IIIA/ IIIB NSCLC. While platin-based second
toxicities are effects to spinal cord, esophagus and and third generation chemotherapy regimens are
heart. With more effective supportive measures about equally effective, they differ in their toxicity
now included early into the treatment, esophageal spectrum. To increase effectiveness of concurrent
toxicity remains no longer a major issue and dose radiochemotherapy, interest is in radiation dose
limiting. Pulmonary toxicity has to be critically escalation, altered fractionation and extending
estimated within the treatment planning phase based chemotherapy to more than 2 cycles. Advantages
on V20 and guided by FEV1, transfer factor (DLCO) of induction chemotherapy over consolidation
and ventilation-perfusion scans. Conclusions: chemotherapy exist in terms of tumor shrinkage
Concurrent deÀnitive chemoradiotherapy protocols prior to radiotherapy allowing lung sparing. Dose
based on cisplatin and vinorelbin and conventionally limiting organs for radiation dose escalation are
fractionated radiotherapy doses of 66 to 74 Gy lung and esophagus. Toxicity data will be analyzed
have become a valuable treatment strategy to for different radiochemotherapy and fractionation
stage III NSCLC patients. Most centers add either regimens. In addition, concepts of adaptive
one or two cycles of induction chemotherapy or radiotherapy, individualized dose escalation and
preferably consolidation chemotherapy to address elective lymphatic drainage irradiation will be
the high systemic risks of the patients. Current reviewed.
research is evaluationg to further intensify radiation
sensitization with EGF-R antibodies (ongoing
RTOG trial), look at the effects of consolidation
Session MTE18: Lymphnode Dissection up of 47.5 months they found the disease free and
overall survival rates were the same in the two groups.
Tuesday, 5 July 2011 In another study by Sugi et al studying just patients
with small (<2cm) T1 non-small cell lung cancers
they also found no difference in survival between
Lymphnode Dissection Tuesday, 5 July 2011 07:00-08:00 patients that had a complete MLND and those that
had sampling alone. The only positive study has
MTE18.1 LYMPHNODE DISSECTION been reported by Wu et all where they examined
Mark S. Allen 532 patients and included stages I, II and III in the
Surgery, Mayo Clinic/United States Of America study population. There was an improvement of 11
months in the median survival in patients that had a
Abstract: Since the advent of surgical resection for MLND compared to those that just had sampling of
lung cancer by Graham’s successful pneumonectomy the mediastinal lymph nodes. The recently reported
and the subsequent demonstration that an anatomical Z0030 study from the American College of Surgery
lobectomy was sufÀcient for a curative lung cancer Oncology group reported on 1,111 patients with T1
procedure the removal of regional and mediastinal or T2 tumors that were clinically N0 or non-hilar
lymph nodes has been thought to be an integral part N1 non-small cell carcinomas of the lung and were
of surgical therapy of lung cancer. The initial impetus randomized to either mediastinal node sampling
for this was from extrapolation of resections of other (removal of a single node from stations 2R, 4R,7
solid organ tumors, such as a lymphadenectomy and 10R for right sided tumors and 5,6,7 and 10L for
with a gastrectomy for stomach cancer and a axillary left sided tumors) or to MLND. The randomization
lymph node dissection as part of a mastectomy for yielded a very similar group of patients in the two
breast cancer. The practice of including routing groups, the only demographic difference was that
lymphadenectomy as a part of lung cancer resection patients in the MLND arm had a median age 1 year
was solidiÀed by two reports from Memorial Sloan older than the sampling arm. The patients were
Kettering Cancer Center stating that mediastinal followed for a median of 6.5 years and there was no
lymph node dissection (MLND) leads to a more difference in the survival between the two groups. Of
favorable long-term survival. Unfortunately, a note, there were 21 (4%) patients that were discovered
routine lymph node dissection is not performed to have at least one positive mediastinal lymph node
in the majority of lung cancer resections. Little when they were randomized to MLND after having
and colleagues found that only 48.1% of patients undergone initial mediastinal lymph node sampling.
undergoing a lung cancer resection had even one These patients were all carefully staged preoperatively
mediastinal lymph node sampled at the time of as well with CT, PET and careful history and physical
surgery. MLND is the gold standard for staging the examinations. It is also important to note that the
mediastinum. Other techniques such as computed performance of a complete MLND did not increase
tomography, proton emission tomography, endoscopic the incidence of lymph leaks, bleeding, bronchial
bronchial ultrasound or even mediastinoscopy all Àstulae or other complications, but did extend the
have a signiÀcant false negative rate and can not be length of the operation by about 15 minutes. The
considered as the ‘best “ method to accurately stage conclusion from the Z0030 trial is that MLND does
the mediastinum. Whether or not MLND increases not improve long term survival or decrease local
survival rate is a separate question. Subgroup analysis recurrence in patients with an early stage lung cancer.
of Intergroup trial 0115 by Keller et al did show When clinical staging, intraoperative sampling and
improved long-term survival in a group of patients visual inspection do not reveal any mediastinal or hilar
with right upper lobe tumors that underwent MLND involvement, a complete MLND is not beneÀcial for
compared to a group that just underwent sampling; patients with an early stage lung cancer. This should
however, this was not a randomized trial and all the not be extrapolated to patients with more advanced
patients had positive N1 or N2 lymph nodes. In a T3 or hilar N1 cancers. Since the trial speciÀcally
randomized trial reported by Izbicki and colleagues in excluded these patients, no conclusions can be made
1998, they were not able to demonstrate a difference concerning this group of patients. In this instance, a
in survival between lung cancer patients undergoing complete MLND would seem prudent until further
resection that had a MLND and those that just had randomized trials clarify the situation.
sampling of suspicious lymph nodes. After a follow-
Lymphnode Dissection Tuesday, 5 July 2011 07:00-08:00 were published by ESTS (European Society for
Thoracic Surgeons), and these clearly described
MTE18.2 LYMPH NODE DISSECTION several procedures used for lymph node assessment
FOR LUNG CANCER in patients with non-small cell lung cancer. These are
Hisao Asamura deÀned as follows: “Selected lymph node biosy”, one
Division Of Thoracicsurgery, National Cancer or multiple suspicious lymph node(s) are biopsied;
Center Hospital/Japan “Sampling”, the removal of one or more lymph nodes
guided by preoperative or intraoperative Àndings
Abstract: Surgery for lung cancer began with simple which are thought to be representative; “Systematic
pneumonectomy some 80 years ago. In the 1930s, nodal dissection”, all mediastinal tissue containing
pioneer surgeons such as Nissen, Graham, and lymph nodes is systematically dissected and removed
Overholt demonstrated that pneumonectomy could within anatomical landmarks. It was recommended
be performed for lung cancer , and a complete cure that at least three mediastinal nodal stations (but
could be expected with this procedure. Based on the always subcarinal) should be excised as a minimum
observation that the tumor often involved locoregional requirement. [RELATIVE ADVANTAGES AND
lymph nodes, hilar/mediastinal LND was proposed DISADVANTAGES OF MLND] The goals of
in combination with pneumonectomy in the 1940s hilar/mediastinal LND are accurate intraoperative
by Allison and Brock. Cahan, then published an staging and improved survival through better local
important article on “radical pneumonectomy”, and control. A more accurate evaluation of the stage
the concept of “radical resection for lung cancer” could be expected by pathological examination of
was introduced for the Àrst time [3]. He described an the dissected lymph nodes. Some data clearly show
operative procedure with resection of the entire lung that systematic LNS or systematic LND improves
(pneumonectomy) and locoregional lymph nodes intraoperative staging in contrast to selected lymph
(MLND) in an en bloc manner. Nine years later, he node sampling, especially in the detection of multi-
published another article on “radical lobectomy”, level N2 disease. According to the results of recent
and showed that lobectomy could be considered as studies on postoperative chemotherapy, a favorable
an alternative to pneumonectomy in the surgical outcome could be achieved for patients with lymph
management of lung cancer without worsening node involvement compared to those without lymph
the prognosis as a radical operation for pulmonary node involvement. Thus, accurate staging by surgical
malignancies. Importantly, he clearly deÀned the exploration of the lymph nodes enables the selection
lobe-speciÀc extent of LND according to the primary of better candidates for adjuvant postoperative
site (lobe) of the disease. Since this landmark article, chemotherapy. These are deÀnitive beneÀts of
hilar/mediastinal LND has been adopted as part accurate staging. On the other hand, the impact of
of the standard technique for malignant disease LND on locoregional control and long-term survival
of the lung. The expected beneÀts of MLND in after surgery has not been clearly deÀned. However,
lung cancer surgery were accurate staging and an the American College of Surgeons Oncology Group
improved prognosis, although the latter point has been (ACOSOG) has just performed a randomized, multi-
controversial until recently. In the 1990s, the pattern institutional, prospective trial that was designed to
of lymphatic spread and its relation to the prognosis determine whether long-term survival is affected
in patients with metastasis at a speciÀc lymph node by mediastinal LND versus LNS at the time of
site were studied in detail. Through such studies, a pulmonary resection for lung cancer (ACOSOG
“lobe-speciÀc approach”, aiming at efÀcient MLND, Z0030 trial). Although the details of this study are to
has recently been proposed. Furthermore, for early be covered by Dr. Allen in this session, it has been
tumors, the therapeutic signiÀcance of MLND needs demonstrated that only 4% of patients had a negative
to be studied further. A “pathology-speciÀc approach” LNS and found to have a positive lymph node at
is another important issue in MLND for lung mediastinal LND and that mediastinal LOND did not
cancer. [DEFINITION of MLND and RELEVENT improve the survival or disease-free survival in early
PROCEDURES] Lymph node dissection (LND), stage lung cancer if preresection surgical staging of
also known as “lymphadenectomy”, needs to be mediastinal and hilar nodes is negative.
clearly deÀned so that it can be distinguished from Keywords: Lung cancer, lymph node dissection,
other related procedures for thoracic malignancies. Lymph node sampling, Surgery
Guidelines for intraoperative lymph node staging
Session MTE20: How to Report PET How to Report PET Wednesday, 6 July 2011 07:00-08:00
Wednesday, 6 July 2011 MTE20.2 HOW TO REPORT PET

Wolfgang A. Weber
Department Of Nuclear Medicine,
How to Report PET Wednesday, 6 July 2011 07:00-08:00 Universitätsklinikum Freiburg/Germany
MTE20.1 HOW TO REPORT PET Abstract: For many years nuclear medicine has
Emile F. Comans used planar gamma camera images with low
Nuclear Medicine & Pet Research, VU Medical spatial resolution for diagnosis and staging of
Center/Netherlands malignant tumors. These images provided little
anatomical detail. Furthermore, most available
Abstract: HOW TO REPORT PET FDG-PET- radiopharmaceuticals visualized tumors by indirect and
CT has become an important modality during the unspeciÀc mechanisms: bone scans with radiolabeled
last decade in the process of staging patients with phosphonates demonstrate the osteoblastic response
a (suspected) primary lung malignancy. Although to a bone metastasis, liver scans with radiolabeled
the diagnostic value of the technique has been colloids show the displacement of the phagocytic
conÀrmed in many clinical studies, there is still room Kupffer cells by liver metastases. Because of these
for improvement when it comes to the predictive limitations nuclear medicine reports frequently had
value in NSCLC, especially with respect to T and N to be somewhat vague and described increased tracer
staging. A few studies have focussed on this subject, uptake “in the area of” some anatomic structure.
showing considerable inter observer variability of Furthermore, the reports often had to include a
the interpretation of PET studies, partly explained differential diagnosis and recommended further
by differences in individual experience. In addition, imaging tests for clariÀcation (“increased tracer uptake
existing guidelines with respect to the quality of in the area of the lower thoracic spine due to metastatic
PET reports in staging cancer patients are limited to disease, degenerative changes or trauma/infection,
the presence of key elements within the PET report. radiographic correlation recommended”). Because of
The aim of the present presentation is to address the such unspeciÀc reports “Nuclear Medicine” has been
issue of the quality of a PET (-CT) report (descriptive mocked as “uNclear Medicine”. With the advent of
part and conclusion part) with respect to effective PET and PET/CT this situation has fortunately changed.
communication of the Àndings to referring physicians. PET radiopharmaceuticals generally demonstrate a
The items that will be discussed in the presentation higher and more speciÀc uptake in malignant tumors
include aspects of the (new) T and N denominators. than tracers for gamma camera imaging. PET scanners
With respect to a (possible) primary lung malignancy (T provide three-dimensional images of the human
denominator) factors like appearance on a (diagnostic body with considerable higher spatial resolution and
or low dose) CT scan, the level of FDG uptake (FDG sensitivity than gamma cameras. The intensity of tracer
avidity), the pattern of uptake (focal, diffuse, central uptake can be quantiÀed in absolute units (such as Bq/
photopenic areas), possible pathological diagnosis, size ml). By normalizing tracer uptake to body mass or body
and loco-regional extension are important elements surface area tracer uptake can be standardized across
to include in the report. With respect to hilar and patients by calculation of standardized uptake values
mediastinal lymph nodes the size, appearance, contrast (SUVs). This allows a standardized display of PET
enhancement, location and intensity of FDG uptake images and reduces inter-observer variability of image
taking into account the partial volume effects in small interpretation. Furthermore, changes in tracer uptake in
nodes should be clearly described (and accurate with response to therapy can be quantiÀed over time. Hybrid
respect to the new IASLC/ATS/ERS staging map) to imaging with PET/CT allows accurate anatomical
facilitate the decision making process of the referring localization of abnormal Àndings on PET. In addition,
physicians, especially to facilitate a multidisciplinary current PET/CT scanners allow the acquisition of state
approach. The presence, location, size, degree of the art, contrast enhanced CT scans. Therefore,
of suspicion and possible routes for pathological PET/CT can provide a comprehensive morphologic
conÀrmation should be clearly described in patients and functional characterization of malignant tumors
with (suspicion for) distant metastases. in a single examination. Reports of PET/CT scans
Keyword: PET report should utilize all this information to accurately describe
the extension of primary tumors and the location of new chemotherapeutic agents were introduced
metastatic disease. For example, increased metabolic into clinics in the 1990s. To circumvent this
activity of lymph nodes in patients with lung cancer situation, a new class of drugs targeting certain
should be localized to speciÀc lymph node stations molecules that play key roles in pathways leading
and not vaguely described as “increased tracer uptake to cancer phenotypes is being actively developed.
in the hilar area”. All efforts should be made to make Discovery of EGFR mutations in lung cancer and
a speciÀc diagnosis regarding the presence or absence its predictive potential for EGFR tyrosine kinase
of metastatic disease. This requires knowledge of inhibitors (TKI) demonstrated how effective the
the typical patterns of loco-regional and metastatic targeted therapy is, when so-called “addicted
spread of lung cancer. The intensity of tracer uptake is oncogene” is pharmacologically inhibited. ALK
important for the differential diagnosis of benign and translocation is another example of such oncogene
malignant lesions, but the pattern of increased tracer addiction. In 2007, Soda et al. identiÀed the gene
uptake (diffuse vs. focal, symmetric or asymmetric) resulting from the fusion of that for echinoderm
should always be considered as well. Furthermore, microtubule-associated protein-like 4 (EML4)
readers need to be aware of the normal distribution and the gene for anaplastic lymphoma kinase
of the used radiopharmaceutical and its variability. (ALK) as a transforming activity in mouse 3T3
Factors inÁuencing the normal distribution, e.g. high Àbroblasts from DNA of lung cancer in a Japanese
skeletal muscle uptake of FDG in non-fasted patients, man with a smoking history. This EML4-ALK
intense colonic uptake of FDG in patients receiving fusion gene results from a small inversion within
metformin, need to be considered for the interpretation chromosome 2p. It is postulated that by fusing
of PET scans. When tracer uptake is quantiÀed by the coiled-coil domain of EML4 with the kinase
standardized uptake values the report should specify domain of ALK, the ALK protein dimerizes without
at what time post injection SUV measurements were ligand binding, leading to oncogenic activation.
made and whether the maximum or average SUV of Rearrangement of the ALK gene is originally
a lesion was measured. For quality control the SUV identiÀed in anaplastic lymphoma as its name shows
of normal organs with a relatively stable and uniform and later in inÁammatory myoÀbroblastic tumors,
FDG uptake, e.g. liver should be measured as well. If whereas point mutation of the ALK gene have been
liver uptake is outside the expected range of 2-3 SUV, described in neuroblastoma. However, EML4-
pitfalls in SUV calculation need to be considered (e.g. ALK fusion appears to be unique to lung cancer.
incorrect decay correction, wrong body weight used for The chromosomal break-points are not always the
SUV calculation, etc). same and multiple EML4-ALK variants have been
Keywords: reporting, quantitÀcation, PET identiÀed. All involve the intracellular tyrosine
kinase domain of ALK beginning at the portion
encoded by exon 20, but EML4 is variably truncated.
Session MTE22: ALK Translocations At least 11 variants have been reported to date. The
most common variants are fusion of exon 13 of
Wednesday, 6 July 2011 EML4 with exon 20 of ALK, and fusion of exon 6a,
b of EML4 with exon 20 of ALK, which are also
referred to as variants 1 and 3a/b, and constitutes
ALK Translocations Wednesday, 6 July 2011 07:00-08:00 33% and 29% of EML4-ALK, respectively. In
addition, EML4 is not a sole fusion partner of ALK.
MTE22.1 ALK TRANSLOCATIONS Two other partners, TFG and KIF5B, have been
Tetsuya Mitsudomi1, Yasushi Yatabe2 identiÀed in lung cancer. EML4-ALK translocation
1
Department Of Thoracic Surgery, Aichi Cancer is present in a distinct subset of lung cancer. It
Center Hospital/Japan, 2Pathology And Molecular tends to occur in patients without a smoking history
Diagnostics, Aichi Cancer Center Hospital/Japan or those of younger age. Histologically, ALK
fusion is associated with histologic subtypes of
Abstract: Lung cancer is the leading cause of adenocarcinoma with acinar, cribriform, or signet-
cancer-related deaths in many countries including ring cell morphology. In our hand, ALK fusion was
Japan. For advanced or recurrent disease, the identiÀed in 30 of 713 adenocarcinoma of the lung
standard platinum doublet therapy seemed to have (4.2%) and 21 of these patients were never smokers.
reached a therapeutic plateau, although various Median age of all the patients were 63 while that
of patients with ALK fusion was 56. There was a primary antibody to ALK and the dextran polymer-
strict mutual exclusionary relationship among ALK based detection reagents and showed high sensitivity
fusion, EGFR mutation and KRAS mutation. PF- and speciÀcity. We also showed that IHC using
02341066 (crizotinib) is an orally available, potent commercially available ALK antibody and high
and selective ATP competitive inhibitor of MET sensitive visualization kit (Envision Flex+ system
and ALK kinases. Clinical activity of crizotinib (DAKO)) was feasible for archival samples and
is certainly promising. In 82 lung caner patients small biopsy specimens with high sensitivity and
with ALK fusion, response rate was 57% with speciÀcity, and thus considered as the best suitable
46 conÀrmed partial responses and 1 conÀrmed method for screening ALK-positive tumors We have
complete response; 27 patients (33%) had stable treated lung cancer as one disease. However it is
disease and median progression free survival was actually an aggregate of many genetically different
9.2 months. The drug resulted in grade 1 or 2 (mild) diseases. IdentiÀcation of novel addicted oncogenes
gastrointestinal side effects. However, like in the and development of their inhibitors as well as
case of EGFR-TKI, acquired resistance seems an efÀcient patient screening methods will be the keys
obstacle, too. Recently two secondary mutations of to novel cancer therapeutics in the 21st century.
the ALK gene (C1156Y, L1196M) were shown to Keywords: Crizotinib, targeted therapy, Tyrosine
be responsible for at least some cases of acquired kinase inhibitor, biomarker
resistance. Interestingly, L1196 of ALK corresponds
to the threonine at position 790 in the EGFR gene,
which is present about half of the cases with acquired Session MTE23: Pulmonary Cytology,
resistance to EGFR-TKI. In a phase II study of IPI- Diagnosis and Molecular Approaches
504 is a novel, water-soluble, potent inhibitor of
heat-shock protein 90 (Hsp90) enrolling 76 patients,
overall response rate was 7%, however among the
three patients with an ALK gene rearrangement, two
had partial responses and the third had prolonged Pulmonary Cytology, Diagnosis and Molecular Approaches
stable disease (7.2 months, 24% reduction in tumor Wednesday, 6 July 2011 07:00-08:00
size). However, only one of 28 EGFR mutated
showed partial response. Although development MTE23.1 RESPIRATORY TRACT
of sensitive and speciÀc diagnosis of ALK CYTOPATHOLOGY: FROM BASIC
rearrangement will be very important given the high MORPHOLOGY TO ADVANCED
efÀcacy of ALK-targeted therapy, there is currently MOLECULAR ANALYSES
no standard method. RT-PCR, Áuorescent in situ Kim R. Geisinger
hybridization (FISH), and immunohistochemistry Pathology, Wake Forest School Of Medicine/United
(IHC) are being evaluated and each method has States Of America
some beneÀts and drawbacks. Since there are many
variants of ALK fusion, PCR should be multiplexed Abstract: Exfolatiative and aspiration cytology
and some times RNA of good quality is difÀcult to has long provided the diagnosis of primary and
obtain from the archival tissues. It is never possible metastatic neoplasms of the respiratory tract. The
to detect ALK fusion to the novel protein by PCR. advent of immunocytochemistry has improved our
In contrast, FISH can theoretically detect any diagnostic abilities. Transbronchial aspirates of
rearrangements including fusion with a novel gene. lymph nodes outside of the lung have added staging
However, proximity of location of EML4 and ALK capabilities. Molecular analyses of cytologic samples
gene within chromosome 2 sometimes obscures the contribute therapeutic and predictive data. Cytologic
signal for rearrangement. IHC is commonly used samples are divided into exfoliative and aspiration
in clinical laboratories and works for formalin- types. The former include sputum, washings,
Àxed, parafÀn-embedded, archival specimens. lavages, and brushings. Aspirations may be
However, ALK expression is generally low even in transthoracic (TTFNA) or transbronchial. The levels
ALK rearranged lung cancer compared with ALK- of diagnostic sensitivity for sputum range from 42-
rearranged lymphoma. Takeuchi et al developed an 97% with an average of 66%. Sensitivity increases
intercalated antibody-enhanced polymer method that with daily numbers of sputum specimens. Sensitivity
incorporates an intercalating antibody between the depends on the location of the mass: central lesions
have a higher sensitivity (71%) compared with heterogeneous, although commonly, cytoplasm is
peripheral masses (49%). SpeciÀcity hovers around abundant and delicate. Cells may be arranged in
99%. The ability to distinguish small cell carcinoma rosettes and trabeculae; this appearance is probably
(SCCA) from nonsmall cell carcinoma (NSCCA) what is responsible for the fact that these tumors
is at least 95%, as with all other cytologic sample may be misinterpreted as adenocarcinoma. It is
types. More direct exfoliative cytology developed probably impossible to determine whether a tumor is
with usage of the Áexible Àberoptic bronchoscope. a typical or an atypical carcinoid. Another problem is
Specimens include brushings, washings, lavages and distinguishing a pure SCCA from a combined tumor.
transbronchial aspirations (TBNA). The Àrst two With the major advances in therapy in NCSLC
are utilized with visualized lesions of the proximal and the recognition of the association of speciÀc
bronchi. Lavages are done for more peripheral tumor cell types with better or worse outcomes
abnormalities. The newest modality is TBNA which and with complications, it is imperative to render
may be done under endoscopic ultrasound guidance diagnoses as speciÀc as possible. In most patients,
(EBUSNA). For central masses, sensitivity for differentiation of squamous cell carcinoma (SQCA)
tissue biopsies, brushings, washings, lavages, and and adenocarcinoma (ACA) is possible. In addition
aspirates averages 74%, 59%, 48%, 40%, and 56%, to keratinization and intercellular desmosomes,
whereas for peripheral masses, sensitivity is 46%, other attributes for SQCA are centrally positioned
52%, 3%, and 37%; bronchoscopic aspirates are nuclei and polygonal contours. Conversely,
generally not done through the bronchoscope for eccentrically located nuclei, delicate cytoplasm,
peripheral nodules. Procurement of multiple different and neoplastic acini support a diagnosis of ACA. A
specimen types during the same bronchoscopic small minority of cytologic interpretations remain
session increases diagnostic sensitivity (88% as NSCLC, NOS. In two studies of preoperative
central lesions; 59% peripheral lesions). A different cytologic diagnoses, concurrence of the cytologic
approach to a patient with suspected lung cancer is and histiologic diagnoses was 88% and 93% with
TTFNA. This can be preformed for centrally situated a better predictive value for ACA. Application of
masses, but it is more often done for more peripheral limited immunocytochemistry (ICC) increases
lesions. TTFNA possess an average sensitivity the accuracy of tumor subtyping. A large number
and speciÀcity of 89% and 96%. In centers which of antibodies are unnecessary. A major goal is to
use on-site evaluation, these levels are higher. The preserve sufÀcient sample for molecular analyses. In
newest method is EBUSNA. This has the major distinguishing SQCA and ACA, the two most widely
advantage of directly visualizing lesions, both used antibodies are p63 and TTF-1. If the latter is
within the bronchial wall and in the mediastinum, positive, the cancer is generally considered to be
in real time. Diagnostic sensitivity ranges from 88- an ACA. If p63 is positive with a negative TTF-1,
95%; speciÀcity usually exceeds 95%. One pitfall then squamous differentiation is present. Another
of aspiration diagnoses of nodes is whether the antigen which points to glandular differentiation is
needle samples a node or a mass within or extending napsin-A. If one needs to conÀrm neuroendocrine
from a bronchus. The morphologist should report differentiation, a single antibody eg, CD56 or
the presence of lymphocytes to assure that the synaptophysin, may be used. This occurs most often
target was a node. In contrast to histopathology, in the diagnosis of LCNEC. A very new arena is the
cytomorphologic criteria to distinguish among use of microRNAs to determine cell types. With the
primary lung neoplasms are not as well established. advent of personalized thoracic oncology, after a
With neuroendocrine tumors (NET), the differential speciÀc diagnostic tumor type is rendered, molecular
diagnosis of SCCA from other family members testing for a variety of mutations may be necessary.
is uncomplicated. Features of SCCA include Though a number of mutations are recognized,
small size, uniformity, coarse chromatin, a lack three basic evaluations are important currently for
of nucleoli, and very high nuclear-to-cytoplasmic therapeutic and predictive purposes: mutations in
ratios. Distinguishing large cell neuroendocrine EGFR, k-ras, and EML4-ALK. Testing may be done
carcinoma is often relatively straightforward. Smears on cell blocks, carcinoma scrapped from smears, and
contain variably dispersed large malignant cells tumor cells in an aliquot dedicated for such tests. For
which typically have a single nucleus with a distinct all three mutations, PCR ampliÀcation of neoplastic
membrane, granular chromatin, and one or more DNA is probably the most widely used. However,
prominent nucleoli. Cytoplasm is volumetrically for EGFR and ALK mutations, ICC , which is very
antibody-dependent, may be of service too. For results of conventionally fractionated radiotherapy

ALK analyses, FISH probes are directed against are poor with only 50% of patients achieving local
commonly translocated chromosomal segments. In control. In an effort to improve these poor outcomes
several studies, the results of mutational analyses on a technique generally known as Stereotactic Body
cytologic material parallels that found in concurrent Radiotherapy (SBRT) has been developed. This
tissue samples. For several decades, no widely involves delivering a dose of up to 60 Gy in no
utilized histiologic grading system existed for the more than 8 fractions using highly conformal
NSCLC. Recently “grading” has been performed on radiotherapy, tight margins and stringent patient
histiologic material from resected tumors wherein the immobilisation and delivered using image guidance.
predominate histiologic pattern dictates the patient’s Two prospective studies have conÀrmed that using
course. Histiologic patterns of adenocarcinomas are such treatment schedules produces local control in
not usually recapitulated in cytologic smears. Several excess of 90%. The largest is from VU university
groups have developed cytologic grading schemes medical centre in Amsterdam using a risk adapted
based solely on nuclear features. In one study, three fractionation scheme of total dose 60 Gy given in
nuclear attributes were included: size, chromatin 3, 5 or 8 fractions, depending on the proximity of
pattern, and membrane contours. Each was assessed the lesion to chest wall, great vessels or other vital
a numerical value which were summed to provide structure (2). Local control was 97% and median
a nuclear score. The nuclear scores correlated well survival 34 months. However a major criticicism of
with prognosis. this study is that pathological proof of cancer was
Keywords: Lung, Cancer, Sensitivity, Molecular, only obtained in 31% of cases. The RTOG carried
Cytomorphology out a multicentre prospective study. Pathological
conÀrmation was mandatory and a dose of 54 Gy in
3 fractions (without inhomogeneity correction) was
Session MTE25: Considerations in prescribed (3). Again local control was excellent at
Setting Up a SBRT Program at my Clinic 98%. In both of these studies pulmonary toxicity
was low with grade 3 toxicity recorded in 3%.
Thus although no randomised control trial of SBRT
and conventionally fractionated radiotherapy has
reported (though such a study is in progress in
Considerations in Setting Up a SBRT Program at my Clinic Scandinavia) SBRT is now accepted as a valid option
Wednesday, 6 July 2011 07:00-08:00 for the treatment of medically inoperable early stage
NSCLC. Indeed a population based study from
MTE25.2 CONSIDERATIONS IN SETTING Amsterdam has shown that the introduction of SBRT
UP A SBRT PROGRAM AT MY CLINIC has led to both an increase in the number of elderly
Michael P. Snee1, Maria Werner Wasik2 (>75) patients with NSLC receiving active treatment
1
Oncology, St James Institute Of Oncology/United with radiotherapy, and an improvement in survival
Kingdom, 2Radiation Oncology, Thomas Jefferson over the time frame that SBRT was introduced (4).
University Hospital/United States Of America These results suggest that SBRT is a treatment option
that should be available for all patients with early
Abstract: Sterotactic Body Radiotherapy (SBRT) stage, peripheral, NSCLC who are not Àt for surgical
for Patients with Early Stage Non Small Cell Lung resection. SBRT is a well tolerated treatment, even in
Cancer (NSCLC): Setting up an SBRT Program those patients traditionally considered at high risk for
Michael Snee MD, Maria Werner-Wasik MD thoracic radiotherapy, such as patients with advanced
NSCLC is a common problem; in England and COPD, as manifested by severely impaired lung
Wales approximately 27,000 cases were diagnosed function, even oxygen dependence. Acute toxicities
in 2008, with a median age of 71 (1). Around 14% are rare and consist of 7% of patients experiencing
present with early stage (IA-B) yet only about half of grade 2 or higher pneumonitis (2% grade 3 or higher)
these patients receive surgery due to signiÀcant co- (5). Predisposing factors for pneumonitis include
morbidity such as Chronic Obstructive Pulmonary interstitial lung disease and a V20 exceeding 10%.
Disease or Cardiovascular Disease (1). Therefore in An emerging toxicity, not previously encountered
the UK a potential of 2,000 patients with NSCLC are in the standard fractionated regimens, is damage to
candidates for curative radiotherapy. However the the tissues of the chest wall, namely the skin, muscle
and ribs, manifesting as dermatitis, possibly skin non-small cell lung cancer: updated results of 257
ulceration, chest wall pain syndrome (myositis) and patients in a Japanese multi-institutional study. J
rib fractures, many times asymptomatic and observed Thorac Oncol 2:S94-S100, 2007. 6.Guckenberger
only as a radiographic Ànding. The incidence of 7-8 M, Wulf J, Mueller G, et al. Dose-response
percent of such chest wall symptoms including rib relationship for image-guided stereotactic body
fractures or myositis and less than 1% developing radiotherapy of pulmonary tumors: relevance of
grade 3 skin reactions was reported (5). The 4D dose calculation. Int J Radiat Oncol Biol Phys
constraints suggested in the literature for the SBRT 74:47-54, 2009. 7.Kestin LL, Grills I, Guckenberger
chest wall dose are 105 Gy and PTVmean BED10 M, Belderbos J, Hope AJ, Werner-Wasik M, Sonke
> 125 Gy demonstrated signiÀcantly higher local JJ, Bissonette JP, Xiao Y and Yan D. Substantial
control than lower doses. An analysis of the multi Dose-Response Relationship with Clinical Outcome
institutional Japanese experience (10) demonstrated for Lung Stereotactic Body Radiotherapy (SBRT)
a 5 year overall survival rate of 92% and 73%, Delivered Via Online Image Guidance. ). Int J Radiat
respectively, in operable patients with stages IA Oncol Biol Phys 78:S14, 2010 8.Onishi H, Shirato
and IB NSCLC treated with SBRT to the BED H, Nagata Y et al. Stereotactic Body Radiotherapy
doses >100 Gy, matching or exceeding historically (SBRT) for Operable Stage I Non-Small-Cell Lung
reported survival rates of similar patients treated Cancer: Can SBRT Be Comparable to Surgery? Int
with lobectomy. Therefore, the Radiation Therapy J Radiat Oncol Biol Phys. 2010 Jul 15. [Epub ahead
Oncology Group (RTOG) and the American of print]
College of Surgeons Oncology Group (ACOSOG) Keywords: SBRT, NSCLC, Stage I NSCLC
are currently opening a Phase III randomized trial
(1021/Z4099) of SBRT vs sublobar resection, with
or without mesh brachytherapy. Eligible patients Session MTE26: Bi- Versus Trimodality
include “borderline resectable” patients, deÀned as Therapy for Locally Advanced NSCLC
those able to have wedge or segmental resection
but not lobectomy. The use of brachytherapy is
left to the choice of each participating institution.
The trial is designed as a non-inferiority study.
1. http://www.nice.org.uk/guidance/index. Bi- Versus Trimodality Therapy for Locally Advanced NSCLC
jsp?action=download&o=53195 2. Lagerwaard FJ., Wednesday, 6 July 2011 07:00-08:00
Haasbeek CJA, Smit EF, et al. Outcomes of risk
adapted fractionated stereotactic radiotherapy for MTE26.1 BI- VERSUS TRIMODALITY
stage I non-small cell lung cancer. Int J Radiat Oncol THERAPY FOR LOCALLY ADVANCED
Biol Phys 70: 685-692, 2008. 3.Timmerman R, NSCLC
Paulus R, Galvin J, et al. Stereotactic body radiation Caro Koning
therapy for inoperable early stage lung cancer. Radiation Oncology, AMC/Netherlands
JAMA 303:1070-1076, 2010. 4. Palma D, Visser
O, . Lagerwaard FJ,et al. Impact of introducing Abstract: Locally advanced Non-Small Lung
stereotactic lung radiotherapy for elderly patients Cancer (NSCLC) forms a group of cancers with
with stage I non-small cell lung cancer: a population- heterogeneous characteristics. Stage IIIA includes
based time trend analyis. J Clin Oncol: 5153-5159, T3N1 to T3N2 and stage IIIB T4N0 to T4N2-3
2010. 5.Grills IS, Hope AJ, Guckenberger M, Kestin tumours according to the staging system of 1997.
LL, Werner-Wasik M, Sonke JJ, Bissonette JP, In 2009 changes were agreed, making stage IIIA
Xiao Y and Belderbos J: A Collaborative Analysis T1a,bN2 and T2a,bN2, T3N1,2 and T4N0,1 and
of Stereotactic Lung Radiotherapy (Lung SBRT) stage IIIB T4N2 and any T,N3. There is a large
Outcomes for Stage I Non-Small Cell Lung Cancer variation in tumour extent, making treatment choices
(NSCLC) using Daily Online Cone-beam CT Image- differentiated processes. Until the early nineties of
Guided Radiotherapy (CBCT-IGRT). Int J Radiat the last century radiotherapy only was the treatment
Oncol Biol Phys 78:S14, 2010 4. http://www.nccn. of choice for stage IIIA and low-volume stage IIIB
org/professionals/physician_gls/pdf/nscl.pdf 5.Onishi NSCLC patients. The overall survival rates were
H, Shirato H, Nagata Y, et al. Hypofractionated poor with a standard dose of 60 Gray in 30 fractions.
stereotactic radiotherapy (HypoFXSRT) for stage I There is a dose-effect relationship for NSCLC: the
higher the radiation dose the higher the loco-regional and 54 pneumonectomies. In the radiotherapy
tumour control probability. At Àrst chemotherapy group (194 patients) 155 continued with two cycles
was combined with radiotherapy in a sequential consolidation chemotherapy of whom 144 (74%)
way. Usually two courses of chemotherapy preceded Ànished the two planned cycles; in the surgery
the radiotherapy. According to a meta-analysis this arm 121 began the consolidation therapy and 111
resulted in an improvement of the 2-year and 5- (55%) patients Ànished it. There were no differences
year overall survival of 4% and 2%, respectively, in overall survival between the two treatment
provided the chemotherapy regimen contained groups. At Àve years the progression-free survival
cisplatin. For many lung cancer physicians this was 27% in the surgery group versus 20% in the
became the standard treatment. A different approach radiotherapy group. Of the pneumonectomy group
was the concomitant use of chemo- and radiotherapy. 14 patients died within 30 days of thoracotomy;
Low-dose cisplatin, applied daily before each of the lobectomy group one patient died. There
radiotherapy fraction or high-dose cisplatin doublets were several grade 3 or 4 toxicities as esophagitis,
or triplets on day 1 and day 21 or 28 yielded nausea and vomiting, and neutrocytopenia. In an
comparable results as those obtained with sequential unscheduled subgroup analysis the survival of
combinations. Several phase III clinical trials the patients, who were treated with a lobectomy
followed comparing sequential versus concurrent after mediastinal downstaging, was superior to
radiochemotherapy leading to two meta-analyses the survival of the patients in the chemo-radiation
published in 2010. They both conÀrmed that group. In both studies patients were selected for
concurrent radiochemotherapy has led to superior operability at forehand. This means that patients with
2- , 3- and 5-year overall survival rates. The gain a favourable stage III only could enter one these two
was 5.3%, 5.7% and 4.5%, respectively (P=0.004). studies. Of the patients participating in the study
Therefore concurrent radiochemotherapy is the by Albain et al 75 % had one N2 positive lymph
new standard treatment of patients with NSCLC node station only. There are many reports nowadays
with stage IIIA and low-volume stage IIIB disease. regarding small numbers of patients, all reporting
This improved survival was accomplished because selected subgroups of patients being operated after
of improved loco-regional control. Differences some combination of concurrent radiochemotherapy.
in distant metastases rates were not observed. Some of them are phase II studies. With the new
The most frequent acute but manageable acute diagnostic tools as EUS, EBUS with biopsies
toxicity was grade 3 or 4 esophagitis in 18% of the and PET/CT the general approach is to map the
patients. Depending on the scheme of chemotherapy status of the limited number of suspect mediastinal
haematological toxicity was observed (high-dose) or lymph nodes in case of tumour response after
hardly any (low-dose). An increase of late toxicity radiochemotherapy. When surgery follows there is
was not observed. The EORTC studied if there is a strong preference for performing a lobectomy, as
a role of surgery for patients with limited stage pneumonectomy is associated with a much higher
IIIA NSCLC. Patients were randomized between mortality and morbidity rate. The value of this highly
surgery and radiotherapy provided the tumour selected combined treatment is not exactly clear.
responded to induction chemotherapy. Of all 582 In a part of the patients who will be operated on,
patients 332 were randomised between 60 Gray NSCLC will be found to have reached a complete
radiotherapy and surgery. There were no statistically remission. Unfortunately markers to assess complete
signiÀcant differences in 5-year survival between response are lacking until now. For the majority
the two arms neither in median survival nor in of the patients with stage IIIA disease concurrent
progression-free survival. In the surgery arm Àve radiochemotherapy however will be the preferred
out of six patients died after they had undergone treatment. Nowadays the radiotherapy techniques
a pneumonectomy. Albain et al reported a phase with IMRT and 4D radiotherapy have improved
III study on stage III NSCLC (T1, T2, T3 with impressively compared to radiotherapy in the era
cN2) patients who were randomly treated after between 1990 and 2005 as well as the diagnostic
two cycles concurrent chemotherapy and 45 Gray tools. New agents as EGFR-blockers, VEGF-
radiotherapy with surgery or with a higher dose inhibitors, apoptosis modulators, PARP-inhibitors
radiotherapy of 61 Gray provided they were without have come to the clinic and can be combined with
progression. In the surgery group (202 patients) modern radiotherapy or/and radiochemotherapy.
there were 155 resections, of which 98 lobectomies This will lead to better selected patients, who can
be treated more and more on an individual base sternectomy and in the case of a large lateral chest
allowing higher doses in the tumour areas while wall resection.The completeness of the resection and
sparing the healthy surroundings. A carefully the histologic grade of the tumor are the strongest
selected subgroup can undergo surgery afterwards. survival predictors.
Especially complex treatment decisions should be Keywords: Chest wall resection and reconstruction,
made after discussion in multidisciplinary meetings. Primary chest wall tumors
Keyword: NSCLC, concurrent radiochemotherapy,
surgery
Chest Wall Tumors, Non Pancoast Wednesday, 6 July 2011 07:00-08:00
Session MTE27: Chest Wall Tumors, Non MTE27.2 CHEST WALL TUMORS, NON
Pancoast PANCOAST
Cengiz Gebitekin
Thoracic Surgery, Uludag Universitesi Tip Fakultesi/
Turkey
Chest Wall Tumors, Non Pancoast Wednesday, 6 July 2011 07:00-08:00 Abstract: Chest wall tumors, benign or malignant,
are classiÀed as primary or secondary (metastatic),
MTE27.1 CHEST WALL TUMORS consisting of 5% to 10% of all resected cases.
Alain Chapelier Primary tumors originate in the bone or muscle of
Thoracic Surgery And Lung Transplantation, Hopital the chest wall whereas secondary tumors originate
Foch/France elsewhere in the body and spread (metastasize) to
the chest wall. Bronchogenic and breast carcinoma
Abstract: Chest wall tumors can be secondary are the most common tumors that may involve
or primary. Clinical features of secondary tumors the chest wall by direct extension. In addition,
include internal (lung, mediastinal) and external all primary malignancies can cause metastases
(breast, skin) malignancies invading the chest wall to the soft tissues or bones of the chest wall.
and metastatic lesions (kidney, breast). Primary chest Virtually all secondary tumors and tumors of the
wall tumors are rare and most of them are malignant, sternum are overwhelmingly malignant. The most
arising from the bone or soft tissues. The location common benign tumors of cartilage and bone is
and the extent of the chest wall tumor and adjacent osteochondromas that frequently originates from the
structures involvement are determined by computed costochondral junction and malignant transfomation
tomography and magnetic resonance imaging. The to chondrosarcoma may be seen. The most common
diagnosis of primary malignant chest wall tumor malignant tumors of the ribs or sternum are usually
(PMCWT) must be conÀrmed by an incisional caused by secondary tumors and chondrosarcoma is
biopsy which will subsequently identify patients the most common primary malignant tumor of the
with a high-grade tumor whose Àrst treatment should chest wall that frequently arises from the anterior
be chemotherapy. Preoperative assessment includes ribs near the costochondral junction than from the
cardiopulmonary tests and PET CT scan. Radical sternum, clavicle, or scapula. In addition, primary
resection can offer a deÀnitive cure of PMCWT soft tissue tumors of the chest wall are typically
but the surgical management may be difÀcult of mesenchymal origin and may arise from any of
because of the local aggressiveness of these tumors. the structures such as fat, Àbrous, vascular, neural,
Extensive chest wall resections in free margins muscular, or dermal tissues. Metastatic involvement
can be nowadays safely done in most cases with may also occur by direct invasion, such as from lung
a carefully planned repair giving enough stability cancer, breast cancer etc..
of the chest wall and adequate airtight closure.
Improvements in reconstruction techniques with Pain is the most common symptom of malignant
PolytetraÁuoroethylene (PTFE) prosthetic patch and chest wall tumors that may be accompanied by
musculocutaneous Áaps have made coverage of wide swelling whereas protrusion as with a lump is
chest wall defects reliable. Rigid reinforcement of the most common symptom of benign tumors.
anterior or anterolateral defects can now be achieved Chest x-rays usually show an abnormality without
with titanium bars and clips after a total or subtotal indicating whether the tumor is malignant or benign.
A CT (computed tomography) or MRI (magnetic Session MTE28: How to Run a Stop

resonance imaging) provides the location and size Smoking Outpatient Clinic
of the tumor as well as give some information about
what type it is. PET/CT and/or bone scan may be
performed in order to exclude distant metastases.
Although an aspiration or core needle biopsy is
the Àrst intervention to diagnose, the diagnosis is How to Run a Stop Smoking Outpatient Clinic Thursday, 7 July 2011
made with either excisional or incisional biopsy. 07:00-08:00
Preoperative identiÀcation of chest wall invasion
may aid surgical planning. MTE28.2 HOW TO RUN A STOP
SMOKING OUTPATIENT CLINIC
Surgical resection and reconstruction for primary Carolyn Dresler
tumors of the chest wall is the most common Tobacco Prevention And Cessation Program,
intervention that provides long term survival. Arkansas Department Of Health/United States Of
Although chest wall reconstruction is unlikely America
necessary for tumors, such as lung cancer, invading
the chest wall, reconstruction is the most commonly Abstract: Depending on the adult smoking
used surgical technique for primary tumors of prevalence in the respective country, many
the chest wall. In cases where surgery is called patients presenting for treatment for a diagnosis
for, reconstruction with prosthesis or soft tissue of lung cancer will still be smoking. As smoking
replacement can be recommended follow-up cessation is critical to providing optimal treatment
procedure to help restore normalcy to the chest’s outcome and longer term survival, it is critical to
structure, appearance, and function. help patients (and their family) to stop smoking
as soon as possible to improve their treatment
Radical resection can offer a deÀnitive cure of outcome. If the patient understands that smoking
PMCWT but the surgical management may be cessation will improve treatment outcome and
difÀcult because of the local aggressiveness of future health improvement, they will be more
these tumours. Extensive chest wall resections with motivated to successfully quit. Reinforcing the guilt
free margins can be nowadays safely done in most feelings or stigma the patient may already have
cases with a carefully planned repair giving enough is counterproductive, and is a signiÀcant concern
stability of the chest wall and adequate airtight of patient and patient advocacy groups. There are
closure. Advances in reconstruction techniques with evidence-based guidelines regarding smoking
PolytetraÁuoroethylene (PTFE) or marlex prosthetic cessation techniques that have resulted from reviews
patches and musculocutaneous Áaps have made of the world’s literature, have been updated, and
coverage of wide chest wall defects reliable. Rigid are very well accepted throughout the medical
reinforcement of anterior or anterolateral defects can and psychological Àelds. Oncologists often must
now be achieved with titanium bars and clips after deal with the health consequences resulting from
a total or subtotal sternectomy and in the case of a persistent smoking and since ongoing smoking
large lateral chest wall resection.The completeness may signiÀcantly affect the outcome of subsequent
of the resection and the histologic grade of the tumor surgery or therapy and negatively impact long-term
are the strongest survival predictors. survival, it is imperative for clinicians treating cancer
Keywords: chest wall, reconstruction, Tumour patients to provide smoking cessation treatment or to
assure a readily available smoking cessation clinic.
Smoking cessation advice includes ‘5 A’s’: ASK
ADVISE ASSESS ASSIST ARRANGE An even
simpler algorithm is ASK, ADVISE and REFER:
The most important step is the Àrst one – ASK the
patient about smoking behavior This question can be
asked in a questionnaire while the patient is waiting
to be seen by the check-in staff or by the nurse as the
patient is being initially seen, but it certainly should
be conÀrmed by the physician. ASK response should
be included in the electronic medical record for therapies alone approximately doubles the Odds
every visit. A comprehensive smoking history would Ratios for quitting over placebo quit rates. The
be most appropriate for either a questionnaire while clinician should ask the patient which they would
the patient is waiting to see the oncologist or perhaps prefer or which they have tried – they probably have
should be asked by the nurse. As there is such a experience with at least one of them. The clinician
paucity of prospective data on smoking status in providing the outpatient clinic counseling must
clinical trials in smoking related diseases, especially be very familiar with the pharmacotherapies to
in oncological studies, such a questionnaire would assist with tobacco cessation: Behavioural Support
provide valuable data on future outcome measures. Motivational interviewing and cognitive behavioural
Questionnaires have been developed from the support is critical throughout the quitting process.
National Health Interview Survey and Behavioral Much support should be provided prior to and
Risk Factor Surveillance System Survey and should early in the quitting process. Many countries have
provide uniformity between datasets – see reference quitlines/telephone support services and this should
1 below. The discussion of quitting smoking should be strongly encouraged. Within the outpatient
be part of the clinical discussion of ‘next steps’ at clinic, between 4-8 visits of 10-20 minutes each is
the very Àrst visit. The clinician should utilize the probably adequate to provide the behavioral support
Àrst visit as the ‘teachable moment’ to emphasize (see smoking cessation guidelines for more speciÀc
or ‘personalize’ the importance and urgency for the recommendations).
patient to stop smoking immediately. The patient
must understand that nicotine addiction is one of References:
the most difÀcult addictions to overcome with the 1. Gritz ER, Dresler CM, Sarna L. Smoking: the
understanding that they probably have tried many missing drug interaction in oncology clinical trials
times to quit. And, with the current diagnosis, the OR ignoring the elephant in the room. Accepted to
patient is very stressed and would not normally CEBP June 2005.
choose such a stressful time to quit. However, 2. Zevin S, Jacob P, Benowitz NL. Dose-related
usually the patient will understand that quitting cardiovascular and endocrine effects of transdermal
smoking is one of the most important contributions nicotine. Clin Pharmacol Ther. 1998;64(1):87-95.
that THEY can currently bring to their therapy and 3. Zevin S, Benowitz NL. Drug interactions with
it is required of them at this point. If the clinician tobacco smoking. An update. Clin Pharmacokinet.
presents such a strong recommendation, the patient 1999;36(6):425-38. Quick Reading List: - an
will often listen. Thus, the ADVISE step is readily evidence-based site containing information in 11
incorporated into the treatment plan. Not only languages on tobacco dependence treatment relative
does the clinician tell the patient to stop smoking, to: efÀcacy, safety, demographics and health effects,
but to stop immediately. This is often an effective health economics, and policy. Re: guidelines: or
approach because one can explain to the patient Quick Guide to Pharmacotherapies for Smoking
what the next clinical steps are (surgery, radiation Cessation
therapy, chemotherapy, etc) and that the outcome can
be affected by continued smoking. The outpatient
clinic can now work with the patient to ‘implement’
this immediate quitting. In the outpatient clinic, an
ASSESSment of the patient’s ‘readiness’ to quit
can be ascertained and motivation provided to help
increase the urgency and desire to quit immediately.
Supportive methodologies to ASSIST with the
quitting process must also be discussed with the
patient. ‘Cold turkey’ – or without any support is
NOT the most successful way to quit smoking. Most
smoking cessation guidelines recommend three
different Àrst-line forms of pharmacotherapy: either
nicotine replacement therapy (NRT), bupropion
(Zyban) or varenicline (Chantix-USA or Champix-
rest of world). See table below. Each of these
Session MTE29: Second Line Treatment

Name Side Effects Precautions Dose Duration Rx or OTC at Relapse of Small Cell
Nicotine Mouth Dentures Heavier Wean OTC
gum soreness; smoker: 4 off by 6
hiccups/ mg Lighter months; Thursday, 7 July 2011
dyspepsia smoker: 12 months
2mg 1-2/ at latest
hr; Up to Second Line Treatment at Relapse of Small Cell Thursday, 7 July 2011
24/day
07:00-08:00
Nicotine Hiccups/ Heavier Wean OTC
lozenge dyspepsia smoker: 4 off by 6 MTE29.2 SECOND LINE TREATMENT AT
mg Lighter months;12 RELAPSE OF SMALL CELL
smoker: months at David S. Ettinger
2mg 1-2/ latest Oncology, Sidney Kimmel Cancer Center At Johns
hr; Up to Hopkins/United States Of America
24/day
*2mg Wean OTC (if Abstract: Small cell lung cancer (SCLC) represents
lozenge off by 6 available less than 15% of all lung cancers.1 In SCLC, because
take 1 months;12 – outside the malignant cells have a high propensity for early
or 2/hr months at US) metastases, only between 30%-40% of patients
depending latest present with limited-disease (LD) at the time of
on light diagnosis. In general for LD-SCLC, the overall
or heavy response rates are 85%-95%, complete response
smoker up rates, 50%-60% median survival ~20 months; and
to 40/day 2-yr DFS rates ~40%. For extensive disease (ED),
Nicotine Irritation 6-16 Wean Rx in the complete response rates are ~20%; median survival
of buccal cartridges/ off by 6 US; OTC 8-10 mos. and almost all patients are dead within
mucosa and day months;12 elsewhere 2 years. Relapse disease is divided into sensitive
throat months at disease (relapsed >3 months after completing front-
latest line therapy).2 In the U.S., for sensitive disease
Nicotine Nasal 8-40 doses/ Wean Rx treatment consists of re-induction with front-line
nasal irritation day off by 6 therapy. Other agents used include oral Etoposide,
spray months;12 Cyclophosphamide, Doxorubicin, Vincristine (CAV),
months at Topotecan (37% ORR) or investigational agents.
latest In patients with sensitive disease, Irinotecan has
Nicotine Local skin Sensitive 21 mg} 6 Duration OTC a response rate > 35%. For refractory disease, the
patch reaction skin wk 14 mg} is as some ORR for Topotecan and Irinotecan was ~6% and
Insomnia 2 wk 7 4% respectively. Docetaxel and Paclitaxel may
mg} 2 wk be active against relapsed SCLC however there is
or 15 mg insufÀcient clinical evidence to use them routinely.
8wk Gemcitabine, has limited activity against previously
Insomnia, Hx of 150 mg q 7-12 wks; Rx treated SCLC. Pemetrexed, a multi-targeted
dry mouth seizure AM x 3 or up to 1 antifolate agent, while active against NSCLC is
or eating days then year inactive against SCLC. Picoplatin, a Cisplatin
disorders 150 mg analog, in a phase II study in patients with refractory
BID SCLC, demonstrated a 4% PR and 43% SD rate.
Nausea 0.5 mg 12 weeks; Rx However, a phase III study comparing Picoplatin
AMx3 can with best supportive care did not meet its endpoint.
days; extend There have been a number of phase II prospective
0.5 mg another 12 studies of combination chemotherapy for relapsed
weeks SCLC with high response rates but median survival
Keyword: tobacco cessation times usually less than 7 months. Amrubicin is a
synthetic-9-amino-anthracycline and topoisomerase
II inhibitor is effective to treat SCLC in Japan. in patients with platinum-refractory small-cell lung
Is its effectiveness due to ethnic variation? In a cancer. J Clin Oncol 2010; 28:2598-603. 5. Jotte R,
phase II study of Amrubicin in Japanese previously Conklin P, Reynolds C, et al. Randomized phase
treated SCLC patients; in sensitive disease patients II trial of single-agent amrubicin or topotecan as
the ORR was 52% with a MST of 11.6 months; second-line treatment in patients with small-cell
in refractory disease patients the ORR was 50% lung cancer sensitive to Àrst-line platinum-based
with a MST of 10.3 months.3 In a phase II US/ chemotherapy. J Clin Oncol 2011; 29:287-93. 6.
EU study of Amrubicin refractory SCLC patients Hirose T, Nakashima M, Shirai T, et al. Phase II
in 63 evaluable patients, the ORR was 21% with trial of amrubicin and carboplatin in patients with
a PFS of 3.3 months and OS of 6.1 months.4 In a sensitive or refractory relapsed small-cell lung
randomized phase II study comparing Amrubicin cancer. Lung Cancer 2011, In Press. 7. Metro G and
to Topotecan in sensitive SCLC patients the ORR Cappuzzo F. Emerging drugs for small-cell lung
was 44% to 15% respectively with an OS of 9.2 cancer. Expert Opinion 2009; 14:591-606. 8. Kim
months to 7.6 months respectively.5 The results YH and Mishima M. Second-line chemotherapy for
of ACT-1: Phase 3 study of Amrubicin in second small-cell lung cancer. Cancer Treatment Reviews
line SCLC compared to Topotecan with OS as its 2011; 37:143-150.
primary endpoint is completed with the results to Keywords: limited disease, extensive disease,
be presented at ASCO 2011. In a Japanese phase II combined modality therapy, novel therapies
trial of Amrubicin and Carboplatin in patient with
sensitive or refractory relapsed SCLC, in 25 patients
treated, the ORR was 36% (58.3% sensitive; 15.4% Session MTE30: Genomics in Lung
refractory); MST overall was 7 months (10 months Cancer
sensitive; 5 months refractory).6 At the present
time, unfortunately, targeted therapy has failed to
demonstrate effectiveness for SCLC. Agents such as
Marimastat, Imatinib, GeÀtinib, Temsirolimus, BEC-
2 and Thalidomide were studied and were ineffective Genomics in Lung Cancer Thursday, 7 July 2011 07:00-08:00
against SCLC. In summary, SCLC is becoming an
“orphan” disease; LD-SCLC is potentially curable. MTE30.2 GENOMICS IN LUNG CANCER
ReÀnement of the combined treatment modalities Bauke Ylstra
should increase the cure rate. New regimens Pathology, VU University Medical Center/
should be evaluated in ED-SCLC patients where Netherlands
the survival rate is still poor. Molecular target
therapy also needs to be studied in the treatment Abstract: In this meet-the-expert session we will
of SCLC. Unfortunately, progress has been slow discuss the current value of genomics for the clinic.
especially for second-line therapy for SCLC.8 Thereby we will mainly focus on the analysis
References 1. Govindan R, Page N, Morgensztern of chromosomal copy number aberrations, since
D, et al. Changing epidemiology of small-cell lung DNA is a robust molecule which can be obtained
cancer in the United States over the last 30 years: from routinely collected archival material (FFPE),
analysis of the surveillance, epidemiologic, and end favourable for clinical implementation. Lung cancer
results database. J Clin Oncol 2006; 24:4539-44. genome analysis has been performed in a research
2. Ardizonni A, Hansen H, Dombernowsky P, et setting ever since the early development of the
al. Topotecan a new active drug in the second-line expression microarray now more than a decade ago.
treatment of small-cell lung cancer, a phase II study In recent years array analysis has made its entrance
of patients with refractory and sensitive disease. in the diagnostic arena. At VU medical center
J Clin Oncol 1997; 15:2090-2096. 3. Onoda S, Amsterdam array comparative hybridization (aCGH)
Masuda N, Seto T, Eguchi K, et al. Phase II trial of is routinely used for clonality screening in the case
amrubicin for treatment of refractory or relapsed of doiuble tumors. Meanwhile we are entering a new
small-cell lung cancer: Thoracic Oncology Research era in genome research with the implementation of
Group study 0301. J Clin Oncol 2006; 24:5448-53. Massively Parallel Sequencing (MPS). The Àrst lung
4. Ettinger DS, Jotte R, Lorigan P, Gupta V, et al. cancer genomes are being deciphered. MPS will also
Phase II study of amrubicin as second-line therapy be followed soon by diagnostic implementation. We
will discuss examples of both arrays and MPS using improvement in ventilator settings ICC removed
clinical specimens and possible implications for the and Extubated 8 days later CXR and CT showed
diagnosis of the NSCLC patient. effective closure of the cavity (in combination with
Keyword: genomics, microarrays, aCGH, copy the expected deÁation of the RUL) Reference:
number, next generation sequencing, NSCLC Travaline JM et al. Treatment of persistent
pulmonary air leaks using endobronchial valves.
Chest 2009;136:355-60
Session MTE31: I Wish…Seconds to Case 3 65 year old man with underlying COPD and
Disaster Cases to Learn From bullous lung disease Complicated by pneumonia
with L parapneumonic collection Pleural ultrasound
done by experienced radiographer in the Radiology
department with patient’s body position noted
Pleural aspiration done 30 minutes later in the
I Wish…Seconds to Disaster Cases to Learn From Thursday, 7 July bronchoscopy suite Despite the patient being in the
2011 07:00-08:00 same position the Áuid had moved- only a small
amount of Áuid was aspirable in posterior axillary
MTE31.1 I WISH... SECONDS TO line/ scapular line and the tube was partially placed
DISASTER CASES TO LEARN FROM before it was realised little Áuid was draining
PLEURAL CASES Repeat pleural ultrasound obtained – no Áuid
David Fielding present- Áuid had “shifted” into more anterior
Thoracic Medicine, The Royal Brisbane And position Tube successfully placed there in mid- ant
Women’s Hospital/Australia axillary line Comments: it seems not only is the
correct position important but pleural Áuid shifts can
Abstract: Case 1. A 68 year old lady presented occur as patients are moved from one position to
with a moderate sized unilateral pleural effusion. another, especially in partially loculated collections
Background history chronic liver disease due to Reference: Havelock T et al. Pleural procedures and
alcoholism Mild ascites Prior tap drained 1 litre of thoracic ultrasound: BTS pleural disaease guidelines
straw Áuid, transudate Repeat pleural aspiration 2010. Thorax 2010;65 suppl 2 ii61-ii76
due to recurrence of Áuid and moderate shortness Keywords: intercostal space, pleural procedures,
of breath INR 1.3 Fluid was “blood stained” 1.7. endobronchial valves
litres drained from “posterior position” Patient
collapsed 3 hours later, unrecordable blood pressure
CXR showed presumed left hemothorax ICC placed I Wish…Seconds to Disaster Cases to Learn From Thursday, 7 July
emergently, went to VATS exploration laceration 2011 07:00-08:00
of intercostal artery conÀrmed Patient died in ICU
1 day later due to multi-organ failur Comments MTE31.2 I WISH... SECONDS TO
Discussion of “safe triangle” Anatomy of intercostal DISASTER CASES TO LEARN FROM
arteries in relation to interspace Reference: Choi Suveer Singh
S. et al. Radiological review of intercostal artery: Respiratory And Intensive Care Medicine, Chelsea &
anatomical considerations when performing Westminster Hospital/United Kingdom
procedures via intercostal space. J Med Imaging and
Radiation Oncol 2010;54:302-306 Abstract: We will discuss the aetiologies behind,
Case 2. A 27 year old lady with community acquired and management of acute massive bronchial
pneumonia, empyema and RUL lung abscess; ICC haemorrhage, illustrated by a case study. Knowledge
placed uneventfully Intubated due to sepsis and of your population is crucial. As such, certain
respiratory failure 48 hours later rupture of the lung conditions are more likely to create bleeding
abscess followed by massive bronchopleural Àstula problems; vascular tumours, esp renal cell
Near impossible to ventiltate: High pressure support metastases, Àbrocavitatory disease, bronchiectasis,
tidal volumes 150ml, 100% oxygen with sats of bleeding diatheses, pulmonary hypertension,
85%, Effective placement of 3 endobronchial valves chronic steroid use, cardiac patients on combination
with instant cessation of leak, preceeded by balloon clopidogrel/asprin. A 75y old Caucasian man with
inÁation demonstrating loss of air leak marked known idiopathic bronchiectasis, and haemoptysis
is presented. He had been investigated years oxyhaemoglobin saturation by pulse oximetry

previously. He was an ex 30 pack year smoker. was above 90%. The patient was transferred to
Bronchiectasis and cavitation of the right lower lobe intensive care unit for close monitoring. The
was felt related to early adult pneumonic illness. patient eventually recovered and the histology of
Subsequent management was as per standards of care the endobronchial biopsy turned out to be arterial
for bronchiectasis. New Haemoptysis, not associated wall. CT thorax later documented this patient had
with clinical infective exacerbation. A plain chest bronchiectasis and the nodular lesion was most
radiograph and ct scan revealed opaciÀcation likely a tortuous artery. These vascular lesions might
and Áuid within cavitation in the right anterior mimic endobronchial tumour and can be pulsative
upper lobe (RB3) and right lower lobe (RB7/8) or non-pulsative. Endobronchial ultrasound might
segments. No explanation for the haemoptysis. be of use in this clinical setting. References 1.
Normal bronchoscopic Àndings, except a slightly Soda H, Oka M, Kohno S, Watanabe M, Takatani
irregular mucosal tag at the junction of the RBI and H and Hara K. Arteriovenous Malformation of the
RB3 subcarina. This was biopsied x 2. Continuous Bronchial Artery Showing Endobronchial Protrusion.
bleeding ensued. When this did not abate through Internal Medicine 1995;34:797-800 2. Katoh O,
observation and suction, a haemorrhage protocol Yamada H, Hiura K, Nakanishi Y and Kishikawa
was initiated. We describe the ensuing steps, through T. Bronchoscopic and angiographic comparison of
to conclusion and diagnosis. Reference is made to bronchial arterial lesions in patients with hemoptysis.
the importance of preparation of staff, equipment, Chest 1987;91;486-489
patient factors. A reminder of Suction, cold Keywords: bleeding, bronchoscopy
saline and adrenaline (1 in 200,000 2ml aliquots)
and balloon blockers is provided. Furthermore,
which steps to take when immediate measures for Session MTE32: How I Practice
haemorrhage control are not successful, and which Concurrent CT-RT for Stage III NSCLC:
multidisciplinary approaches are to be considered. Patient Selection, Toxicity Management
Keyword: bronchoscopy, haemorrhage, and Outcomes at my Center?
bronchiectasis, balloon blocker, protocol

I Wish…Seconds to Disaster Cases to Learn From Thursday, 7 July
2011 07:00-08:00
How I Practice Concurrent CT-RT for Stage III NSCLC: Patient
MTE31.3 I WISH... SECONDS TO Selection, Toxicity Management and Outcomes at my Center?
DISASTER CASES TO LEARN FROM Thursday, 7 July 2011 07:00-08:00
Bing Lam
Medicine, Hong Kong Sanatorium & Hospital/Hong MTE32.1 HOW I PRACTICE
Kong CONCURRENT CT-RT FOR STAGE
III NSCLC: PATIENT SELECTION,
Abstract: A 49 year old gentleman presented with TOXICITY MANAGEMENT AND
episodic blood stained sputum. He was an ex-light OUTCOMES AT MY CENTER?
smoker and had no chronic illness. Bronchoscopy Hak Choy
was performed to rule out endobronchial lesion. Radiation Oncology, UT Southwestern Medical
A small nodular lesion was seen at the oriÀce of Center/United States Of America
right middle lobe bronchus and biopsy of the lesion
resulted in massive bleeding and hypovolaemic Abstract: Lung cancer remains the one of the
shock. The patient was immediately turned to largest cause of cancer related death in the World.
right lateral passion and bronchoscope placed just Approximately 80% of lung cancer patients will
proximal to the bleeding site. Normal saline was have non-small cell lung cancer and of those 40%
infused at full rate and intensive care unit staff was (32% of the total) will have locally advanced disease
paged to prepare for single lung intubation. Bleeding which is normally not amenable to surgical resection.
continued until the whole right lung was drowned, Radiotherapy plays a key role in the treatment
though blood pressure was stabilized and all along of these patients whether it be part of a curative
treatment plan or indicated for the palliation and How I Practice Concurrent CT-RT for Stage III NSCLC: Patient
prompt relief of symptoms including hemoptysis, Selection, Toxicity Management and Outcomes at my Center?
dyspnea due to bronchial obstruction or persistant Thursday, 7 July 2011 07:00-08:00
pain. The involvement of the radiation oncologist
in the treatment of lung cancer is certainly standard MTE32.2 HOW I PRACTICE
practice and requires close consultation with both CONCURRENT CHEMO-
medical oncologists as well as thoracic surgeons to RADIOTHERAPY (CT-RT) FOR STAGE
determine optimal treatment. There has certainly III NSCLC: PATIENT SELECTION,
been a progression in the approach to locally TOXICITY MANAGEMENT AND
advanced non-small cell lung cancer over the last OUTCOMES AT MY CENTER?
two decades. Radiotherapy alone was the traditional Francoise Mornex1, Nicolas Girard2
1
standard therapy for stage III disease however it Radiotherapy Oncology, Lyon-sud Hospital/France,
2
was associated with poor survivals. A progression of Respiratory Medicine, Thoracic Oncology, Louis
randomized trials have shown that survivals can be Pradel Hospital/France
improved with the addition of chemotherapy in either
a sequential or concurrent fashion. While concurrent Abstract: Concurrent CT-RT is the standard
therapies are associated with a improved outcomes treatment of locally-advanced NSCLC. According
in patients who have a good performance status they to the results of the Meta-Analysis of Radiotherapy
are also associated with increased toxicities. The goal from the Lung Cancer Collaborative Group
of all cancer therapies is to increase the therapeutic (LCCG), concurrent CT-RT leads to a signiÀcant
ratio; that is, to increase the probability of cure while survival beneÀt of 6.6% at 3 years when compared
minimizing the toxicity. Theoretically, all cancers with sequential CT-RT. In order to reproduce such
can be cured if a sufÀcient dose of radiation can be result, patients should be accurately selected in a
delivered to all clonogens without causing undue routine practice setting. In addition to the careful
toxicity to the patient. Obviously, this is not the evaluation of co-morbidities which are frequent in
case in most instances. Precise target localization, in patients with NSCLC, pulmonary function tests are
theory, can improve the therapeutic ratio by allowing crucial, as a forced expiratory volume in 1 second
more conformal radiation delivery, enabling one to lower than 1L or 40%, and/or a monoxide diffusing
escalate the tumor dose while sparing surrounding capacity lower than 60% of the theoretical values
normal tissue. In the last decade, conventional usually contra-indicate standard radiotherapy.
2-dimensional (2-D) radiotherapy, based on surface Chemotherapy may be delivered only to medically-
anatomy and bony landmarks, has given way to the Àt patients with PS<2. The major objectives of
computed tomography (CT)-based 3-D radiotherapy, radiotherapy treatment planning are to deliver a
which allowed for the use of internal anatomy. Great total dose ranging from 66 to 70 Gy on the Gross-
interests are now emerging in the Àeld of radiation Tumor Volume (GTV), using a standard fractionation
oncology in tracking the motion of the tumor and scheme (one 2 Gy-fraction per day), without risking
surrounding normal tissue, either from day to day acute toxicities on non-tumoral tissues. The lung
or during each treatment session, and in delivering V20 (percentage of pulmonary volume receiving
treatments that adapt to the detected motion. at least 20 Gy) has to be lower than 30% and the
Commercially available 4-D CT imaging capabilities lung V30 lower than 20% (and even less in case of
and various strategies to deliver the radiation dose chronic obstructive pulmonary disease) to avoid
to the moving target made the implementation of acute and late radiation-induced pneumonitis. The
this new paradigm possible. In this session, we will volume of oesophagial tissue has to be limited
discuss the how to intergrate systemic therapy as as much as possible. Concurrent CT-RT leads to
well as advanced technology for stage III NSCLC. higher oesophagial toxicity rates compared with
Keyword: locally advanced non small cell lung sequential treatment (18% vs. 3% in the LCCG
cancer meta-analysis); however, oesophagial toxicity may
not be considered as dose-limiting, as symptomatic
treatments usually allow the continuation of radiation
administration. A more concerning -and potentially
under-evaluated- toxicity is late cardiac toxicity,
which may occur in 5-8% of patients. The maximum
dose delivered to the cardiac tissue is 40 Gy, with a real-time re-delineation of volumes and adaptation of
cardiac V20 lower than 60%. Only limited data are dosimetric variables. Beyond radiotherapy progress,
available regarding the actual compliance of clinical optimization of chemotherapy is also crucial, as
trials with these quality control recommendations. systemic recurrences are frequent after CT-RT.
Repositioning accuracy along treatment courses In the US, etoposide and cisplatin combinations
is crucial. Variations are estimated to be 6 mm on are the most frequently used following trials
average, with errors higher than 10 mm in a third of conducted by the SouthWest Oncology Group. In
the patients, for an estimated loss of tumor control Europe, vinorelbine and cisplatin associations are
up to 5%. Recently-developed cone-beam CT-scan also popular. In order to deliver higher doses of
allows highly accurate tridimensional veriÀcation of chemotherapy and to increase systemic control rates,
the position of the tumor volume and other organs several investigators developed mixed therapeutic
before radiation delivery. Current optimization of sequences, associating induction and/or consolidation
radiotherapy include the development of Intensity chemotherapy, before and/or after concurrent CT-
modulated radiotherapy (IMRT), consisting of a RT. Some data suggest that consolidation protocols
real-time modeling of the contours and the amount may increase progression-free survival, but further
of photons delivered within the radiation beam, studies are needed. Moreover, the routine practice
using a programmed movement of the blades of favors induction chemotherapy, (1) allowing to
the collimator. This allows the administration of start the initiation of the treatment sequence while
beams of variable shapes during a single sequence, preparing the patient for radiotherapy with shorter
possibly proving to be helpful to target tumors that delays, (2) potentially obtaining a tumor response
are close to critical tissues, including the heart, and decreasing the targeted volume, and (3) leading
the spinal cord, or the brachial plexus. Our group to select most appropriate patients that do not
reported the interest of IMRT and non coplanar present with early progression. One debated issue
Àelds to reduce lung and heart V20. Standard is whether the pre- or the post-treatment volume
practice of radiotherapy is to deliver radiation under should be the reference for dose prescription in this
shallow breathing, and it is then necessary to add setting. New cytotoxic agents are currently being
sufÀcient margins, so that the prescription dose is investigated in combination with radiotherapy. We
reached everywhere within the moving tumor. For recently reported the initial results of a phase I trial
intra-thoracic tumors, cranio-caudal breath-induced evaluating the feasibility of combining full-dose
movements may range from 7 mm in the upper lobes pemetrexed to optimized radiotherapy to a total dose
to 65-70mm in the lower lobes. “4D techniques” of 66 Gy. This regimen is currently further evaluated
are based on dosimetry performed at several times in a phase II trial. Associations with cetuximab
during the respiratory cycle, and determination of the are also promising, producing high response rates
best phase to deliver radiation. Several techniques (62%) and prolonged survival (23 months). The
have been reported: respiratory control, which French Intergroup has launched a phase II trial
involves assisted or voluntary blocking of respiration evaluating cetuximab with cisplatin-pemetrexed
in a selected phase of the respiratory cycle; “Breathe- combined with concurrent radiotherapy to a total
Adapted RadioTherapy” or respiratory gating dose of 66 Gy (protocol IFCT 08-03). Overall,
consists of activating the photon-beam only when concurrent chemoradiation is the standard treatment
the motion amplitude coincides with a pre-selected of locally-advanced NSCLC. The recent and future
sector of the respiratory cycle; respiratory tracking optimization of radiation delivery and chemotherapy
involves intentionally moving the irradiating beam regimens allows signiÀcant improvements in tumor
so that it follows the movement of the tumor. The response rates and overall survival to occur in the
typical device for 4D-techniques is a pneumotach majority of patients. These developments make
apparatus with real-time visual monitoring. The radiotherapy one of most effective and promising
clinical evaluation of 4D-techniques is currently curative option in thoracic oncology.
ongoing. Another area of investigation is adaptative Keywords: Radiotherapy, Lung cancer,
radiotherapy, a radiation-delivery process where Chemotherapy
the treatment plan is modiÀed repeatedly during the
treatment course, using a systematic feedback of
tumor response to re-optimize treatment plan. Such
process requires cone-beam CT-scan imaging, and
Session MTE33: Superior Sulcus Tumor of-care.1 Current surgical standard-of-care

with N2 Disease recommends a lobectomy rather than a wedge
resection; in addition to an en bloc resection of the
adjacent involved structures.1 Classically, the
extensive posterior lateral approach has been used,
but the anterior approach provides an additional
Superior Sulcus Tumor with N2 Disease Thursday, 7 July 2011 07:00- opportunity using either a full or partial sternotomy
08:00 or manipulations/resection of the clavicle to provide
exposure to the upper extremity neural and vascular
MTE33.1 SUPERIOR SULCUS TUMOR structures for various types of resection to be
WITH N2 DISEASE performed. Minimally invasive techniques have also
Kemp H. Kernstine been utilized to improve postoperative morbidity.7
Home, Home/United States Of America Incomplete resection appears to have little to no
survival improvement compared with no resection.8
Abstract: Pancoast or superior sulcus non-small cell With recent surgical advancements, the current
lung cancer (NSCLC) is uncommon and a locally contraindications to surgical resection, as they relate
advanced form of lung cancer, because of its to Pancoast lesions, include metastatic disease,
anatomical location, early diagnosis by radiological contralateral N3 disease, extensive brachial plexus
imaging and surgical resection alone is challenging. and vertebral involvement and performance status
According to the ACCP guidelines, it is deÀned as an greater than 2. Postoperative radiation therapy
apical lung tumor that involves at the least the whether by external beam or brachytherapy does not
parietal pleura and above the level of the second rib.1 appear to improve survival. Two-thirds of patients
The characteristic constellation of symptoms occurs recur and of those two-thirds recur locoregionally.
in approximately 40% and is attributed to local The brain is the most common site of recurrence, 40
invasion: radiating arm pain that may eventually to 80% of those patients that recurred systemically,
develops into paresthesias, paresis and paralysis; especially adenocarcinoma and large cell. The bone
Horner’s syndrome or components of it; and local is the second most common site. In 110 selected
chest wall or shoulder pain.2 The true incidence of patients with Pancoast NSCLC studied from 1995 to
Pancoast NSCLC is difÀcult to determine as apical 1999, the Àrst multi-institutional prospective
non-locally advanced upper lung cancers are often Pancoast trial was performed by the Southwestern
misclassiÀed as Pancoast; thus, comparison analyses Oncology Group group (SWOG), S9416, with
of single institution and retrospective trials provide mediastinoscopy-deÀned absence of metastatic
only inferences to the true issues for Pancoast disease and were treated with etoposide and
patients. In the 6th AJCC staging system those factors cisplatin, each 50 mg/m2 in 2 cycles over 6 weeks
conferring a poor prognosis include: T4 compared with concurrent 45 Gy radiation.9-10 80% were able to
with T3, advanced nodal involvement, subclavian undergo thoracotomy and a 94% pathologically-
vascular invasion, Horner’s syndrome and longer negative surgical margin (R0) rate. Of those that
duration of symptoms. Prior to the 1950s, these were resected, 36% (32/88) had a pathologic
patients were considered inoperable, survival complete response (pCR), 56% were found to have
estimates were 10-14 months after diagnosis in either pCR or minimal disease. As a result of the
untreated patients.3 Then, 65 Gy of postsurgical induction therapy, no chest wall resection was
adjuvant radiation was found to achieve longterm necessary in 13 of 88(15%) resected patients.
survival.4 In the 1960s, chemotherapy combined with Induction-related mortality was 2.7%, 8.2%
radiation, 30-35 Gy, noted survival improvement in a progressed on treatment and the surgical mortality
small group of patients.5 Chemotherapy and radiation was 2.3% with a 52% morbidity. 67% were capable
or radiation alone without surgery, although of initiating the planned adjuvant two cycles of
palliative, have not consistently improved survival or cisplatin and etoposide, but 45% completed it. The
quality-of-life (QOL), especially in those patients overall survival (OS) was 55% at 2 yrs and 70%, for
with rib destruction, scalene node involvement, poor those that had a pCR. R0 and pCR were risk factors
performance status and a weight loss greater than 5% for longterm survival. For those that relapsed,
of baseline.6 Now, for those undergoing a curative systemic recurrence signiÀcantly outnumbered local
attempt, trimodality therapy is considered standard- recurrence, nearly 6 to 1 and for those that recurred
systemically, nearly 1/3 occurred in the brain only. biological and anatomical/physiological features of
These recurrent tumor results were dramatically the location of origin. None of the prospective phase
different from those found in the case-controlled II trials included PET, EBUS/EUS and none
observations previously reported. The Japan Clinical speciÀcally reported on the quality of their
Oncology Group study (JCOG) 9806 conÀrmed the lymphadenectomy. However, with the positive
SWOG Àndings in a similar phase II trial with results of the large recently reported intergroup trial
clinically negative mediastinums, the Pancoast and the European cooperative group trial, patients
patients were treated with 2 cycles of with non-bulky and non-multi-station N2 disease are
mitomycin,vincristine and cisplatin combined with likely to have a beneÀcial effect with induction
concurrent 45 Gy of radiation over a 6 week time therapy.12-13 Further research is necessary with
period.11 In contrast to S9416, this trial included current and more aggressive mediastinal staging. In
patients that supraclavicular lymph node conclusion, the 3 well-performed focused phase II
involvement (ipsilateral N3). Resection was Pancoast trials have demonstrated that few patients
performed 2-4 weeks after the last radiation dose. progress or die using concurrent induction
95% of patients completed induction therapy with a chemoradiotherapy. Resectability is 70-80%. The R0
1.3% mortality. 76% underwent thoracotomy and rate is approximately 90% and 10-20% of patients
68% of all eligible patients had an R0 resection with will be able to avoid chest wall resection. It is
16% (12/75) of them having a pCR, 21% of those unclear whether adjuvant chemotherapy provides
that were resected. The 3- and 5-yr survival was 61% any survival advantage and also unclear how to treat
and 56%, respectively. Survival with and without the patients with surgical residual disease. In the
pCR was 70% and 24%, respectively. 52% relapsed, future, opportunities for research in this patient
13% locoregionally alone and 27% systemically population are signiÀcant. A combination of
alone and 12% with both local and distant relapse. minimally invasive surgical techniques as well as
Given some initial positive results from locally more aggressive and consistent surgical methods and
advanced NSCLC clinical trial, consolidative therapy the type, timing and sequence of chemotherapy,
with docetaxel was added to the regimen studied in especially utilizing the more recently discovered
S9416 and in a phase II fashion in S0220. In 44 biomarker-directed therapy may increase
evaluable patients, 84% completed therapy. 66% respectability and the rate of surgical cure. . Over the
underwent thoracotomy and all had an R0 resection last 15 years we know much more about the
with a 66% pCR. 45% of the patients enrolled prevention and treatment of induction-related side
underwent consolidative therapy, 69% of those that effects and providing patients with supportive
underwent surgical resection. The 3-yr OS was 60%. management to improve survival and QOL.
The use of consolidative therapy in this group of tri- Intensity-modulated radiation therapy is likely to
modality treated Pancoast patients appears less improve the effectiveness, yet reduce the
favorable. The long-term results of this patient complication rate and possibly allow increased
population are soon to be published. From the radiation doses to achieve pCR. PET, EBUS/EUS
prospective data to date, induction therapy appears to and brain MRI have been more recently introduced
improve Pancoast resectability, increases the pCR and consistently used in the evaluation of the
and thus improves longterm survival likelihood. Pancoast NSCLC patients. Additionally, the use of
Local recurrence is reduced and quality-of-life circulating biomarkers and tumor cells may all
appears to be improved. It is estimated that in the provide prognostic and treatment-related information
highly selected group of surgical patients with to improve results. Hopefully, bringing all of these
Pancoast disease that N2 disease is approximately techniques to bear will provide a superior long-term
10-20%. However, in the single institution and survival. 1. Shen KR, Meyers BF, Larner JM, Jones
retrospective case control series, there is inconsistent DR. Special treatment issues in lung cancer: ACCP
deÀnition of Pancoast tumors and unbiased means to evidence-based clinical practice guidelines (2nd
conÀrm it and inconsistent means of staging the edition). Chest 2007;132:290S-305S. 2. Arcasoy SM,
mediastinum both clinically and surgically, thus we Jett JR. Superior pulmonary sulcus tumors and
do not know the true rate of N2 disease in Pancoast Pancoast’s syndrome. The New England journal of
NSCLC. Likely, the rate is greater than in other medicine 1997;337:1370-6. 3. Paulson DL. The
locally advanced disease possibly due to the survival rate in superior sulcus tumors treated by
insidious nature of Pancoast NSCLC or to the presurgical irradiation. Jama 1966;196:342. 4. Haas
LL, Harvey RA, Langer SS. Radiation Management Abstract: Treatment strategy for Pancoast tumor
of Otherwise Hopeless Thoracic Neoplasms. Journal Young Mog Shim, MD, PhD Department of
of the American Medical Association 1954;154:323- Thoracic and Cardiovascular Surgery, Samsung
6. 5. Shaw RR, Paulson DL, Kee JL. Treatment of Medical Center, Sungkyunkwan University School
Superior Sulcus Tumor by Irradiation Followed by of Medicine, Seoul, Republic of Korea Non-small
Resection. Annals of surgery 1961;154:29-40. 6. cell lung cancer (NSCLC) of the superior sulcus,
Millar J, Ball D, Worotniuk V, Smith J, Crennan E, also known as Pancoast tumor is one of the most
Bishop M. Radiation treatment of superior sulcus challenging thoracic malignant diseases because of
lung carcinoma. Australasian radiology 1996;40:55- their frequent invasion of adjacent vital structures
60. 7. Truin W, Siebenga J, Belgers E, Bollen ECM. such as the subclavian vessels, brachial plexus,
The role of video-assisted thoracic surgery in the and spine. In 1932, a radiologist, Henry Pancoast
surgical treatment of superior sulcus tumors. originally described this tumor as a carcinoma
Interactive cardiovascular and thoracic surgery (of uncertain origin) arising in the extreme apex
2010;11:512-4. 8. Ginsberg R, Martini N, Zaman M, of the chest, associated with shoulder or arm
et al. InÁuence of surgical resection and pain, atrophy of the hand muscles, and Horner’s
brachytherapy in the management of superior sulcus syndrome.1 The clinical manifestation of the
tumor. The Annals of thoracic surgery 1994;57:1440- Pancoast syndrome consists of a constellation of
5. 9. Rusch VW, Giroux DJ, Kraut MJ, et al. characteristic symptoms, including pain down
Induction chemoradiation and surgical resection for the arm, weakness and numbness along the
non-small cell lung carcinomas of the superior distribution of C8/T1–2, Horner’s syndrome and
sulcus: Initial results of Southwest Oncology Group radiographic evidence of destruction of the Àrst
Trial 9416 (Intergroup Trial 0160). The Journal of rib or vertebral body. However, any patients with
thoracic and cardiovascular surgery 2001;121:472- a tumor in the typical location of the apex of the
83. 10. Rusch VW, Giroux DJ, Kraut MJ, et al. lung and inÀltration of the Àrst rib are diagnosed
Induction chemoradiation and surgical resection for with a Pancoast tumor, regardless of whether
superior sulcus non-small-cell lung carcinomas: Horner’s syndrome or pain radiating down the arm
long-term results of Southwest Oncology Group is present. Thorough preoperative assessment is
Trial 9416 (Intergroup Trial 0160). J Clin Oncol mandatory because superior sulcus NSCLC are,
2007;25:313-8. 11. Kunitoh H, Kato H, Tsuboi M, et by deÀnition, cancers of stage IIB or greater and
al. Phase II trial of preoperative chemoradiotherapy surgery can lead to substantial morbidity. CT of
followed by surgical resection in patients with the chest and upper abdomen, whole-body PET,
superior sulcus non-small-cell lung cancers: report of and brain MRI need to be done to investigate the
Japan Clinical Oncology Group trial 9806. J Clin primary tumor and mediastinal lymph nodes and to
Oncol 2008;26:644-9. 12. Albain KS, Swann RS, rule out the possibility of extrathoracic metastasis.
Rusch VW, et al. Radiotherapy plus chemotherapy Since Pancoast tumors with mediastinal nodal
with or without surgical resection for stage III non- metastases (N2 or N3 disease) do not usually beneÀt
small-cell lung cancer: a phase III randomised from surgical resection due to a poor prognosis,
controlled trial. Lancet 2009. 13. van Meerbeeck JP, mediastinoscopy is needed to conÀrm the presence
Kramer GW, Van Schil PE, et al. Randomized of mediastinal involvement. In addition, the degree
controlled trial of resection versus radiotherapy after of nerve-root involvement should be assessed
induction chemotherapy in stage IIIA-N2 non-small- through careful neurological evaluation. Resection
cell lung cancer. J Natl Cancer Inst 2007;99:442-50. of the T1 nerve root is generally well tolerated, but
injury to the C8 root or lower trunk of the brachial
plexus results in signiÀcant sequelae, including
Superior Sulcus Tumor with N2 Disease Thursday, 7 July 2011 07:00- loss of hand and arm function. Pain extending
08:00 along the ulnar aspect of the forearm and hand is
consistent with T1 involvement and intrinsic hand
MTE33.2 SUPERIOR SULCUS TUMOR muscle weakness implies the C8 root or lower
WITH N2 DISEASE trunk is affected. Pulmonary function tests and
Young Mog Shim cardiac risk evaluation need to be done to assess
Departement Of Thoracic And Cardiovascular whether patients can tolerate pulmonary resection.
Surgery, Samsung Medical Center/Korea Initially, Pancoast tumors were considered to be
inoperable and incurable. However, since Shaw disease or tumor regression underwent anatomical
and Paulson reported 18 patients who received pulmonary resection followed by two additional
radiotherapy followed by complete en-bloc resection cycles of chemotherapy. Of the 110 patients enrolled,
with excellent local control and favorable survival 83 (75%) underwent thoracotomy, the induction
in 1961,2 induction radiotherapy (30 Gy over 2 regimen was well tolerated and only Àve patients
weeks) and en-bloc resection via an extended had grade 3 or higher toxic effects. A third of
posterolateral thoracotomy became the standard for patients had a complete pathologic response (n=28)
superior sulcus NSCLC and for the next 30 years, and another third (n=26) had minimum residual
the basic therapeutic strategy for these tumors microscopic disease in the resected specimen.
remained unchanged. Several studies based on this Based on this trial, concurrent chemoradiation
strategy showed similar results to those of Shaw followed by surgical resection and chemotherapy is
and Paulson, and they deÀned adverse prognostic currently recommended for patients with resectable
factors, including presence of mediastinal nodal tumors of the superior sulcus. However, patients
metastases, spine or subclavian vessel involvement, with marginally resectable superior sulcus tumors
and incomplete resection.3-5 In the largest series should undergo concurrent chemoradiation before
from Memorial Sloan-Kettering Cancer Center,4, surgical re-evaluation. Furthermore, for patients
5
which included 225 patients treated between with unresectable tumors in the superior sulcus,
1974 and 1988, although operative mortality was deÀnitive radiotherapy with chemotherapy is
low (4%), complete resection was achieved in recommended. Therefore, when considering the
only 64% of T3N0 and 39% of T4N0 tumors and appropriate approach for superior sulcus tumors, it
locoregional recurrence was common. These results is important to determine whether patients would
underscored the need for new treatment strategies beneÀt from surgical resection, which can be
to increase both local control and overall survival. inÁuenced by the chances of complete resection and
During the late 1980s and the 1990s, several the presence of mediastinal lymph node metastasis.
thoracic surgical groups developed new approaches During the past 40 years, the development of
for resection of superior sulcus tumors. Dartevelle effective combined modality treatments and of new
and colleagues developed an anterior transcervical surgical approaches has substantially increased
method for cancers affecting the subclavian vessels.6 local control and overall survival for patients with
This led to widespread acceptance of the anterior these tumors. Future studies are needed to address
approach and its modiÀcations including the the continuing difÀculties of systemic relapse after
transmanubrial osteomuscular sparing approach, surgery. References 1. Pancoast HK. Superior
addition of posterior or anterolateral thoracotomy pulmonary sulcus tumor. JAMA 1932;99:1391-1396.
to facilitate exposure to the lung and spine, and 2. Shaw RR, Paulson DL, Kee JL Jr. Treatment of
use of hemiclamshell thoracotomy. However, the superior sulcus tumor by irradiation followed
although development of these approaches for by resection. Ann Surg 1961;154:29-40. 3. Rusch
complete resection of superior sulcus tumors was VW, Parekh KR, Leon L, et al. Factors determining
a major advance in surgical management of these outcome after surgical resection of T3 and T4 lung
technically challenging tumors, overall survival at 5 cancers of the superior sulcus. J Thorac Cardiovasc
years remained approximately 30% even in highly Surg 2000;119:1147-1153. 4. Komaki R, Roth
selected patients. During the 1980s and 1990s, the JA, Walsh GL, et al. Outcome predictors for 143
success of combined modality treatment for stage patients with superior sulcus tumors treated by
IIIa (N2) NSCLC led to the development of a large, multidisciplinary approach at the University of Texas
prospective, multicenter, phase II trial (Southwest MD Anderson Cancer Center. Int J Radiat Oncol
Oncology Group 9416, INT 0160).7 Induction Biol Phys 2000;48:347-354. 5. Ginsberg RJ, Martini
chemoradiation followed by surgery is a logical N, Zaman M, et al. InÁuence of surgical resection
treatment strategy for the superior sulcus tumors, and brachytherapy in the management of superior
because local control is a challenge for these tumors. sulcus tumor. Ann Thorac Surg 1994;57:1440-1445.
In this trial, 110 eligible patients were enrolled 6. Dartevelle PG, Chapelier AR, Macchiarini P, et al.
with mediastinoscopy negative, clinical T3-4 N0-1 Anterior transcervical-thoracic approach for radical
superior sulcus tumors. Induction therapy included resection of lung tumors invading the thoracic inlet.
two cycles of etoposide and cisplatin with 45 Gy J Thorac Cardiovasc Surg 1993;105:1025-1034. 7.
of concurrent radiotherapy. Patients showing stable Rusch VW, Giroux DJ, Kraut MJ, et al. Induction
chemoradiation and surgical resection for non-small targeted therapies. An example is mutation analysis
cell lung carcinomas of the superior sulcus: initial of the EGFR gene, which is routinely used in many
results of Southwest Oncology Group trial 9416 pathology laboratories to guide treatment with
(intergroup trial 0160). J Thorac Cardiovasc Surg an EGFR TKI in speciÀc clinical situations. The
2001;121:472-483. expectation is that in the near future the number
Keyword: Pancoast tumor, Superior sulcus tumor of targets to be tested with molecular methods
will increase. For example, testing for the EML4-
ALK translocation via FISH may be indicated in
Session MTE34: Molecular Tools, Tissue a well deÀned subgroup of tumors. In addition,
Requirements the evolving genome-wide platforms for analysis
of gene expression signatures, post-translational
modiÀcations, as well as chromosomal, mutation,
DNA methylation and protein proÀling will result
in novel analyses to be applied to tissue samples,
Molecular Tools, Tissue Requirements Thursday, 7 July 2011 07:00- all having their own requirements in terms of tissue
08:00 quality, quantity and processing. Most molecular
methods are non-morphology-based, and require
MTE34.1 MOLECULAR TOOLS, TISSUE extraction of target material (DNA, RNA or protein)
REQUIREMENTS from the tumor sample. For many applications
Peter Mazzone1, Peter J. Snijders2 Àxation with buffered formalin is far from ideal or
1
Respiratory Institute, The Cleveland Clinic/United even disastrous, because it induces cross-linking
States Of America, 2Pathology, VU University and fragmentation of these bio-molecules. It is well
Medical Center/Netherlands known that for reliable mRNA analysis samples
ideally should be snap-frozen. Many DNA analyses,
Abstract: The Promise of Personalized Care: on the other hand can be applied to formalin-Àxed,
There have been many advances in our ability to parafÀn-embedded (FFPE) tissue, as long as the
characterize lung cancer, and our understanding of degree of DNA fragmentation does not interfere
the importance of doing so. These advances have with the quality of the assay. Mutation analysis of
been fostered by progress in our knowledge of the EGFR gene can be done on FFPE tissue since
the pathophysiologic mechanisms responsible for this method is applied to short fragments of target
lung cancer development and treatment response, DNA that are pre-enriched by PCR for the various
the availability of new technologies, and the exons or parts thereof. All molecular methods
application of this knowledge in clinical trials. To have their sensitivity limits and require minimal
meet the promise of personalized care the multiple amounts of input material. Since the integrity of
disciplines involved in the evaluation and treatment DNA is affected by formalin, more input from
of lung cancer must carefully synchronize the FFPE specimens than from frozen specimens is
steps required to characterize each lung tumor. In required to get equally reliable results. In addition,
this session we will discuss the principle of novel admixture of too many normal cells with tumour
molecular techniques, the processing requirements cells in a tissue specimen can result in a failure
necessary to apply these methods, the clinical to detect the tumor-speciÀc alteration since it is
evidence supporting tissue characterization, and the masked by the wild-type genotype represented by
ability of available lung tissue sampling methods to the normal cells. In some instances pathologist-
provide tissue for modern analyses. Novel Molecular guided macro- or micro-dissection of tumor cell
Techniques, Principle and Processing: Classically, areas from tissue sections is necessary to enrich for
lung tumor tissue is required to conÀrm a diagnosis tumor cells. Clinical Evidence Supporting Tumor
of lung cancer, via standard light microscopy +/- Characterization: The response rates to, and risks
immunohistochemistry (IHC). The introduction of of, various systemic agents have been shown to be
novel classes of therapeutic agents, effective in only linked to histology. Examples include the improved
subgroups of patients, has rapidly changed clinical response rates to pemetrexed in patients with
practice. Companion diagnostics with molecular adenocarcinoma, and the improved survival of those
methods are necessary to select those patients who with non-squamous histologies when bevacizumab
will derive the greatest clinical beneÀt from these is added to standard care. In addition, knowledge of
tumor histology now allows us to selectively apply advances in tumor characterization have changed
molecular testing to tumors more likely to show a the way we evaluate and treat lung cancer. The
given molecular alteration. EGFR mutations and application of new molecular tools requires careful
EML4-ALK translocations occur almost solely interaction between personnel from all specialties
in adenocarcinomas. Those with mutations in the involved in lung cancer management to ensure tissue
EGFR and those who harbor the EML4-ALK is appropriately sampled, handled, and tested
translocation have been shown to beneÀt from Àrst- Keywords: molecular tools, tissue requirements
line therapy with agents targeting these pathways.
Multiple additional biomarker signatures are being
studied, capable of predicting response to therapy, Session MTE35: Rare Mediastinal
prognosticating outcomes, or identifying targets for Tumors
future targeted therapies. Capability of Lung Tissue
Sampling Methods to Support Modern Analyses:
The majority of lung cancers are diagnosed by non-
surgical biopsies, since they are locally advanced or
metastatic at the time of presentation. Non-surgical Rare Mediastinal Tumors Thursday, 7 July 2011 07:00-08:00
approaches include bronchoscopy and transthoracic
needle biopsies. Recent advances in bronchoscopic MTE35.1 RARE MEDIASTINAL TUMORS
sampling of lung nodules include nodule targeting Paul Van Schil
via electromagnetic navigation and peripheral Thoracic And Vascular Surgery, Antwerp University
ultrasound. These techniques have improved Hospital/Belgium
the yield of bronchoscopy for smaller, more
peripheral lung nodules. Endobronchial ultrasound Abstract: The mediastinum is deÀned as the
and endoscopic ultrasound guided sampling of anatomical compartment between both lungs.
mediastinal and hilar lymph nodes allow real-time Mediastinal tumors rarely occur but are fascinating
visualization of biopsies from these sites. EBUS due to their surprising complexicity and variety
and EUS have greatly improved the diagnostic in many different ways. Variety of mediastinal
yield of endosonographic sampling of intrathoracic compartments and organs Although no universal
adenopathy. Rapid on-site evaluation (ROSE) of agreement exists, the mediastinum is commonly
cytology specimens obtained during non-surgical divided into a superior compartment above a
biopsies has been shown to improve the yield of straight line from the sternal angle of Louis to the
testing and shorten the length of these procedures. vertebral column and an inferior part below this
In addition to advances in non-surgical approaches, imaginary line. The latter is composed of an anterior
video assisted approaches have been able to reduce compartment in front of the heart, a middle at the
complications and length of stay related to surgical level of the heart, and a posterior part lying behind
biopsy. Several authors have reported the yield from the heart. Each compartment contains different
small, non-surgical biopsies for the diagnosis of organs and structures, varying from heart and great
lung cancer, histologic classiÀcation, and molecular vessels to lymphatic tissue and pluripotent cells.
testing. The results have shown promise for the Variety of histologic types and tumours As well
ability of these procedures to obtain adequate tissue in young as old patients, a lot of different primary
to assist with modern analyses. An approach to tissue tumors and cysts are encountered in the mediastinum
sampling for lung cancer now needs to consider and these are summarized in table 1. Also metastases
molecular testing when determining how many may occur in the mediastinum. Variety of symptoms
samples to take. A practical approach would be to Mediastinal tumors can grow to a large size before
take 2-4 extra samples after a diagnosis is likely to symptoms appear. Pressure on surrounding structures
have been established, so that material is available may result in hoarseness, dyspnea, dysphagia and
and can be appropriately processed for additional superior vena cava syndrome. Various paraneoplastic
testing. Currently, it is not clear if the molecular syndromes have been described as myasthenia gravis
changes within a lung cancer are heterogeneous and pure red cell aplasia in case of thymoma. Variety
frequently enough between the primary site, of diagnostic means Chest computed tomography
mediastinal nodes, and metastatic sites, to warrant (CT), magnetic resonance imaging and positron
sampling of more than one area. Summary: Recent emission tomography provide exact anatomical
delineation of a tumor and may suggest a speciÀc international collaboration and deÀne uniform
entity. To obtain a precise histological diagnosis, standards in diagnosis and treatment of these tumors.
CT-guided puncture, endoscopic or endobronchial References 1. Date H. Diagnostic strategies for
ultrasound, mediastinoscopy, mediastinotomy and mediastinal tumors and cysts. Thorac Surg Clin.
video-assisted thoracic surgery are utilized (1). In 2009 Feb19(1):29-35, vi. 2. Girard N, Mornex F, Van
case of suspicion of lymphoma, germ cell tumor Houtte P, Cordier JF, van Schil P. Thymoma: a focus
or thymoma, large biopsies are required. Well- on current therapeutic management. J Thorac Oncol.
circumscribed tumors in young patients should 2009 Jan4(1):119-26. Table 1.
be excised at once not to breach the surrounding Superior mediastinum Substernal goiter Ectopic
capsule. Variety of therapeutic strategies Operable thyroid
lesions are treated by surgical excision. Minimally Inferior mediastinum Anterior Thymoma Thymic cyst Germ
invasive and even robotic techniques can be applied cell tumors Pleuropericardial
cysts
if a complete resection can be obtained by this
Middle Lymphoma Bronchogenic cyst
approach. In case of incomplete resection or capsular
Posterior Neurogenic tumors
invasion adjuvant radio- or chemotherapy may be Enterogenic cysts
indicated. Inoperable lesions and lymphomas are
treated by a combination of chemo- and radiotherapy. Keywords: mediastinal tumors, Thymoma
In selected cases induction therapy may be a valid
approach to downstage a locally aggressive tumor.
Salvage surgery may be attempted in tumors that are Rare Mediastinal Tumors Thursday, 7 July 2011 07:00-08:00
not responsive anymore to chemo- or radiotherapy.
Long-term survival depends on histologic type and MTE35.2 RARE MEDIASTINAL TUMORS
completeness of resection. Thymoma Thymomas Hendrik Dienemann
are rare intrathoracic tumors but they are the most Department Of Surgery, Thoraxklinik, University Of
common tumors in the anterior mediastinum. Heidelberg/Germany
Commonly used staging systems include the
Masaoka – Koga and World Health Organisation Abstract: Mediastinal tumors encompass a variety
(WHO) classiÀcations, based on peroperative and of histologies and may be primary, metastatic
pathological Àndings. Surgery is the cornerstone of or result from direct invasion. Compared with
the management of thymomas, initially being useful intrapulmonary lesions mediastinal tumors are
for precise pathological diagnosis and staging, and rare. Due to the proximity of vital structures
in most cases ensuring at the same time the Àrst-line mediastinal lesions and complexity of anatomy
therapy (2). Complete resection is, after tumor stage, it is sometimes challenging to diagnose and treat
the most constant and signiÀcant prognostic factor those lesions. On the one hand, size and location
for progression-free and overall survival. Adjuvant within the speciÀc mediastinal compartment often
radiotherapy is recommended in incompletely give a hint on its nature. On the other hand, tumors
resected thymomas. In primary unresectable may expand and thus grow beyond compartment
thymomas, multimodal strategy nowadays include boundaries which makes evaluation and treatment
induction chemotherapy, extensive surgery, more difÀcult. This overview is directed towards
adjuvant radiotherapy, and in some cases, adjuvant rare primary lesions. The anterior mediastinum
chemotherapy. Most popular chemotherapy regimens is the most common site of primary mediastinal
make use of cisplatin, adriamycin, etoposide, lesions and more than 50% are malignant. The most
cyclophophamide or ifosfamide. The management of common lesions are thymic tumors, lymphomas,
thymomas requires cooperation between clinicians, germ cell tumors, cysts and parathyroid adenomas.
surgeons, and pathologists from establishing the Malignant tumors are more likely to cause symptoms
diagnosis to organizing the therapeutic strategy and than benign lesions. Differential diagnosis of
evaluating the prognosis. As a consequence of their tumors in the middle mediastinum has to take into
rarity, no prospective randomized trials are available account lymphomas, granulomas and cysts like
and collaborative studies are warranted in order to bronchogenic, pericardial and esophageal cysts. In
evaluate and improve current therapeutic standards. the posterior mediastinum predominantly neurogenic
Recently, the International Thymic Malignancies tumors exist. All compartments alone or together
Interest Group (ITMIG) was created to stimulate may be the origin of still less common tumors,
among these leiomyosarcomas, paragangliomas and stage, which needs non-surgical treatment Àrst and
others. From a practical point of view the following sometimes salvage surgery when a good response is
questions come up when a mediastinal tumor is documented. A variety of procedures with speciÀc
detected by chest radiograph and conÀrmed by CT diagnostic yield and inherent risks exist (Àne-needle
scan and/or MRI: 1) is any further imaging test (e.g. aspiration, core needle biopsy, incisional biopsy
PET, Sestamibi) useful, available and necessary? via mediastinoscopy/parasternal mediastinostomy/
2) Should AFP, beta-HCG or serum calcium video-assisted thoracoscopy). The choice of biopsy
levels be checked? 3) Is the lesion encapsulated technique depends on the localization of the tumor,
or more likely to inÀltrate adjacent structures thus clinical aspects and the condition of the patient and
indicating technical difÀculties in terms of removal the availibility of techniques. Fine-needle aspiration
or inoperability? 4) If encapsulated, should the may be performed by endo-esophageal ultrasound
lesion be removed without prior biopsy? 5) If (EUS) or endo-bronchial ultrasound (EBUS),
pre-therapeutic pathological typing is regarded however the diagnostic yield is dependent on the
as mandatory, which mode of biopsy is useful? experience of the investigator and the pathologist
1) Extent, morphology, density and relation to and does not reliably distinguish between thymoma
surrounding structures will be evaluated by CT scan and lymphoma. Incisional biopsies, especially
and MRI. PET is helpful for staging in patients with during transpleural approach, bear the risk of tumor
(suspected) malignant thymic tumors. Sestamibi is implants and pleural dissemination. Decision
recommended for localizing parathyroid tissue. 2) making for the surgeon: Since the introduction
Increased AFP- and beta-HCG-levels are present of video-assisted thoracoscopy the threshold for
in most patients with non-seminomatous germ direct exploration and surgical removal has been
cell tumors, whereas a minority of patients with lowered. Today, for patients with mediastinal cysts
seminomas has increased beta-HCG-, but never or solid capsulated tumors with short diameters
elevated AFP- levels. Serum calcium might lead to in any compartment extirpation by VATS prior to
detection of parathyroid adenoma. 3) Encapsulated biopsy has become standard, being both diagnostic
solitary tumors with normal AFP- and beta-HCG- and therapeutic. Thymic carcinomas, thymomas,
levels most often correspond to thymic tumors germ cell tumors and lymphomas in their advanced
or mature teratomas if located in the anterior stages may have similar radiographic appearance
mediastinum. Cystic lesions are typically well- but different treatment algorithms. Therefore, clear
demarcated. Tumors in the posterior mediastinum histologic diagnosis is required.
especially when located in the paravertebral Keywords: mediastinum, tumor, radiologic
region qualify for direct surgical exploration. 4) appearance, role of surgery
Since seminomas are sensitive to chemo- and
radiotherapy, they should be veriÀed by biopsy
when beta-HCG-levels are elevated. In patients with Session MTE36: ALK Diagnostics
non-seminomatous germ cell tumors, identiÀed by
elevated AFP- and beta-HCG-levels, chemotherapy Thursday, 7 July 2011
may be initiated without prior conÀrmation.
Residual tumor should undergo complete surgical
removal. As far as an intraspinal extension of a ALK Diagnostics Thursday, 7 July 2011 07:00-08:00
tumor in the paraspinal compartment can be safely
excluded, it may be assumed that the tumor can be MTE36.1 ALK DIAGNOSTICS
completely removed by a transpleural approach, Jin-Haeng Chung1, Marileila Varella-Garcia2
1
otherwise a combined neurosurgical/thoracic surgical Pathology, Seoul National University Bundang
procedure is necessary. 5) Since primary mediastinal Hospital/Korea, 2University Of Colorado Cancer
lymphomas like Hodgkin disease and B-cell- Center, University Of Colorado School Of Medicine/
lymphoma are Àrst of all „non-surgical“ diseases, a United States Of America
tissue diagnosis is mandatory whenever the CT scan
shows a lesion that extends symmetrically to the Abstract: Transforming rearrangements of the
hilar regions and/or indicates involvement of other anaplastic lymphoma kinase (ALK) gene have been
vital structures. An important differential diagnosis recognized in a subset of human hematological
is a malignant thymoma/thymic carcinoma of higher and solid malignancies (1). In 2007, an ALK gene
rearrangement creating an in-frame fusion protein evaluation of ALK expression in anaplastic large
between echinoderm microtubule-associated protein- cell lymphoma and inÁammatory myoÀbroblastic
like 4 (EML4) and ALK was described in NSCLC tumors, was found to be unreliable in NSCLC (17).
(2). The novel fusion gene arose from an inversion on Recently, the mouse monoclonal anti-human antibody
2p [inv(2)(p21p23)] that joined exons 1–13 of EML4 CD246 (clone 5A4; Novocastra) and the rabbit
to exons 20–29 of ALK. In consequence, the ALK monoclonal anti-human CD246 (clone D5F3; Cell
tyrosine kinase domain is constitutively activated as Signaling Technology) have been shown to detect
well as the downstream signaling pathways of MAPK, ALK fusion protein in lung adenocarcinomas with
PI3K/AKT, and STAT3 (2-4). Since then, numerous very high sensitivity and speciÀcity (16, 17). As ALK
transforming in-frame fusion variants involving immunoreactivity shows heterogeneous staining
different breakpoints in EML4 and ALK and other pattern, the scoring system including the intensity
fusion partners, including TFG, KIF5B, and PPFIBP1 and frequency of staining to assign semiquantitative
have been described in NSCLC (2-10). scores (0 to 3+) improves the positive predictive value
Detection of ALK gene fusions is currently indicated of ALK FISH results (16). Additionally, complex
as a predictive marker of treatment response to small strategies to improve the accuracy of ALK protein
molecule inhibitors of ALK in NSCLC. A recent detection in lung cancer including ampliÀcation of the
Phase I study evaluating the role of Crizotinib, a signal with a tyramide cascade (13) or intercalation of
potent dual inhibitor of ALK and MET, in NSCLC an antibody-enhanced polymer (8) also seems to be
found complete or partial response in the majority advantageous.
of ALK-rearranged tumors (11). International Detection of ALK rearrangement by FISH using
randomized Phase II and III studies comparing the commercially available break apart ALK probe
efÀcacy of Crizotinib therapy to standard second- (Abbott Molecular) has been the method of choice
line chemotherapy in ALK FISH positive advanced for patient selection in current clinical trials. Scoring
NSCLC patients are underway. The overall incidence of a minimum of 50 tumor cells is recommended
of ALK gene rearrangements in NSCLC is low and a specimen is considered positive for ALK
(<5%) (12); however, is signiÀcantly higher in rearrangement when >15% of the cells show split
adenocarcinomas with further notable predilection for signals or single red (3’ ALK) signals (13, 16, 18,
acinar and solid histologic subtypes with signet-ring 19). However, because the EML4 and ALK loci are
features (12-14). Higher rates of ALK rearrangement mapped relatively close on 2p, the interpretation of
are encountered in never/light smokers while a positive rearrangement through the introduction of
discordant Àndings are reported in relation to age, a gap between the red and green probes in formalin-
gender, and stage (15, 16). Àxed, parafÀn-embedded tissue sections can be
In this period of personalized health care, the ability challenging. This distance is estimated using the
to accurately identify patients as truly positive or signal size as a reference, therefore analyses must
negative for ALK rearrangement is essential for be performed by experienced laboratory personnel.
appropriate therapy selection and outcome assessment. Moreover, it is recommended that a 2-person scoring
For that purpose, the pathologist’s role is becoming approach be adopted when the percentage of positive
more crucial than ever. Since the clinical and cells is close to the cut-off due to the subtle nature of
demographic features of the ALK-enriched patients some positive cases. Customized FISH strategies have
group is overlapped with EGFR-mutated NSCLC, also been proposed to overcome this limitation (18-
the establishment of strategies for identiÀcation of 20) but no approach has reached clinical validation.
ALK-rearranged lung cancer has been of great clinical In this session, Dr. Chung will present results
interest and become a critical issue. Studies so far indicating that ALK IHC scoring is a robust measure
have indicated a need to improve stratiÀcation of of the protein overexpression to predict ALK
these patients to guide the most appropriate speciÀc rearrangement and might be useful in selecting
therapies in small biopsy samples and other routine lung cancers for speciÀc targeted therapy. The ALK
anatomic pathology pulmonary specimens such as IHC scoring can be especially helpful in assessing
cytology cell blocks and touch preparations. diagnosis in a range of settings, for instance, in
Detection of ALK overexpression by patients with adenocarcinoma histology and never-
immunohistochemistry (IHC) has been largely smokers to minimize tissue loss by repeated genetic
explored. Early on, the mouse monoclonal anti-human analysis in the small biopsy samples. Dr. Varella-
CD246 (clone ALK1; Dako) antibody, utilized for Garcia will discuss technical details, explore the
advantages and examine strategies to overcome challenging, for it entails many aspects, related to
limitations of the FISH platform. both patients’ and physicians’ perceptions, mentality
References: 1. Palmer RH, et al. Biochem J 420:345- and expectations.
61, 2009. Estimation of cardiac risk
2. Soda M et al. Nature 448:561-6, 2007. Risk assessment for pulmonary resection must
3. McDermott U et al. Cancer Res 68:3389-95, 2008. include a preliminary cardiac evaluation. Patients
4. Koivunen JP et al. Clin Cancer Res 14:4275-83, deemed at prohibitive cardiac risk should be
2008. evaluated and treated as per American Heart
5. Choi YL et al. Cancer Res 68:4971-6, 2008. Association/American Society of Cardiology
6. Rikova K et al. Cell 131(6):1190-203, 2007. guidelines. Those with low cardiac risk or with
7. Takeuchi et al. Clin Cancer Res 14:6618-24, 2008. optimized treatment can proceed with pulmonary
8. Takeuchi et al. Clin Cancer Res 15:3143-9, 2009. assessment.
9. Horn L, Pao W. J Clin Oncol 27:4232-4235, 2009. For patients whose exercise capacity is limited,
10. Takeuchi K et al. Clin Cancer Res epub ahead those with a RCRI 2 or those with known or newly
print doi:10.1158/1078- suspected cardiac condition, non-invasive cardiac
0432.CCR-11-0063, 2011 evaluation is designed to identify the relatively
11. Kwak EL et al. N Engl J Med 363:1693-1703, small proportion of patients needing intensiÀed
2010 interventions to control heart failure or arrhythmias
12. Solomon B et al. J Thor Oncol 4:1450-1454, or to treat underlying myocardial ischemia.
2009. Appropriately aggressive cardiac interventions
13. Rodig SJ et al. Clin Cancer Res 15:5216-23, should be instituted prior to surgery in patients who
2009. would need them irrespective of the planned surgery.
14. Takahashi T et al. Ann Surg Oncol 17:889-97, However, prophylactic coronary revascularization
2010. prior to surgery in patients who otherwise do not
15. Lin E et al. Mol Cancer Res 7:1466-76, 2009. need such a procedure does not appear to reduce
16. Paik et al. J Thor Oncol 6:466-472, 2011 perioperative risk.
17. Mino-Kenudson M et al Clin Cancer Res Systematic measurement of DLCO
16:1561-71, 2010. Carbon monoxide lung diffusion capacity (DLCO)
18. Shaw AT et al. J Clin Oncol 27:4247-53, 2009. has Àrstly been shown to be a predictor of adverse
19. Varella-Garcia M et al. J Clin Oncol 28:18s, 2010 outcomes after pulmonary resection in the 1980s’.
(suppl; abstr 10533) Predicted postoperative DLCO (ppoDLCO),
20. Perner S et al. Neoplasia 10:298 –302, 2008. calculated in the same manner as ppoFEV1, has
Keywords: IHC, FISH, ALK, gene fusion been shown to be a reliable predictor of pulmonary
complications and mortality by several investigators.
However, until now, DLCO measurement has been
Session MTE37: Pulmonary Risk mainly reserved to patients with abnormal FEV1
Assessment for Curative Therapy based on the wrong assumption that FEV1 and
DLCO are correlated parameters. Indeed, recent
papers have shown that the correlation coefÀcients
Sunday, 3 July 2011
between FEV1 and DLCO in different subsets of
lung resection candidates are invariably below 0.5,
Pulmonary Risk Assessment for Curative Therapy Sunday, 3 July 2011 indicating poor correlation and that Indeed a more
16:28-16:28 than 40% of patients with normal FEV1 (>80%) may
have DLCO < 80%. More studies have demonstrated
MTE37.1 PULMONARY RISK that a reduced ppoDLCO is a reliable predictor of
ASSESSMENT FOR CURATIVE cardiopulmonary morbidity and mortality not only
THERAPY in patients with reduced FEV1 but also in those
Alessandro Brunelli with normal respiratory function. Hence there is no
Thoracic Surgery, Ospedali Riuniti Ancona/Italy justiÀcation to reserve this test to selective group of
patients with compromised FEV1. This parameter
Abstract: Introduction Determining the risk for should be measured in all lung resection candidates.
pulmonary resection in patients with lung cancer is The role ppoFEV1
Predicted postoperative FEV1 (ppoFEV1), estimated continuous monitoring of various cardiologic

by taking into account the number of unobstructed and pulmonary parameters, it is standardized and
segments to be removed during operation, has easily reproducible in different settings, and in
represented the pivotal parameter in preoperative addition to VO2peak, which certainly remains the
evaluation. most important parameter associated with exercise
Most recent evidences however have shown its capacity, it provides several other direct and derived
limited role in patients with pulmonary obstructive measures that permit, in case of a limited aerobic
disease and airÁow limitation both in terms of reserve, to precisely identify possible deÀcits in
prediction of surgical risk and in the estimation the oxygen transport system. The use of CPET
of deÀnitive residual pulmonary function. In this appears therefore of particular importance in those
regard, several studies have shown the minimal loss patients deemed at high surgical risk. Indeed the
or even the improvement of FEV1 after pulmonary recently published ERS-ESTS functional guidelines
lobectomy in the obstructed patients, questioning recommended its use in patients with cardiac
the traditional operability criteria mostly based on co-morbidity or impaired pulmonary function or
pulmonary expiratory measures. Nearly one third of both, and in those patients with a reduced exercise
COPD patients may actually improve their FEV1 3 tolerance at low-technology exercise tests (such
months after pulmonary lobectomy for cancer. as stair climbing test or shuttle walk test). It is
Owing to the scarce ability to predict the surgical generally accepted that a VO2peak above 20 ml/
risk in these patients ppoFEV1 should not be used kg/min or greater than 75% of predicted represents
alone for patients selection. a safe threshold to undergo any kind of pulmonary
Exercise tests: the global physical assessment resection. On the other hand, a value below 10 ml/
Exercise testing is increasingly used in the kg/min or lower than 35% of predicted usually
preoperative evaluation of lung resection candidates, contraindicates a major pulmonary resection.
since it allows global assessment of the physical Selected reference
Àtness. 1. Brunelli A, Charloux A, Bolliger CT, Rocco
Low-technology tests such as stair climbing test and G, Sculier JP, Varela G, Licker M, Ferguson MK,
shuttle walk test can provide only a rough estimation Faivre-Finn C, Huber RM, Clini EM, Win T, De
of the aerobic capacity of the patients without Ruysscher D, Goldman L, on behalf of the European
providing much information on the causes that are Respiratory Society and European Society of
behind the performance. Thoracic Surgeons joint task force on Àtness for
They are typically ideal as screening tests, but for radical therapy. ERS/ESTS clinical guidelines on
their inherent limited monitoring cannot be used Àtness for radical therapy in lung cancer patients
alone to exclude patients from operation. (surgery and chemo-radiotherapy). Eur Respir J
Shuttle walk test: regression analysis showed in one 2009; 34:17-41.
study that 25 shuttles on the shuttle walk test indicate Keywords: Pulmonary function, Exercise test,
a VO2peak of 10mL/kg/min and for this reason this Preoperative evaluation, Surgical risk
cut off has been largely used to select patients for
operation. However, recent evidences have shown
that this test tends to underestimate the exercise
capacity at the lower range of VO2max questioning
its role in patients’ selection for operation.
Stair climb: Several studies have shown the ability
of stair climbing test to predict surgical risk in
candidates for lung resection. A recent large study
conÀrmed in 640 patients submitted to major lung
resection that those climbing less than 12 m had a
2-fold and 13-fold higher rates of complications and
mortality compared to those climbing higher than 22
m (less than 1% mortality rate).
Cardiopulmonary exercise test: Compared to low-
technology test CPET has several advantages. It
is performed in a controlled environment with
GRAND ROUNDS SESSIONS COPD is the most common comorbidity (50-60% of

patients with lung cancer) and is associated with an
increased risk of developing lung cancer (RR 2.3-
Session GR01: Boundaries of 4.0). These factors limit the amount of additional
Bronchoscopy: Central Hilar Lesions parenchyma that can be surgically resected or
exposed to radiation. When determining the strategy
for a patient with a subsequent primary tumor, the
Monday, 4 July 2011
clinician also has to anticipate additional subsequent
primary lesions in the future. Detection and
Boundaries of Bronchoscopy: Central Hilar Lesions Monday, 4 July staging The classic screening method for centrally
2011 10:30-12:00 located early lung cancer is sputum cytology. This
method however, is limited by low sensitivity
GR01.1 A SUBSEQUENT PRIMARY IN due to sampling error, technical difÀculties in the
A COPD PATIENT WITH PREVIOUS preparation of samples and signiÀcant variations
LOBECTOMY FOR EARLY STAGE LUNG in intra- and interobserver agreement. White light
CANCER Áexible bronchoscopy (WLB) has enabled visual
Johannes M.A. Daniels, Thomas G. Sutedja inspection of the central airways, but its sensitivity
Pulmonary Diseases, VU University Medical Center/ for detecting early lung cancer remains low.
Netherlands AutoÁuorescence bronchoscopy (AFB) utilizes the
spectral differences in Áuorescence and absorption
Abstract: Non-small cell lung cancer (NSCLC) is properties of normal and (pre-)malignant epithelium.
the most common cause of cancer deaths worldwide. AFB performs better than WLB with a sensitivity of
The reason for the unsatisfactory overall 5-year 44-82%. The drawback of the increased sensitivity
survival rate of approximately 15% mainly lies in of AFB is a reduced speciÀcity of 46-75%. Other
the often advanced stage of the disease at the time of techniques for the detection of central lesions include
diagnosis and the inability to cure metastatic disease. high magniÀcation videobronchoscopy, narrow
Even for early stage lung cancer (stage I & II), band imaging and optical coherence tomoghraphy.
which is usually treated with curative intent, 5-year Staging of central airway lesions can be performed
survival is only about 50-60%. This is caused by with multidetector CT scan (preferably 1mm
both subsequent lung cancer primaries and metastatic slice thickness) and FDG-PET scan. Although
disease. In contrast, the prognosis of early central FDG-PET scan has not been studied extensively,
squamous lung cancer in-situ (stage 0) is excellent at preliminary data show that FDG uptake in a central
90%. The World Health Organization has classiÀed lesion indicates squamous cell carcinoma of
(pre-)malignant squamous lesions in nine categories, considerable size which probably precludes curative
raging from normal to invasive cancer.[1] Both the bronchoscopic treatment. Information about airway
invasive potential of these lesions and the need for wall invasion and lymph node involvement can be
curative treatment are controversial. The natural obtained by EBUS. Treatment Up to 30% of the
history of premalignant lesions is difÀcult to study patients with early proximal lung cancer require
because these lesions are often asymptomatic and bilobectomy or pneumonectomy, and the remaining
discovered by chance. In addition, most centers treat 70% require lobectomy.[5] Frequent comorbidities in
the lesions at the time of detection rather than await these patients such as COPD often limit the amount
the development of invasion. Reported progression of lung parenchyma that can be resected. Surgery
rates of carcinoma in-situ (CIS) to invasive is therefore not necessarily the only and primary
cancer vary from 20-67% despite bronchoscopic choice. As a result there is signiÀcant interest in the
therapy in some instances.[2-5] This underscores use of various bronchoscopic modalities to treat early
the need for effective detection and treatment central lung cancers. Commonly used bronchoscopic
strategies, especially in patients with a reasonable treatment techniques include electrocautery, argon
life expectancy. Subsequent primary central lung plasma coagulation, cryotherapy, Nd:YAG laser,
cancer is challenging for clinicians because these photodynamic therapy and intraluminal irradiation
patients already underwent parenchymal resection therapy or brachytherapy. When bronchoscopic
or radiotherapy for their Àrst cancer. In addition, treatment fails or if the lesion is locally too
comorbidities are common in this population. advanced, surgery can still be performed if the
patient is operable.[6,7] Up to date no trials have surgical resection for T1N0 lung cancer patients.
compared surgical and bronchoscopic techniques for Respiration 2004;71:391-396.
early squamous lung cancer. The reported outcomes Keywords: Minimal invasive, COPD, Lung cancer,
of bronchoscopic treatment are comparable to bronchoscopy
surgical treatment. The cost of treatment and follow-
up of bronchoscopically treated small stage IA
cancers in inoperable patients was 30% of the cost of Boundaries of Bronchoscopy: Central Hilar Lesions Monday, 4 July
standard surgery in matched operable patients in one 2011 10:30-12:00
published cost effectiveness analysis, and obviously
surgical procedures are associated with greater GR01.2 DIAGNOSIS AND TREATMENT
morbidity.[8] Treatment success with bronchoscopic OUTCOMES OF EARLY CENTRAL
techniques strongly depends on accurate staging. LUNG CANCER -INCLUDING A CASE OF
Selected lesions should be limited to mostly Áat type SYNCHRONOUS DOUBLE SQUAMOUS
squamous cell CIS and microinvasive cancer. It is PRIMARIES-
also obvious that lesions with nodal involvement Hidetoshi Honda, Jitsuo Usuda, Norihiko Ikeda
cannot be regarded as early stage proximal lung Surgery, Tokyo Medical University/Japan
cancer. If a patient is not eligible for surgical
resection or bronchoscopic treatment, radiotherapy Abstract: Sputum cytology is the only examination
can be an alternative. During this session we will that can detect early central lung cancer. However,
present a COPD patient with a subsequent primary even when atypical cells are seen in sputum, it
proximal lesion. With audience and the experts can be difÀcult to localize the lesions. So, it is a
important issues regarding the detection, work-up challenge for even experienced bronchoscopist.
and treatment of such lesions will be discussed. The Ànding rate of carcinoma in situ (CIS) is in
References 1.WHO. Histological typing of lung patients with abnormal sputum cytology Àndings
and pleural tumors. 3rd ed. Berlin: Springer-Verlag; was only 29%. One reason for this is that white light
1999. 2.Venmans B, van Boxem T, Smit E, Postmus bronchoscopy (WLB) cannot detect early lesions
P, Sutedja T. Outcome of bronchial carcinoma due to a lack of abnormal Àndings. To resolve this
in situ. Chest 2000;117:1572-1576. 3.Deygas N, problem, autoÁuorescence bronchoscopy (AFB) was
Froudarakis M, Ozenne G, Vergnon JM. Cryotherapy developed in the early 1990s. AFB has been reported
in early superÀcial bronchogenic carcinoma. Chest to be useful in diagnosing early central lung cancer
2001;120:26-31. 4.Bota S, Auliac J, Paris C, Metayer and dysplasia. But, based on the Japanese guideline,
J, Sesboue R, Nouvet G, Thiberville L. Follow-up the following can be said about AFB; Many reports
of bronchial precancerous lesions and carcinoma have claimed it to be useful for diagnosis of early
in situ using Áuorescence endoscopy. Am J Respir stage bronchial lesions. There is no deÀnitive
Crit Care Med, 2001;164:1688-1693. 5.Nakamura conclusion regarding its superiority for diagnosis of
H, Kawasaki N, Hagiwara M, Ogata A, Saito M, early central lung cancer. It is not currently covered
Konaka C, Kato H. Early hilar lung cancer-risk for by the Japanese insurance system, and it falls within
multiple lung cancers and clinical outcome. Lung the category of exploratory medical therapy. This is
Cancer 2001;33:51-57. 6.Sutedja TG, Codrington a bit disappointing, but we have experienced many
H, Risse EK, Breuer RH, van Mourik JC, Golding cases of patients in which this technique proved to
RP, Postmus PE. AutoÁuorescence bronchoscopy be extremely useful. We found many synchronous
improves staging of radiographically occult lung and metachronus multiple primary lung cancer
cancer and has an impact on therapeutic strategy. lesions using AFB. Also our department assesses
Chest 2001;120:1327-1332. 7.Vonk-Noordegraaf tumor depth by Optical coherence tomography
A, Postmus PE, Sutedja TG. Bronchoscopic (OCT) as a reference when determining indications
treatment of patients with intraluminal microinvasive for PDT. OCT is a non-invasive imaging technique
radiographically occult lung cancer not eligible in which images of living tissue are taken using
for surgical resection: a follow-up study. Lung light instead of ultrasound. OCT can obtain high-
Cancer 2003;39:49-53. 8.Pasic A, Brokx HA, Vonk resolution, cross-sectional microscopic images of
Noordegraaf A, Paul RM, Postmus PE, Sutedja TG. tissue, potentially enabling optical biopsy in place
Cost-effectiveness of early intervention: comparison of conventional excisional biopsy. Diagnosis of
between intraluminal bronchoscopic treatment and early central lung cancer enables highly invasive
surgery to be avoided and successful treatment to for diagnosis in the bronchial surface, it should be
be achieved by PDT. We report herein the diagnosis used in conjunction with techniques such as OCT
and treatment outcomes of early central lung cancer, for diagnosis of invasion depth. Combined use of
and cases of multiple primary lung cancer cases AFB, OCT and PDD can lead to more accurate
including early central lung cancer at our institution. diagnosis and treatment of early central lung cancer.
Patient Selection and Methods In our institute, this The primary treatment option for early central lung
examination is mainly performed for lung cancer cancer is surgical resection. However, due to the
patients before treatment as well as high risk cohort; incidence of synchronous lung cancer and decreased
patients with abnormal sputum cytology Àndings basic respiratory function in many patients, PDT
and post-operative follow up patients. Between July is gaining recognition as it enables preservation of
2004 and July 2008 at Tokyo Medical University respiratory function. It is thus recommended by the
Hospital, we investigated 440 cases using AFB and U.S. National Cancer Institute. At our institution, the
performed biopsy on all regions even in the case complete response rate to PDT is 94% and outcomes
of abnormality. OCT was additionally performed are favorable.
in patients in whom lung cancer was suspected Keywords: Early central lung cancer,
following AFB. For patients diagnosed with early synchronous lung cancer, photodynamic therapy,
central lung cancer on both techniques, PDD using AutoÁuorescence bronchoscopy
AFB was performed, the superÀcial invasion range
of the focus was more clearly determined, and PDT
was applied. Results 550 sites were recognized to Session GR02: Difficult Surgery
be abnormal by AFB. These lesions were biopsied
and histologically evaluated. There was no statistical Tuesday, 5 July 2011
difference between WLB and AFB in detecting
cancerous lesions, however, the extent of invasion
was objectively evaluated by AFB. 50% of dysplasia Difficult Surgery Tuesday, 5 July 2011 10:30-12:00
were diagnosed by both WLB and AFB while 41% of
such lesions were detected only by AFB, which were GR02.1 LOCAL RECURRENCE AFTER
invisible by WLB. AFB showed statistically better DEFINITIVE CHEMORADIATION: IS
performance to diagnose dysplasia than WLB alone. SALVAGE SURGERY INDICATED?
So, it is useful for determining the extent of the Jack A. Roth, Jenifer Marks
irradiation target for PDT. Reduced autoÁuorescence Thoracic & Cardiovascular Surgery, The University
was observed in 91 regions of 75 patients diagnosed Of Texas M.D. Anderson Cancer Center/United
with lung cancer. Through combined use of OCT, States Of America
69 regions of 64 of these patients were diagnosed as
early central lung cancer. PDD was positive in 68 Abstract: About 30% of non-small cell lung cancer
regions. The complete response rate for PDT was (NSCLC) patients initially present with locally and
94% (tumor size 1.0 cm). And multiple lung cancer regionally advanced cancer (IIIA or IIIB)(1,2). Several
cases were noted 22 patients (34.4%, 22 of 64), treatment strategies are commonly used for this
10 had synchronous multiple lung cancer lesions group of patients including induction chemotherapy
whereas 12 had metachronous multiple lung cancer followed by surgery and postoperative radiation
lesions. All subjects were male heavy smokers. therapy, induction chemoradiation followed by
Among the 22 patients, 10 patients received PDT surgery, and deÀnitive radiation therapy with
for the second and third cancers after undergoing concurrent chemotherapy(chemoradiation). Isolated
radical surgery for peripheral lung cancer, 1 patient local and regional recurrences occur in about 25%
received radical surgery for the second cancer of patients who receive deÀnitive chemoradiation(3).
that appeared in the peripheral lung Àeld after When this occurs the question of surgical resection
PDT, and 11 patients received PDT for all lesions for residual or recurrent disease is frequently raised.
after onset of multiple early central lung cancer. Chemoradiation given prior to surgery is most often
All patients who received PDT for multiple lung used as an induction therapy. The dose is usually
cancer lesions achieved CR, and are still alive. 50Gy or less and surgery is planned six to eight
Conclusion AFB is useful for localization of early weeks after the completion of chemoradiation. In
central lung cancer; however, as it is only indicated contast, patients undergoing salvage surgery for local
recurrences following deÀnitive chemoradiation have by salvage surgical resection from January of
received 60Gy or more and the surgery takes place 8 2001 to July 2010. All patients received deÀnitive
or more weeks after the patient was initially treated. chemotherapy and radiotherapy, either sequential or
The higher dose of radiation and longer interval concurrent, at the discretion of the treating physician.
between radiation and surgery with possible increase The mean radiation dose was 64Gy (range 60-74Gy).
in Àbrosis could increase the risk of surgery. Thus it The mean time from completion of treatment to
would be useful to assess the operative risks and long salvage resection was 41.5 weeks (range 8 to 144
term survival for patients undergoing salvage lung weeks). Sixty three percent (10/16) of patients had
resection. However, most institutions have a very lobectomy, bilobectomy or sleeve lobectomy. The
limited experience with this group of patients. Most indication for resection was progression in 5 patients,
patients receiving deÀnitive chemoradiation were persistent disease in 9 patients, and recurrence of
treated because either the tumor was so extensive disease in 2 patients. Four of 16 (25%) patients had a
that complete resection was considered unlikely pneumonectomy, and two of 16 (12.5%) underwent
or the patient had co-morbidities such as poor sublobar resections. Eight intercostal muscle Áaps,
pulmonary or cardiac function that made the risk of 2 pericardial fat pad Áaps, and 1 pectoral Áap
surgery excessive. In these situations, if surgery was were used for stump coverage. Sixty three percent
not possible initially, it is generally not possible after of patients were downstaged pathologically post
chemoradiation. Thus very few series of salvage lung treatment, while only 1 patient (6%) was upstaged.
resections have been reported, and those that have Perioperative mortality was 12.5% at 30 days and
been reported are very small. The most extensive 18.8% at 90 days. Overall median survival was 14
experience with surgery following chemoradiation is months. Surgery following chemoradiation carries
the experience with induction chemoradiation in the a high operative morbidity and mortality. Survival
setting of tri-modality therapy. Although lower doses is limited. Thus patient selection is critical. Because
of radiation therapy are given and surgery occurs of the increased risk, conÀrmation of recurrent or
after a planned time interval, this is an instructive residual cancer is mandatory. Muscle Áap coverage
experience to review to assess surgical risks of the bronchial stump is a critical component of
following chemoradiation. Albain reported 14 of 16 the operation. Reference List 1. Chansky K, Sculier
patients died postoperatively after pneumonectomy JP, Crowley JJ, et al. The International Association
following chemoradiation to 45Gy(4). Thomas for the Study of Lung Cancer Staging Project:
reported operative mortality increased from 2.3% prognostic factors and pathologic TNM stage in
to 7.5% for lobectomy and 5.5% to 14% for surgically managed non-small cell lung cancer. J
pneumonectomy following induction chemoradiation Thorac Oncol 2009;4:792-801. 2. Rami-Porta R,
to 45Gy compared to induction chemotherapy Ball D, Crowley J, et al. The IASLC Lung Cancer
alone in a large randomized clinical trial(5). Sonett Staging Project: proposals for the revision of the
reported a group of forty patients treated with 59Gy T descriptors in the forthcoming (seventh) edition
induction chemoradiation. No operative mortality of the TNM classiÀcation for lung cancer. J Thorac
was seen, but signiÀcant complications occurred Oncol 2007;2:593-602. 3. Fournel P, Robinet G,
in seven patients(6). Bauman reported the largest Thomas P, et al. Randomized phase III trial of
series of patients having salvage lung resection(7). sequential chemoradiotherapy compared with
Over an eight year period, 24 patients who had concurrent chemoradiotherapy in locally advanced
received a median of 63.9 Gy (all >59Gy) had 14 non-small-cell lung cancer: Groupe Lyon-Saint-
lobectomies and 10 pneumonectomies with 83% of Etienne d’Oncologie Thoracique-Groupe Francais
the patients stage IIIA or IIIB at initial diagnosis. de Pneumo-Cancerologie NPC 95-01 Study. J
There was one operative death (pneumonectomy) Clin Oncol 2005;23:5910-5917. 4. Albain KS,
and 14 major complications. Median progression- Swann RS, Rusch VW, et al. Radiotherapy plus
free survival was 12 months. Four patients in the chemotherapy with or without surgical resection
series did not have residual cancer despite positive for stage III non-small-cell lung cancer: a phase III
PET scans. We performed a retrospective review randomised controlled trial. Lancet 2009;374:379-
of the University of Texas MD Anderson Thoracic 386. 5. Thomas M, Rube C, Hoffknecht P, et al.
and Cardiovascular Surgery prospective database Effect of preoperative chemoradiation in addition
to identify patients who received curative intent to preoperative chemotherapy: a randomised trial in
chemotherapy and radiotherapy (>59Gy) followed stage III non-small-cell lung cancer. Lancet Oncol
2008;9:636-648. 6. Sonett JR, Suntharalingam usually non-small cell lung cancers that typically
M, Edelman MJ, et al. Pulmonary resection after produce unrelenting pain in the arm and shoulder,
curative intent radiotherapy (>59 Gy) and concurrent weakness and atrophy of small muscles of the
chemotherapy in non-small-cell lung cancer. Ann hand, and Horner’s syndrome. They occur with an
Thorac Surg 2004;78:1200-1205. 7. Bauman JE, incidence of less than 5% of all lung cancers. CT is
Mulligan MS, Martins RG, et al. Salvage lung routinely indicated when an apical lesion is detected
resection after deÀnitive radiation (>59 Gy) for by chest radiography. The extent of invasion of the
non-small cell lung cancer: surgical and oncologic tumor into adjacent structures is better determined
outcomes. Ann Thorac Surg 2008;86:1632-1638. with MRI. PET, while not well studied in this
Keywords: Surgery, Radiation Therapy subset of patients, is generally performed as part
of the routine workup because it may be helpful in
the evaluation of mediastinal nodal involvement
Difficult Surgery Tuesday, 5 July 2011 10:30-12:00 and distant metastases. The precise nature of the
lesion, as elsewhere, cannot be determined without
GR02.3 CIRCULATORY pathologic diagnosis. Bronchoscopic biopsy is
COMPLICATIONS AFTER typically low yield due to the peripheral location
PNEUMONECTOMY of the tumor. On the other hand, CT or ultrasound
Anton Vonk Noordegraaf guided transthoracic needle biopsy is diagnostic in
Pulmonology, VU Medical Center/Netherlands up to 95% of cases. Sqamous cell carcinoma used
to be the most frequent pathology, which is now
Abstract: Pneumonectomy is associated with a switched to adenocarcinoma. Pancoast tumors are
major amputation of the pulmonary vascular bed, and the most challenging thoracic malignancies to treat
transmigration of the heart and large vessels to the because of their frequent direct invasion not only
side of pneumonectomy. Although pneumonectomy to the Àrst rib but also to adjacent vital structures
is rarely complicated with pulmonary hypertension, such as the brachial plexus, subclavian vessels, and
transmigration of the heart and large vessels might the spine. According to the report from Japanese
cause all sort of circulatotoiry impairments in the Association for Thoracic Surgery, only 139 cases
long run. Diagnosis of these complications can be (0.5%) were for Pancoast tumors among 27,387
difÀcult due to the altered position of the heart and cases surgically treated for primary lung cancer in
large vessels. This lecture aimed to provide insight 2008. Contraindications of surgery are the presence
in the nature of these complications by focussing of distant metastases and mediastinal lymph
on a sery of cases who experienced circulatory node involvement. A speciÀc problem represents
complications after pneumonectomy. Emphasis supraclavicular lymph nodes, which can be involved
will be laid on the diagnostic process and possible in these patients more frequently. There is a debate
treatments of those conditions. whether such supraclavicular lymph nodes should
Keywords: pneumonectomy, Surgery, right be classiÀed as N3 or still should be considered to
ventricle, pulmonary veins be local node areas in view of the special location of
the tumor. Invasion to the brachial plexus above T1
indicate inoperable. However, involvement of the
Difficult Surgery Tuesday, 5 July 2011 10:30-12:00 subclavian vessels is not contraindication because
complete resection with vascular reconstruction
GR02.4 PANCOAST TUMORS may be performed. Pancoast tumors with vertebral
Hiroshi Date invasion were long considered a contraindication
Dept. Thoracic Surgery, Kyoto University/Japan to surgical resection. However, several reports
suggest that en bloc resection of these tumors
Abstract: Pancoast tumors or superior sulcus with vertebrectomy is technically possible with
tumors are neoplasms of pulmonary origin that encouraging long-term survival. The choice of
are located in the most apical recess of pulmonary surgical approach is very important for en bloc
sulcus and that arise from the lung apex. Dr. Henry resection of Pancoast tumors. Basically, there are
Pancoast reported the clinical and radiographic two approaches, anterior approach and posterior
features of lung tumors in the superior sulcus, approach. The posterior approach was developed by
which were named after him. Pancoast tumors are Paulson and his colleagues and is now often called
Paulson’s approach. After placing the patient in the Session GR03: Mesothelioma -
lateral decubitus position, an incision extending around Oncological and Supportive
the tip of the scapula up to the level of C7 provides Management
excellent exposure of the posterior chest wall including
the transverse processes, the vertebrae and the roots of
the thoracic nerves. However, this approach does not Wednesday, 6 July 2011
allow a direct and safe visualization of all anatomical
structures composing the thoracic inlet. As a result, Mesothelioma - Oncological and Supportive Management
resection of the subclavian vessels is difÀcult with this Wednesday, 6 July 2011 10:30-12:00
approach. Dartevelle and his colleagues developed an
anterior transcervial approach. The patient is placed GR03.1 MESOTHELIOMA - DILEMMAS
in the spine position and the L-shaped incision runs IN ONCOLOGICAL MANAGEMENT
along the anterior border of the sternocleidomastoid Jan P. Van Meerbeeck
muscle and continues laterally at the level of the second Respiratory Medicine, Ghent University Hospital/
intercostals space. The excision of the median portion Belgium
of the clavicle provides excellent exposure of the entire
thoracic inlet, which allows for a safe resection and Abstract: Recent progress has reshaped the
reconstruction of subclavian vessels. Grunenwald and clinical landscape in the treatment of MPM. We
his colleagues modiÀed the Dartevelle approach from have now more effective chemotherapy and from
transclavicular to transmanubrial, through a manubrial current evidence, it is clear that histone deacetylase
L-shaped transaction and Àrst costal cartilage resection, inhibitors represent a potentially new treatment
which allows sparing the clavicle and its muscular modality in MPM. Among current investigational
insertions. Shoulder articulations and stability of the drugs, mesothelin targeted therapies, dendritic cell
scapular girdle are respected, thus avoiding functional based immunotherapy and gene therapy hold promise
and cosmetic consequences of clavicle resection. The and should be further explored. Despite these,
surgical treatment of Pancoast tumors continues to actual treatment is still amenable to improvement.
evolve but typically involves multimodality therapy. Several factors have hampered the development
The changing paradigms in the treatment of non-small of more effective regimens for mesothelioma.
cell lung cancer since the late 1990s resulted in the MPM is uncommon, is heterogeneous, staging
introduction of induction chemoradiotherapy followed is unreliable, response assessement is difÀcult
by surgical resection in the treatment plan of Pancoast and most drugs do not work. For the staging, the
tumors. Recently two similar studies were reported International Mesothelioma Interest Group are
on a multi-institutional phase II trial of a trimodality actually collaborating with the IASLC to include
approach, one from USA and the other from Japan. malignant pleural mesothelioma in its proposals
Southwest Oncology Group tested an induction for the 8th edition of TNM classiÀcation. The
regimen of concurrent chemoradiotherapy (cisplatin, ability to measure reproducibly tumour response
etoposide and 45 Gy radiation) followed by surgery for to treatment is vital in the development of new
110 patients with Pancoast tumors. The authors reported drugs and therapeutic combinations, particularly for
that completeness of resection was 76% and treatment the conducting of phase II studies. Conventional
related death occurred in 1.8%. Five-year survival was response criteria have always been difÀcult to apply
44% for all patients and 54% after complete resection. to malignant mesothelioma due to its unique pattern
Japan Clinical Oncology Group used mitomycin, of growth. Because the selection of measurement
vindesine, cisplatin and 45 Gy concurrent radiation sites in mesothelioma is difÀcult, RECIST criteria
as induction regimens for 76 patients. Complete could be applied differently by different investigators
resection was achieved in 68% and treatment related and that’s why the ModiÀed RECIST criteria have
death occurred in 3.5%. Fiver-year survival was 56%. been developed. Based on the complex growth
Induction chemoradiotherapy followed by surgical pattern of MPM, response evaluation in this cancer
resection has become the standard treatment for patients entity is still challenging. Results on value of
with Pancoast type non-small cell lung cancer. Áuoro-2-deoxy-D-glucose and positron emission
Keywords: Superior sulcus tumor, induction tomography imaging ((SUVmean, tumor lesion
chemoradiotherapy, Pancoast tumor glycolysis (TLG) and tumor volume (PETvol)) in
response assessment in MPM are promising. Where
do we go from here with the systemic therapy for consider the need for enhanced coordination and
MPM? We need better drugs, probably by more collaboration. The currently paucity of treatment
accurate preclinical investigation and we have options with good clinical outcome for MPM
to use better the drugs we have: in maintenance means also that signiÀcant research remains to
therapy, in special populations, in multimodality discover biomarkers for the early detection of MPM.
setting. More selectivity regarding the “promising” Suggestions to develop a central mesothelioma
drug we choose to move from the bence to the virtual tissue bank may also contribute to the
clinic and fewer “me too” trials are warranted. ultimate goal to identify druggable targets and
Better designed trials that are adequately powered, to develop personalized treatment for the MPM
multicenter, preferable with randomized phase II patients.
design to balance for heterogeneity, with appropriate Keywords: mesothelioma, therapy
endpoints (PFS, OS, QoL) and with correlative
studies built in, are mandatory. Methods to assay
individual tumor characteristics are warranted in Mesothelioma - Oncological and Supportive Management
order to avoid toxicity in patients who may not Wednesday, 6 July 2011 10:30-12:00
respond to treatment and losing precious time in
a disease associated with a short survival. Drug GR03.3 MESOTHELIOMA - DILEMMAS
resistance proÀles have been reported to various IN ONCOLOGICAL MANAGEMENT
malignant diseases including NSCLC, SCLC, breast, Paul Baas1, J A. Burgers1, Jan P. Van Meerbeeck2
1
ovarian, colon, esophageal and carcinoid tumours. Thoracic Oncology, The Netherlands Cancer
Recently the feasibility of performing off-site in vitro Institute/Netherlands, 2Pulmonology, University
drug resistance assays on resected mesothelioma Hospital Ghent/Belgium
specimens is reported. For clinical implementation,
a chemoresistance test applicable to pemetrexed Abstract: In this Grand Round we will discus the
should be useful. The effectiveness of assay-directed dilemmas that are usually encountered when patients
therapy is promising and need to be addressed in with a diagnosis of malignant pleural mesothelioma
prospective trials. Multiple biologicals have been are referred for therapy. In this Grand Round we
studied or are still under investigation, however a lot aim to identify and discuss the pitfalls in this special
of them seems to fail. It is of great importance that group of patients. In the Àrst case we will discus the
the molecular biologic research should focus more indications for chemotherapy and will focus of the
on mesothelioma-speciÀc pathways and biomarkers, selection of the patient; which subtype of tumour can
instead of copying mechanisms and treatments that best be treated; what is the optimal chemotherapy
were successful in other tumour types. Looking schedule; is there an indication for th use of a
at the list of new VEGFR-inhibitors being tested targeted agent together with the chemotherapy; how
in MPM, one can question if it is a wise use of can we best evaluate the response to treatment and is
the limited patient resources to perform so many there a role for maintenance therapy. In the second
“me too” trials in this uncommon disease? One case we will discuss the possible indications for
can question whether trials with so-called targeted surgery: what are the surgical options; what can one
agents in an unselected population of mesothelioma achieve with it; which patient is the best candidate;
patients are appropriate. With the use of array how radical is the surgery from an oncological point
technology there will be certainly an implicit gain of view; should it be combined with other types of
in the identiÀcation of new potential prognostic treatment modalities and what kind of complications
or biomarkers or important pathways in the MPM can one expect.
pathogenesis, which can individually be worked up Keywords: mesothelioma, Chemotherapy, Surgery
for independent validation. The concern for many
researchers is the lack of concordance between
studies. Nevertheless, an potential successful
approach may be to collate all the available data to
a database to identify networks of MPM pathways
which might allow for the identiÀcation of novel
therapeutic approaches for the treatment of MPM.
Research funders and the research community should
Mesothelioma - Oncological and Supportive Management Session GR04: Intra-Operative Decision

Wednesday, 6 July 2011 10:30-12:00 Making
GR03.5 DESTRUCTIVE PAIN SURGERY

FOR INTRACTABLE CHEST PAIN IN
LUNG CANCER (MESOTHELIOMA)
Yucel Kanpolat Intra-Operative Decision Making Thursday, 7 July 2011 10:30-12:00
Professor Of Neurosurgery, President Of The Turkish
Academy Of Sciences/Turkey GR04.1 PLEURAL LAVAGE CYTOLOGY
Haruhiko Kondo, Tomohiro Maniwa, Mitsuhiro
Abstract: Chest pain is an important complication Isaka, Takehiro Okumura, Kazuo Nakagawa,
of lung cancer, especially mesothelioma. Nearly Yasuhisa Ohde
all of the patients with mesothelioma complain of Division Of Thoracic Surgery, Shizuoka Cancer
chest pain. There is no special efÀcient treatment Center/Japan
for mesothelioma, but there is an extremely
useful method for mesothelioma pain, known as Abstract: PLC is a cytological examination of
a destructive procedure and termed cordotomy. the aspirated saline which was instilled into and
Cordotomy is a special destructive method based on retrieved from the pleural cavity during surgery
lesioning of the anterolateral part of the upper spinal for lung cancer. PLC is done immediately after
cord (C1-C2). thoracotomy before resection (PLC-Pre) or after
resection (PLC-Post) or both. The results of PLC-
Methods Post, PLC-Pre, and both have been reported as
Computed tomography (CT)-guided cordotomy has early as 1984 by Eagan 1), in 1989 by Kondo 2), in
been performed in the Department of Neurosurgery, 1991 by Okumura 3), respectively. The signiÀcance
Ankara University, School of Medicine for 20 years of PLC The positive results for malignant cells
and in the private practice of the author. Over this in the PLC have been reported as an independent
period, CT-guided cordotomy was performed 248 poor prognostic factor 4)-8). PLC was deemed as
times in 224 patients. The majority, 211 cases, synonymous with minimal intrapleural dissemination
suffered from intractable pain related to malignancy. (IPD) or malignant pleural effusion (MPE), i.e. T4
In the malignancy group, pulmonary malignancies (in TNM6) or M1a (in TNM7) disease in several
(68 patients), Pancoast tumors (15 patients) and reports. However, as the cases accumulated, we have
mesotheliomas (26 patients) represented the majority experienced many patients with positive PLC results
of cases, at 48.9%. otherwise stage I who survived long time without
disease, which is unlikely for clinically obvious
Results IPD or MPE 6),9). As for the recurrence site in the
Following cordotomy, 92.5% of patients reported PLC positive cases, the intrapleural recurrences
initial pain relief, grade 1 and 2. In the cancer group, are relatively common but distant metastases occur
selective cordotomy was achieved in 83% of the more often4), 9). Recently International Pleural
patients. Lavage Cytology Collaborators 10) have reported the
results of meta-analysis from the individual data of
Conclusion the 8763 patients with PLC study in 11 institutes.
Cordotomy is an efÀcient reliable option in the There are 511 (5.8%) patients with positive PLC
management of pulmonary carcinoma, especially in results. As for the prognostic analysis, they reported
mesothelioma. that it may be appropriate to upstage patients
by 1 T category. In the IASLC staging manual,
PLC-Pre are recommended to be performed as a
simple technique of intra-operative staging and
future validation studies are expected 11). Issues
concerning PLC It is not determined which should
be regarded as more important, PLC-Pre or PLC-
Post. Although some authors report as PLC-Post is
more strong impact on the postoperative prognosis,
it might reÁect the contamination of cancer cells by consecutive resections. J Thorac Cardiovasc Surg
surgical manipulation in the disease with other poor 2003; 126: 1911-5. 6. Lim E, Ali A, Theodorou P,
prognostic factors, i.e. nodal metastasis, lymphatic Nicholson AG, Ladas G, Goldstraw P. Intraoperative
and vascular invasion and so on. And the method of pleural lavage cytology is an independent prognostic
PLC, for example the amount of poured saline, the indicator for staging non-small-cell lung cancer.
need of immunocytochemistry, etc., is not uniÀed. J Thorac Cardiovasc Surg 2004; 127: 1113-8. 7.
Accuracy of cytological examination is also an Vicidomini G, Santini M, Fiorello A, Parascandolo
issue. There may occur in false negative or false V, Calabro B, Pastore V. Intraoperative pleural
positive results even with a very low incidence. lavage: is it a valid prognostic factor in lung cancer?
How should we do during lung cancer surgery in Ann Thorac Surg. 2005; 79: 254-7. 8. Aokage K,
concerns of PLC? 1. If there is a moderate amount of Yoshida J, Ishii G, Enatsu S, Hishida T, Nishimura
pleural effusion, sample it and send for cytological M, Nishiwaki Y, Nagai K. The impact on survival
examination. Presence of cancer cells in pleural of positive intraoperative pleural lavage cytology
effusion corresponds to M1a. 2. PLC-Pre should in patients with non-small-cell lung cancer. J
be performed in all cases with no or little pleural Thorac Cardiovasc Surg 2010; 29: 1246-52. 9.
effusion at thoracotomy. 3. If PLC-Pre is reported as Satoh Y, Hoshi R, Ishikawa Y, Horai T, Okumura S,
positive for cancer cells, re-explore the pleural cavity Nakagawa K. Recurrence patterns in patients with
attentively and any suspicious pleural nodules should early stage non-small cell lung cancers undergoing
be sent for frozen section. Video-thoracoscopy is positive pleural lavage cytology. Ann Thorac Surg.
advisable for the exploration of pleural cavity before 2007; 83: 197-202 10. International Pleural Lavage
thoracotomy. 4. In surgical stage I or II cases, the Cytology Collaborators. Impact of positive pleural
indication for resection should not changed by the lavage cytology on survival in patients having
results of PLC-Pre, because there remains a chance lung resection for non-small-cell lung cancer: An
for cure by radical resections. 5. In surgical stage international individual patients data meta-analysis.
IIIA or IIIB, or N2, T3 or T4 cases, remind that PLC J Thorac Cardiovasc Surg. 2010; 139: 1441-6. 11)
positive correspond to upstaging by 1 T category and Staging Manual in thoracic Oncology. International
reconsider the curability and indication for resection. Association for the Study of Lung Cancer. Pp.85-86.
6. PLC-Post is suggested to be performed, because Goldstraw P, Ed. Editorial Rx Press, Orange Park,
it is one of the important prognostic factors with FL, USA 2009.
simple technique. 7. Prospective randomized study Keywords: Pleural lavage cytology, Surgery for lung
for adjuvant chemotherapy in the pathological stage cancer, Intraoperative staging
I or II with positive PLC is expected in near future.
References 1. Eagan RT, Bernatz PE, Payne WS,
Pairolero PC, Williams DE, Goellner JR, Piehler Intra-Operative Decision Making Thursday, 7 July 2011 10:30-12:00
JM. Pleural lavage after pulmonary resection for
bronchogenic carcinoma. J Thorac Cardiovasc GR04.2 UNSUSPECTED N2 NODE
Surg. 1984; 88: 1000-3. 2. Kondo H, Naruke T, Paul Van Schil
Tsuchiya R, Goya T, Suemasu K, Yamagishi K, Thoracic And Vascular Surgery, Antwerp University
et al. Pleural lavage cytology immediately after Hospital/Belgium
thoracotomy as a prognostic factor for patients
with lung cancer. Jpn J Cancer Res. 1989; 80: 233- Abstract: N2 disease consists of a very
7. 3. Okumura M, Ohshima S, Kotake Y, Morino heterogenous population ranging from intranodal
H, Kikui M, Yasumitsu T. Intraoperative pleural involvement of a single mediastinal lymph node
lavage cytology in lung cancer patients. Ann Thorac station to bulky N2 disease. In general, a distinction
Surg. 1991; 51: 599-604. 4. Kondo H, Asamura H, can be made between 4 subgroups [1]. Subset IIIA1
Suemasu K, Goya T, Tsuchiya R, Naruke T, et al. includes incidental nodal metastases found on Ànal
Prognostic signiÀcance of pleural lavage cytology pathologic examination of the resection specimen;
immediately after thoracotomy in patients with lung IIIA2 single station, nodal metastases recognized
cancer. J Thorac Cardiovasc Surg. 1993; 106: 1092- intraoperatively; IIIA3 single or multiple stations,
7. 5. Okada M, Sakamoto T, Nishio W, Uchino K, nodal metastases detected by prethoracotomy staging
Tsuboshima K, Tsubota N. Pleural lavage cytology and IIIA4 bulky or Àxed multistation N2 disease.
in non-small cell lung cancer: Lessons from 1000 Subsets IIIA1 and IIIA2 are often considered
together and called “unsuspected or surprise N2” factors are clinical N2 on chest CT, multilevel N2
[2]. In the 7th TNM classiÀcation of lung cancer the disease, T3 tumors or subcarinal zone involvement
concept of nodal zones was introduced grouping [2]. Relatively positive prognostic factors are a
several lymph node stations into 7 speciÀc zones complete R0 resection, T1 and T2 tumors, single-
[3]. What is the best intra-operative strategy when level N2 involvement and clinical stage N0,1.
a surgeon is confronted with surprise N2? The Ànal Factors that are probably less important include
aim of every surgical treatment for non-small cell histology, extent of resection, location of the
lung cancer (NSCLC) is complete resection, also tumor and the presence of involved N1 nodes.
after induction therapy. In this respect, speciÀc Tumors of the left upper lobe with involvement of
criteria have been established by a working group the aortopulmonary lymph nodes have a similar
of the International Association for the Study of prognosis as tumors in another location with single
Lung Cancer (IASLC) [4]. Complete resection nodal involvement. In every patient, rigorous
implies that the primary tumor is completely preoperative staging by imaging, minimally invasive
removed, no macroscopic tumor is left behind, or invasive techniques is necessary to decrease
microscopically the margins are free, a systematic the incidence of unsuspected N2 disease (Àg.1).
or lobe-speciÀc systematic nodal dissection has Patients that are carefully staged preoperatively have
been performed, and the highest mediastinal lymph a higher chance of obtaining a complete resection
node is negative. In which patients is surgical when surprise N2 is encountered. Resection can be
treatment generally indicated? In 1971 Paulson performed when the surgeon is quite conÀdent that
deÀned the term “surgical salvage”, consisting a complete resection will be obtained, especially
of % 5 year survival - % operative mortality of when favorable prognostic factors are present as
resection - % operative mortality of exploratory listed above. A general algorithm for N2 disease is
thoracotomy [5]. When this Àgure approaches provided in Àg. 1. Currently, a more personalized
zero or becomes negative, surgical therapy is treatment for N2 disease is advocated [8]. According
not indicated anymore. This concept is still valid to the American College of Chest Physicians
today. For precise N staging during thoracotomy a (ACCP) adjuvant platinum-based chemotherapy is
systematic nodal dissection as advocated by Graham indicated in patients with a good performance status
and Goldstraw should be performed [6]. With this who are found to have unsuspected N2 disease [1].
technique, dissection of mediastinal, hilar and lobar Sequential postoperative radiotherapy should also
lymph nodes proceeds in a systematic fashion. be considered but for deÀnite recommendations
Graham and Goldstraw reviewed their results in results of ongoing trials are awaited for (Lung
240 patients with clinical T1-3 N0-1 NSCLC [6]. Adjuvant Radiotherapy, Lung ART trial). The
Preoperative mediastinoscopy was performed when IASLC prospective database which was created
lymph nodes larger than 1.5 cm were present on in preparation of the 8th TNM classiÀcation will
computed tomography (CT) of the thorax. The rate hopefully determine whether the concept of nodal
of exploratory thoracotomy was only 3 %. In 20 zones remains valid and provide a more deÀnite
% of patients N2 disease was found. There was no answer on the prognosis of speciÀc N2 subsets.
subgroup with 0 % incidence of N2 involvement In conclusion, surprise N2 will probably never be
and skip metastases were found in 34 % of patients completely eliminated but with careful preoperative
with N2 disease. Peripheral tumors less than 2 cm staging, it is unlikely to Ànd unresectable N2
had a 24 % incidence of lymph node metastases. So, disease. On the condition that a complete resection
systematic nodal dissection is the gold standard for can be obtained, the surgeon may proceed with
accurate N staging during thoracotomy. Guidelines the surgical procedure. Adjuvant chemotherapy is
for intraoperative lymph node staging were further indicated followed by radiotherapy in patients with
deÀned by a working group of the European Society a good performance status References 1. Robinson,
of Thoracic Surgeons (ESTS) [7]. As a minimum L.A. Chest, 2007. 132(3 Suppl): p. 243S-265S.
criterion at least three hilar and three mediastinal 2. Detterbeck, F. J Thorac Oncol, 2008. 3(3): p.
lymph node stations should be removed; regarding 289-302. 3. Rusch, V.W. J Thorac Oncol, 2009.
the latter, the subcarinal lymph nodes should always 4(5): p. 568-77. 4. Rami-Porta, R. Lung Cancer,
be included. Can we identify any intraoperative 2005. 49(1): p. 25-33. 5. Paulson, D.L. J Thorac
factors that will deÀne prognosis when surprise Cardiovasc Surg, 1971. 62(4): p. 554-62. 6. Graham,
N2 is encountered? Relatively negative prognostic A.N. J Thorac Cardiovasc Surg, 1999. 117(2): p.
246-51. 7. Lardinois, D. Eur J Cardiothorac Surg, the pathology of these lesions by needle biopsy
2006. 30(5): p. 787-92. 8. Vansteenkiste, J. Expert due to low diagnostic yield. Although radiologic
Opin Pharmacother, 2010. 11(10): p. 1605-9. Àndings are important, some reports showed that
there were no signiÀcant differences between benign
and malignancy with respect to shape, margin, and
attenuation value. However, when GGO lesions were
larger than 10mm, the chance of malignancy was
67%. When the lesions are diagnosed as malignancy
from pathologic or radiologic Àndings, next problem
is to deÀne whether these lesion are lung to lung
metastasis or synchronous multiple primary lung
cancer (MPLC). In reality, it is impossible to
accurately differentiate between the two when the
cell types are identical. Although accurate diagnosis
might be possible with molecular biological Àndings,
most clinicians have adopted the criteria of Martini.
Patients with MPLC have a relatively favorable Àve
year survival rate. Some authors showed that node-
Keywords: N2 disease, combined modality negative T1-2 patients with multifocal NSCLC in
treatment the same lobe or a different lobe had a favorable
3-year actuarial survival rate of 66.5% and 63.6%,
respectively. Okada et al. reported that 3.1% of
Intra-Operative Decision Making Thursday, 7 July 2011 10:30-12:00 second primary lung cancer was synchronous and
Àve-year survival rate from initial treatment of
GR04.3 MANAGEMENT OF PATIENTS cancer was 70.3%. They concluded that aggressive
WITH ANOTHER PULMONARY operative approach for node negative early stage and
NODULES OTHERWISE OPERABLE oncologically sound parenchymal sparing procedure
NON-SMALL CELL LUNG CANCER would be possible. However, other authors showed
Sanghoon Jheon unfavorable results than that of Okada’s report. One
Thoracic And Cardiovascular Surgery, Seoul of the reasons for the inconsistent results is perhaps
National University Bundang Hospital/Korea the possibility that some with lung to lung metastasis
had been included, and not ruled out. In regards
Abstract: With the increasing application of high- to lung to lung metastasis, a new revision of the
resolution computed tomography (HRCT) scan, TNM classiÀcation of lung cancer was established
small pulmonary nodules have been more frequently and published in 2009. The results of this study
detected. Recently, ground-glass opacity (GGO) showed that T4 tumors classiÀed by the presence of
lesions have been found with greater ease in patient additional nodules in the lobe of the primary tumor
with primary lung cancer. Therefore, rather than have better prognosis than other T4 tumors, which
attempting to detect these nodules intraoperatively, also has a very similar prognosis to T3 tumors. In
it is common to detect preoperatively with HRCT. addition, the study illustrated to reclassify M1 of
For non-small cell lung cancer (NSCLC), it is additional nodules on the ipsilateral different lobe to
difÀcult to deÀne these satellite nodules, including be classiÀed as T4. Japan Lung Cancer Registration
GGO, prior to surgery on the HRCT. First of all, it is Committee, the largest study, enrolled 317 patients
important to determine the probability whether these with intrapulmonary metastasis in primary lobe,
lesions are benign or malignant. CT-guided needle 128 patients with intrapulmonary metastasis in
aspiration biopsy is possible unless the nodule size non-primary lobe. The Àve-year survival rates were
is less than 1cm or deeply located. If it is impossible 26.8% and 22.5%, respectively, with no statistically
to perform tissue conÀrmation, other methods such signiÀcant difference between two groups. In
as, imaging features of CT or max SUV of PET/ patients with operable non-small cell lung cancer,
CT may be helpful to differentiate between benign controversy about nodules detected preoperatively
and malignancy. Recently, multiple GGO lesions or intraoperatively has to be addressed in order
are another concern. It is not feasible to conÀrm not to lose the opportunity for a curative resection.
Based on above Àndings, I am presenting the data of makes complete resection unlikely or N2/N3 disease
patients who underwent surgical resection for MPLC neoadjuvant chemoradiotherapy followed by surgery
or for ipsilateral pulmonary metastasis in major when down staging is achieved or deÀnitive chemo
hospitals in Korea. (-radio) therapy is indicated. Take into consideration
Keyword: satellite nodules, non-small cell lung that lymph node metastasis adjacent to the T4 tumor
cancer, surgery is a „regional“ lymph node metastasis in a N2/
N3 position and may therefore not have the same
oncological meaning than in non-central tumors.
Intra-Operative Decision Making Thursday, 7 July 2011 10:30-12:00 Adjuvant treatment should be discussed in all
cases. Occasionally T4 tumors are not deÀnitively
GR04.4 UNSUSPECTED T4 BY diagnosed before surgery and detected or proven
EXTENSION during the operation. However in most cases it
Walter Weder can be anticipated from CT scans and a possible
Thoracic Surgery, University Hospital Zurich/ intraoperative strategy can be discussed in advance.
Switzerland In a T4 stage found deÀnitively at surgery we would
follow the same principles as described above and
Abstract: In the 7th edition of the TNM staging perform resection, when it will be complete but stay
system T4 Non-small-cell lung cancer (NSCLC) with an exploratory thoracotomy only when surgery
is deÀned as tumors inÀltrating the mediastinal will be incomplete. In T4 cases with inÀltration
structures such as the heart, the great vessels, the of the left atrium usually along the pulmonary
oesophagus, vertebrae or the carina. It includes vein or inÀltration of the central pulmonary artery,
furthermore tumors with satellite nodules in other cardiopulmonary bypass may be needed. Long term
lobes of the same side. The T4 stage is diagnosed survivors are observed in all series. T4 due to a
in general by imaging techniques such as chest-CT, secondary tumor in another lobe is always known
PET/PET-CT or MRI. InÀltration into structures before from the CT-scan, but in many cases the
is radiologically proven when a destruction of deÀnitive histology is found intraoperatively. A
the organ is seen or the tumor is visible beyond lobectomy in combination with a segmentectomy
the layer of the respected organ. A tumor in close or a pneumonectomy in larger tumors should be
contact to structures, even for a wide area, indicates considered for all cases in absence of N2-disease.
a possible inÀltration in approximately 50% DeÀnitive T4-stage may be found at surgery but
only. In these cases further diagnostic measures can be anticipated in advance in most of the cases
should be applied such as mediastinoscopy, VATS, from the chest CT. It is of importance that a strategy
transoesophageal ultrasound or others. For carinal is discussed beforehand and careful staging with
inÀltration bronchoscopy is essential and diagnostic. exclusion of mediastinal lymph node involvement
Satellite nodules are usually detected on CT as or distant metastases is mandatory. Furthermore an
solitary nodules of unknown origin, and may vary in evaluation of the pulmonary status after resection
size; they are rarely numerous. There is no uniform must be calculated and the risks known.
standard of care applied for known T4 NSCLC
since treatment depends from various cofounding
factors such as the extent of inÀltration, the nodal
status, co-morbidities of the patients overall status
and its tolerability of treatment, risk of procedures,
availability of treatment options and surgical
skills. Recommendations are based on relatively
small sized single center retrospective case series.
Patients with a T4-stage need to be discussed in a
multidisciplinary tumour board with presence of an
experienced thoracic surgeon. Upfront surgery is
recommended for T4, N0 or T4, N1 when a radical
resection is achievable with an acceptable mortality
and morbidity. 5-year survival varies from 19-57%.
In presence of either extended inÀltration which
PRO-CON SESSIONS eliminates unnecessary passes during the procedure.

However conventional TBNA is a blind procedure
preventing target visualization and therefore the yield
Session PC01: Endoscopic Highlights for TBNA varies widely (14-91%). A meta-analysis
of 12 studies in 910 evaluable patients demonstrated
Tuesday, 5 July 2011 a sensitivity of 76%. The speciÀcity was very high
(96%). Although the sensitivity was moderate, the
patients included in the TBNA studies had enlarged
Endoscopic Highlights Tuesday, 5 July 2011 10:30-12:00 mediastinal lymph nodes. The high false negative
rate makes TBNA less useful for complete staging
PC01.1 TBNA IS THE ISSUE, NOT EBUS of the mediastinum. Therefore, TBNA would
GUIDED probably be the preferred minimal invasive method
Kazuhiro Yasufuku for patients with radiographic evidence of enlarged
Division Of Thoracic Surgery, Toronto General mediastinal lymph nodes adjacent to the airways,
Hospital/Canada since bronchoscopy is usually performed in lung
cancer patients and assessment for endobronchial
Abstract: During the staging process of non-small lesions can be performed during the same procedure.
cell lung cancer (NSCLC), accurate mediastinal On the other hand, endobronchial ultrasound-
lymph node staging is a critical factor which guided transbronchial needle aspiration (EBUS-
affects patient outcome. Several different invasive TBNA) utilizes ultrasound technology built into
and non-invasive modalities exist for mediastinal a Áexible bronchoscope for real-time ultrasound
staging. Invasive tests include mediastinoscopy, guided sampling of mediastinal and hilar lymph
thoracoscopy, transbronchial needle aspiration nodes. Similar to conventional TBNA, EBUS-
(TBNA), transthoracic needle aspiration (TTNA), TBNA has access to all of the mediastinal lymph
endoscopic ultrasound-guided Àne needle aspiration nodes accessible by mediastinoscopy as well as N1
(EUS-FNA) and endobronchial ultrasound- nodes. Recent studies show that EBUS-TBNA has
guided transbronchial needle aspiration (EBUS- equivalent sensitivity to mediastinoscopy for lung
TBNA). Each of the invasive tests has limitations cancer staging. Due to the real-time procedure,
for particular locations, has particular risks and EBUS-TBNA can also correctly stage patients
requires speciÀc skills. Invasive tests are often with normal mediastinum on imaging. The cost-
times used to conÀrm staging of lung cancer, but effectiveness of EBUS-TBNA has also been shown
also used for the conÀrmation of the diagnosis. The in studies comparing mediastinoscopy, EBUS-
determination of the best approach out of these tests TBNA, conventional TBNA for mediastinal staging
depends on the clinician’s assessment of the patient. in NSCLC. Ongoing studies are looking at the
Cervical mediastinoscopy has been considered comparison of EBUS-TBNA to mediastinoscopy,
the “Gold Standard” for mediastinal staging in but currently there is no evidence to suggest that
NSCLC. However, there is increasing interest in EBUS-TBNA will replace mediastinoscopy. It will
minimally invasive endoscopic mediastinal staging be important to incorporate new minimally invasive
techniques. Transbronchial needle aspiration endoscopic techniques in the algorithm of lung
(TBNA) for mediastinal staging is performed cancer staging. EBUS-TBNA may be considered for
through the bronchoscope under local anesthesia. initial staging of NSCLC in patients with suspicious
It can be performed as an outpatient procedure mediastinal lymph nodes on non-invasive staging,
with no signiÀcant morbidity. The needle catheter, provided negative results are conÀrmed by surgical
which comes in various sizes, is passed through staging. This will allow mediastinoscopy to be
the working channel of the bronchoscope and reserved for re-staging after induction treatment.
guided to the area of interest. The needle is then EBUS-TBNA also has potential for providing
advanced through the tracheobronchial wall into molecular diagnosis.
the lymph node. TBNA can be performed from the Keywords: Staging, EBUS, TBNA, Lung cancer
hilar and mediastinal lymph nodes adjacent to the
tracheobronchial wall. Aspiration biopsies are then
obtained. Rapid on-site cytologic evaluation of the
aspirates improves the yield, is cost-effective and
Endoscopic Highlights Tuesday, 5 July 2011 10:30-12:00 the tracheobronchial wall into the lymph node. The
expected difÀculty of angulating a bronchoscope
PC01.2 TBNA IS THE ISSUE, NOT EBUS with more rigid needle inserted is overcome in
GUIDED the EBUS scope with an angled side port exit for
Ko P. Wang1, Robert Browning2 the bronchoscope working channel. This ability to
1
Interventional Pulmonology, Johns Hopkins effectively use a more rigid needle in TBNA is likely
Hospital/United States Of America, 2Chest one of the most signiÀcant advantages of EBUS
Diagnostic Center, Harbor Hospital/United States Of TBNA, allowing for more effective back and forth
America shearing or coring movement during biopsy. The
methodology for EBUS TBNA is essentially the
Abstract: Transbronchial needle aspiration (TBNA) same as for conventional TBNA with few exceptions.
has been used for over three decades to sample the In conventional TBNA location of the puncture site
mediastinum and hilar lymph nodes for diagnosis is identiÀed visually using the endoscopic view of
and staging. First described in Argentina in 1949 by the airway and the natural landmarks that correlate
Dr. Eduardo Schieppati using a rigid bronchoscope to the CT image of the mediastinum as described in
and rigid needle. This technique was Àrst adapted 1994 by Wang. This map included endobronchial,
to the Áexible bronchoscope in 1983 at Johns anatomic, and CT correlation for 11 of the most
Hopkins Hospital, by Wang et al. In the Àrst report common locations for mediastinal adenopathy that
for staging of lung cancer, the overall diagnostic can be reliably reached from the airways. While this
yield for staging was 85% for lung cancer and 96% map was created for the bronchoscopist performing
in right side lesions. Over the past several decades, TBNA to enhance their ability to successfully locate
numerous experts have reported their diagnostic and biopsy the target lymph nodes, it correlates
yield using this technique with a sensitivity and very closely to the latest IASLC staging system and
speciÀcity of over 90%. Recent development of the is sufÀcient for staging purposes. Unlike biopsy
endobronchial ultrasound (EBUS) for TBNA has from the esophagus, the airways have distinctive
generated special attention and interest in TBNA landmarks to identify the areas where the lymph
technique and has been shown to be more reliable nodes consistently reside. With experience, these
and sensitive than conventional technique by a few landmarks are very reliable and do not require
experts and is being recommended in guidelines as ultrasound guidance to locate. In our routine clinical
a Àrst line diagnostic procedure for all mediastinal practice of TBNA diagnosis or staging of lung
and hilar adenopathy. EBUS TBNA is different than cancer, TBNA is performed on mediastinal and
conventional TBNA in several signiÀcant ways. hilar lymph nodes using the conventional method
First and most obvious is the ability to visualize and Àrst followed by EBUS TBNA. This approach
locate the target lymph node with ultrasound beyond is extremely practical and efÀcient when using a
the bronchial wall and perform the needle aspiration standard bronchoscope initially and then switching
with real time ultrasound guidance. Visualization of to the EBUS scope. In diagnostic cases, the largest
the lesion before biopsy and during biopsy may not lymph nodes were selected for biopsy. For staging,
play any important role once the lesion is entered, biopsy site and order were based on the highest level
but it does ensure the lesion is reached. Direct of possible staging for the patient (i.e. N3, N2, N1).
visualization of the needle in the lesion does not Same number of punctures were performed with
guarantee an adequate specimen. The EBUS needle and without EBUS on each station. In 200 patients
design is a continuous hollow metallic shaft with reviewed, 183 had specimens both with conventional
a sharp needle tip housed in a plastic catheter. The TBNA and EBUS. 36 patients had mediastinum
lengths of the outer plastic catheter and the working or hilar lymph nodes positive for lung cancer.
length of the needle can be adjusted at the proximal EBUS TBNA was the exclusive positive diagnostic
end of the needle apparatus. SigniÀcance of the modality in 7 patients. Conventional TBNA was
adjustable working lengths of the catheter and needle the exclusive positive diagnostic modality in 12
is trivial since the scope length is Àxed and the patients. Recommendations for EBUS TBNA to
target lesions are usually close to tracheobronchial become the exclusive modality for staging of lung
wall. The longer and more rigid design of the EBUS cancer regardless of the size of the lymph node is
needle compared to conventional TBNA needles premature. The EBUS bronchoscope and needle
allows for easier and deeper penetration through apparatus is more uncomfortable for the patient
and more difÀcult to use. The availability and cost patient, who survived for 18 years after surgery.
of the equipment are also signiÀcant barriers to its In 1951, Cahan suggested that pneumonectomy
widespread use. Continuous improvement of the with regional lymph node dissection should be a
equipment, instruments and technology is needed. routine procedure for lung cancer in 1951. Then
In fact, the EBUS bronchoscopes have already in 1960, Cahan reported the Àrst 48 cases that
begun this evolution. Olympus second generation successfully underwent lobectomy with regional
EBUS scope has increased its working channel lymph node dissection, which was called “radical
diameter from the original 2.0 mm to a larger 2.2 lobectomy.” Since then, this procedure was
mm channel that can accommodate a wider array of universally accepted and has remained a standard
intstruments. The Pentax EBUS scope has further surgery for lung cancer. As for sublobar resection,
reduced the scope outer diameter while preserving segmentectomy was initially used for the resection
the superior optics of the videobronchoscope. In the of localized bronchiectasis as reported by Churchill
end, no matter what the technology, the success of and Belsey (1939). In 1973, Jensik reported their
TBNA relies on the operator’s skill, understanding 15-year successful experience of segmentectomy
of the anatomy, and the technique in obtaining the for lung cancer patients. However, the use of
biopsy. EBUS is an exciting and useful technological sublobar resection as deÀnitive management of
advancement that has important applications in NSCLC has been a controversial issue. Lung Cancer
TBNA as well as in training. Still today, for most Study Group (LCSG) (1995) conducted the only
pulmonologist in the world, conventional TBNA randomized trial comparing sublobar resection
is the simplest, safest and most cost effective with lobectomy for stage IA NSCLC patients. They
procedure for staging of lung cancer in the vast observed a 75% increase in recurrence and a 50%
majority of patients. 1 Wang KP, Brower R, Haponik increase in cancer death in the patients undergoing
EF, Stiegelman S. Flexible transbronchial needle sublobar resection, compared to those in the patients
aspiration for staging of bronchogenic carcinoma, undergoing lobectomy. This is the reason why
Chest 1983; 84(5): 571-6. 2 Patel NM, Pohlman A, lobectomy has remained a standard lung cancer
Husain A, et al. Conventional transbronchial needle surgery for a half century since Cahn’s successful
aspiration decreases the rate of surgical sampling report in 1960. Controversies in sublobar resection
of intrathoracic lymphadenopathy. Chest 2007; for patients with small-sized NSCLC Sublobar
131:773-8. 3 Wang KP. Staging of bronchogenic resection is a lung parenchyma-preserving surgery
carcinoma by bronchoscopy. Chest 1994; 106:588- with limited nodal dissection. However, even small-
93. 4 Wang KP, Browning R; Transbronchial needle sized lung cancer less than 2 cm in size shows hilar
aspiration with or without endobronchial ultrasound. and mediastinal nodal disease with an incidence
Thoracic Cancer, 2010 Jul;1(2):87-93. of more than 20%. Although positron emission
Keywords: bronchoscopy, TBNA, EBUS, Lung tomography (PET) is considered to be the most
Cancer Staging sensitive and accurate investigation for screening
of lymph node involvement, with a sensitivity
of 79 to 85% and speciÀcity of 90 to 91% in a
Session PC02: Early Lung Cancer meta-analysis, the assessment of nodal status by
PET is not reliable in patients with microscopic
Wednesday, 6 July 2011 nodal metastasis. Riquet (1989) reported that lung
cancer metastasizes so easily to the mediastinum
that selection of the patients for limited surgery
Early Lung Cancer Wednesday, 6 July 2011 16:30-18:00 should be discussed carefully. Furthermore, lung
cancer has a phenomenon termed “skip metastasis”
PC02.1 WHEN IS LEBECTOMY BEST? consisting of N2 disease without N1 involvement
Shun-Ichi Watanabe with the incidence of 20-38% in N2 patients.
Division Of Thoracic Surgery, National Cancer Therefore, lobectomy with hilar and mediastinal
Center Hospital/Japan lymph node dissection is considered to be a basic
standard procedure for lung cancer. Differences in
Abstract: History of standard surgical procedure survival between sublobar resection and lobectomy
for lung cancer In 1933, Graham reported the However, with the recent development of the CT
Àrst successful pneumonectomy for a lung cancer scanner, the number of very early-stage lung cancer
showing ground-grass opacity (GGO) on CT is rising Early Lung Cancer Wednesday, 6 July 2011 16:30-18:00
as well, and a new therapeutic strategy for nodal
dissection has been required. Proposals of sublobar PC02.2 WHEN IS LIMITED RESECTION
resection for small-size lung cancer less than 2 cm BEST?
have been undertaken in some previous reports. Young Mog Shim
Many retrospective studies of sublobar resection Department Of Thoracic And Cardiovascular
have already been undertaken for stage IA NSCLC Surgery, Samsung Medical Center/Korea
patients. Regarding surgery for compromised stage
IA patients, Hoffmann (1980), Landreneau (1997) Abstract: Limited resection for early-stage lung
and Campione (2004) showed no signiÀcant survival cancer Young Mog Shim, MD, PhD Department of
difference between sublobar resection and lobectomy Thoracic and Cardiovascular Surgery, Samsung
group. Okada (2001) and Koike (2003) conducted Medical Center, Sungkyunkwan University School
the comparative study between intentional sublobar of Medicine, Seoul, Republic of Korea Lobectomy
resection and standard lobectomy in patients with with mediastinal lymph node dissection is the
tumors 20mm or less in diameter. They showed no treatment of choice for patients with stage IA non-
signiÀcant difference in survival between two groups small cell lung cancer (NSCLC).1 Current
and suggested that sublobar resection was acceptable recommendations for lobectomy as the standard
operation for small-sized lung cancer. Nakamura treatment for early-stage NSCLC is based on the
(2005) reported the results of meta-analysis of 14 only randomized trial comparing lobectomy and
comparative studies showing survival difference sublobar resection for the treatment of T1N0 NSCLC
between lobectomy and sublobar resection. He reported by the Lung Cancer Study Group (LCSG) in
showed survival after lobectomy was slightly better 1995.2 The main Àndings of this study were a
at 1, 3, and 5 years, but the differences were not threefold increase in local recurrence rate and a 75%
signiÀcant. Therefore, lobectomy with mediastinal increased risk of overall recurrence in the sublobar
dissection could be an excessive resection for selected group compared with the lobectomy group. A similar
patients with early lesion. Lobectomy, however, still increase in local recurrence among patients
remains to be a standard procedure for most patients undergoing sublobar resection was shown in a
with lung cancer, simply because there has been prospective non-randomized multi-institutional study
no universally accepted guidelines for conducting by Landreneau and coworkers in 1997.3 For these
sublobar resection in the clinical settings. We should reasons, lobectomy has remained the gold standard
wait the Ànal results of clinical trials shown in the for the treatment of early-stage NSCLC, whereas
following chapter. Clinical trials regarding sublobar sublobar resection is considered to be a compromised
resection vs. lobectomy and future perspective procedure for high-risk patients with poor
Currently, a prospective, randomized, multi- cardiopulmonary function unable to tolerate an
institutional phase III trial for small-sized (<=2 cm) anatomic lobectomy. However, with the use of
lung cancer patients is being conducted by Cancer and recently developed methods of radiographic
Leukemia Group B (CALGB 140503) to determine investigation and lung cancer screening programs,
the effectiveness of an intentional sublobar resection tumors are being identiÀed at earlier stages and
for small-sized peripheral tumors. Similar study is also smaller sizes than ever before. Moreover, the
being conducted by Japan Clinical Oncology Group growing use of high-resolution computed
(JCOG 0802). Since the clear evidence regarding tomographic scans have increased the detection of
the survival beneÀt of sublobar resection for lung more indolent tumors with ground-glass opacity
cancer patient is lacking so far, lobectomy should (GGO) features such as bronchioloalveolar
be an appropriate therapy for medically operable carcinoma. Although lobectomy is the standard
lung cancer patient at the moment. Abovementioned extent of surgical resection for stage I NSCLC, it is
randomized trials will clearly deÀne the role of unclear whether lobectomy is really needed for such
sublobar resection in patients with stage I patients. small lesions (i.e. less than 2 cm in diameter) with
As the number of early-stage peripheral lung cancers indolent behavior. Based on these circumstances,
is increasing, the surgical procedure for lung cancer there has been renewed interest in the use of sublobar
should be tailored to each case in the near future. resection such as anatomic segmentectomy or wedge
Keywords: sublobar resection, Surgery, Lung cancer, resection.4-7 Patients with smaller tumors are less
lobectomy likely to have regional or distant metastases at the
time of diagnosis, and have an overall better undergoing limited resection, Àve had
prognosis. Over the last decade, several studies have adenocarcinoma, one had atypical adenomatous
demonstrated improved survival and decreased hyperplasia, and the remaining patients had benign
recurrence rates for patients with tumors 2 cm or less etiology. The authors suggested that some pure
in diameter.4-7 Okada and colleagues4 reported the GGOs would never progress to clinical disease.
outcomes of extended segmentectomy or lobectomy Based on these Àndings, new concepts are introduced
in patients with T1N0 tumors 2 cm or less and such as adenocarcinoma in situ (AIS) and minimally
showed a 5-year survival rates of 87.1% in the invasive adenocarcinoma (MIA) for small solitary
segmentectomy group and 87.7% in the lobectomy adenocarcinomas with either pure lepidic growth
group (p = 0.8008). Koike et al5 reported a 9-year (AIS) or predominant lepidic growth with 5 mm
experience in which 159 patients were treated with invasion (MIA) to deÀne patients who will have
lobectomy and 74 were treated with sublobar 100% or near 100% disease-speciÀc survival,
resection for T1N0 peripheral NSCLC 2 cm or less respectively.10 Therefore, it is also not known
in diameter. The 5-year survival was 89.1% for the whether pulmonary resection is really necessary for
sublobar resection group, compared with 90.1% for such small lesions with GGO features. When making
the lobectomy group. Recently, Kates et al6 evaluated decisions regarding which type of resection to
2090 stage I NSCLC tumors 1 cm or less from the recommend, surgeons must balance the potential
Surveillance Epidemiology and End Results registry. long-term beneÀts of more extensive resections with
Among these, 688 patients underwent sublobar the risks of perioperative complications, decreased
resection. There was no difference in overall or lung postoperative lung function, and potential limited
cancer-speciÀc survival between the sublobar ability to resect any future new primary lung cancers
resection and lobectomy groups. Not surprisingly, that may develop. With the use of limited resection
even in the LCSG report2 and Landreneau’s study3, such as segmentectomy and wedge resection, further
although the locoregional recurrence rate for the preservation of lung volume can be achieved,
sublobar resection group was signiÀcantly higher perioperative morbidity and mortality can potentially
than for the lobectomy group, the 5-year survival be reduced, and opportunities for additional lung
rates were similar between the two groups. resection in the future could be maintained for
Furthermore, there are several major criticisms second primary lung cancer. Over the past decade,
against the 1995 LCSG report. First, substantially many studies have suggested that limited resection
many patients in the sublobar resection group and lobectomy may lead to similar survival among
(32.8%) underwent a wedge resection. A wedge patients with small stage IA tumors. These Àndings
resection is not as effective as anatomic need to be further conÀrmed in randomized
segmentectomy because immediate regional lymph controlled trials. References 1. Spira A, Ettinger DS.
nodes related to the tumor are not always removed, Multidisciplinary management of lung cancer. N
and the margin between the surgical staple line and Engl J Med 2004;350(4):379-392. 2. Ginsberg RJ,
tumor is more likely to be smaller. Second, patients Rubinstein LV. Randomized trial of lobectomy
with tumors up to 3 cm in diameter were included in versus limited resection for T1 N0 non-small cell
the LCSG study. Smaller tumors ( 2cm in diameter) lung cancer. Ann Thorac Surg 1995;60:615-623. 3.
are more likely to have comparable outcomes with Landreneau RJ, Sugarbaker DJ, Mack MJ, et al.
sublobar resection when compared with lobectomy. Wedge resection versus lobectomy for stage I
For the GGO type of tiny lesions, especially those (T1N0M0) non-small cell lung cancer. J Thorac
less than 1 cm in diameter, the question has been Cardiovasc Surg 1997;113:691-700. 4. Okada M,
raised whether surgical resection itself is really Yoshikawa K, Hatta T, et al. Is segmentectomy with
needed. Since patients diagnosed with Noguchi type lymph node assessment an alternative to lobectomy
A (pure BAC) have a 100% 5-year survival rate8, for non-small cell lung cancer of 2 cm or smaller?
they may not need surgical resection. Kodama et al Ann Thorac Surg 2001;71:956-961. 5. Koike T,
reviewed the natural history of pure GGO through Yamato Y, Yoshiya K, et al. Intentional limited
long-term observation in 19 patients.9 The size of pulmonary resection for peripheral T1 N0 M0 small-
pure GGO did not change in eight patients, increased sized lung cancer. J Thorac Cardiovasc Surg
slightly (up to 5 mm) in six patients, and increased 2003;125:924-928. 6. Kates M, Swanson S,
by more than 5 mm in Àve patients during a follow- Wisnivesky JP. Survival following lobectomy and
up of 2 years or more. Among the 10 patients limited resection for the treatment of stage I non-
small cell lung cancer 1 cm in size: a review of several directions focus on the target while sparing
SEER data. Chest 2011;139:491-496. 7. Okada M, the adjacent normal tissues with high accuracy. This
Nishio W, Sakamoto T, et al. Effect of tumor size on technique basically derived from that of radiosurgery
prognosis in patients with non-small cell lung for intracranial lesions allows us to deliver high dose to
cancer: the role of segmentectomy as a type of lesser the target leading to high control of the tumor without
resection. J Thorac Cardiovasc Surg 2005;129:87-93. causing signiÀcant cytotoxicities associated with the
8. Noguchi M, Morikawa A, Kawasaki M, et al. treatment. By SBRT, the biological effect of radiation
Small adenocarcinoma of the lung. Histologic on tumors is increased as the overall treatment time
characteristics and prognosis. Cancer 1995;75:2844- is shortened. With many encouraging outcomes in
2852. 9. Kodama K, Higashiyama M, Yokouchi H, et retrospective studies, several prospective clinical
al. Natural history of pure ground-glass opacity after trials have been performed world-wide. Retrospective
long-term follow-up of more than 2 years. Ann and prospective studies published in the past decade
Thorac Surg 2002;73:386-393. 10. Travis WD, have established the feasibility, safety, and efÀcacy
Brambilla E, Noguchi M, et al. International of SBRT in stage I NSCLC using a variety of dose
Association for the Study of Lung Cancer / American regimens and technologies. To date, lung SBRT results
Thoracic Society / European Respiratory Society demonstrate good local control and suggest improved
international multidisciplinary classiÀcation of lung overall survival compared to historical controls of
adenocarcinoma. J Thorac Oncol 2011;6(2):244-285. fractionated radiotherapy. The overall survival rate for
Keyword: limited resection, early lung cancer subgroup of medically operable patients who rejected
surgery in a large retrospective study was almost
comparative to that of surgical series. Concerning
Early Lung Cancer Wednesday, 6 July 2011 16:30-18:00 toxicities, SBRT is an almost safe and confortable
treatment. But rib fracture is a common adverse
PC02.3 WHEN IS SBRT BEST? effect when the tumor locates peripherally and severe
Hiroshi Onishi1, Shuya Nagata2, Masahiro Hiraoka3, radiation-related pneumonitis occasionally occur
Yutaka Kokubo4, Katsuyuki Karasawa5, Yoshiyuki mostly in the patients having basic pulmonary Àbrosis.
Shioyama6, Rikiya Onimaru7, Etsuo Kunieda8, Taro As the clear dose-constraint for mediastinal organs has
Shibata9 not been demonstrated, the safety of SBRT for cases
1
Department Of Radiology, Yamanashi University with a central lesion has not been assured. When the
School Of Medicine/Japan, 2Radiation Oncology, tumor recurred only locally after SBRT in operable
Hiroshima University/Japan, 3Radiation Oncology, patients, salvage radical surgery can be operated
Kyoto University/Japan, 4Foundation For safely. Ongoing prospective trials are exploring proper
Biomedical Research And Innovation/Japan, dose and fractionation schedules for central or T2
5
Komagome Metropolitan Hospital/Japan, 6Kyushu tumors, a difference between SBRT and conventional
University/Japan, 7Hokkaido University/Japan, radiotherapy mostly in the inoperable population, and
8
Tokai University/Japan, 9JCOG Data Center, a role of SBRT for operable patients. Japan Clinical
National Cancer Center/Japan Oncology Group (JCOG) protocol-0403 is the Àrst
phase II trial of stereotactic body radiation therapy
Abstract: With the recent popularization of computed for medically operable T1N0M0 non-small cell lung
tomography (CT) screening, early stage lung cancers cancer. In the result of the operable 64 patients, the
are increasingly detected at an early stage. For rates of 3-year local control, overall survival, and
patients with stage I (T1 or 2, N0, M0) non-small progression-free survival were 86.0%, 76.0%, and
cell lung cancer (NSCLC), resection of full lobe and 54.5%, respectively. Grade 3 toxicities were chest
systemic lymph nodes represents standard treatment pain in 1 (1.5%), dyspnea in 2 (3.1%), hypoxia in 1
but can be associated with signiÀcant morbidity (1.5%), and pneumonitis in 2 (3.1%). No grade 4 and
and even mortality, particularly because patients 5 toxicity was observed. According to good results
suffering from lung cancer are often elderly with high of these retrospective or prospective studies, some
comorbidity rates. Stereotactic body radiotherapy phase III prospective trials comparing SBRT versus
(SBRT) has emerged as one of the treatment options surgery (lobar resection) have been started, but the
for stage I non-small cell lung cancer (NSCLC), patient accrual seems to be difÀcult. Recently trials
mainly in medically inoperable patients. SBRT is a exploring the efÀcacy and safety of sublobar resection
new treatment modality where narrow beams from for patients with smaller tumors or who are unÀt for
lobar resection have been made by surgeon. SBRT placed within the tumor to dispersive electrodes
essentially should be compared to such a less invasive that are placed on the patient. As the RF energy is
and less radical surgery. Concerning a comparison applied, frictional heating of tissues results with cell
of SBRT with other non-surgical treatment modality death occurring at temperatures beyond 60ºC. In
for stage I NSCLC, radiofrequency ablation (RFA) is most cases RFA is performed using a percutaneous
worse in local control and more invasive than SBRT. approach with CT guidance. RFA can be used
A higher procedure-related morbidity and mortality for patients with primary lung cancer and limited
rate than SBRT has been reported, mainly caused pulmonary metastases. RFA is most effective for
by pneumothorax and hemorrhage. So SBRT is smaller tumors (3cm or less), although tumors up
recommended rather than RFA for most of cases. But to 5cm can be effectively ablated. Unlike resection,
RFA may be useful for cases with local recurrence lymph nodes are not removed, and occult nodal
after SBRT. Particle beam therapy enables better dose disease may be missed, leading to local-regional
distribution than SBRT and better local control may failure as well as understaging of disease. When
be achieved by carbon therapy, but survival rate is comparing results of RFA to surgical resection, and
not different among these modalities. The treatment other new technologies such as SBRT, it should
cost is very high in the particle therapy. So SBRT can be considered that different deÀnitions are used
be recommended as a Àrst choice for patients with to deÀne patterns of failure. SpeciÀcally local
peripherally located tumor. Particle-beam therapy may recurrence rates for SBRT and RFA are often quoted
have an advantage in cases with a central tumor or as being superior to those after wedge resection.
pulmonary Àbrosis. In conclusion, though surgery has However, in the surgical literature local recurrence
been a standard treatment for operable stage I NSCLC will usually include hilar, sometimes mediastinal,
and the ultimate efÀcacy of SBRT in operable patients as well as parenchymal recurrence within the same
is difÀcult question to answer, the best timing of SBRT lobe, which is not the case with reports of non-
is when the tumor locates peripherally in a medically operative therapies such as RFA or SBRT. Another
inoperable patients who have no pulmonary Àbrosis, concern is that it is not guaranteed that there will be
and marginally operable patients who hope less 100% tumor destruction with an adequate therapeutic
invasive treatment. The combination of initial SBRT margin when ablation is used, although ablation is
followed by salvage surgery when local recurrence more likely to be successful for smaller tumors, and
occurs may become a new strategy for marginally may be improved with new ablation technologies
operable cases. In patients with central tumor or such as microwave, cryotherapy or irreversible
pulmonary Àbrosis, SBRT should be performed very electroporation. Patients with stage I lung cancer
cautiously. Life is limited. The 150-year survival rate can be considered in 3 groups; namely; 1) standard
of humans must be 0%. All of the so-called “radical” risk operable (usually treated with lobar resection
treatments are then “palliation”. Hence, whether SBRT 2) High-risk operable patients (usually treated with
is selected Àrst or not in operable patients depends on sublobar resection) and 3) medically inoperable
their own philosophy, not on the acquired survival time (unable to tolerate any form of lung resection and
after SBRT or other treatment modalities only. usually treated with external beam radiation). RFA is
Keywords: stage I non-small cell lung cnacer, a good option for the medically inoperable patients
Operable, stereotactic body radiotherapy, Inoperable and may potentially be considered for some high-risk
operable patients. RFA should be avoided for tumors
closely abutting large vessels such as pulmonary
Early Lung Cancer Wednesday, 6 July 2011 16:30-18:00 vessels at the hilum. This is because there is a
heat-sink effect that will prevent effective heating
PC02.4 WHEN IS RADIOFREQUENCY and cancer destruction, and additionally there is
ABLATION BEST? the potential risk of bleeding. RFA is effective for
Hiran C. Fernando tumors in the lung periphery, as well as the middle
Cardiothoracic Surgery, Boston Medical Center, 3rd of the lung, where lobar resection may be the only
Boston Uniiversity/United States Of America feasible resection available. In this case RFA will
avoid the need for lobectomy, for a patient who is in
Abstract: RFA is being used increasingly to treat the high-risk operable group.
lung tumors. RF energy consists of an alternating Keywords: radiofrequency ablation, Lung cancer,
current that moves from an active electrode that is pulmonary metastases
SESSION Y: YOUNG or not to pursue a career - and or life - in academic

medicine? FOR - Desire to carry out research -
INVESTIGATOR’S SESSION Desire to teach - Intellectual stimulation - InÁuence
of a mentor or role model AGAINST - Lack of
autonomy - Low income (that’s relative) - Family
Sunday, 3 July 2011 considerations - Competing pressures to do clinical
service, teach and do research Once you decide to go
Young Investigator’s Session Sunday, 3 July 2011 07:00-11:00 into academic medicine, you have to make a decision
about either doing (1) basic or translational laboratory
Y.1 HOW TO PLAN AN ACADEMIC investigation such as in: - Cancer genetics - Cancer
CAREER IN LUNG CANCER cell biology - Tumor cell invasion and metastases
David S. Ettinger - Tumor immunology - Cancer etiology - Cancer
Oncology, Sidney Kimmel Cancer Center At Johns pharmacology or (2) clinical investigation combined
Hopkins/United States Of America with clinical care as in: - Experimental therapeutics
of cancer - Design and execution of phase I, II, III
Abstract: Before I go any further, let’s reÁect for clincal trials - Health services/outcomes research
a moment on the title. Can you plan an academic It is challenging for any single individual to be an
career in lung cancer? Does planning work or do active participant in both basic/translational research
other factors come into play - like coincidence/happy and clinical investigation (bench to bedside) and do
accident/also known as being in the right place at the it all well. The more common alternative is for the
right time, having the ability and the opportunity to laboratory and clinical scientist to COLLABORATE.
form lasting and productive relationships, having the In general, to be successful in academic medicine,
good fortune to be successful at what you do. Let’s see one has to “focus”, have a single area of emphasis.
what you think as you reÁect on our discussion today. In this case, lung cancer. As a clinical investigator
When I was asked to give this talk, I asked myself in lung cancer, the goal is to become an expert in
“why”? Was it because I am an older person?, seen the natural history, diagnosis and management of
perhaps as smart?, hardworking, successful; or was it the disease while any laboratory research should
just because I’ve been at the same institution for 38 relate to lung cancer. Mentor selection is often the
years? You be the judge. For you to understand a bit most crucial decision you will make in becoming
about me, I will present to you a short autobiographic an academician. The mentor will often inÁuence
sketch. I have been at Johns Hopkins since 1973. I the speciÀc area of research interest. The mentor
did my fellowship there in medical oncology and should have an established reputation in their Àeld
was given the opportunity to stay on the faculty as and have time to mentor. The mentor’s experience
a clinical investigator, rising from an instructor to and interest in mentorship can be assessed by the
professor by the age of 50 and then in 1993, I received level of satisfaction and academic success of former
an endowed professorship. I was interested in new students. - Can you have more than one mentor?
drug development and combined modality therapies Yes - Must the mentor be in your institution? No
especially in lung cancer. My group helped to develop Successful candidates for an academic position in
Paclitaxel as part of my NCI phase I contract when lung cancer demonstrate the following: - Evidence of
I was the principal investigator. I have authored broad clinical training with focused expertise in lung
or co-authored over 200 articles in peer-reviewed cancer (particularly important for a clinical research
journals, edited 3 books, and am presently Editor- position). - Strong foundation for an independent
in-Chief of the journal Current Treatment Options scientiÀc career as evidenced by authorship of peer-
in Oncology. I am panel chair of three National reviewed publications and presentations at national
Comprehensive Cancer Network (NCCN) clinical meetings. - Initial grant support (particularly important
practice guidelines including NSCLC. I am an active for laboratory research). - Positive professional image
member in ECOG and RTOG besides both national at the interview, demonstrating good interpersonal
and international professional organizations. Based skills. To understand academic medical centers,
on both my own life experiences and my observation you should read Joseph V. Simone’s article entitled
of the lives and careers of many others over the “Understanding Academic Medical Centers: Simone’s
years, what are some key factors - both for and Maxims (Clin Cancer Res 1999; 5:2281-2285. Two
against - that inÁuence your decision as to whether important maxims are (1) the institution does not love
you and (2) you are not irreplaceable. If you embark relevant papers to pick up any omissions. There are
on an academic career in lung cancer you should of course reviews published that summarise current
do the following: - Enjoy what you do - Strive for knowledge or recent publications on speciÀc topics.
perfection - Be a professional - Be able to “reinvent Many are good but treat them cautiously. There
yourself” if you wish to stay at an institution you like - are two types: the expert review and the systematic
Be a team player So, can you plan an academic career review. The former, written by acknowledged or
in lung cancer? The answer is not a simple one - not self-proclaimed experts, may be good but may be
just “yes” or “no.” I would suggest that, as you look biased not only in the literature selected but in its
at your career options, you must develop and exercise interpretation and summary. Beware of any review
your skills in self-knowledge, observation, reÁection, that does not how the literature was identiÀed,
planning and Áexibility. selected and evaluated. Systematic reviews do
Keywords: Clinical research, Basic science/ attempt to provide an objective summary with an
translational research, Academic career, Mentor explicit search strategy, a clear method for assessing
the quality of each paper and a systematic summary
of the evidence, including a synthesis of key
Young Investigator’s Session Sunday, 3 July 2011 07:00-11:00 outcomes in a meta-analysis. Both have strengths
and weaknesses: the expert review is likely to be
Y.4 USING THE PUBLISHED biased but can give a useful expert perspective; the
LITERATURE EFFECTIVELY systematic review is more likely to be objective
Fergus Macbeth but its conclusions still may be biased. Clinical
Centre For Clinical Practice, National Institute For guidelines are another useful source of information
Health And Clinical Effectiveness/United Kingdom and a means of keeping up to date. But also need
to be viewed with some caution. Questions to ask
Abstract: The published clinical literature is huge. include: 1.Who created them? A professional body
Medline currently cites over 25,000 papers between or another agency, (e.g. governmental or insurance).
2007 and 2011 for ‘lung neoplasm’. It would be Each will have a different perspective and be trying
impossible for anybody to read more than 1% a year to inÁuence practice in different ways. 2. Were they
and that would be good going. Why do we need this developed according to international standards, with
literature? As conscientious health professionals inclusive group membership, systematic review of
we need to keep up to date. Secondly it is the the literature and an explicit method of developing
inescapable platform for any new research. But it recommendations? So, all published literature
can also itself be the subject of research. In this needs to be approached with healthy scepticism.
presentation I will give some on using this resource High impact journals may still publish misleading
effectively. Subscribing to a service that provides or frankly fraudulent articles and any research
an update is helpful, but it may be important to publication is likely to contain methodological Áaws,
Ànd all past publications. The provision of on line frank omissions or more or less obvious personal
information has made things easier and often a bias. A core skill for any health professional or
search engine like Google may be an efÀcient way clinical researcher is critical appraisal. Many guides
of getting things. But sophisticated enquiries will have been written about this but here are a few hints.
mean using one of the dedicated databases such as If you are interested in a paper, whether primary
MedLine. It needs training or a tame information research or a systematic review, and feel its results
specialist to use the search terms most efÀciently or conclusions may be relevant to your clinical
and to create speciÀc search strategies that avoid practice or research, don’t just read the Abstract and
getting only a few irrelevant, titles or a vast list Conclusions. Start by reading the Methods (probably
that has to sifted one by one. You need to decide the least read but most important part of any paper)
whether you want a sensitive search which will and understand what they were trying to do and
Ànd all the relevant papers at the expense of a how they did it. Look for any omissions, errors or
signiÀcant dross; or a speciÀc one that includes only lack of clarity. Next scrutinise the results. Did they
relevant titles but misses others. It is important to follow the methods they described and were key
remember that the databases themselves may not data clearly reported? Did those logically lead to
be complete and so if you want to Ànd all relevant the results they claim? Look at the authors’ conÁicts
papers, go through the references lists of most of interest and assess what biases they might have.
Finally read the conclusions and discussion. Are Young Investigator’s Session Sunday, 3 July 2011 07:00-11:00
conÀdent in the results are valid and do you agree
with the conclusions? Look out for any subsequent Y.5.1 THE FUTURE ROLE OF
correspondence to see what arguments and defence it DIFFERENT SPECIALISTS IN
has generated. The published literature is an essential MULTIMODALITY MEDICINE (LUNG
platform for research and must be reviewd in order: CANCER) - MEDICAL ONCOLOGIST
· Not to repeat the research · Not to repeat the Enriqueta Felip
mistakes · To identify the real gaps in the knowledge Oncology Department, Vall D’Hebron Hospital/
· Find the best methods. The literature itself can be Spain
the subject to of research and carrying out a thorough
high quality systematic review is an important form Abstract: Suspected lung cancer is often identiÀed
of research in itself which is not only educational but by the primary care physician and patients are then
a source of publications needing no labs or patients usually referred to a hospital for diagnosis. Lung
but just good methods, a critical mind, attention to cancer diagnosis and management is complex and
detail and plenty of time. Plump up your resumé with requires a multidisciplinary approach. State-of-the-
a systematic review or two! Finally the published art care of lung cancer patients requires the input
literature would be nothing without peer review . from many specialists in pneumology, pathology,
Few apart from editors know how variable it quality thoracic surgery, radiology, medical oncology, and
and usefulness are. Only accept to peer review radiation oncology among others. How to achieve
a paper if you believe you have the appropriate a multidisciplinary approach in lung cancer?
knowledge and have no clear conÁicts of interest. Multidisciplinary meetings to discuss lung cancer
Assess the scientiÀc quality (originality, appropriate patients provide the ideal forum for exchange of
methods, clearly described and believable results, professional opinions. Regular tumors committee
justiÀable conclusions, relevant discussion) and meetings are therefore, recommended at each
the presentation (well written, clear tables, helpful institution, at which there should be representation
Àgures and illustrations). Write an overall summary from a number of specialist areas, so that the patient
of what the paper is trying to show and a brief receives the best attention and optimal disease
opinion of its quality, relevance and importance. management. All new lung cancer patients should
Then, if need be, provide line by line comment on be discussed in depth. Medical oncologists should
any major Áaws, errors and omissions. Ensure that take an active part in the multidisciplinary process of
you are accurate and fair and that all your criticisms which tumor committee meetings are an integral part.
can be reasonably substantiated. In conclusion this What should be the skills for a medical oncologist
huge creature can be tamed and exploited in a variety working in lung cancer? Medical oncologists
of ways to promote evidence-based clinical practice working with thoracic malignancies require: · A
and highly quality research. But like a wild animal deep knowledge of prevention of lung cancer and
it needs to be treated with caution and respect. Use familiarity with the risk factors for the development
all its strengths and recognise all its hazards and of lung cancer. Medical oncologists should be aware
weaknesses. of lung cancer screening studies, and smoking
Keyword: Lung Cancer. Published literature. cessation strategies. · Willingness to participate in
Systematic reviews a multidisciplinary approach. Medical oncologists
should participate fully in the tumors committee
meetings. They must have extensive knowledge of
non-invasive and invasive risk assessment work-
up, the staging system, prognostic factors, criteria
of inoperability and indications for and value of
surgery, chemotherapy and radiotherapy, particularly
in locally advanced disease. · Experience in
determining key factors for treatment selection as
well as in the use and indications of chemotherapy,
biological agents and supportive care strategies. ·
Good communication skills. In lung cancer, effective
communication with patients is important in order to
decrease their anxiety and distress. Furthermore, it is adenocarcinoma update was the adaptation of lung
crucial to maintain a good level of interaction among cancer classiÀcation to embrace biopsy and cytology
all professionals involved in the management of the material (1,2). WHO classiÀcations are based
lung cancer patient. Clinical research in thoracic primarily on resections whilst this is reality for only
malignancies Clinical investigation is essential for a minority of cases of lung cancer. As a result, we
ongoing medical education. For medical oncologists, now have recommendations for terminology that
clinical trials are the basis of clinical research. There will hopefully lead to more uniform classiÀcation for
is also a need to work in cooperative groups in all patients undergoing both biopsy and cytological
order to arrive at relevant Àndings in investigation. examination. It is pathologists especially who must
Furthermore, it is important for the physicians embrace this terminology to allow consistency in
treating lung cancer to understand the disease at a diagnosis, especially when patients are to be entered
molecular level and for them to be familiar with into drug trials. At the same time, the limitations of
emerging technologies. Medical oncologists should needle aspirations etc., in terms of sample size and
collaborate in the development and consolidation of requirements made of the tissue, need to be balanced.
thoracic clinical research units. One cannot have a patient with all material sent for
molecular review and no diagnosis, equally all the
material should not be smeared on a single slide
Young Investigator’s Session Sunday, 3 July 2011 07:00-11:00 for diagnosis. The 7th TNM staging revision (3) has
brought additional responsibility to the pathologist,
Y.5.2 THE FUTURE ROLE OF not just continuing to provide minimum data sets
DIFFERENT SPECIALISTS IN for national data collection, but proposing that
MULTIMODALITY MEDICINE (LUNG microscopic examination by the pathologist be used
CANCER) - PATHOLOGIST to distinguish synchronous primaries from satellite
Andrew G. Nicholson nodules rather than clinically documenting their
Departement Of Histopathology, Royal Brompton macroscopic presence as multifocal tumours. Of
And HareÀeld NHS Foundation Trust/United note, morphological review has proved as accurate
Kingdom as gene proÀling in distinguishing synchronous
primaries from satellite nodules (4). There was
Abstract: To look at the role of the pathologist also a call for more investigation into the relevance
in a multidisciplinary setting To understand that of histopathological criteria to TNM staging, for
tissue usage needs to be planned in an increasingly example extent of pleural invasion (5,6), and it is up
molecular era. To become aware of the balance to pathologists with interest in lung cancer to involve
required between routine morphological diagnosis themselves in groups informing the 8th revision.
and ancillary data in relation to optimal patient The next decade will see further requirements
management. The last decade has seen rapid for immunohistochemical and moelcular data
advances in the Àeld of lung cancer, with signiÀcant alongside morphological diagnosis. As well as
impact on the diagnostic pathologist. A key looking for genetic abnormalities such as EGFR
aspect is increasing recognition of the need for and other mutations, there is testing for excision
multidisciplinary review, borne out by the recently repair cross-complementation group-1 (ERCC-
published revision of adenocarcinoma classiÀcation 1), thymidylate synthase (TS) and (ribonucleotide
(1) where previous iterations were criticised for reductase messenger-1) RRM-1, in relation to
being too “for pathologists by pathologists.” potential activities of platin-based, pemetrexed-based
The importance of multidisciplinary review is and gemcitabine-based therapies (7). However,
emphasized in relation to the increasing requests pathologists must not forget the importance of
for molecular data, the need for further sampling routine morphological diagnosis as this still remains
in relation to equivocal or ‘non-speciÀc’ categories the cornerstone of global lung cancer classiÀcation.
of diagnosis, and whether clinical features may Reference List 1. Travis WD, Brambilla E, Noguchi
assist in reÀning diagnosis and deciding future M, et al. International Association for the Study of
management. The pathologist must be part of Lung Cancer/American Thoracic Society/European
these discussions, especially ensuring judicious Respiratory Society international multidisciplinary
use of tissue, in particular preservation of positive classiÀcation of lung adenocarcinoma. J Thorac
cytological specimens. One of the products of the Oncol 2011;6:244-285. 2. Nicholson AG, Gonzalez
D, Shah P, et al. ReÀning the Diagnosis and EGFR to the therapeutic decision through multidisciplinary
Status of Non-small Cell Carcinoma in Biopsy meetings with the surgeons, radiotherapists,
and Cytologic Material, Using a Panel of Mucin radiologists, pathologists. Depending on the country
Staining, TTF-1, Cytokeratin 5/6, and P63, and of origin they may be also involved in the medical
EGFR Mutation Analysis. Journal of Thoracic treatment of lung cancer (chemotherapy and targeted
Oncology 2010;5:436-441. 3. International Union therapies). Regarding this speciÀc role, there is at
Against Cancer (UICC). TNM classiÀcation of present much more controversy. Across European
malignant tumours. 7 ed. New York: Wiley-Liss; countries, medical oncologists are mainly those
2009. 4. Girard N, Deshpande C, Lau C, et al. who conduct chemotherapy treatments for example
Comprehensive histologic assessment helps to in Spain, Italia, United Kingdom, Germany....
differentiate multiple lung primary nonsmall cell whereas in France, for example, pulmonologists
carcinomas from metastases. Am J Surg. Pathol. are on historical grounds, strongly involved in the
2009;33:1752-1764. 5. Shimizu K, Yoshida J, Nagai medical treatment of lung cancer patients. In US,
K, et al. Visceral pleural invasion classiÀcation in generally speaking, chemotherapy is delivered by
non-small cell lung cancer: a proposal on the basis medical oncologists. There are some noticeable
of outcome assessment. J Thorac. Cardiovasc. Surg. exceptions such as the editor in chief of the Journal
2004;127:1574-1578. 6. Osaki T, Nagashima A, of Thoracic Oncology, Jim Jett. As a matter of fact,
Yoshimatsu T, Yamada S, Yasumoto K. Visceral thoracic oncology is now considered as a major part
pleural involvement in nonsmall cell lung cancer: of the medical organizations dealing with respiratory
prognostic signiÀcance. Ann. Thorac. Surg. diseases. For example, in the European Respiratory
2004;77:1769-1773. 7. Coate LE, John T, Tsao MS, Society (ERS), thoracic oncology group which
Shepherd FA. Molecular predictive and prognostic was part of the clinical assembly has been replaced
markers in non-small-cell lung cancer. Lancet Oncol. in 2010 by an assembly indicating that thoracic
2009;10:1001-1010. oncology has become a strong pillar of the society
Keywords: Lung cancer, pathology, Histopathology . Since this decision, European guidelines in the
Àeld of Thoracic Oncology have been published
either by the ERS alone or in association with the
Young Investigator’s Session Sunday, 3 July 2011 07:00-11:00 European Society of Thoracic Surgeons regarding
the preoperative assessment of lung cancer patients
Y.5.3 THE FUTURE ROLE OF or the management of malignant mesothelioma.
DIFFERENT SPECIALISTS IN Collaboration has also been established with the
MULTIMODALITY MEDICINE (LUNG European Society of Medical Oncology and the
CANCER) - PULMONOLOGIST European Society for Therapeutic Radiology and
Elisabeth Quoix Oncology and two meetings have been held by the
Pulmonary Medicine Department, Strasbourg European Multidisciplinary Conference in Thoracic
University Hospital/France Oncology. Also Thoracic Oncology is now part of
the HERMES (Harmonised Education in Respiratory
Abstract: Lung cancer is the Àrst cause of death Medicine for European Specialists) besides post-
by cancer in the developed and developing world graduate courses which were organised for many
. While its incidence is decreasing in males in years by the ERS during the annual congress. The
developed world, there is still an important increase American College of Chest Physicians also edit
in females. Looking at the present situation, recommendations about treatment of lung cancer
pulmonologists are by deÀnition involved in the on a regular basis, recommendations that concern
prevention (especially regarding smoking habits) not only the pretherapeutic management of lung
the diagnosis and the pre-treatment evaluation cancer but also medical treatment. this seems to
(disease extent assessment and medical assessment indicate that at least North American pulmonologists
especially for surgical management). Taking into are interested in the therapeutic management of
account that they are especially trained in chest lung cancer. The future role of pulmonologists
imaging, bronchoscopy and pulmonary function in the multimodality management of lung cancer
testing, there is no controversy about their role in will probably be deÀned by the health politics of a
the diagnosis and pre-therapeutic evaluation of a given country, by the relative number of medical
lung cancer. As such they are entitled to participate oncologists and pulmonologists in this country which
will determine either restriction or encouragement Young Investigator’s Session Sunday, 3 July 2011 07:00-11:00
for chemotherapy delivery by chest physicians.
Above all, it will depend on the training received Y.5.4 THE FUTURE ROLE OF
and in this respect the organization of this training DIFFERENT SPECIALISTS IN
by the ScientiÀc Societies of Respiratory Diseases MULTIMODALITY MEDICINE (LUNG
is of paramount importance. The pulmonologist is CANCER) - RADIOTHERAPIST
at a crucial place for lung cancer management as Billy W. Loo
he is the only one who holds the tools of diagnosis Radiation Oncology, Stanford University & Cancer
making. Whether he wants or not to participate to the Center/United States Of America
therapeutic management depends on him for a great
part. Abstract: The role of the Radiation Oncologist in
References the multimodality treatment of lung cancer continues
1. Ferlay J, Parkin DM, Steliarova-Foucher E. to increase. Numerous technological advances
Estimates of cancer incidence and mortality in in imaging and radiation treatment delivery have
Europe in 2008. Eur 2010;46(4):765-81 Epub 2010 increased both the indications and therapeutic
Jan 29. window for radiation therapy. Future improvements
2. Ferlay J, Shin HR, Bray F, Forman D, Mathers in early detection of lung cancer as well as more
C, Parkin DM. Estimates of worldwide burden of efÀcacious individualized and molecularly-targeted
cancer in 2008: GLOBOCAN 2008. Int J Cancer systemic therapies will only increase the potential for
2010;Epub ahead of print. localized radiation therapy to improve cure rates and
3. Sculier JP, Vansteenkiste J, Schonfeld N, prolong survival in both early and advanced stage
Scherpereel A. Thoracic oncology in Europe: lung cancer. For Radiation Oncologists, the future is
the ERS action plan by the Thoracic Oncology bright!
Assembly. Eur Respir J 2010;36(6):1227-8. Keywords: Radiation Therapy, Stereotactic ablative
4. Brunelli A, Charloux A, Bolliger CT, et al. ERS/ radiotherapy (SABR), Image-guided radiation
ESTS clinical guidelines on Àtness for radical therapy (IGRT)
therapy in lung cancer patients (surgery and chemo-
radiotherapy). Eur Respir J. 2009;34(1):17-41.
5. Scherpereel A, Astoul P, Baas P, et al. [Guidelines Young Investigator’s Session Sunday, 3 July 2011 07:00-11:00
of the European Respiratory Society and the
European Society of Thoracic Surgeons for the Y.5.5 THE FUTURE ROLE OF
management of malignant pleural DIFFERENT SPECIALISTS IN
mesothelioma]. Eur Respir J 2010; 35: 479–495 MULTIMODALITY MEDICINE (LUNG
6. Robinson LA, Ruckdeschel JC, Wagner H, Jr., CANCER) - SURGEON
Stevens CW. Treatment of non-small cell lung Gavin M. Wright
cancer- Thoracic Surgery, St Vincent’s Hospital/Australia
stage IIIA: ACCP evidence-based clinical practice
guidelines (2nd edition). Chest. 2007;132(3 Abstract: Traditional Thoracic Surgeon has up
Suppl):243S-265S. to now been a highly skilled technician, with a
7. Socinski MA, Crowell R, Hensing TE, et al. large grounding in cardiovascular and respiratory
Treatment of non-small cell lung cancer, stage IV: physiology, anatomy and pathology. Traditional
ACCP evidence-based clinical practice guidelines Thoracic Surgeon has often been non-specialized,
(2nd edition). Chest. 2007;132(3 Suppl):277S-289S. with a signiÀcant workload of cardiac or general
Keywords: pulmonologist, medical oncologist, Lung surgery to contend with. As such, it has been
cancer, Chemotherapy difÀcult for all but a minority of thoracic surgeons
to be complete surgical oncologists. Before this
decade, that probably mattered little. Patients with
lung cancer lived or died according to whether
they had a complete lung cancer resection.
It was accepted that some patients would be
explored and closed up. There was no adjuvant
chemotherapy, no evidence of beneÀt for doing
more complete node dissections, and proving a

recurrence histologically didn’t really change
the ongoing palliative management of a patient.
Palliative surgery extended to spraying in some
talc for a recurrent pleural effusion. The 20-25%
of presenting patients that could have a resection
only expected their surgeon to cure about 50% of
them and for the rest it was “bad luck” and over to
the medical and radiation oncologists to deal with.
The result of advances in survival is that this

chronic disease will need more sustainable palliative
measures. There will be more aggressive surgical
palliation and the long-term returns will justify this
intervention.
The increasing need for palliation with minimal
invasion will see Future Thoracic Surgeon widening
the surgical armamentarium to include endobronchial
The last decade has seen some fairly monumental techniques, implantable catheters and more novel
changes that have radically altered this traditional methods of obtaining good tissue biopsies.
surgical paradigm. The changes to the staging Tissue will also be needed for research purposes as
system places more emphasis on very accurate recent collaborations have shown that there are still
staging, and now it actually matters. Finding just mutations to be found if you have a large enough “n”
a single microscopically positive mediastinal node for the particular tumour subtype. Surgeons need to
will mean a patient will get adjuvant chemotherapy be involved with the laboratory researchers and the
and improve their chances of being alive at 5 years latter need to actively engage the surgeons if they
by 4-15%. PET scanning, EBUS and improved are to be successful. The increasing need for tissue
spiral CT technology should result in fewer futile for clinical and research purposes will probably
operations, and surgeons should now hold their increase the workload for Future Thoracic Surgeon.
complete resection benchmark rate at well over This, along with the increased VATS Wedge
90%. It is now more important than ever to get workload from lung cancer screening will more
an accurate histological diagnosis, even in stage than compensate for the probable reduction in major
IV disease, as choice of chemotherapy agent is anatomical lung cancer resections.
now dependent on histology. Being able to biopsy Leadership in the multidisciplinary meeting is a
patients to determine mutational status (e.g. EGFR, role that should be sought by the dedicated Future
ALK, FGFR1) is now critical for increasing overall Thoracic Surgeon. This will mean being educated
survival and quality of life. Adenocarcinoma is no and updated in the fundamentals of all the managing
longer a single disease, and with comprehensive disciplines, and also knowing where other surgical
histological subtyping Future Thoracic Surgeon specialists can assist in palliation and tissue
can offer better prognostication. It is now possible acquisition. Future Thoracic Surgeon must now
to explain the wide variation in survival with truly be the consummate surgical oncologist while
adenocarcinoma by the predominant subtype. continuing with the successes of Traditional Thoracic
Surgeon.
Keywords: histology, palliative care, lymph node
dissection, neoadjuvant
Young Investigator’s Session Sunday, 3 July 2011 07:00-11:00 that oncology should be taught as a separate subject.
Surveys of medical undergraduates have shown that
Y.6 IMPROVING ACCESS TO over the last decade students had less contact with
EDUCATION AND CANCER CARE IN patients and retain some misconceptions about cancer.
DEVELOPING COUNTRIES Only one quarter of Egyptian doctors knew that breast
Michael Barton cancer was commonest in post-menopausal women.
Sw Clinical School, Faculty Of Medicine, Univesity A survey of 139 medical students at the University
Of NSW/Australia of Malaysia showed that 29% had rarely visited
a radiotherapy department and only 35% had the
Abstract: Cancer in Low and middle income knowledge to prescribe morphine for cancer pain.
countries. Over half of all cases of cancer in the world
arise in people in low and middle income (LMI) In order to deliver appropriate standards of cancer
countries. These are countries where the average teaching an undergraduate program should incorporate
annual income is less than US$9386. By 2020 it is a national or international standard curriculum and a
estimated that 70% of cases of cancer will occur in minimum number of essential experiences. Because
LMI countries. assessment drives education, students’ knowledge,
skills and attitudes relating to cancer should be
The causes and distribution of cancer types in LMI assessed and the outcomes of such assessment
differ from high income countries with a greater should inform the curriculum. An example of a
proportion of cancers related to preventable causes cancer curriculum that reÁects the diversity of cancer
such as HPV, viral hepatitis and smoking. This and knowledge that is required is the Cancer Council
the perceived cost of cancer treatment have lead to Australia’s Ideal Curriculum in Oncology for
a one-sided emphasis on cancer prevention from Medical Students (http://www.cancer.org.au//policy/
some international organisations. Despite this cancer Publications/IdealOncology.htm).
treatment is delivering signiÀcant services in LMI.
The multidisciplinary nature of cancer care means Access to education about cancer has been improved
that cancer requires special attention to develop by new internet resources for health professionals.
comprehensive cancer control plans with involvement Information technology offers new opportunities to
of health professionals, administrators, politicians and deliver education resources to larger audiences. The
academics. Applied Sciences of Oncology Course (ASOC) was
sponsored by International Atomic Energy Agency
Health professionals and specialists need relevant and (IAEA). It is a free course in English aimed at trainee
ongoing education about cancer that has often been oncologists. ASOC comprises 80 one-hour modules of
missing from teaching programs. Cancer treatment interactive teaching on CD ROM. The program arose
can be effective and is within the reach of most low from a long-standing face-to-face teaching course. It
and middle income countries. is available from http://www.iaea.org/Publications/
Training/Aso/register.html . In two years it has been
Education about cancer: SigniÀcant gains in cancer downloaded over 2000 times.
outcomes can be made by improving education
of health professionals about cancer. Medical The Virtual University for Cancer Control and
undergraduate education about cancer leaves Regional Training Network (VUCCnet) is a new
many practitioners ill-prepared to deal with it. All initiative of the Program for Action on Cancer
practitioners need some knowledge of cancer. Those Treatment (PACT) of IAEA to establish a training
practicing in rural areas may need more knowledge network for oncologists between four centres in
because of their isolation from tertiary services. sub-Saharan Africa. It aims to increase the number
Many oncologists feel that they do not have adequate of trainees and support them with a range of on-line
access to students because of entrenched attitudes resources and mentoring in radiation medicine.
within universities aimed at protecting established
teaching programs and leaving little room to adapt Cure4Kids (https://www.cure4kids.org/ums/home/)
teaching to the changing needs of society. 80% of from St Jude’s Hospital provides medical education
Argentinean oncologists felt that oncology teaching on children’s cancer with interactive forums, wikis
for undergraduates was inadequate and 73% thought and on-line seminars. By establishing collaborations
with centres in LMI countries they have demonstrated Young Investigator’s Session Sunday, 3 July 2011 07:00-11:00
improvements in survival from childhood cancers.
Y.7 AN EXAMPLE OF A
Access to cancer care: Cancer treatment programs MULTIDISCIPLINARY PATIENT AND
must be supported along with prevention programs. TREATMENT DECISION MEETING
While many cancers may be preventable this will Emile F. Comans
not help the current cases of cancer or those that will Nuclear Medicine & Pet Research, VU Medical
develop in the next 10 to 20 years. Center/Netherlands
Cancer treatment in LMI has a different focus because Abstract: Accurate staging and tailored therapy
of the different types of tumours and because patients are key elements with respect to the evaluation of
present with more advanced stage cancers. Between (suspected) lung cancer patients. The diagnostic
50% and 80% of breast cancers in LMI countries workup of patient has become increasingly complex
were advanced at diagnosis compared with 15% in during the last years. This can be explained in part by
High Income countries, and 56% of cervix cancers in the extensive use of various conventional (laboratory
Bangalore, India were Stage III compared with 15% tests, bronchoscopy, physical examination) and
in High Income countries. More advanced cancers are new (multislice CT, PET-CT, MRI, and EBUS/
less likely to be amenable to surgery and therefore are EUS) diagnostic tests. In addition, the therapeutic
more likely to be treated by radiotherapy. options in NSCLC patient have increased both in
a quantitative (RFA ablation treatment, combined
Radiotherapy has a signiÀcant role because tumours modality treatment) and in a qualitative (VATS
present later and surgical expertise is often limited. procedures, stereotactic radiotherapy) manner.
Most surgeons are general surgeons or gynaecologists. The aim of this presentation is to give young
Radiotherapy is one of the most cost-effective forms docters(potentially) involved in the decision making
of cancer treatment. A study of 11 countries showed process of a multidisciplinary lung oncology
that the average cost of cobalt treatment was $4.87. meeting suggestions that may help them in their
Estimates suggest that radiotherapy is the treatment (future) role within such a team. A clinical case will
of choice in 47% and 67% of cancer patients. Yet a be presented to illustrate the need to have access
survey of 72 LMI countries found 24 countries with to essential information available for effective
populations over 1 million that did not have any communication between the participants of the
radiotherapy service. Access to chemotherapy drugs is meeting. Adequate preparation of the meeting and
difÀcult although many countries purchase the WHO case presentation, including complete patient data
“Essential Drugs list”. (patient demographics, (smoking) history, Àndings
from physical examination and laboratory test results
The provision of safe and effective oncology services including pulmonary function tests) and the results
is complex. It requires a substantial capital investment of additional diagnostic tests (conventional X-ray,
in radiotherapy equipment and specially-designed CT scans, PET-CT and Àndings from bronchoscopy)
buildings as well as ongoing investment in drugs, should be available during the meeting. From
maintenance and replacement of the equipment, expert the perspective of an imaging specialist (nuclear
teams of doctors, therapists, physicists, and nurses. medicine physician) with extensive experience
Even if funds are available, the necessary medical, in lung cancer staging and a member of such a
scientiÀc and technical expertise is in short supply in multidisciplinary team frequently encountered
many countries. This is the main constraint in many dilemmas and elements for discussion will be
LMI countries. addressed. The presenter will focus on conditions
that are essential for effective communication
Improvements in access will only come with good between the different disciplines (pulmonologists,
service planning, investment in equipment, linkages surgeons, oncologists, radiotherapists, pathologists
between facilities to reduce the risks of isolation, and imagers) to facilitate the (further) diagnostic
access to information, and appropriate educational evaluation and come to the optimal choice of
resources. therapy.
Keywords: access, cancer care, education Keyword: Multidisciplinary
ORAL SESSIONS versus zoledronic acid (ZA) for preventing SREs

in patients with bone metastasis from solid tumors
(except breast and prostate) or with multiple
Session O01: Conference President’s myeloma.
Selection Methods: Patients were randomized 1:1 to receive
either monthly subcutaneous denosumab 120
mg or intravenous ZA 4 mg (dose adjusted for
Monday, 4 July 2011
renal impairment). Daily calcium and vitamin
D supplementation was recommended. The
Conference President’s Selection Monday, 4 July 2011 10:30-12:00 primary endpoint of time to Àrst on-study SRE has
previously been presented. An exploratory analysis
O01.01 OVERALL SURVIVAL was performed analyzing overall survival among
IMPROVEMENT IN PATIENTS WITH patients with lung cancer (non-small cell lung cancer
LUNG CANCER TREATED WITH [NSCLC] or small cell lung cancer [SCLC]).
DENOSUMAB VERSUS ZOLEDRONIC Results: In 801 patients with lung cancer (N=1776),
ACID: RESULTS FROM A RANDOMIZED overall survival was prolonged by 1.2 months
PHASE 3 STUDY with denosumab over ZA (median 8.9 months
Giorgio Scagliotti1, Vera Hirsh2, Salvatore Siena3, denosumab, 7.7 months ZA; HR 0.80 [0.67–0.95];
David Henry4, Penella Woll5, Christian Manegold6, P=0.01). Improved survival was seen among
Philippe Solal-Celigny7, Gladys Rodriguez8, Maciej those with NSCLC (n=702) receiving denosumab
Krzakowski9, Nilesh D. Mehta10, Lara Lipton11, José (median 9.5 months denosumab, 8.1 months ZA;
A. García-Sáenz12, Jose Pereira13, Kumar Prabhash14, 0.78 [0.65–0.94]; P=0.01). Further analysis by
Ciuleanu Tudor-Eliade15, Vladimir Kanarev16, Amy histological type showed denosumab was associated
Feng17, Ira Jacobs17 with prolonged survival over ZA in squamous cell
1
Clinical And Biological Sciences, University Of carcinoma (8.6 months denosumab, 6.4 months ZA;
Turino/Italy, 2Department Of Oncology, McGill 0.68 [0.47–0.97]; P=0.035) and adenocarcinoma
University Health Centre/Canada, 3Ospedale sub types (0.80 [0.62–1.02]; P=0.075). Survival
Niguarda Cà Granda/Italy, 4Joan Karnell Cancer in patients with SCLC (n=109) was 7.6 months
Center/United States Of America, 5Weston Park with denosumab versus 5.1 months with ZA (0.81
Hospital, University Of ShefÀeld/United Kingdom, [0.52–1.26]; P=0.36). Incidence of overall adverse
6
Klinikum Mannheim/Germany, 7Clinique Victor events (AEs) among patients with lung cancer was
Hugo/France, 8South Texas Oncology And balanced between groups (96.8% denosumab, 95.4%
Hematology/United States Of America, 9Medical ZA), with serious AEs occurring less frequently
Oncology, The Maria Sklodowska-curie Institute with denosumab (66.0% denosumab, 72.9% ZA).
Of Oncology/Poland, 10Oncology Hematology Cumulative incidence of osteonecrosis of jaw was
Associates Of Northern Illinois/United States Of also balanced (0.7% denosumab, 0.8% ZA; P=1.0).
America, 11Western Hospital/Australia, 12Hospital Rates of hypocalcemia were 8.6% denosumab versus
Clínico San Carlos/Spain, 13Oncopneumology 3.8% ZA.
Department, Instituto Do Cancer Arnaldo Vieira De Conclusion: In this exploratory analysis among
Carvalho/Brazil, 14Medical Oncology, Tata Memorial patients with lung cancer, denosumab was associated
Hospital/India, 15Institutul Oncologic I. Chiricuta/ with an improved overall survival compared with
Romania, 16Regional Oncology Dispensary With ZA. This observation warrants further investigation.
Inpatient Sector/Bulgaria, 17Amgen Inc./United Keywords: non-small cell, small cell, Overall
States Of America survival, Clinical trial
Background: Denosumab (XGEVA™), a fully

human anti-RANKL monoclonal antibody, is
approved in the United States to prevent skeletal-
related events (SREs) in patients with solid tumors
and bone metastasis including lung cancer. We
present here survival data for patients with lung
cancer participating in a phase 3 trial of denosumab
Conference President’s Selection Monday, 4 July 2011 10:30-12:00 Conference President’s Selection Monday, 4 July 2011 10:30-12:00
O01.02 RANDOMIZED PHASE 3 TRIAL O01.03 BRITISH THORACIC ONCOLOGY

OF AMRUBICIN VERSUS TOPOTECAN GROUP TRIAL, BTOG2: RANDOMISED
AS SECOND-LINE TREATMENT FOR PHASE III CLINICAL TRIAL OF
SMALL CELL LUNG CANCER (SCLC) GEMCITABINE COMBINED WITH
Joachim Von Pawel1, Robert Jotte2, David R. Spigel3, CISPLATIN 50MG/M2 (GC50) VERSUS
Mark A. Socinski4, Mary E.R. O’Brien5, Eugene CISPLATIN 80MG/M2 (GC80) VERSUS
Paschold6, Joerg Mezger7, Martin Steins8, Léon CARBOPLATIN AUC 6 (GCB6) IN
Bosquée9, Jeffrey Bubis10, Kristiaan Nackaerts11, Jose ADVANCED NSCLC
M. Trigo12, Philip Clingan13, Wolfgang Schütte14, David Ferry1, Lucinda Billingham2, Hugh Jarrett2,
Paul Lorigan15, Martin Reck16, Manuel Domine17, David Dunlop3, Joyce Thompson4, Muthu Kumar5,
Frances Shepherd18, Richard Mcnally19, Markus Geraldine Skailes6, Marianne Nicolson7, Riyaz
Renschler19 Shah8, Pauline Leonard9, A Chetiyawardana10, Paula
1
Zentrum für Pneumologie und Thoraxchirurgie, Wells11, Conrad Lewanski12, Penella Woll13, Barbara
Asklepios Fachkliniken München-Gauting/Germany, Crosse14, Michelle Hill2, Sarah Pirrie2, Kenneth J.
2
US Oncology/United States Of America, 3Sarah O’Byrne15
1
Cannon Research Institute/United States Of America, Oncology, New Cross Hospital/United Kingdom,
4 2
Lineberger Comprehensive Cancer Center/United University Of Birmingham/United Kingdom,
States Of America, 5Royal Marsden NHS Foundation 3
Medical Oncology, Beatson West Of Scotland
Trust/United Kingdom, 6Piedmont Hematology Cancer Centre/United Kingdom, 4Birmingham
Oncology Associates/United States Of America, Heartlands Hospital/United Kingdom, 5Derby Royal
7
St. Vincentius-Kliniken/Germany, 8Thoraxklinik Hospital/United Kingdom, 6Royal Preston Hospital/
am Universitätsklinikum/Germany, 9C.H.U. Sart- United Kingdom, 7Aberdeen Royal InÀrmary/United
Tilman/Belgium, 10Florida Oncology Associates/ Kingdom, 8Kent Oncology Centre/United Kingdom,
United States Of America, 11University Hospital 9
Whittington Hospital/United Kingdom, 10Manor
Gasthuisberg/Belgium, 12Hospital Universitario Hospital/United Kingdom, 11Whipps Cross Hospital/
Virgen De La Victoria/Spain, 13Southern Medical United Kingdom, 12Imperial College Healthcare/
Day Care Centre/Australia, 14Krankenhaus United Kingdom, 13University Of ShefÀeld/United
Martha-Maria Halle-Doelau/Germany, 15Christie Kingdom, 14HuddersÀeld Royal InÀrmary/United
Hospital NHS Foundation Trust/United Kingdom, Kingdom, 15Oncology, St James’s Hospital/Ireland
16
Krankenhaus Großhansdorf, Zentrum für
Pneumologie und Thoraxchirurgie/Germany, Background: Platins are considered the key
17
Fundación Jiménez Díaz. Universidad Autónoma drugs in the treatment of stage IIIB/IV NSCLC.
De Madrid/Spain, 18Princess Margaret Hospital/ Carboplatin has been reported as inferior to
Canada, 19Celgene Corporation/United States Of cisplatin in meta-analyses (Ardizzoni et al 2007,
America JNCI , 99, 847) and the optimal dose of cisplatin
has not been subjected to meta-analysis or large
Abstract under Embargo - will be presented in a RCT and is unclear.
press conference during WCLC 2011. Methods: Patients were eligible if they had
histologically proven NSCLC, performance
status (PS) 0-2, stage IIIB/IV disease and had a
glomerular Àltration rate (GFR) of > 60 mL per
min calculated using the Wright equation. They
were randomised to gemcitabine (1250mg/m2)
combined with cisplatin 50mg/m2 , cisplatin 80mg/
m2 or carboplatin AUC 6, all for up to 4 cycles. The
dose of carboplatin was calculated using the Calvert
equation. Quality of life was assessed with standard
tools. At the time of analysis 1223 deaths had been
reported, allowing the trial to be analysed according
to the statistical plan.
Results: This trial randomised 1363 patients, Conference President’s Selection Monday, 4 July 2011 10:30-12:00
between April 2005 and November 2009. The
arms of the trial were well balanced for PS, stage O01.05 PARAMOUNT: PHASE III
and age. Median age of all patients was 63 years, TRIAL RESULTS OF MAINTENANCE
32% were PS0, 60% PS1 and 8% PS2. The median PEMETREXED PLUS BEST SUPPORTIVE
delivered dose intensity (planned = 100%) in the CARE (BSC) VERSUS PLACEBO PLUS
three arms for platinum were GC50 99%, GC80 BSC IMMEDIATELY FOLLOWING
96% and GCb6 87% and for gemcitabine were INDUCTION TREATMENT WITH
95%, 88% and 80% respectively. During treatment PEMETREXED PLUS CISPLATIN FOR
the proportion of patients on each treatment arm ADVANCED NONSQUAMOUS NON-
who experienced at least one grade 3 or 4 adverse SMALL CELL LUNG CANCER (NSCLC)
event was GC50 27%, GC80 41% and GCb6 57%. Luis Paz Ares1, Filippo De Marinis2, Mircea Dediu3,
At time of analysis there were 140 patients alive Michael Thomas4, Jean-Louis Pujol5, Paolo Bidoli6,
with a median follow-up of 21 months. Response Olivier Molinier7, Tarini P. Sahoo8, Eckart Laack9,
rates were signiÀcantly different between the Martin Reck10, Jesus Corral11, Symantha Melemed12,
arms; GC50 23%, GC80 33% and GCb6 28% (P William John12, Nadia Chouaki13, Annamaria H.
= 0.01). Median survival in the arms were GC50 Zimmermann12, Carla Visseren-Grul14, Cesare
8.3 months, GC80 9.5 months and GCb6 10.0 Gridelli15
1
months, with the GC50 treatment arm statistically Medical Oncology, University Hospital-Virgen
selected as the one that differs from the other two. Del Rocio/Spain, 2Medical Oncology, San Camillo-
For the subsequent primary comparisons of non- Forlanini Hospital/Italy, 3Institute Of Oncology/
inferiority of GC50 v GC80 (HR=1.11) and GCb6 Romania, 4Thoracic Oncology, Thoraxklinik/
v GC80 (HR=0.96), the 95% conÀdence interval University Of Heidelberg/Germany, 5Montpellier
for the cisplatin dose comparison (0.96, 1.27) did Academic Hospital/France, 6S. Gerardo Hospital/
not exclude the pre-deÀned inferiority region of Italy, 7Le Mans Regional Hospital/France,
8
HR>1.2 whereas the 95% conÀdence interval for Jawaharlal Nehru Cancer Hospital And Research
the GCb6 v GC80 comparison (0.84, 1.10) fell well Center/India, 9University Hospital Of Hamburg-
below this inferiority region. Eppendorf/Germany, 10Hospital Grosshansdorf/
Conclusion: In advanced NSCLC the dose of Germany, 11University Hospital - Virgen Del Rocio/
cisplatin is important with GC50 giving the Spain, 12Eli Lilly And Company/United States
poorest outcome in terms of overall survival and Of America, 13Eli Lilly And Company, Suresnes/
response rate. GCb6 is not inferior to GC80, thus France, 14Eli Lilly And Company, The Netherlands/
in combination with gemcitabine and in relation to Netherlands, 15S. Giuseppe Moscati Hospital/Italy
survival time carboplatin is clinically equivalent to
that of cisplatin but other factors such as quality of Abstract under Embargo - will be presented in a
life may have an inÁuence on choice of treatment. press conference during WCLC 2011.
Keywords: Advanced NSCLC, BTOG2, Cisplatin,
gemcitabine
A revised/updated abstract may be included in

at the 14th World Conference on Lung Cancer.
Conference President’s Selection Monday, 4 July 2011 10:30-12:00 Center/Ukraine, 9Omsk Regional Oncology Center/
Russian Federation, 10Oncology, Oncology Institute
O01.06 EPIDERMAL GROWTH FACTOR Ion Chiricuta/Romania, 11Thoracic Surgery
RECEPTOR (EGFR) EXPRESSION AS Department, Zaporizhzhya State Medical University/
A PREDICTOR OF SURVIVAL FOR Ukraine, 12Medical Oncology Department, Institute Of
FIRST-LINE CHEMOTHERAPY PLUS Oncology/Romania, 13Department Of Pulmonology,
CETUXIMAB IN FLEX STUDY PATIENTS St George Hospital/Hungary, 14Department Of
WITH ADVANCED NON-SMALL CELL Oncology, University General Hospital Of Elche/
LUNG CANCER (NSCLC) Spain, 15Department Of Biostatistics & Epidemiology,
Robert Pirker1, Luis Paz Ares2, Wilfried Eberhardt3, Amgen Inc./United States Of America, 16Department
Maciej Krzakowski4, Stephan Störkel5, Steffen Of Biostatistics And Epidemiology, Amgen Inc./United
Heeger6, Anja Von Heydebreck6, Christopher Stroh6, States Of America, 17Department Of Oncology, Amgen
Kenneth J. O’Byrne7 Inc./United States Of America, 18Sarah Cannon
1
Department Of Medicine 1, Medical University Of Research Institute And Tennessee Oncology, PLLC/
Vienna/Austria, 2Hospital Universitario Virgen Del United States Of America
Rocio/Spain, 3University Duisburg-Essen/Germany,
4
Maria Sklodowska-Curie Institute Of Oncology/ Background: The objective of the phase 3
Poland, 5Helios Hospital Wuppertal/Germany, MONET1 study was to assess whether treatment
6
Merck Kgaa/Germany, 7St James’s Hospital/Ireland with motesanib, a selective oral inhibitor of vascular
endothelial growth factor (VEGF) receptors 1, 2,
Abstract under Embargo - will be presented in a and 3, the platelet-derived growth factor (PDGF)
press conference during WCLC 2011. receptor and Kit, in combination with carboplatin/
paclitaxel (C/P) improves overall survival (OS)
compared with placebo plus C/P among patients with
Conference President’s Selection Monday, 4 July 2011 10:30-12:00 advanced NSCLC and among a subset of those with
adenocarcinoma histology.
O01.07 MONET 1 – AN INTERNATIONAL, Methods: This randomized, placebo-controlled,
RANDOMIZED, DOUBLE-BLIND, double-blind study enrolled patients with
PLACEBO-CONTROLLED PHASE histologically conÀrmed, unresectable stage IIIB
3 STUDY OF MOTESANIB IN (with pericardial or pleural effusion), stage IV, or
COMBINATION WITH CARBOPLATIN/ recurrent nonsquamous NSCLC. Exclusion criteria
PACLITAXEL IN PATIENTS WITH included prior chemotherapy, adjuvant chemotherapy
ADVANCED NONSQUAMOUS NON– within 52 weeks of randomization, and prior
SMALL-CELL LUNG CANCER (NSCLC) targeted therapies. Based on recommendations from
Giorgio Scagliotti1, Ihor Vynnychenko2, Yukito the Independent Data Monitoring Committee, the
Ichinose3, Keunchil Park4, Kaoru Kubota5, Fiona study protocol was amended to exclude patients
Blackhall6, Robert Pirker7, Oleksandr Popovych8, with squamous histology owing to the high rate
Rinat Galiulin9, Tudor-Eliade Ciuleanu10, Oleksandr of hemoptysis observed in this population. All
Sydorenko11, Mircea Dediu12, Zsolt Papai-Szekely13, patients were to receive C (AUC, 6 mg/mL·min)
Natividad Martínez Banaclocha14, Sheryl Mccoy15, and P (200 mg/m2) IV on day 1 of each 3-week
Bin Yao16, Yong-Jiang Hei17, David R. Spigel18 cycle (for up to 6 cycles). Patients were randomized
1
Department Of Clinical And Biological Sciences, 1:1 to also receive motesanib 125 mg once daily
University Of Turin, S. Luigi Hospital/Italy, 2Sumy (QD) continuously orally (Arm A) or placebo
Regional Oncology Centre/Ukraine, 3Thoracic continuously orally (Arm B). Randomization was
Oncology, National Kyushu Cancer Center/Japan, stratiÀed by weight loss, sex, disease stage, and
4
Samsung Medical Center, Sungkyunkwan University prior adjuvant chemotherapy. Treatment continued
School Of Medicine/Korea, 5Thoracic Oncology until disease progession, unacceptable toxicity, or
Division, National Cancer Center Hospital/Japan, death. The primary endpoint is OS time. Secondary
6
Medical Oncology, The Christie National Health endpoints include progression-free survival (PFS),
Services Foundation Trust/United Kingdom, objective response rate, and prespeciÀed biomarker
7
Department Of Medicine I, Medical University Of analysis. Per the amended protocol, the study has
Vienna/Austria, 8Donetsk Regional Antineoplastic a planned sample size of 1060 and is designed to
have 80% power to detect hazard ratios for OS of long follow-up. We studied the incidence and risk
1.25 among nonsquamous patients and 1.3 for the factors for chest wall pain (CWP) and rib fractures
subset of patients with adenocarcinoma histology. in patients who were treated with SABR at a single
The comparison of OS between Arms A and B will center.
be performed using a 2-sided log-rank test with a 3% Methods: Between 2003-2009 500 patients with
(Ơ=0.03) signiÀcance level for nonsquamous patients 530 tumors underwent SABR for stage I NSCLC
and 2% (Ơ=0.02) for adenocarcinoma patients. (T1N0=307; T2N0=223) using a risk-adapted
Descriptive data for clinical outcomes (PFS and OS) fractionation scheme consisting of 3 fractions of
will also be presented for patients with squamous 20Gy (T1, not adjacent to chest wall), 5 fractions
cell histology (n=360) who were randomized prior to of 12Gy (T1, adjacent to chest wall or T2) or 8
the protocol amendment. Adverse event data will be fractions of 7.5Gy (central lesions). Target volumes
reported for all patients with nonsquamous histology, were derived using a 3mm-margin added to tumor
the patient subset with adenocarcinoma, and patients positions observed on 4D-CT scans. SABR was
with squamous cell histology. All presented data will delivered with 8-12 non-coplanar static beams, and
be from the primary analysis, which is anticipated to planning was dedicated to avoid hotspots in the chest
be completed in March 2011. wall. Toxicity data were collected in a prospective
Results: This is a latebreaking abstract. database and scored using CTC-AE v4.03. Follow-
Conclusion: This is a latebreaking abstract. up CT scans were performed at 3, 6 and 12 months
Keywords: motesanib, carboplatin/paclitaxel, post-SABR, and yearly thereafter.
non-squamous non-small-cell lung cancer, Overall Results: Median follow-up was 33 months. Overall
survival survival and local control rates were 53.1% and
90.4% at three years, respectively. Early onset of
A revised/updated abstract may be included in chest wall pain after SABR was reported in 32
the Late Breaking Abstract Supplement, available patients (6.4%), and represented Grade 1-2 in 27
at the 14th World Conference on Lung Cancer. patients (5.4%) and Grade 3 in 5 patients (1.0%).
Chest wall erythema was observed in 2.8%. Any
late CWP was reported in 25 patients (5.0%). The
Session O02: Radiation Oncology I actuarial rates of severe CWP and rib fractures at
three years post-SABR were 2.2% (10 patients)
Monday, 4 July 2011 and 2.7% (8 patients). Only two patients with
fractures had Grade 3 CWP. The median time to
developing severe CWP and rib fractures was 4 and
Radiation Oncology I Monday, 4 July 2011 14:30-16:00 24 months post-SABR, respectively. The median
tumor-chest wall distance in patients with Grade 3
O02.01 CHEST WALL TOXICITY CWP and rib fractures were 0mm (range 0-24mm)
FOLLOWING RISK-ADAPTED and 2mm (range 0-5mm), respectively. Patients
STEREOTACTIC RADIOTHERAPY FOR who developed CWP had a signiÀcantly larger
EARLY STAGE LUNG CANCER tumor volume (p=.007) and shorter tumor-chest
Eva Marrit Bongers, Cornelis J. Haasbeek, Frank J. wall distance (p=.007) than patients without CWP.
Lagerwaard, Ben Slotman, Suresh Senan
Radiation Oncology, VU University Medical Center/
Netherlands
Background: Stereotactic ablative body

radiotherapy (SABR) achieves local control rates
in stage I non-small cell lung cancer (NSCLC) Conclusion: Severe chest wall pain and rib fractures
that are comparable to those reported after surgery. are uncommon after risk-adapted Àxed-beam SABR,
Chronic chest wall toxicity is observed in up to particularly in tumors located 5mm or more from the
30% of patients undergoing lobectomy (Karmaker, chest wall.
2004). The exact incidence of chest wall toxicity Keywords: early stage non-small cell lung cancer,
after SABR is unknown, as few reports are available chest wall toxicity, stereotactive ablative body
on large numbers of patients with sufÀciently radiotherapy
Radiation Oncology I Monday, 4 July 2011 14:30-16:00 60 Gy, 66 Gy, 70Gy, and 80 Gy in 43, 32,
20, and 7 patients, respectively. Fourteen patients
O02.02 BRACHIAL PLEXOPATHY IN developed clinical symptoms consistent with brachial
APICAL NON-SMALL CELL LUNG plexopathy: 3 RIBP, 7 TRBP, 1 RIBP and TRBP,
CANCER TREATED WITH DEFINITIVE and 2 trauma-related. All patients who developed
RADIATION: DOSIMETRIC ANALYSIS RIBP or TRBP received chemotherapy. Locoregional
AND CLINICAL IMPLICATIONS control was 75% and median follow-up was 31.5
Smith Apisarnthanarax1, Michael J. Eblan1, Michael months (range, 8-44) for RIBP patients and 13% and
N. Corradetti1, J N. Lukens1, John P. Christodouleas1, 13.0 months (range, 4-44) for TRBP patients. Of the
Corey J. Langer2, Tracey Evans2, James Stevenson2, 29 patients with local failure, 24% developed TRBP.
Eric Xanthopoulos1, Annemarie T. Fernandes1, Mean Mean
Median
CTCAE Maximal Prescribed
Ramesh Rengan1 No.
v.4.0
Chemo-
Brachial Tumor
time to
1 (%) therapy symptoms
Radiation Oncology, Abramson Cancer Center, Grade Plexus Dose Dose
(range)
(range) (range)
University Of Pennsylvania/United States Of
79.0 Gy ± 4.5
America, 2Hematology/Oncology, Abramson Cancer Radiation- 4
II: 3 III: 1
Concurrent 2 84.6 Gy ± 2.7
1.0 (76.0- months
Induced (4%) Sequential 2 (79.1-90.9)
Center, University Of Pennsylvania/United States Of 80.0) (4-27)
America 67.0 Gy ± 6.0

Tumor- 8 Concurrent 6 47.2 Gy ± 12.6
II: 5 III: 3 1.8 (59.4- months
Related (8%) Sequential 2 (53.0-81.5)
76.0) (1-42)
Background: Radiation dose escalation for apical
non-small cell lung cancer (NSCLC) may be limited Conclusion: The brachial plexus frequently receives
by the proximity of tumors to the brachial plexus. The radiation doses exceeding historical RTOG dose
radiation tolerance of the brachial plexus and radiation- constraints (60-66 Gy) in NSCLC patients with
induced brachial plexopathy (RIBP) are understudied apical tumors treated with deÀnitive radiation or
in this group of patients. We report on the incidence of chemoradiotherapy. No patient who received a
RIBP and tumor-related brachial plexopathy (TRBP) maximal dose of < 79 Gy to the brachial plexus
and associated dosimetric parameters in NSCLC developed radiation-induced plexopathy, while a
patients treated with curative intent. high percentage of patients are at risk for developing
Methods: We evaluated the records of NSCLC symptomatic tumor-related brachial plexopathy
patients with primary upper lobe, superior if their primary disease is not controlled. These
mediastinal nodal, or supraclavicular/cervical Àndings strongly suggest that primary tumor control
neck disease treated with deÀnitive radiation with adequate doses of radiation outweighs the low
or chemoradiotherapy between 2004 and 2010. risk of RIBP in this population of patients.
Dosimetric data were gathered on ipsilateral brachial Keywords: RADIATION, Brachial plexopathy,
plexuses contoured on radiation treatment plans Lung cancer
according to published RTOG atlas guidelines.
Brachial plexopathy was deÀned as the development A revised/updated abstract may be included in
of new neuropathic pain, motor weakness, or the Late Breaking Abstract Supplement, available
sensory disturbances in the ipsilateral shoulder/ at the 14th World Conference on Lung Cancer.
arm after treatment and was categorized as RIBP
(no tumor progression), TRBP (presence of local
tumor progression in proximity to brachial plexus), Radiation Oncology I Monday, 4 July 2011 14:30-16:00
or trauma-related. Locoregional control and survival
data were collected. O02.03 STEREOTACTIC ABLATIVE
Results: Ninety-two patients were identiÀed (stage RADIOTHERAPY (SABR) IN
I 14, II 4, III 65, IV 9) with a median follow-up POTENTIALLY OPERABLE STAGE I
and survival time of 16.5 months (range, 1-70) and NON-SMALL CELL LUNG CANCER
12.5 months (range, 1-38), respectively. The mean PATIENTS
prescribed radiation dose was 68.9 Gy ± 0.7 (range, Frank J. Lagerwaard1, Naomi E. Verstegen1, Cornelis
57.4-84.0). Seventy-two patients (80%) received J. Haasbeek1, Ben Slotman1, M. A. Paul2, Egbert F.
either concurrent (n=52) or sequential (n=20) Smit3, Suresh Senan1
1
chemotherapy. The mean maximal brachial plexus Radiation Oncology, VU University Medical Center/
dose was 59.7 Gy ± 2.8 (range, 0.5-90.9) and was Netherlands, 2Department Of Thoracic Surgery, VU
University Medical Center/Netherlands, 3Department were 9.7% and 14.0% at 5 years, respectively. The
Of Pulmonary Diseases, VU University Medical 5-year freedom-from-recurrence rate was 78.7%.
Center/Netherlands SABR could be completed in all patients, and 42%
of patients reported no early side effects. Observed
Background: The local control rates reported after early side-effects were fatigue (25%), cough (14%),
stereotactic ablative radiotherapy (SABR) for stage local chest wall pain (11%) and dyspnea (10%), with
I NSCLC are similar to those reported after surgical some patients reporting more than one side effect.
resection. In reaction to the high local control rates Grade 3 radiation pneumonitis and rib fractures
and low toxicity observed after SABR, Àt patients in were late complications, seen in 2% and 3% of
the Netherlands have increasingly elected to undergo patients, respectively.
SABR instead of surgery in recent years. We studied Conclusion: Potentially operable patients
SABR outcomes in a group of potentially operable undergoing SABR had a median OS exceeding 5
stage I NSCLC treated at a single center. years and a local control rate of 93% at 5 years.
Methods: In an institutional prospective database, These Àndings are comparable to results found in
24% (n=177) of lung SABR cases treated between surgical series and support ongoing randomized
2003 and 2010 were classiÀed as potentially clinical trials that compare surgery and SABR in
operable. These patients were retrospectively potentially operable stage I NSCLC patients.
identiÀed by excluding the following patient Keywords: Stage I non-small cell lung cancer,
categories: those with double lung tumors or other Operable, Stereotactic ablative radiotherapy
concurrent malignancy; those who had undergone
prior high-dose radiotherapy or pneumonectomy;
those with a COPD GOLD 3-4; and those with a Radiation Oncology I Monday, 4 July 2011 14:30-16:00
WHO performance score 3 or with or other (mostly
cardiovascular) co-morbidity precluding surgery. O02.05 OUTCOMES OF MEDICALLY
The operable group consisted of 101 males and 76 OPERABLE PATIENTS WITH NON-
females with a median age of 76 years. Total SABR SMALL CELL LUNG CARCINOMA
dose was 60 Gy, delivered in 3, 5 or 8 fractions in (NSCLC) TREATED WITH IMAGE-
1-2 weeks treatment time. Choice of fractionation GUIDED STEREOTACTIC BODY
depended on tumor size (T1 tumors 60%; T2 RADIATION THERAPY (IG-SBRT)
tumors 40%) and location. Median Charlson co- Andrew Hope1, Larry Kestin2, José Belderbos3,
morbidity score was 2 (range 0-5). Patients without Matthias Guckenberger4, Maria Werner Wasik5, Ying
a histological diagnosis, but with a FDG-PET- Xiao5, Di Yan2, Jean Pierre Bissonnette1, Jan Jakob
positive new or growing lesion with CT features of Sonke3, Inga Grills2
1
malignancy were accepted, as surgical publications Radiation Oncology, Princess Margaret Hospital
report a <4% incidence of benign disease when And University Of Toronto/Canada, 2Radiation
the same Dutch tumor boards identiÀed patients Oncology, William Beaumont Hospital/United States
for surgery. For patients lost to follow-up, survival Of America, 3Radiation Oncology, The Netherlands
status was obtained using the national population Cancer Institute - Antoni Van Leeuwenhoek Hospital/
registration system containing information about all Netherlands, 4University Hospital Wuerzburg/
inhabitants of the Netherlands. Germany, 5Radiation Oncology, Thomas Jefferson
Results: Median follow-up was 32 months. The University & Hospitals, Inc/United States Of
median overall survival (OS) was 61.5 months with America
1-, 3- and 5-year survivals of 94.7%, 84.7% and
51.3%, respectively. The 30-day mortality after Background: IG-SBRT has been primarily
SABR was 0%, while predicted 30-day mortality employed in patients who are not operative
for a lobectomy derived using the Thoracoscore candidates, a generally less healthy population.
predictive model [Falcoz ‘07] would have been The purpose of this study is to compare outcomes
2.6% in this patient cohort. OS at 3 years in patients following IG-SBRT in medically operable vs.
either with (n=59) or without (n=118) a histological medically inoperable patients in an international
diagnosis did not differ signiÀcantly (96% versus multi-institutional patient cohort.
81%, respectively, p=.39). The local control rate at 5 Methods: Five international institutions contributed
years was 93%, and regional and distant failure rates information on patients treated with IG-SBRT for
early stage (T1-T2N0M0) NSCLC. Multiple patient declining a thoracotomy treated with IG-SBRT
parameters including patient age, gender, tumor had overall survival and cancer-speciÀc outcomes
size and histology, pulmonary function, treatment equivalent to historic controls from surgical series.
regimen, and patient outcomes were recorded for Although additional follow-up is required, our data
both operable and inoperable patients. Operable support the continued investigation of IG-SBRT as
patients treated with SBRT had been offered surgery an equivalent alternative to surgical treatment in
after consultation with a thoracic surgeon and operable patients.
declined. Statistical comparison employed Fisher’s Keywords: stereotactic body radiation therapy
exact test or t-test. Multivariate proportional hazards (SBRT), Non-small cell lung cancer (NSCLC),
regression was employed to determine the effect medically operable
of operability on outcome. Overall survival, (OS),
disease free survival (DFS), and local/regional/
distant failure (LF/RF/DF) were estimated with Radiation Oncology I Monday, 4 July 2011 14:30-16:00
Kaplan-Meier methods.
Results: With a median follow-up of 1.5y for O02.06 COST-EFFECTIVENESS
surviving patients, 483 patients were identiÀed ANALYSIS COMPARING
with median age of 73 (42-93). In these patients, CONVENTIONAL VERSUS
505 tumors with median tumor size 2.6cm (0.8- STEREOTACTIC BODY RADIOTHERAPY
8.5cm) were most commonly treated with dose/ FOR SURGICALLY INELIGIBLE STAGE I
fractionations of 48Gy/4# (n=128) or 54-60Gy/3# NON-SMALL CELL LUNG CANCER
(n=231); 448 (87%) were in inoperable patients Gunita Mitera1, Anand Swaminath2, David Rudoler1,
and 57 (13%) in operable patients declining Colleen Seereeram1, Meredith E. Giuliani2, Natasha
surgery. Operable patients had higher mean ECOG Leighl3, Padraig Warde4, Eric Gutierrez4, Mark
performance status (PS) (0.8 vs. 1.1, p=0.02), Dobrow4, Peter Coyte1, Terence Yung2, Andrea
%-predicted FEV1 (77% vs. 64%, p<0.01), and Bezjak2, Andrew Hope2
1
%-predicted DLCO (62 vs. 53%, p=0.001). Health Policy Management And Evaluation,
There were no signiÀcant differences in operable/ University Of Toronto/Canada, 2Department Of
inoperable patients with regard to mean age Radiation Oncology, Princess Margaret Hospital/
(73.1/73.5y), tumor size (2.7/2.8cm), T-stage (T1 Canada, 3Medical Oncology, Princess Margaret
64%/68%), tumor grade (2.3/2.3), pre-treatment Hospital/Canada, 4Cancer Care Ontario/Canada
FDG SUV(7.0/7.9), or time from PET to treatment
(6.4/6.7 weeks). For all patients, the 2-year OS and Background: Patients with stage I non-small cell
CSS were 62% and 89% respectively. The 2-year OS lung cancer (NSCLC) who are either ineligible
for operable patients was 78% vs. 58% for medically for or refuse surgery have two curative intent
inoperable patients (p=0.006). On univariate treatment options: conventional radiotherapy
analysis, operability correlated with OS (HR: 2.37, (CRT) or stereotactic body radiotherapy (SBRT).
p=0.008) as did ECOG PS (HR: 1.53, p<0.001), No randomized trials have compared these two
male gender (HR: 1.70, p=0.001), DLCO (HR: approaches. The purpose of this study was to conduct
0.917, p=0.005), GTV size (HR: 1.204, p=0.001), a cost-effectiveness analysis (CEA) comparing
and interval between PET and treatment (HR: 1.035, SBRT to CRT for stage I NSCLC patients within the
p=0.03). There were no signiÀcant differences context of a publicly funded health care system.
between operable/inoperable patients at two years Methods: All patients with stage I NSCLC treated
in LF (2%/7%), RF (10%/12%), DF (10%/21%), or in a single large cancer center with either CRT or
CSS (93%/89%). On multivariate analysis including SBRT from January 2002 – June 2010 were included
operability, tumor size, gender, and performance in the analysis, with SBRT being offered from 2004.
status, operability remained signiÀcantly associated Direct medical costs from the perspective of the
with OS (p=0.04). With a pulmonary function Ontario public health care system were calculated,
measure (absolute DLCO) included in the model, including physician billing, labour costs for radiation
operability was no longer signiÀcantly associated therapists, physicists, nurses, equipment maintenance
with survival (p=0.09), consistent with a relationship staff, information technology support staff, and
between pulmonary function and medical operability. hospitalization due to acute adverse events. In
Conclusion: In this dataset, operable patients addition, the subset of direct radiation treatment
delivery costs excluding physician billings and Radiation Oncology I Monday, 4 July 2011 14:30-16:00
hospitalization was calculated. Direct costs were
obtained from professional groups, manufacturers O02.07 STEREOTACTIC ABLATIVE
and funding agencies at 2010 Canadian prices. RADIOTHERAPY (SABR) IN PATIENTS
Missing costs were derived from published literature WITH STAGE I NON-SMALL CELL LUNG
or expert opinion. The effectiveness outcome of CANCER: A COMPARISON OF PATIENTS
interest for both analyses was life-years gained. WITH AND WITHOUT PATHOLOGICAL
Time-to-event data was captured using Kaplan- PROOF
Meier and log-rank statistical methods. One-way Naomi E. Verstegen, Frank J. Lagerwaard, Cornelis
and two-way sensitivity analyses were carried out J. Haasbeek, Ben Slotman, Suresh Senan
to determine which factors most inÁuenced overall Radiotherapy, VU Medical Centre/Netherlands
costs.
Results: From January 2002 – June 2010, 170 Background: Several small prospective studies have
patients (51 CRT; 119 SBRT) were treated, with reported local control rates exceeding 85% after
a median follow-up of 24 months. Mean overall stereotactic ablative radiotherapy (SABR) for stage
survival for the CRT group was 2.83 years (95%CI: I non-small cell lung cancer (NSCLC). In contrast
1.8 - 4.1 years), and 3.86 years (95% CI: 3.2 - NR) to reports from the USA and Japan, the majority of
for the SBRT group (p=0.06). The mean estimated patients accepted for SABR in the Netherlands do not
life-years gained (LYG) with SBRT compared to have a pathological diagnosis, as the likelihood of a
CRT treatment was 1.03 years. Total mean direct benign 18FDG-PET positive pulmonary lesion is low in
costs for CRT were $6,885 overall, and $5,989 for Western European populations. We compared outcomes
radiation treatment delivery costs. In the SBRT arm, of patients who underwent SABR with (N=209) and
mean costs were $8,042, and $6,962 for treatment without (N=393) pathological proof of malignancy at
delivery only. The mean incremental cost per patient our centre.
treated with SBRT was $1,156, $972 speciÀcally Methods: SABR was delivered between 2003 and
for treatment delivery. The incremental costs per 2010 using online patient-setup to a total dose of 60
LYG for SBRT over CRT were $1,120 from the Gy in 3, 5 or 8 fractions, depending on tumor size
public payer perspective, and $942 including and location. Patients were referred from 68 Dutch
treatment delivery costs only. A one-way sensitivity centres. Patients without histological diagnosis but
analysis showed that varying survival difference with a 18FDG-PET-positive lesion with CT features
and direct labour costs +/-20% led to the largest of malignancy were accepted by a multidisciplinary
changes in incremental cost for both analyses. When tumor board, as the surgical literature reported a <4%
simultaneously adjusting both survival difference incidence of benign disease following similar patient
and direct labour costs by +/-5% to +/-30% in a two- selection for surgery in the Netherlands. The majority
way sensitivity analysis to account for selection bias, (70%) were considered to be medically inoperable or
potential stage migration, and efÀciency of SBRT were at high risk for surgical mortality; the remainder
over time, the incremental cost per LYG for SBRT had refused surgery. Patients with multiple tumors were
versus CRT is still within the threshold for accepting excluded from this analysis. The SABR population
a new health technology. consisted of 361 males (60%) and 141 females (40%)
Conclusion: In this Àrst study of the cost- with a median age of 75 years. Follow up consisted of
effectiveness of SBRT over CRT in a publically routine chest CT scans obtained at 3, 6 and 12 months
funded health care system, SBRT appears highly cost and yearly thereafter. Local control was deÀned as the
effective. absence of local progression and 18FDG-PET scans
Keywords: stereotactic body radiotherapy, were obtained in case of suspected relapse. Both
conventional radiotherapy, Cost-effectiveness SABR cohorts were compared using the Student T-test
analysis, Stage I NSCLC and Chi-Square test and outcome parameters were
calculated using Kaplan-Meier analysis.
Results: Median follow-up was 23 months. Both
patient cohorts were well balanced with respect to age,
gender, co-morbidity score and performance score.
Patients with pathology had a signiÀcantly larger tumor
diameter (p < .001) and a higher predicted FEV1%
value (p=.031). No signiÀcant difference could be Surgery - Staging Monday, 4 July 2011 14:30-16:00
demonstrated between both SABR cohorts in overall
survival and recurrence patterns at three years (table 1). O03.02 MEDIASTINOSCOPY AFTER
NEGATIVE ENDOSONOGRAPHY
3-year endpoints PA+ PA- IN LUNG CANCER STAGING.
Overall survival 55.4% 54.4% P = .93 SUBANALYSIS OF ASTER WITH FOCUS
Local control 90.4% 91.5% P = .92 ON CT.
Kurt G. Tournoy1, Robert C. Rintoul2, Christophe
Regional control 90.3% 87.9% P = .83
Dooms3, Ellen Deschepper4, Jouke Annema5
Distant control 79.6% 79.8% P = .95 1
Respiratory Medicine - Thoracic Oncology, Ghent
Disease free survival 72.1% 73.2% P = .98 University Hospital/Belgium, 2Department Of
Thoracic Oncology, Papworth Hospital/United
Conclusion: Both baseline patient characteristics Kingdom, 3Respiratory Oncology Unit, University
and clinical outcomes were similar between Hospitals Leuven/Belgium, 4Biostatistics, Ghent
pathology- proven and unproven patients with stage University Hospital/Belgium, 5Respiratory Medicine
I lung cancer treated using SABR. This indicates - Thoracic Oncology, Leiden University Medical
that it is very improbable that previously reported Centre/Netherlands
outcomes were biased by inclusion of benign lesions.
Keywords: Stereotactic ablative radiotherapy, Background: Mediastinal staging in non-small
SABR, Radiotherapy, Stage I NSCLC cell lung cancer with endosonography (EUS-FNA
plus EBUS-TBNA) followed by mediastinoscopy
is more sensitive to detect nodal metastasis as
Session O03: Surgery - Staging compared to mediastinoscopy alone (ASTER trial,
JAMA 2010;304:2245). However 11 patients need to
Monday, 4 July 2011 undergo a mediastinoscopy to detect one with N2/3
missed by endosonography. We analysed if lymph
node size measured on CT scan can identify patients
Surgery - Staging Monday, 4 July 2011 14:30-16:00 in whom the mediastinoscopy can be omitted.
Methods: In ASTER, 123 patients were randomized
O03.01 COMPARISON OF DIAGNOSTIC to endosonography followed by mediastinoscopy
YIELD OF ENDOSCOPIC ULTRASOUND if the former did not show mediastinal metastasis.
STAGING OF NON-SMALL CELL LUNG Sensitivity, negative predictive value (NPV) and
CANCER (NSCLC) PERFORMED WITH number of mediastinoscopies needed to detect one
USE OF ENDOBRONCHIAL ULTRASOUND false negative endosonography were calculated in the
(EBUS) AND/OR ENDOESOPHAGEAL cases with complete data (n=120; 98%).
ULTRASOUND (EUS) WITH INVASIVE Results: With CT, 74 patients had enlarged
STAGING OF NSCLC PERFORMED WITH mediastinal nodes (10mm), the prevalence of
USE OF TRANSCERVICAL EXTENDED N2/3 was 65 (54-75)%. Sensitivity and NPV of
MEDIASTINAL LYMPHADENECTOMY endosonography was 86 (74-93) and 77 (60-88)%.
(TEMLA) Adding mediastinoscopy increased sensitivity and
Marcin Zielinski1, Artur Szlubowski2, Marcin NPV to 96 (87-99) and 93 (77-98)%. In the 46
Kolodziej3, Stanislas Orzechowski3, Ewa patients without enlarged mediastinal nodes (N0/1)
Laczynska3, Juliusz Pankowski4, Magdalena the prevalence of N2/3 was 39 (26-54)%. Sensitivity
Jakubiak4, Anna Obrochta4 and NPV of endosonography was 89 (67-97) and 93
1
Thoracic Surgery, Pulmonary Hospital/Poland, (79-98)%. Adding mediastinoscopy did not improve
2
Bronchoscopy Unit, Pulmonary Hospital/Poland, this. In patients with enlarged vs normal-sized
3
Pulmonology, Pulmonary Hospital/Poland, mediastinal nodes, the number of mediastinoscopies
4
Pathology, Pulmonary Hospital/Poland needed to detect one false negative endosonography
is 6 vs. inÀnite (p=0.026).
Abstract under Embargo - will be presented in a Conclusion: A negative endosonography should
press conference during WCLC 2011. be followed by a mediastinoscopy in patients with
enlarged mediastinal nodes on CT. In the absence
of enlarged nodes, a mediastinoscopy following a and low N1 LN counts). We tested interventions

negative endosonography can be omitted. speciÀc to each site.
Keywords: Staging, endosonography / EBUS- Methods: We used a special pre-labeled specimen
TBNA / EUS-FNA, Mediastinoscopy, CT-scan collection kit to facilitate collection of N2 LN
(special specimen collection) and developed a lung
re-dissection protocol to retrieve discarded N1 LN
Surgery - Staging Monday, 4 July 2011 14:30-16:00 (special pathology examination). We performed a
3 arm case-control study: Arm 1, routine surgical
O03.03 A COMPARISON OF LN collection + routine pathology examination;
INTERVENTIONS TO IMPROVE Arm 2, routine specimen collection + special
INTRAOPERATIVE LYMPH NODE (LN) pathology examination; Arm 3, special specimen
COLLECTION AND PATHOLOGIC collection + special pathology examination. The
EXAMINATION OF LUNG RESECTION chi-square, Fisher-Freeman-Halton and Wilcoxon-
SPECIMENS. Mann-Whitney tests were used as appropriate for
Raymond U. Osarogiagbon1, Robert A. Ramirez2, comparisons.
Christopher G. Wang3, Laura E. Miller3, Jonathan Results: Patient characteristics were similar across
Ellichman4, Glenn P. Schoettle4, Alim Khandekar4, the 3 arms (Table). The number of N1 LN examined
Samuel G. Robbins5, Thomas O’Brien6, Jeffrey was higher in arms 2 and 3, compared to arm 1
Gibson5 (p<0.0001); there was no difference between arms 2
1
Multidisciplinary Thoracic Oncology, University and 3 (p= 0.23). Arm 3 had more N2 LN examined
Of Tennessee Cancer Institute/United States Of than arm 1 (p<0.0001), or arm 2 (p <0.006); there
America, 2Department Of Hematology/oncology, was no difference between arms 1 and 2 (p= 0.14).
University Of Tennessee Cancer Institute/United The total number of LN examined was signiÀcantly
States Of America, 3Department Of Internal higher in arms 2 and 3 than arm 1 (p<0.0001), and
Medicine, University Of Tennessee Health Science also in arm 3 compared to arm 2 (p<0.05). There
Center/United States Of America, 4Thoracic And were strong trends towards increase in number of
Cardiovascular Surgery, University Of Tennessee LN with metastasis, and proportion of patients with
Medical Group/United States Of America, 5Thoracic node-positive disease, in arms 2 and 3, compared to
And Cardiovascular Surgery, Germantown Methodist arm 1.
Hospital/United States Of America, 6Department
Of Pathology, Duckworth Pathology Group/United
States Of America
Background: Accurate determination of

pathologic (p) lymph node (LN) status is vital for
prognostication, post-operative management and
cross-comparison of outcomes after resection of lung
cancer. The location and number of positive LN,
and (in pN0 patients) the number of examined LN,
have prognostic value. Patients with unexamined LN
(pNx) have worse survival than T-category matched
pN0 patients; those with pN1 but no examined
mediastinal (N2) LN, have worse survival than
pN1 patients with at least 1 examined N2 LN. In
the US, 18% of lung cancer resections are pNx; the
median number of N1 LN examined is 3; 42% have Conclusion: Introduction of corrective interventions
no examined N2 LN; the median number of N2 to improve LN examination was feasible and
LN examined is between 0 and 1. We hypothesized effective. The combination of intraoperative and
that these statistics reÁect problems in both intra- pathology laboratory interventions are required to
operative collection of LN (especially stations 2 to optimally improve pathologic staging accuracy.
10) and in the pathology laboratory processing of A randomized phase III study of these corrective
submitted specimens (especially the problem of pNx interventions is indicated.
Keywords: Pathologic staging, Quality mediastinal nodal dissection. We found 35% of skip
improvement, Comparative effectiveness, lung nodal metastases in the group of patients using US
cancer surgery guided mediastinal lymphadenectomy. The incidence
of N2 metastases seemed to be more frequent in
A revised/updated abstract may be included in adenocarcinoma patients (p<0.005), but skip N2
the Late Breaking Abstract Supplement, available metastases were signiÀcantly higher (p<0.001) in
at the 14th World Conference on Lung Cancer. squamous cell carcinoma patients. Although skip
metastases involved more often upper mediastinal
lymph nodes and one station level, the difference
Surgery - Staging Monday, 4 July 2011 14:30-16:00 was not found statistically signiÀcant (p<0.227).
Complications rate showed no difference between
O03.05 INCREASED NUMBER OF SKIP analyzed groups of patients.
MEDIASTINAL NODAL METASTASES IN Conclusion: Higher number and location of
THE IIIA/N2 NSCLC DETECTED USING analyzed mediastinal nodal stations in patients with
INTRAOPERATIVE ULTRASOUND FOR resected NSCLC using hand held ultrasound probe
MEDIASTINAL LYMPHADENECTOMY suggested to be of great oncology signiÀcance.
Nenad Ilic1, Josko Juricic2, Josko Banovic1, Dragan Procedure showed absolute safety and high accuracy.
Krnic1, Nives Frleta Ilic1, Z Covic1, Darko Ilic1 Our results indicated that intraoperative US may
1
Thoracic Surgery Department, University Surgical have important staging implication. Further clinical
Hospital/Croatia, 2University Surgical Hospital/ studies should be carried out in order to improve
Croatia intraoperative staging in NSCLC patients.
Keyword: NSCLC, N2 disease, intraoperative
Background: To study the incidence and ultrasound, skip mediastinal metastases
characteristics of mediastinal nodal metastases
without N1 nodal metastases (wskip-N2 metastasesw)
in patients with resected pIII/A/N2 non-small Surgery - Staging Monday, 4 July 2011 14:30-16:00
cell lung cancer (NSCLC) using intraoperative
ultrasound (US) for mediastinal lymphadenectomy. O03.06 ESTABLISHING GUIDELINES
Methods: A total of 240 NSCLC patients who FOR THE USE OF ENDOBRONCHIAL
underwent RO surgical resection followed by ULTRASOUND VERSUS
systemic mediastinal nodal dissection in four years MEDIASTINOSCOPY IN INVASIVE
time period (2005-2008) were retrospectively STAGING OF NON SMALL CELL LUNG
reviewed. Intraoperative hand held ultrasound probe CANCER
was used for systematic mediastinal nodal dissection Michael F. Humer, Sana Z. Shahram, Bill Nelems
in a group of 120 patients and compared with the Interior Group, BC Thoracic Surgery/Canada
group of 120 patients who underwent lung resections
and standard systematic mediastinal nodal dissection. Background: Traditionally, mediastinoscopy has
Mapping of the lymph nodes by their number and been the main method for conducting invasive
station followed by histopathologic evaluation was mediastinal lymph node assessment in non-small cell
performed. Median follow-up was 38 (range, 10 - lung cancer (NSCLC). Endobronchial ultrasound
52) months. Patients data were statistically analyzed. (EBUS-TBNA) is a potential, less invasive method
Results: The surgical procedure used depended for sampling mediastinal lymph nodes. There is
on the extent of the disease, as well as the currently a lack of evidence directly comparing
cardiopulmonary reserve of the patients and was EBUS to mediastinoscopy; this evidence is necessary
comparable in both groups of patients. Operating to establish guidelines for when each method is
time was prolonged for 12 (6 – 20) minutes indicated in the mediastinal staging of NSCLC,
in patients with US guided mediastinal nodal while acknowledging that both methods have
dissection, but number and stations of evaluated limitations.
lymph nodes was signiÀcantly higher (p<0.001) in Methods: From January 15, 2007 to January 14,
the same group of patients. Skip nodal metastases 2011, 618 patients had concurrent mediastinal
were found in 24% of patients without N1 nodal lymph node sampling by both EBUS-TBNA and
involvement in the patients using standard systematic mediastinoscopy in a Thoracic surgery practice in
British Columbia; routine PET-CT scans were not Keywords: Endobronchial Ultrasound,
performed. EBUS versus mediastinoscopy results Mediastinoscopy, NSCLC staging, Mediastinal
were compared for all cases in which NSCLC was Sampling
detected. If the results did not agree, a false negative
(FN) was assigned to the method that had a negative A revised/updated abstract may be included in
result. Accuracy for each method was assessed by the Late Breaking Abstract Supplement, available
lymph node station (4R, 4L, 7, 10R), lymph node at the 14th World Conference on Lung Cancer.
size according to CT assessment, and the presence of
lymphocytes in the sample (EBUS-TBNA).
Results: Preliminary analysis of the Àrst two years of Surgery - Staging Monday, 4 July 2011 14:30-16:00
the data resulted in a 9.3% (27/290) mediastinoscopy
and 6.8% (20/290) EBUS-TBNA false negative rate. O03.07 EFFECTIVENESS OF EXTENDED
The majority of mediastinoscopy false negatives BILATERAL MEDIASTINAL LYMPH
occurred at the subcarinal lymph node station, 7. NODE DISSECTION THROUGH A
Of the 20 false negative cases for EBUS-TBNA, MEDIAN STERNOTOMY IN PATIENTS
only two occurred when diagnostic lymphocytes WITH LYMPH NODE METASTASIS TO
were noted in the specimen. Complete analysis THE MEDIASTINUM IN NSCLC OF THE
of the data will allow for a robust comparison of LEFT LUNG.
each method’s efÀcacy by lymph node station, Toshiya Yokota, Shingo Ikeda, Enjo Hata
adequacy of sample, and size of node according to Surgery Respiratory Center, Mitsui Memorial
CT assessment. Figure 1 shows an initial comparison Hospital/Japan
of EBUS-TBNA versus mediastinoscopy.
Background: The removal of the whole regional
lymphatic system together with primary tumor
is one of the fundamental rules in oncological
surgery. According to the study of regional
lymphatic drainage, we considered reasonable
lymphadenectomy contributes the post-operative
survival of the patient with non-small lung cancer
(NSCLC). And we had devised Systemic extended
bilateral mediastinal dissection and lung resection
through a median sternotomy (ND3 operation).
Methods: We retrospectively studied 282 patients
[196 male and 86 female, mean ages 59.8 years
(range, 38-75)], underwent ND3 operation due to
NSCLC, from January 1988 till December 2009. The
patients with NSCLC who are estimated to be able to
Conclusion: Once the current analysis of all 618 conventional radical operation and aged 75 year-old
EBUS/mediastinoscopy cases during the study or less becomes the adaptation of ND3 operation.
period (Jan ‘07-’11) is complete, it will be possible Results: Postoperative survival rates calculated with
to conclude whether or not the trends observed in Kaplan-Meier method. Clinicalpathological data
the preliminary analysis continue, and if they are were compared according to the p stage. Overall
signiÀcant. Complete analysis will consist of a 5-year survival rate in the 282 patients of left lung
comparison of EBUS/mediastinoscopy accuracy by primary was 65.6%. Operative mortality in 282
lymph node station (4R, 4L, 7, 10R), size of node patients was 2.8%. Lymph node metastasis to the
on CT scan and the presence of lymphocytes in the mediastinum was conÀrmed in 85 (30.1%) patients
sample. These results will inform the goal of this (pN2 was 51 patients,pN3Ơ was 23 patients, pN3ơ
project: to establish guidelines for clinical decision- was 1 patient, pN3Ƣ was 10 patients). According to
making in Thoracic surgery practice regarding the pathological stages, Àve-year survival rate was was
use of EBUS-TBNA and/or Mediastinoscopy for 90.8% in stage IA ,72.8% in stage IB,63.7% in stage
invasive mediastinal lymph node assessment in IIA, 62.7% in stageIIB,46.5% in stageIIIA,39.1% in
NSCLC. stageIIIB. Five-year survival rate was 47.4% in pN2
cases, and 47.2% in pN3Ơ cases. new IASLC/ATS/ERS classiÀcation of lung ADC
Conclusion: Comparing with our historical data and based on predominant morphology: adenocarcinoma
reported data in the patients underwent conventional in situ (AIS), minimally invasive adenocarcinoma
bilateral mediastinal nodal dissection, the post- (MIA), non-mucinous lepidic (LPD), acinar (ACI),
operative survival rates were improved. The survival papillary (PAP), micropapillary (MIP), solid (SOL),
of patients with N2 and pN3Ơ left lung primary invasive mucinous adenocarcinoma (IMA), and
would be remarkably improved. colloid adenocarcinoma (COL). Log-rank test and
Keywords: ND3 operation, lymphadenctomy Cox proportional hazard model were used to analyze
the association between histologic subtypes and
A revised/updated abstract may be included in recurrence-free survival (RFS).
the Late Breaking Abstract Supplement, available Results: There were 304 (62%) females and 183
at the 14th World Conference on Lung Cancer. (38%) males with a median age of 69 (23-96). By
stage, 357 (73%) stage were IA and 130 (27%)
stage IB. Three overall prognostic groups were
Session O04: Classical Pathology: identiÀed (Figure). Low grade consisting of AIS/
Adenocarcinoma MIA (n=23) had 100% 3-year RFS. Intermediate
grade consisting of LPD predominant (n=66),
PAP predominant (n=93), and ACI predominant
Monday, 4 July 2011
(n=194) experienced 3-year RFS of 93%, 90% and
84%, respectively. High grade consisting of SOL
Classical Pathology: Adenocarcinoma Monday, 4 July 2011 14:30- predominant (n=64), MIP predominant (n=26), and
16:00 IMA/COL (n=21) experienced 3-year RFS of 76%,
43%, and 57%, respectively. SigniÀcant difference
O04.01 VALIDATION OF THE was observed among the three grades (p<0.001).
PROPOSED IASLC/ AMERICAN On multivariate analysis, high histologic grade was
THORACIC SOCIETY (ATS)/ EUROPEAN signiÀcantly associated with shorter RFS even after
RESPIRATORY SOCIETY (ERS) adjusting for stage, lymphatic invasion, and vascular
INTERNATIONAL MULTIDISCIPLINARY invasion (HR 2.12, 95% CI 1.13-3.98, p=0.020).
CLASSIFICATION OF LUNG
ADENOCARCINOMA (ADC)
Kyuichi Kadota1, Kei Suzuki2, S. P. D’Angelo2,
Natasha Rekhtman2, Andre L. Moreira2, Camelia S.
Sima2, Gregory J. Riely2, Christopher G. Azzoli2,
Mark G. Kris2, Valerie W. Rusch2, Prasad S.
Adusumilli2, William D. Travis2
1
Department Of Pathology And Surgery, Memorial
Sloan-Kettering Cancer Center/United States Of
America, 2Memorial Sloan-Kettering Cancer Center/
United States Of America
Background: Recently, the IASLC/ATS/ERS

proposed a new histologic classiÀcation of lung ADC
with an emphasis on the prognostic signiÀcance of
morphologic subtypes in resected tumors. The aim
of this study is to validate this classiÀcation using a Conclusion: Our data provide further validation
large cohort of stage I ADC patients. that the proposed IASLC/ATS/ERS classiÀcation
Methods: H&E slides of 487 stage I lung ADC of ADC deÀnes prognostically important histologic
patients from a single institution (2002 to 2009) were subsets that show signiÀcant differences in RFS.
evaluated. Comprehensive histological subtyping This classiÀcation may be helpful to stratify patients
was performed to estimate the percentage of each for additional intervention/therapy.
histological subtype and to identify the predominant Keywords: lung, Adenocarcinoma, histologic
subtype. The tumors were classiÀed according to the classiÀcation, recurrence
Classical Pathology: Adenocarcinoma Monday, 4 July 2011 14:30- 64%, moderate in 34%, and severe in 3%. The median
16:00 mitotic count per 10 high power Àelds was 0 in AIS and
MIA, and 1 in LPD. No recurrences occurred in AIS and
O04.02 CLINICOPATHOLOGIC MIA while 4% of LPD had disease recurrence (5-year
CHARACTERISTICS OF recurrence free survival: 88%, median time to recurrence:
ADENOCARCINOMA IN SITU 2.9 years, range: 1.6-3.8 years). These 4 tumors which
(AIS), MINIMALLY INVASIVE had recurrence were all stage IA with mean tumor size
ADENOCARCINOMA (MIA), AND 1.8 cm (range 1.1-2.5). Three patients underwent wedge
LEPIDIC PREDOMINANT (LPD) resections and 1 lobectomy, and the mean distance
ADENOCARCINOMA OF THE LUNG between surgical margin and tumor was 0.4 (range
(LAC): MEMORIAL SLOAN-KETTERING 0.2-0.5). In addition, 2 tumors had 20% micropapillary
CANCER CENTER EXPERIENCE component and one of them had lymphatic invasion.
Kyuichi Kadota1, Kei Suzuki2, Akihiko Yoshizawa3,
Noriko Motoi4, Camelia S. Sima2, Gregory J. Riely2,
Valerie W. Rusch2, Prasad S. Adusumilli2, William D.
Travis2
1
Department Of Pathology And Surgery, Memorial
Sloan-Kettering Cancer Center/United States Of
America, 2Memorial Sloan-Kettering Cancer Center/
United States Of America, 3Shinshu University/
Japan, 4Cancer Institute Hospital Of Japanese
Foundation For Cancer Research/Japan
Background: AIS, MIA, and LPD in the new IASLC/

ATS/ERS LAC classiÀcation are newly deÀned
subtypes with favorable prognosis. However, because
these tumors are newly deÀned, there is little known
about their characteristics. The aim of this study is to Conclusion: Patients with AIS and MIA
investigate the clinical and pathologic characteristics demonstrated similar clinical characteristics with
of AIS, MIA, and LPD in a large series from a single smaller tumor size, earlier T stage, milder nuclear
institution. atypia, and no recurrence in contrast to LPD.
Methods: H&E slides of 972 stage I LAC that Keywords: adenocarcinoma in situ, minimally
underwent surgical resection between 1995 and 2009 at invasive adenocarcinoma, lung, lepidic
Memorial Sloan-Kettering Cancer Center were reviewed.
AIS, MIA, and LPD cases were identiÀed, and their
clinical characteristics were compared. Classical Pathology: Adenocarcinoma Monday, 4 July 2011 14:30-
Results: Patient demographics are outlined in the Table. 16:00
We identiÀed 3 (2%) patients with AIS, 32 (23%) with
MIA, and 107 (75%) with LPD representing 0.3%, O04.03 CORRELATION BETWEEN
3.3%, and 11% of the total series. The median age was THIN-SECTION CT FINDINGS,
60 in AIS, 69 in MIA, and 69 years in LPD. Females HISTOPATHOLOGICAL, MOLECULAR
composed 67% of AIS, 72% of MIA, and 65% of LPD. AND CLINICAL FINDINGS OF MIXED
Never smokers composed 33% of AIS, 22% of MIA, and GROUND-GLASS OPACITY (PART-
25% of LPD. Sublobar resections were performed for SOLID GGO) OF SMALL PLMONARY
66% in AIS, 50% in MIA, and 27% in LPD. The median AENOCARCINOMAS.
tumor size was 1.2 cm in AIS, 1.4 cm in MIA, and Haruhiro Saito1, Yuji Sakuma2, Shuji Murakami1,
1.7 cm in LPD. T1a tumors were found in 100% AIS, Tomoyuki Yokose2, Tetsuro Kondo1, Kimitoshi
88% in MIA, and 63% in LPD. Atypical adenomatous Nawa1, Hiroyuki Ito1, Masahiro Tsuboi1, Funihiro
hyperplasia (AAH) was present in 0% of AIS, 13% of Oshita1, Yoichi Kamdeda2, Haruhiko Nakayama1,
MIA, and 10% of LPD. For nuclear atypia, 100% of AIS Kouzo Yamada1
1
showed mild nuclear atypia. MIA showed mild atypia Thoracic Oncology, Kanagawa Cancer Center/
in 91% and moderate in 9% while LPD showed mild in Japan, 2Pathology, Kanagawa Cancer Center/Japan
Background: Thin-section CT (TS-CT) provides type; 43 cases). Average percentages of pathological

us with more precise images of small pulmonary component areas were GwS type; BAC; 74%, C/
carcinomas. Thin-slice sections with thicknesses of CwB; 25%, invasive areas; 0.6% (0-3.9%) and
0.5 mm-1mm accurately reÁect histopathological Heterogeneous type; BAC; 68%, CwB; 31%,
Àndings. Mixed Ground-glass Opacity (part-solid invasive areas 0.4% (0-5.6%) and SwG type; BAC
GGO) is one characteristic Ànding of pulmonary 39%, CwB; 33%, invasive areas 25.6% (0-95.6%).
adenocarciomas. These Àndings are various in The average size of invasive areas of the SwG/Solid
appearance, for example; some contain mainly GGO types were larger than the SwG/Air types (5.2mm
components, and some contain mainly solid portions. vs 0.5mm). Invasive areas were identiÀed in every
CT Àndings of mixed GGO, pathological Àndings type of mixed GGO tumor. Invasive areas of more
and a clinical prognosis have been reported. We do than 5mm or percentages greater than 10%, were
not fully understand the correlation between TS-CT recognized in overlapping type tumors of SwG and
Àndings of mixed GGO, histopathological invasive Solid types. Mutation ratios of EGFR were 60% in
areas, molecular and clinical Àndings. GwS, 87% in Het and 55% in SwG. In only one case
Methods: We retrospectively reviewed records and involving SwG/Solid type, the patient suffered a
TS-CT Àndings of 86 patients with mixed GGO relapse and died.
tumors. All patients had undergone surgical resection Conclusion: Each type of mixed GGO present
between 2002 and 2005. Tumor diameters measured unique characteristics of histopathological, molecular
20mm or less in size. All TS-CT images were and clinical Àndings. Our results indicate that
acquired by Aquillion CT scanner (Toshiba Medical evaluating TS-CT Àndings of mixed GGO, by way
System). TS-CT images of tumors were obtained at of lung and mediastinal window setting images, is an
135kVp at 250mAs with 0.5-1mm section thickness. important consideration in speculating on the size of
All images were photographed using mediastinal histopathological invasive areas.
(level, 40HU; width, 400HU) and lung (level, Keywords: mixed GGO, Thin-section CT,
-600HU); width, 1600HU) window settings. All TS- Adenocarcinoma, Invasion
CT images on lung window setting were classiÀed
as: (1) GGO with solid type (GwS; solid portion
areas less than 50% of tumor), (2) Heterogeneous Classical Pathology: Adenocarcinoma Monday, 4 July 2011 14:30-
type (heterogenous increased density), (3) Solid 16:00
with GGO type (SwG; Solid portion areas more than
50% of tumor). TS-CT images were classiÀed by O04.05 REPRODUCIBILITY OF INVASION
evaluating lung and mediastinal window settings; IN PULMONARY ADENOCARCINOMA.
(A) air-containing type (maximum diameter of tumor AN INTERNATIONAL INTEROBSERVER
opacity on mediastinal window images was less STUDY
than or equal to half of that seen on lung window Erik Thunnissen1, Marybeth Beasly2, Alain Borczuk3,
images), (B) Solid-density type (maximum diameter Elisabeth Brambilla4, Lucian R. Chirieac5, Sanja
of tumor opacity on mediastinal window images Dacic6, Douglas Flieder7, Adi F. Gazdar8, Kim
was more than half of that seen on lung window Geisinger9, Yuichi Ishikawa10, K M. Kerr11, Yuko
images) (Chest 133; 441, 2008). Histopathological Minami12, Sylvie Lantejoul4, Yoshihiro Matsuno13,
Àndings (HE and EVG stained) were evaluated by Andre L. Moreira14, Noriko Motoi10, Andrew
measuring percentages of pathological component G. Nicholson15, Masayuki Noguchi16, Daisuko
areas using NIH image software. Component areas Nonaka17, Giuseppe Pelosi18, Iver Petersen19, Natasha
consisted of (1) Bronchioalveolarcell carcinomas Rekhtman17, Victor L. Roggli20, William D. Travis14,
(BAC), (2) Collapse and/or Collapse with BAC Ming S. Tsao21, Ignacio Wistuba22, Haodong Xu2,
(CwB), (3) Invasive area. We analyzed EGFR/Kras Yasushi Yatabe23, Dirk J. Kuik24
1
mutations, the clinical Àndings, and then we studied Pathology, VUMC/Netherlands, 2Pathology,
the correlations between these Àndings. Mount Sinai Faculty Medicin/United States Of
Results: In all 86 cases, tumors were well- America, 3Pathology, Columbia University/United
differentiated adenocarcinomas. GwS type; 15 States Of America, 4Institut Albert Bonniot, Inserm
cases (Air-type; 12 cases, Solid-type; 3 cases), U823/France, 5Pathology, Brigham And Women’s
Heteogenous type; 23 cases (Air-type; 23 cases) Hospital/United States Of America, 6Department
and SwG type 48 cases (Air-type; 5 cases, Solid- Of Pathology, University Of Pittsburgh School Of
Medicine/United States Of America, 7Pathology, Fox no-invasion and deÀnite non-invasive combined;
Chase Cancer Center/United States Of America, undetermined) was 0.39 ± 0.50. In 6/64 cases the
8
Pathology, University Of Texas Southwestern diagnosis of invasion was unanimous. In 15 the
Medical Center/United States Of America, same 9/28 pathologists favored invasion while 9/28
9
Pathology, Wake Forest University Baptist Medical different pathologists consistently favored non-
Center./United States Of America, 10Pathology, The invasion.
Cancer Institute, Japanese Foundation For Cancer Conclusion: The reproducibility threshold was fair
Research/Japan, 11Aberdeen Royal InÀrmary/ to enable an assessment of invasion in pulmonary
United Kingdom, 12Pathology, Graduate School adenocarcinoma by using a POWERPoint image-
Of Human Comprehensive Sciences, University based method. Pathologists applied existing criteria
Of Tsukuba/Japan, 13Department Of Surgical of invasion according to two different approaches:
Pathology, Hokkaido University Hospital/Japan, one more restrictive and conservative, the other
14
Pathology, Memorial Sloan-Kettering Cancer more lenient in diagnosis of invasion in pulmonary
Center/United States Of America, 15Imperial adenocarcinoma. Improved deÀnition of invasion
College London/United Kingdom, 16Department is necessary and collective effort is underway to
Of Pathology, Graduate School Of Comprehensive resolve these discrepancies.
Human Sciences, University Of Tsukuba/Japan, Keywords: Adenocarcinoma, pathology, Invasion
17
Mem Sloan-Kettering Cancer CTR/United
States Of America, 18Pathology, Fondazione Irccs
National Cancer Institute/Italy, 19Pathology, Classical Pathology: Adenocarcinoma Monday, 4 July 2011 14:30-16:00
Universitätsklinikum Jena/Germany, 20Pathology,
Duke University Medical Center/United States Of O04.06 STROMAL INVASION
America, 21Princess Margaret Hospital/Canada, AND MICROPAPILLARY
22
University Of Texas MD Anderson Cancer Center/ PATTERN IN 226 CONSECUTIVE
United States Of America, 23Aichi Cancer Center SURGICALLY RESECTED STAGE
Hospital/Japan, 24Epidemiology And Biostatistics, I LUNG ADENOCARCINOMAS:
VUMC/Netherlands HISTOPATHOLOGIC CATEGORIES FOR
PROGNOSIS PREDICTION
Background: Histological subtyping of pulmonary Yi-Chen Yeh1, Yu-Chung Wu2, Cheng-Yu Chen1,
adenocarcinoma has been associated with predictive Wen-Hu Hsu2, Teh-Ying Chou1
1
and/or prognostic features, but inconsistencies Institute Of Clinical Medicine, Yang-Ming
may originate from difÀculties in interpretation University/Taiwan, 2Department Of Surgery, Taipei
due to subjective application of existing criteria. Veterans General Hospital/Taiwan
This study aimed to establish the reproducibility of
judging invasion amongst pulmonary pathologists Background: Adenocarcinoma has become the most
worldwide. prevailing malignant tumor of lung worldwide. There are
Methods: In a ring study 28 pathologists involved substantial differences of patient outcome after surgical
with the IASLC reviewed haematoxilin and resection in the early-TNM-stage lung adenocarcinomas.
eosin stained microscopic images of relevant or Methods: We retrospectively examined 226 consecutive
controversial areas of adenocarcinomas, pasted surgically resected stage I lung adenocarcinomas to
into a POWERPoint presentation showing typical search for prognosticators supplementing the TNM
invasion (n=20), no invasion (n=20) and ‘problem staging. With input from the recent literature, we
cases’ (n=24), submitted by 10 group members. All restructured the Sakurai’s 4-tier grading system for lung
cases were randomized (JK) and for each case the adenocarcinomas into a new categorical classiÀcation
reviewer provided a diagnosis on invasion divided according to stromal invasion and micropapillary pattern.
into 5 categories: invasion, deÀnite or probable; no- Category A tumors have pure bronchioloalveolar growth
invasion, deÀnite or probable; and undetermined. pattern (i.e., bronchioloalveolar carcinoma). Stromal
Kappa score was calculated. invasion in the form of central Àbrotic focus is absent
Results: Mean Kappa for invasion for all 5 in category B tumors and present in category C tumors.
categories was 0.40 ± 0.50 (mean and SD), while Category B is subclassiÀed into Category B1, which
Kappa for invasion is for 3 categories (probable has areas of bronchioloalveolar growth, and B2, which
invasion and deÀnite invasion combined; probable does not. Category C is subclassiÀed into Category C1,
which has invasive tumor cells in the periphery of central Classical Pathology: Adenocarcinoma Monday, 4 July 2011 14:30-
Àbrotic focus, and C2, which has invasive tumor cells in 16:00
the center of central Àbrotic focus. Based on the absence
or presence of micropapillary pattern, the category O04.07 INTEROBSERVER
C2 tumors are further subclassiÀed into C2a and C2b, AGREEMENT IN THE NUCLEAR
respectively. GRADING OF PRIMARY
PULMONARY ADENOCARCINOMA:
Category Description A COLLABORATIVE MICROSCOPY
A Adenocarcinoma with pure bronchioloalveolar growth PROJECT
pattern / without stromal invasion (i.e., Bronchioloalveolar
carcinoma)
Yoshimasa Nakazato1, Akiko M. Maeshima2,
B Invasive adenocarcinoma without central Àbrotic focus Yuichi Ishikawa3, Yasushi Yatabe4, Junya Fukuoka5,
B1 Presence of bronchioloalveolar growth pattern (in periphery) Tomoyuki Yokose6, Yasuhiko Tomita7, Yuko
B2 Absence of bronchioloalveolar growth pattern Minami8, Hisao Asamura9, Keisei Tachibana1,
C Invasive adenocarcinoma with central Àbrotic focus Tomoyuki Goya10, Masayuki Noguchi8
1
C1 Invasive tumor cells in the periphery of central Àbrotic focus Division Of Diagnostic Pathology, Gunma
C2 Invasive tumor cells in the center of central Àbrotic focus Prefectural Cancer Center/Japan, 2Pathology
C2a C2 tumor without micropapillary growth pattern Division, National Cancer Center Hospital/Japan,
C2b C2 tumor with micropapillary growth pattern 3
Pathology, Cancer Institute Hospital/Japan,
4
Pathology And Molecular Diagnostics, Aichi
Results: The 5-year disease-free survival rates for Cancer Center Hospital/Japan, 5Surgical Pathology,
categories B1 (17 cases), B2 (13 cases), C1 (9 cases) Toyama University Hospital/Japan, 6Pathology,
and C2 (187 cases) are 100%, 83.9%, 100%, and Kanagawa Cancer Center/Japan, 7Pathology, Osaka
61.2%, respectively (p = 0.003). Category C2a (120 Medical Center For Cancer And Cardiovascular
cases) has better 5-year disease-free survival rate Diseases/Japan, 8Pathology, Graduate School Of
compared to that of Category C2b (67 cases) (66.6% Human Comprehensive Sciences, University Of
versus 51.2%, p = 0.017). Tsukuba/Japan, 9Thoracic Surgery, National Cancer
Center Hospital/Japan, 10Surgery, Institute Of
Medical Sciences, Kyorin University/Japan
Background: Nuclear grading involves an evaluation of

the size and shape of tumor cell nuclei and the percentage
of tumor cells that are in the division phase of the cell
cycle. This grading can be applied prognostically for
estimating the malignancy of pulmonary adenocarcinoma
(Nakazato Y. et al, Cancer, 2010). However, according to
the World Health Organization ClassiÀcation of Tumors,
its prognostic value for pulmonary adenocarcinoma has
not been assessed. In the present study, we assessed the
degree of interobserver agreement on nuclear grading of
primary pulmonary adenocarcinoma.
Methods: We selected 122 primary pulmonary
Conclusion: The histopathologic categorical adenocarcinomas 2 cm or less in diameter. Eight
classiÀcation proposed here provides a concise and pathologists independently evaluated the nuclear factors
precise scheme for outcome prediction in early-stage using the nuclear grading system devised by Nakazato
lung adenocarcinomas. et al. We divided the cases examined into two groups:
Keyword: Adenocarcinoma, Lung, Stromal those positive and those negative in terms of nuclear
Invasion, Micropapillary Pattern, Prognosis grading. The modiÀed version of the WHO classiÀcation,
Noguchi’s classiÀcation, and the proportion of the
A revised/updated abstract may be included in bronchioloalveolar carcinoma (BAC) component were
the Late Breaking Abstract Supplement, available also examined by the same pathologists. Interobserver
at the 14th World Conference on Lung Cancer. agreement was evaluated using the kappa statistic. The
disease-free survival curves were drawn according to the
Kaplan–Meier method and analyzed with the logrank test. Molecular Pathology I, ALK Monday, 4 July 2011 14:30-16:00
Results: The mean (±SD) kappa values for the modiÀed
WHO classiÀcation, Noguchi’s classiÀcation and nuclear O05.02 DETECTION OF ALK GENE
grading were 0.46+0.09, 0.48+0.09, and 0.58+0.09, REARRANGEMENT IN NON-SMALL-
respectively. The cases judged as negative by nuclear CELL LUNG CANCER : A COMPARISON
grading showed a signiÀcantly better prognosis (5-year OF FLUORESCENCE IN SITU
disease-free survival rate, 91.8+2.7%) than the positive HYBRIDIZATION AND CHROMOGENIC
cases (68.6+3.1%). IN SITU HYBRIDIZATION WITH
Conclusion: Nuclear grading is useful for prognostic CORRELATION OF ALK PROTEIN
evaluation of pulmonary adenocarcinoma. The EXPRESSION
interobserver agreement on nuclear grading is Hyojin Kim1, Seol-Bong Yoo1, Ji-Young Choe2, Jin
signiÀcantly higher than that for the modiÀed WHO Ho Paik1, Xianhua Xu1, Hiroaki Nitta3, Jin-Haeng
classiÀcation or Noguchi’s classiÀcation, suggesting that, Chung1
1
clinicopathologically, nuclear grading is a quite reliable Pathology, Seoul National University Bundang
prognostic factor for small adenocarcinomas. Hospital/Korea, 2Pathology, Seoul National
Keywords: Nuclear Grading, Pulmonary University College Of Medicine/Korea, 3Medical
Adenocarcinoma, Interobserver Agreement, modiÀed Innovation, Ventana Medical Systems, Inc./United
version of the WHO classiÀcation States Of America
Background: Accurate determination of ALK

Session O05: Molecular Pathology I, ALK rearrangement is important in lung cancer patients,
especially in determining their eligibility for
Monday, 4 July 2011 crizotinib therapy. Fluorescence in situ hybridization
(FISH) has been regarded as the gold standard
method for detecting ALK rearrangement. However,
Molecular Pathology I, ALK Monday, 4 July 2011 14:30-16:00 FISH requires a Áuorescence microscope, the
signals are labile and rapidly fade over time. This
O05.01 ALK FUSION AND MET study evaluates the concordance between ALK
AMPLIFICATION AS MOLECULAR gene rearrangement in NSCLC assessed by ALK
BIOMARKERS AND THERAPEUTIC FISH and a newly developed ALK chromogenic
TARGETS IN ADVANCED LUNG in situ hybridization (CISH) and correlates the
ADENOCARCINOMAS IN THE LUNG results with ALK protein expression assessed by
CANCER MUTATION CONSORTIUM* immunohistochemistry (IHC).
Marileila Varella-Garcia1, John A. Iafrate2, William Methods: A total of 465 formalin-Àxed and parafÀn
Pao3, Lynne Berry4, Suresh Jhanwar5, Elizabeth embedded non-small-cell lung cancer (NSCLC)
Koehler4, Dara L. Aisner1, Mark G. Kris6, Wilbur samples were analyzed by ALK FISH (PathVysion®,
Franklin1, Yu Shyr4, David Kwiatkowski7, Paul Vysis, Abbott) and ALK CISH. For comparison, all
Bunn1, Marc Ladanyi5 specimens were stained by immunohistochemistry
1
Cancer Center, University Of Colorado School Of (clone 5A4) and interobserver reproducibility was
Medicine/United States Of America, 2Massachusets assessed.
General Hospital/United States Of America, Results: We found that agreement between the
3
Hematology Oncology, Vanderbilt Ingram Cancer pathologists on the CISH-determined ALK status
Center/United States Of America, 4Dept. Of was achieved in 449 patients (96.6%) and ALK
Biostatistics, Vanderbilt University Medical Center/ rearrangement was identiÀed in 18 patients (4.0%)
United States Of America, 5Pathology, Memorial in CISH method. Among these cases, 443 cases
Sloan-Kettering Cancer Center/United States Of (95.3%) had results matching the corresponding
America, 6Medicine, Memorial Sloan-Kettering FISH Results: 17 rearranged, 425 wild types and 1
Cancer Center/United States Of America, 7Brigham discordant case. There was high concordance in the
And Women’s Hospital/United States Of America assessment of ALK gene rearrangement between
FISH and CISH techniques (Kappa coefÀcient =
Abstract under Embargo - will be presented in a 0.92) and between observers (Kappa coefÀcient =
press conference during WCLC 2011. 0.97). In addition, there was high concordance in
the ALK gene status and ALK protein expression HE-stained slides of whole tumor specimen were
between CISH and IHC tests (Kappa coefÀcient = reviewed. The statistic correlation between histologic
0.82). factors and chimeric variation were calculated using
Conclusion: CISH is a highly reproducible and SPSS software.
practical method to detect ALK gene rearrangement Results: Distributions of predominant subtype,
and correlated well with ALK protein expression. differentiation or cell type in ALK-chimeric
Because, CISH allows a concurrent analysis variants are summarized in Tables. There was no
of histological features of the tumors and gene correlation between chimeric variants and histologic
rearrangement, it appears to be useful method in predominant subtypes (p=0.354, chi-square test),
determining ALK gene rearrangement. differentiation (p=0.255) and cell type (p=0.329).
Keywords: Lung cancer, ALK, Áuorescence in situ The percentage of subtypes and signet ring cells (sig)
hybridization, chromogenic in situ hybridization in each tumor was as following (mean and range);
lepidic 16.4 (0-80), papillary 31.6 (0-80), acinar
A revised/updated abstract may be included in 24.8 (0-90), micropapillary 8.9 (0-40), solid 18.4 (0-
the Late Breaking Abstract Supplement, available 100), and sig 10.9 (0-60). Table 1 ALK genotype and
at the 14th World Conference on Lung Cancer. Predominant subtype of adenocarcinoma
Genotype lepidic acinar pap micropap solid TOTAL

Molecular Pathology I, ALK Monday, 4 July 2011 14:30-16:00 EML4-ALK V1 5 1 4 0 5 15
EML4-ALK V2 0 1 5 0 1 7
O05.03 MORPHOLOGIC DIVERSITY EML4-ALK V3 2 6 4 1 2 15
OF ALK-ALTERED LUNG EML4-ALK V4 0 0 1 0 0 1
ADENOCARCINOMA; NO STRONG EML4-ALK V5 0 0 1 0 0 1
CORRELATION WITH CHIMERIC EML4-ALK V6 1 0 0 0 0 1
VARIANTS EML4-ALK V7 0 0 1 0 0 1
Noriko Motoi1, Kengo Takeuchi1, Seijiro Sato1, KIF5-ALK K17 1 0 0 0 0 1
Yuki Togashi1, Satoko Hatano1, Shin Karita1, Yuichi KIF5-ALK K24 0 0 0 0 2 2
Saito1, Hiroshi Ono1, Kentaro Inamura1, Sakae TOTAL 9 8 16 1 10 44
Okumura2, Yuichi Ishikawa1
1
Division Of Pathology, Japanese Foundation Table 2 ALK genotype and Tumor Differentiation/
For Cancer Research/Japan, 2Thoracic Surgical Cell type
Oncology, Cancer Institute Hospital/Japan
Genotype wel mod por TOTAL mixed mucinous non-mucinous TOTAL
Background: A subset of lung cancer harbors the EML4-ALK V1 3 6 6 15 13 0 2 15
transforming fusion gene joining the EML4 or EML4-ALK V2 0 5 2 7 7 0 0 7
KIF5 gene and the anaplastic lymphoma kinase EML4-ALK V3 4 8 3 15 11 3 1 15
gene (ALK), which is dramatically response to a EML4-ALK V4 0 1 0 1 1 0 0 1
targeted inhibitor of ALK kinase, such as crizotinib. EML4-ALK V5 0 1 0 1 1 0 0 1
The goal of this study is to clarify the histologic EML4-ALK V6 1 0 0 1 1 0 0 1
characteristics of ALK-altered lung adenocarcinoma EML4-ALK V7 0 1 0 1 1 0 0 1
(ALK-LAC) using the newly proposed IASLC/ KIF5-ALK K17 1 0 0 1 0 0 1 1
ATS/ERS classiÀcation and the correlation between KIF5-ALK K24 0 0 2 2 2 0 0 2
morphology and genotype (chimeric variant). TOTAL 9 22 13 44 37 3 4 44
Methods: Surgically resected 44 ALK-LAC detected
by combination of immunohistochemistry, FISH Conclusion: This study clearly showed the diversity
and multiplex RT-PCR were examined the following of histologic pattern of ALK-LAC. There was no
detailed histopathologic Àndings; the percentage of strong correlation between morphologic pattern and
each histologic subtypes (lepidic. acinar, papillary, genotype of ALK chimeric gene. Using surgically
micropapillary and solid), tumor differentiation removed specimens, allowing an examination of
(well, moderate, poor), and tumor cell types large area, our data indicated that characteristic
(mucinous, non-mucinous, or mixture of both) based patterns of ALK-LAC, such as acinar/cribriform
on the new IASLC/ATS/ERS classiÀcation of LAC. structure or presence of sig/mucinous cells, could be
a minor component of the tumor. EGFR mutations were mutually exclusive. ALK
Keywords: ALK lung adenocarcinoma, ALK rearranged patients tend to be younger than EGFR
chimeric gene, Adenocarcinoma subtype, mutated or WT/Negative patients (median age of 53,
Adenocarcinoma classiÀcation 59 and 62 years, respectively). Patients with ALK
positive tumors were predominantly never smokers
(67%) and adenocarcinomas (83.4%) with equal
Molecular Pathology I, ALK Monday, 4 July 2011 14:30-16:00 distribution for sex. ALK positive and EGFR mutant
patients have a better survival than WT/WT patients
O05.05 DIAGNOSTIC METHODS, (p=0.003 and p=0.03). IHC was perfomed in tissue
PREVALENCE AND CLINICAL samples from surgical resections, biopsies or cell
OUTCOMES OF PATIENTS WITH ALK blocks. Out of 71 patients analized for FISH, ALK
POSITIVE NON SMALL CELL LUNG IHC was perfomed in 64 and in 7 cases there was no
CANCER tissue enough to perform the analysis. All patients
Pablo Martinez1, Javier Hernandez-Llosa2, Josep with ALK FISH negative tumors were also negative
Castellvi2, Natalia Tallada2, Susana Cedrés1, M. for ALK IHC. Out of 6 patients positive for ALK
A. Montero2, Victor Rodriguez-Freixinos1, Isaac FISH, 5 were also analized for ALK IHC: Four were
Nuñez1, Guillem Argiles1, Nuria Mulet-Margalef1, positive and 1 negative.
Davis Torrejon1, Santiago Ramón Y. Cajal2, Conclusion: The prevalence of ALK rearrangement
Enriqueta Felip1 is 8.5% in a caucasian selected population of
1
Medical Oncology Department, Vall D´Hebron NSCLC. ALK positive patients have different
University Hospital/Spain, 2Pathology Department, clinical features and a better prognostic than EGFR
Vall D´Hebron University Hospital/Spain WT and ALK negative patients. IHC with D5F3
mAb against ALK is a promising method for
Background: ALK rearrangement represents a novel detecting ALK positive NSCLC patients.
molecular target in a subset of non small cell lung Keywords: IHC, ALK, NSCLC, FISH
cancers (NSCLC). Our aim is to explore Áuorescence
in situ hibridation (FISH) and inmunohistochemistry
(IHC) as diagnostic methods, prevalence and clinical Molecular Pathology I, ALK Monday, 4 July 2011 14:30-16:00
outcomes of ALK positive NSCLC in a selected
population of patients. O05.06 IMPRECISE REPORTING OF ALK
Methods: patients with NSCLC previously screened FISH RESULTS IN TUMOR SPECIMENS
for EGFR mutation at our institution bettween FROM PATIENTS WITH NON SMALL
June 2006 and January 2010 were selected. ALK CELL LUNG CANCER: POTENTIAL
rearrangement was identiÀed by using FISH and the IMPLICATIONS.
value of IHC (D5F3 monoclonal antibody-mAb) was Harry Raftopoulos1, Richard J. Gralla1, Shyamal
explored. For FISH ALK expression, a positive result Bastola1, Michael Esposito2
1
was deÀne as more than 15% of tumor cells positive Medical Oncology, Hofstra North Shore-LIJ School
for split red and green signals or single red signals. Of Medicine/United States Of America, 2Pathology,
For IHC ALK protein expression positivity was Hofstra North Shore-LIJ School Of Medicine/United
deÀned as tumor-speciÀc staining of any intensity in States Of America
10% of the tumor cells.
Results: Ninety-two patients were identiÀed. Data Background: An inversion within chromosome
is available for 71 patients: median age was 61 2p resulting in formation of a fusion gene product
years (range 36-83), 80% were adenocarcinomas, comprising portions of the echinoderm microtubule
7% squamous and 13% NOS carcinomas. Fifty- associated protein-like 4 (EML4) and the ALK
one percent of the patients were female. All were genes was discovered in 2007 in NSCLC cell lines
caucasian. Thirty-two percent of the patients were and in 3-5% of archived clinical specimens (Soda,
never smokers and 30% former smokers. Six (8.5%) Nature, 2007). Crizotinib, an ALK-inhibitor, was
patients were ALK rearranged positive by FISH, shown to have a 57% response rate in highly pre-
9 (12.7%) were EGFR mutant, and 56 (78.8%) treated NSCLC patients who harbored the EML4-
were wild type for EGFR and negative for ALK ALK rearrangement (Kwak, NEJM, 2010). In
FISH (WT/Negative). ALK rearrangements and all ongoing studies with crizotinib, eligibility to
receive the agent is determined by demonstrating unclear. Most patients exhibited hyperdiploidy of
15% or more of cells have the ALK rearrangement ALK - an as yet indeterminate anomaly with no
by break-apart Áuorescence in-situ hybridization evidence supporting use of ALK inhibitors in this
(FISH). Other abnormalities, including lesser levels setting. Hyperdiploidy appears to be a non-speciÀc
of rearrangement, as well as increases in gene copy event since patients with a kras mutation and with
number are demonstrated by the same FISH test. an EML4-ALK translocation, both displayed
However, none of these other abnormalities have hyperdiploidy. Failure to emphasize the lack of
been correlated with beneÀt from crizotinib, nor are evidence and merely enumerating abnormalities has
they known to confer any prognostic value. These the potential to spur inappropriate prescription of
additional anomalies are not reported when testing ALK inhibitors. Reporting needs to highlight EML4-
is performed by the current research studies. The ALK translocations as the only current predictive
goal of this study was to assess the quality of ALK- Ànding supporting use of crizotinib. Other reported
FISH reports issued by a commercial laboratory abnormalities should be clearly identiÀed as being of
with respect to distinguishing between predictive unknown signiÀcance at this time.
abnormalities (EML4-ALK rearrangement>15%) Keyword: ALK-FISH Test Reporting
and other incidental Àndings.
Methods: Between June 1, 2010 and January 31,
2010, 11 patient samples from our institution were Molecular Pathology I, ALK Monday, 4 July 2011 14:30-16:00
sent to Genzyme laboratories for ALK FISH testing.
Reports were classiÀed as normal or abnormal and O05.07 IMMUNOHISTOCHEMICAL
the abnormalities enumerated. Kras and EGFR SCREENING FOR ANAPLASTIC
mutation test results from the same specimens were LYMPHOMA KINASE (ALK)
collected. REARRANGEMENT IN ADVANCED NON-
Results: Reports on ALK testing performed by SMALL CELL LUNG CANCER PATIENTS
Genzyme were available for 11 patients. EGFR (11 June Koo Lee1, Heae Surng Park2, Dong-Wan Kim1,
patients) and Kras (10 patients) mutation analyses Kimary Kulig3, Tae Min Kim1, Se-Hoon Lee1, Yoon-
were available. Only one patient harbored an EML4- Kyung Jeon2, Doo Hyun Chung2, Deo Seog Heo1
1
ALK translocation in > 15% of cells, but 9 of 11 Department Of Internal Medicine, Seoul National
reports were noted to be abnormal. The table below University Hospital/Korea, 2Department Of
summarizes our Àndings Pathology, Seoul National University Hospital/
Korea, 3Molecular Epidemiology Research, PÀzer
95% ConÀdence Oncology/United States Of America
Number Percent
Intervals
TOTAL 11 100% - Background: Fluorescent in situ hybridization
ALK abnormal 9 82% 48 - 98% (FISH) is currently used to detect non-small cell
>15 % EML4-ALK lung cancer (NSCLC) patients with anaplastic
1 9% 0 - 41%
translocation*
lymphoma kinase (ALK) gene rearrangement, who
<15 % EML4-ALK
translocation*
1 9% 0 - 41% are candidates for ALK inhibitor therapy. However,
ALK hyperdiploidy* 9 82% 48 - 98%
FISH may not be a practical method for screening for
EGFR mutation 1 9% 0 - 41% ALK-positive patients in a large population due to its
KRAS mutation 2 20% 3 - 56% cost and difÀculty in interpretation. We investigated
*ALK translocation and hyperdiploidy observed in same patients the role of immunohistochemistry (IHC) to screen
for ALK rearrangement in advanced NSCLC
Conclusion: The small number of specimens in Methods: We identiÀed 1,100 stage IIIB or IV
this sample and the high percentage abnormalities NSCLC patients without squamous cell histology
listed without giving particular focus emphasize from the Seoul National University Hospital NSCLC
the potential problems in current ALK-FISH test database. To enrich for ALK-positive cases, we
results reporting by this commercial laboratory. selected 262 patients who were either EGFR wild-
Such ambiguous reporting may exist with other type or non-responders to previous EGFR tyrosine
laboratories and for other molecular tests. While the kinase inhibitors (TKI). ALK IHC using monoclonal
majority of specimens were reported as “abnormal”, antibody 5A4 (Novocastra) and ALK FISH using
the clinical meaning of most of these abnormalities dual-color break-apart probes (Abbott) were
performed on formalin-Àxed, parafÀn-embedded Background: Lung cancer is the leading cause of

tissue. Two hundred six biopsied and 56 surgically cancer-related death worldwide. Reduced mortality
resected specimens were included in this study. is expected from early detection combined with
Immunoreactivity was scored from 0 to 3. FISH was treatment. AutoÁuorescence bronchoscopy (AFB)
regarded as positive when the break-apart signals were is a valid strategy for detecting premalignant
seen in more than 15% of 50 or more tumor cells. endobronchial lesions in the central airways. During
Results: ALK protein was expressed in 28 (10.7%) AFB, sites showing abnormal autoÁuorescence
tumors in 262 patients. ALK FISH was positive in 25 can be biopsied for (histo)pathological evaluation.
(9.5%) cases, consisting of 16 tumors (12.9%) out of However, to data no biomarker is available that
124 EGFR wild-type patients and 9 tumors (6.5%) can reliably predict lung cancer risk in individual
out of 138 EGFR TKI non-responders. All patients subjects who present with AFB-visualized
with IHC scores of 3 (n=9) were FISH-positive and premalignant lesions. Our present study was set out
all patients with scores of 0 (n=234) were FISH- to identify AFB-visualized squamous metaplastic
negative. Among patients with IHC scores of 1 and (SqM) lesions with malignant potential by DNA
2, Àve (80.0%, 5/6) and eleven (84.6%, 11/13) were copy number proÀling.
FISH-positive, respectively. The sensitivity and Methods: As referral center in the Netherlands, we
speciÀcity of ALK IHC with reactivity score of 1 or prospectively collected since 1998 an extensive,
more were 100% and 98.7%, respectively. clinically and histopathologically annotated
Conclusion: IHC can be a useful test for screening archive of paired FFPE and frozen AFB-guided
ALK FISH-positive cases in advanced NSCLC. endobronchial biopsies of subjects at risk of lung
Advanced NSCLC patients with tumors showing cancer based on smoking habits, COPD, and/or
mild to moderate staining for ALK IHC should be history of cancer, and who underwent regular AFB-
considered to perform FISH study. examinations. Within our cohort of 474 subjects,
Keywords: Non-small cell lung cancer, anaplastic 6 (1.3%) subjects showed rapid progression from
lymphoma kinase, immunohistochemistry, FISH squamous metaplasia (SqM) to carcinoma (in situ)
(further referred to as cases). Immunostaining
patterns (p53, p63 and Ki-67) and DNA copy number
Session O06: Biomarkers I proÀles (i.e., chromosomal gains and losses) of this
unique set of progressive SqM lesions (n=6) were
Monday, 4 July 2011 compared to a subset of SqM lesions of subjects
(n=23) that did not progress towards carcinoma (in
situ) (i.e., controls). DNA copy number alterations
Biomarkers I Monday, 4 July 2011 14:30-16:00 (CNAs) were determined by array comparative
genomic hybridization (arrayCGH) analysis (4x44K
O06.01 DNA COPY NUMBER Agilent) on genomic DNA that was isolated on laser-
ALTERATIONS IN SQUAMOUS capture micro-dissected areas of the lesion. SpeciÀc
METAPLASTIC LESIONS VISUALIZED copy number alterations linked to endobronchial
BY AUTOFLUORESCENCE cancer risk were identiÀed and accuracy to predict
BRONCHOSCOPY PREDICT LUNG endobronchial cancer in this series was determined.
CANCER Results: Clinicopathologic characteristics and
Robert A. Van Boerdonk1, Thomas G. Sutedja2, Peter immunostaining patterns were not related to clinical
J. Snijders1, Emilie Reinen1, Saskia M. Wilting1, outcome of SqM lesions. On the other hand, the
Mark A. Van De Wiel3, Frederik B. Thunnissen1, mean number of CNAs in SqM biopsies of cases
Sylvia Duin1, Clarissa Kooi1, Bauke Ylstra1, Chris (22%, range 0.48-39%) was signiÀcantly higher as
J. Meijer1, Gerrit A. Meijer1, Katrien Grunberg1, compared to controls (0.09%, range 0.00-1.32%,
Johannes M. Daniels2, Pieter E. Postmus2, Egbert F. p<0.01). Chromosomal regions signiÀcantly more
Smit2, Daniëlle A. Heideman1 frequently altered in cases were 3p26.3-p11.1,
1
Pathology, VU University Medical Center/ 3q26.2-q29, 9p13.3-p13.2, and 17p13.3-p11.2
Netherlands, 2Pulmonary Diseases, VU University (FWER<0.10). In cases, baseline-detected CNAs
Medical Center/Netherlands, 3Epidemiology & persisted in subsequent biopsies taken from the
Biostatistics, VU University Medical Center/ initial site (median 93%, range 68-99%), and levels
Netherlands increased towards cancer progression (p=0.028).
CNAs at 3p26.3-p11.1, 3q26.2-29, and 6p25.3- silencing of SATB1 was examined in cell lines by
24.3, predicted endobronchial cancer risk for AFB- 5-Aza 2-deoxycytidine and Trichostatin A treatment,
visualized SqM with 97% accuracy. and chromatin immunoprecipitation.
Conclusion: Our data strongly suggest that DNA Results: SATB1 was expressed in normal bronchial
copy number alterations predict endobronchial tissue, in the pseudostratiÀed columnar epithelium of
cancer in individual subjects diagnosed with bronchi or terminal bronchioles, but not in peripheral
AFB-visualized SqM, and may be used to guide lung alveoli. SigniÀcant loss of SATB1 expression
intervention to prevent lung cancer. was found in squamous preinvasive lesions and in
Keywords: AutoÁuorescence bronchoscopy, NSCLCs, including adenocarcinomas, squamous cell
Early Detection, Lung cancer, DNA copy number and large cell carcinomas (P=0.001), compared with
alteration matched normal bronchial epithelium. We found
that loss of SATB1 independently predicted poor
cancer-speciÀc survival in squamous cell carcinoma
Biomarkers I Monday, 4 July 2011 14:30-16:00 patients (HR 2.06, 95% CI 1.1-3.7, P=0.016). Loss
of SATB1 was also signiÀcantly associated with
O06.02 LOSS OF EXPRESSION OF THE poor cancer-speciÀc survival in SCLC patients
CHROMATIN REMODELLING PROTEIN (HR 14.48, 95% CI 1.3-164.0, P=0.03), however
SATB1 IS PROGNOSTIC IN SQUAMOUS further investigation of a larger sample is warranted.
CELL CARCINOMA. Treatment of lung cancer cell lines A549 and H520
Christina I. Selinger1, Wendy A. Cooper2, Sam with the histone deacetylase inhibitor Trichostatin
Al-Sohaily1, Dessislava N. Mladenova1, Laurent A resulted in up-regulation of SATB1, suggesting
Pangon1, Catherine W. Kennedy3, Brian Mccaughan4, that SATB1 is epigenetically silenced in these cell
Maija R.J. Kohonen-Corish1 lines. SATB1 was associated with a decrease in the
1
Cancer Research Program, Garvan Institute Of active chromatin mark, acetylated histone H3K9,
Medical Research/Australia, 2Tissue Pathology And and an increase in the repressive polycomb mark,
Diagnostic Oncology, Royal Prince Alfred Hospital/ trimethylated H3K27, in the squamous cancer cell
Australia, 3Department Of Surgery, StrathÀeld line NCI-H520 cells relative to normal bronchial
Private Hospital/Australia, 4Cardiothoracic Surgery, epithelial cell line NL20.
Royal Prince Alfred Hospital/Australia Conclusion: This is the Àrst study showing that
SATB1 is expressed in the bronchial epithelium
Background: Lung cancer is the leading cause of and that this expression is lost in early preinvasive
cancer-related mortality and requires more effective squamous lesions and is associated with poor
molecular markers of prognosis and therapeutic prognosis in squamous cell carcinoma patients. As
responsiveness. ‘Special AT-rich binding protein 1’ SATB1 can act as a transcriptional activator or a
(SATB1) is a global genome organiser that recruits repressor, loss of SATB1 in early lung lesions may
chromatin remodelling proteins to epigenetically result in the widespread disruption of tissue-speciÀc
regulate hundreds of genes in a tissue-speciÀc epigenetic modiÀcations. This may cause abnormal
manner. SATB1 overexpression has been reported to activation or repression of key cancer genes, which
be a powerful predictor of poor prognosis in breast leads to promotion of lung tumorigenesis. Thus
cancer, but the signiÀcance of SATB1 expression has SATB1 is an epigenetic regulator, which may itself
not been previously evaluated in lung cancer. be epigenetically silenced in lung cancer.
Methods: Lung cancer samples were obtained from Keywords: SATB1, squamous cell carcinoma,
patients treated at the Royal Prince Alfred Hospital, biomarker
Sydney, between 1996 and 2002, and analysed by
immunohistochemistry for SATB1 expression. The
cohort totalled 257 patients, including 14 SCLCs
and 243 NSCLCs. Association between SATB1
expression and patient survival was determined with
the Kaplan-Meier log-rank and Cox proportional
regression models in univariate and multivariate
analyses. Only lung cancer-speciÀc deaths were
included in the survival analysis. Epigenetic
Biomarkers I Monday, 4 July 2011 14:30-16:00 multivariate analysis. A model including the three
miRNAs discriminates three prognostic groups:
O06.04 A THREE-MICRORNAS Group 1: patients with the three miRNAs under
SIGNATURE ACCURATELY the deÀned cut-off (n=129), Group 2: among the
DISCRIMINATES THREE PROGNOSTIC remaining patients, patients with miR21 under Q1,
GROUPS IN EARLY-STAGE NSCLC independently of the status of the two other miRNAs
PATIENTS IN THE IFCT-0002 TRIAL (n=82), and Group 3: all remaining patients (n=65).
Céline Mascaux1, Guenaelle Levallet2, Emmanuel In univariate analysis, Group 1 showed the best
Bergot3, Laurence Baudrin4, Martine Antoine5, OS (> 83 months), Group 2 intermediate OS (66
Geraldine Anthoine6, Virginie Westeel7, Armelle months), and Group 3 the worse OS (36 months,
Lavolé8, Elisabeth Quoix9, Didier Debieuvre10, Julien p=0.001, log-rank test). Adjusted HRs for OS with
Mazières11, Jean-Louis Pujol12, Denis Moro-Sibilot13, Group 3 as reference were 0.445, 95%CI [0.290-
Franck Morin4, Bernard Milleron8, Gérard Zalcman3 0.682], p=0.0002 and 0.632, 95%CI [0.406-0.986],
1
Medical Oncology, University Of Colorado/United p=0.043 for Group 1 and 2, respectively. Harrell’s
States Of America, 2Pathology, Caen University concordance index of 0.83, 95%CI [0.67-0.95]
Hospital/France, 3Chest Medicine Department, showed a good predictive accuracy. A Àrst bootstrap
Caen University Hospital/France, 4IFCT/France, with 300 random resampling showed the stability
5
Pathology, Tenon University Hospital/France, of the miR model which signiÀcantly predicted OS
6
Intensive Care And Thoracic Oncology, Institut in 260 samples (86.7%). The reproducibility of the
Jules Bordet/Belgium, 7Chest Medicine Department, model was conÀrmed by a second similar bootstrap
Besançon University Hospital/France, 8Pulmonary procedure, the c-indexes of the created models
Medicine Department, Tenon University Hospital/ ranging from 0.74 to 0.85.
France, 9Pulmonary Medicine Department, Conclusion: A miRNA model associating miR15a,
Strasbourg University Hospital/France, 10Pulmonary miR21, and miR210, accurately discriminates three
Medicine Department, Haute Saône Community prognostic groups in early-stage NSCLC patients
Hospital/France, 11Pulmonary Medicine Department, treated by perioperative chemotherapy. Predicted or
Toulouse University Hospital/France, 12Pulmonary validated targets of those three miRs include Rho
Medicine Department, Montpellier University and Ras regulators, angiogenesis and invasion genes,
Hospital/France, 13Chest Medicine Department, hippo pathway and DNA repair genes.
Grenoble University Hospital/France Keywords: MicroRNAs, Early Stage NSCLC,
prognostic markers
Background: No survival differences was observed
between any arms in the 528 early stage NSCLC
randomized patients of the IFCT-0002 phase 3 trial Biomarkers I Monday, 4 July 2011 14:30-16:00
comparing two chemotherapy timing, all pre- vs.
peri-operative, and two regimens, CDDP-Gem O06.05 ASSOCIATION OF SEQUENCE
vs. CBDCA-Pac (V. Westeel, ASCO 2009). We VARIATIONS IN MICRORNAS WITH
hypothesized that microRNA (miRNA) expression PROGNOSIS OF NON-SMALL CELL
proÀle could discriminate prognostic groups in these LUNG CANCER IN KOREAN PATIENTS
patients. Kyong-Ah Yoon, Jihye Han, Hyekyoung Yoon,
Methods: Total RNA was extracted from 277 Sohee Park, Geon Kook Lee, Hyun-Sung Lee, Jae Ill
parafÀn-embedded surgical macrodissected Zo, Jin Soo Lee
specimens. Expression of 17 miRNAs was Research Institute And Hospital, National Cancer
successfully analyzed by Taqman qRT-PCR in 276 Center/Korea
(99%) samples. Multivariate analysis with Cox
model for overall survival (OS) was validated with a Background: MicroRNAs (miRNAs) have been
two-step bootstrap resampling analysis. studied to identify their functional signiÀcance as the
Results: Low miR210 (under the median) miR21, regulators of target gene expression via translational
and miR15a, (under the Àrst quartile) expression repression. Recently, some polymorphisms in
signiÀcantly predicted a better survival when miRNAs have been known to modify miRNA
adjusted for stage and number of administered regulation by inÁuencing the miRNA processing
cycles, the two clinical variables inÁuencing OS in and/or miRNA-mRNA interaction. Single nucleotide
polymorphisms (SNPs) in miRNAs could be used as Biomarkers I Monday, 4 July 2011 14:30-16:00
the genetic markers to predict cancer susceptibility as
well as the prognosis of cancer. Here we investigated O06.06 THREE MIRNAS IDENTIFIED
the association of seven SNPs in precursor (pre- FOR THE EARLY DETECTION OF
miRNA) and primary miRNAs (pri-miRNA) and SQUAMOUS CELL CARCINOMA OF
cancer risk, recurrence and survival of patients with THE LUNG IN ONE TESTING COHORT
non small cell lung cancer (NSCLC). AND 2 INTERNATIONAL VALIDATION
Methods: Five SNPs in pre-miRNAs (rs11614913/ COHORTS
mir-196a2, rs2910164/mir146a, rs6505162/mir423, Céline Mascaux1, Geraldine Anthoine2, John
rs2289030/mir492, rs895819/mir27a) and two SNPs Eckelberger1, York E. Miller3, Timothy C. Kennedy3,
in pri-miRNAs (rs7372209/mir26a-1, rs213210/ Robert L. Keith3, William J. Feser4, Anna E. Barón4,
mir219-1) were genotyped in 803 NSCLC patients Annick Haller2, Wilbur Franklin5, Arsene Burny2,
and 853 controls. Lung cancer risk was analyzed Fred R. Hirsch6, Jean-Paul Sculier2
1
with the genotyping results of cases and controls. Medical Oncology, University Of Colorado/United
Recurrence and patient survival was examined in 444 States Of America, 2Intensive Care And Thoracic
patients who underwent surgical resection and also Oncology, Institut Jules Bordet/Belgium, 3Division
had available clinical information. The association Of Pulmonary Sciences And Critical Care Medicine,
of SNPs and survival was analyzed with multivariate Veterans Administration Medical Center/United
Cox hazards regression models considering age, States Of America, 4Biostatistics And Informatics,
sex, smoking status, histology, stage, and additional Colorado School Of Public Health/United States
treatment after surgical operation as the confounding Of America, 5Pathology, University Of Colorado/
factors. United States Of America, 6Medical Oncology And
Results: In case-control study, variant allele Pathology, University Of Colorado/United States Of
of rs228930 was associated with reduced lung America
cancer risk (adjusted OR = 0.79, 95% CI = 0.65-
0.95, P = 0.014 in additive model). In stratiÀed Background: Early diagnosis of lung cancer is
analyses by histologic type, this effect of rs228930 anticipated to reduce its mortality rate. Recently, the
was only signiÀcant in adenocarcinoma group, results of the NSLT CT screening trial showed a 20%
not in squamous cell carcinoma group. Among reduction in lung cancer mortality. However, there
444 patients, there were 84 recurrences and 72 is still a need for improved screening methods and
deaths. Patients with homozygous TT genotype to identify the most optimal screening population.
of rs11614913 showed signiÀcantly decreased The detection of biomarker(s) in the blood or
recurrence-free survival (RFS) compared with CC sputum could help to stratify high-risk populations
and CT genotype carriers (adjusted HR = 1.52, for screening studies, to detect central lung cancers
95% CI = 1.03-2.23, P = 0.035). The genotypes that are difÀcult to visualize by CT, and to identify
of rs213210 (AG+GG) were also associated with lesions at higher risk that require further invasive
reduced RFS (adjusted HR = 1.63, 95% CI = 1.02- investigations. Previously, we identiÀed a microRNA
2.60, P = 0.041). Moreover, RFS was signiÀcantly proÀle (Mascaux et al, ERJ, 2009) that characterizes
decreased in patients with higher number of risk pre- and early cancerous stages in the bronchi of
alleles of two SNPs of rs11614913 and rs213210. individuals at high-risk for lung cancer. Here we
Conclusion: Our Àndings suggest that validate the best candidate biomarkers for early
polymorphisms of rs11614913 in mir-196a2 and detection of lung cancer.
rs213210 in mir219-1 are associated with the Methods: From the Àrst study that we published on
prognosis of Korean patients with NSCLC after 60 fresh frozen bronchial biopsies from patients at
surgical operation. high risk for lung cancer, we selected the six best
Keyword: miRNA polymorphisms, prognosis, candidate microRNAs for the early detection of
NSCLC lung cancer. We evaluated the expression level of
these microRNAs with qRT-PCR Taqman assays
applied to two different validation sets of fresh
frozen bronchial biopsies : 72 biopsies from the Jules
Bordet Institute, Brussels, Belgium and 36 biopsies
from the University of Colorado Denver, USA.
1
Results: In the Brussels cohort, a signiÀcant Medicine, Northshore University Healthsystem/
differential expression between high-grade lesions/ university Of Chicago/United States Of America,
2
early invasive squamous cell carcinoma (SCC) and Biomedical Engineering, Mccormick School Of
lower grade lesions was conÀrmed for 4 microRNAs. Engineering And Applied Science, Northwestern
Two of these microRNAs, MirA and MirB, showed University/United States Of America, 3Medicine,
highly signiÀcant up-regulation in two patient groups Northshore University Research Institute, Suite 313/
tested (SCC only or SCC and high-grade lesions) as United States Of America
compared to three different control groups (group 1:
normal mucosa of healthy never-smokers, group 2: Background: Lung cancer (LC) screening with low
morphologically normal mucosa of high-risk (ex-) dose CT (LDCT) has been shown to reduce deaths
smokers, or group 3: group 2 + low-grade lesions). by ~20%. However, the low prevalence of LC, even
MirA was highly up-regulated in SCC biopsies as in high risk smokers, makes this inefÀcient and
compared to group 1 (49 fold change (x), p=0.0009, contributes to the high false positive rate. Therefore,
area under the curve (AUC)=0.96 ; 95% CI : 0.86- a minimally intrusive test pre-screen for LDCT
1.06), group 2 (26x, p<0.0001, AUC=0.93 ; 0.84- would be of major beneÀt. The buccal cavity is ideal
1.02) and group 3 (30x, p<0.0001, AUC=0.93 ; in that it is the “molecular mirror” for LC (Sidransky,
0.85-1.00). MirB was also highly up regulated by Cancer Prev Res 2008). We have developed a suite
30x (p=0.001, AUC=1 ; 1.00-1.00), 18x (p=0.0002, of optical techniques (Gastroenterology 2011) that
AUC=0.89 ; 0.78-1.00), and 21x (p<0.0001, enables detection of microarchitectural changes of
AUC=0.9 ; 0.81-0.99) in SCC as compared to groups Àeld carcinogenesis and have demonstrated that
1, 2 and 3, respectively. Combining MirB and MirA buccal interrogation is feasible (Cancer Res 2010).
did not add signiÀcantly to the AUC of the MirA. In order to improve diagnostic performance, we
The Denver cohort did not include any healthy, evaluated potential synergism between optical and
never-smokers nor any samples with a higher grade molecular markers using microRNAs which have
than carcinoma in situ (CIS). Results were validated increasingly been recognized as a key epigenetic
for 3 microRNAs. MirA was up-regulated in CIS by modulator in carcinogenesis.
42x and 52x as compared to normal mucosa from Methods: Cases were patients with conÀrmed or
(ex-)smokers (group 2) and to the later group plus suspected LC. Controls were current/past smokers
low-grade lesions (group 3), respectively, and MirB without cancer. The buccal mucosa was interrogated
by 11x and 14x, respectively. in situ with a novel Àberoptic probe using low
Conclusion: The high potential of three microRNAs coherence enhanced backscattering spectroscopy
to discriminate between SCC and normal mucosa (LEBS), which evaluates cellular features that are
of healthy never-smokers or from high-risk (ex-) 10-20 times smaller than detectable by conventional
smokers as shown previously in a Àrst set of microscopy (Cancer Res 2009). The Àberoptic
biopsies was conÀrmed in two other international probe was used to take 5 measurements from the
validation sets. Thus, these biomarkers are very good visually normal buccal mucosa (500 milliseconds/
candidates for the early detection and diagnosis of measurement). The contralateral cheek was gently
lung cancer. brushed and placed in tri-reagent. For molecular
Keywords: microRNA, Early Detection, Biomarkers markers, we selected microRNAs as a novel
modulator of gene expressions using Taqman low
density miRNA array cards (ABI).
Biomarkers I Monday, 4 July 2011 14:30-16:00 Results: The Buccal mucosa was interrogated in
40 patients (21 LC/19 controls) who were well
O06.07 LUNG CANCER RISK matched for demographic factors. As seen in the
STRATIFICATION THROUGH BUCCAL Àgure, the composite LEBS marker was signiÀcantly
FIELD CARCINOGENESIS DETECTION: elevated in patients harboring lung cancer. With
COMPLEMENTARY ROLE FOR MICRO- regards to the microRNA, we noted 67 markers
ARCHITECTURE AND MICRORNA were statistically signiÀcantly altered. For diagnostic
BIOMARKERS studies, we focused on three microRNAs that were
Thomas A. Hensing1, Nikhil Mutyal2, Dhananjay most associated with the presence of neoplasia
Kunte3, Daniel Ray1, Andrew Radosevich2, Ashwaty (Mir 21, 106b, 367). The area under the ROC curve
Menon3, Hemant Roy3, Vadim Backman2 (AUROC) for LEBS, microRNA, and both markers
combined was 0.9, 0.89 and 1.00, respectively. Research Centre/Canada, 2Surgery/thoracic Surgery,
Vancouver General Hospital/Canada, 3Pathology
And Laboratory Medicine, Vancouver General
Hospital/Canada, 4Medical Oncology, British
Columbia Cancer Agency/Canada, 5Department
Of Pathology, University Health Network, Princess
Margaret Hospital And University Of Toronto/
Canada, 6Hamon Center For Therapeutic Oncology
Research, University Of Texas Southwestern Medical
Center/United States Of America, 7National Human
Genome Research Institute, National Institutes Of
Health/United States Of America
Background: Traditionally non-small cell lung

cancer (NSCLC) has been regarded as a single
disease entity in terms of systemic therapy; however,
Conclusion: We demonstrate that buccal recent evidence suggests that the two major subtypes
interrogation with LEBS and microRNA was of NSCLC, adenocarcinoma (AC) and squamous
able to discriminate between cases and controls. cell carcinoma (SqCC) respond differently to
Importantly, the combination of microRNA and both molecular targeted and newly developed
micro-architecture appeared synergistic. While chemotherapies. Therefore, we hypothesize that
promising, one needs to be circumspect given identifying the molecular differences between the
the modest number of patients thus requiring tumor subtypes will have a signiÀcant impact in
independent dataset validation to show robustness designing novel therapies that can improve the
(lack of overÀtting or confounding). Intriguingly treatment outcome.
this suggests that there are important biological Methods: DNA was isolated from 261 primary
interactions between epigenetic (microRNA) and NSCLC tumors (169 AC and 92 SqCC). Integrative
micro-architectural (LEBS) factors. Large scale analysis of genome wide DNA copy number,
clinical studies are ongoing to validate this novel methylation and gene expression proÀles was
paradigm for LC screening. performed to identify critical subtype-speciÀc
Keywords: Screening, Lung cancer, microRNA molecular alterations. Copy number proÀles
were generated by array comparative genomic
hybridization and the Fisher’s exact test was used
Session O07: Genetics and Epigenetics to compare frequencies of alteration for each
subtype. DNA methylation proÀling was performed
Monday, 4 July 2011 using the Illumina InÀnium HumanMethylation27
platform. Expression proÀles were generated using
the Affymetrix U133 Plus 2 platform, and data
Genetics and Epigenetics Monday, 4 July 2011 14:30-16:00 was normalized using RMA. Survival analysis
was performed using the statistical toolbox in
O07.01 DIVERGENT GENOMIC AND the program Matlab on publicly available gene
EPIGENOMIC LANDSCAPES OF LUNG expression microarray datasets with survival data.
CANCER SUBTYPES UNDERSCORE Functional identiÀcation of gene networks and
THE SELECTION OF DIFFERENT canonical signalling pathways was performed using
ONCOGENIC PATHWAYS the Ingenuity Pathway Analysis program.
Greg L. Stewart1, Larissa A. Pikor1, Ian M. Wilson1, Results: The characterization of the genomic and
Bradley P. Coe1, Raj Chari1, Kelsie Thu1, John epigenomic landscapes of AC and SqCC revealed
Yee2, John C. English3, Nevin Murray4, Ming S. 778 genes altered at the DNA level with subsequent
Tsao5, John D. Minna6, Adi F. Gazdar6, Calum E. gene expression changes, that were selected for
Macaulay1, Stephen Lam1, Wan Lam1, William W. during lung tumor development in a subtype-speciÀc
Lockwood7 manner. Analysis of 200 additional NSCLC tumors
1
Integrative Oncology, British Columbia Cancer conÀrmed that these genes are responsible for
driving the differential development and resulting Genetics and Epigenetics Monday, 4 July 2011 14:30-16:00
phenotypes of AC and SqCC. Importantly, we
identiÀed key oncogenic pathways disrupted in each O07.03 COINCIDENCE OF MUTATIONS
subtype that likely serve as the basis for differential IN KEY GENES: A COMPARISON OF
behaviors in tumor biology and clinical outcomes. ADENOCARCINOMA AND SQUAMOUS
Downregulation of HNF4a target genes was the CELL CARCINOMA OF THE LUNG.
most common pathway speciÀc to AC, while SqCC Simon Dearden1, James Stevens1, Gillian Ellison1,
demonstrated disruption of numerous histone Andrew Thomas2, Carolyn Gokhale3, Kamlesh
modifying enzymes as well as the transcription Mohan4, John Gosney4, Martin Walshaw4
1
factor E2F1. Lastly, through in silico screening of R&D Genetics, Personalized Healthcare &
candidate therapeutic compounds using subtype- Biomarkers, Astrazeneca/United Kingdom,
2
speciÀc pathway components, we identify HDAC Oncology Imed, Astrazeneca/United Kingdom,
3
and PI3K inhibitors as potential treatments tailored Central Manchester University Hospitals NHS
to lung SqCC. Foundation Trust/United Kingdom, 4Liverpool
Conclusion: The speciÀc genes and networks Heart & Chest Hospital; Royal Liverpool University
identiÀed in this study provide essential starting Hospital/United Kingdom
points for elucidating mechanisms of tumor
differentiation and developing tailored therapeutics Background: Mutations are common events in
for lung cancer treatment. More generally, our results NSCLC, with mutations in key genes deÀning
conÀrm at the molecular level that these lung cancer speciÀc molecular subtypes. Patterns of mutation
subtypes are distinct disease entities and should coincidence in adenocarcinoma of the lung have
be studied separately when designing treatment been widely reported. However, the patterns of
strategies and testing new drugs in clinical trials. mutation coincidence in squamous cell carcinoma
Keywords: Subtype, Genomics, squamous cell of the lung are less well known. Here we report
carcinoma, Adenocarcinoma data obtained from mutation screening in a panel of
genes, EGFR, KRAS, TP53, LKB1, BRAF and the
EML4-ALK translocation in samples from NSCLC
Genetics and Epigenetics Monday, 4 July 2011 14:30-16:00 patients with adenocarcinoma and squamous cell
carcinoma histologies. This is the Àrst report of these
O07.02 LUNG ADENOCARCINOMA genes being screened together in a panel of NSCLC
GENOMES OF NEVER SMOKERS adenocarcinoma and squamous tumour samples.
EXHIBIT A GREATER EXTENT OF Methods: A total of 157 samples were screened.
GENOMIC INSTABILITY THAN THOSE These comprised 105 tissue samples collected
OF SMOKERS from lung resection specimens using standard
Kelsie Thu1, Daiana Becker1, Raj Chari2, Wei operating procedures, and 52 primary tumour explant
Zhang3, Calum E. Macaulay1, Adi F. Gazdar3, samples. Within this study group there were 77
Stephen Lam1, Wan Lam4 adenocarcinoma, 58 squamous and 22 samples from
1
Integrative Oncology, Bc Cancer Research Centre/ other subtypes. Mutation screening was performed
Canada, 2Genetics, Harvard Medical School/United using Sanger sequencing (EGFR, LKB1, BRAF and
States Of America, 3Hamon Center For Therapeutic TP53), ARMS (BRAF) and pyrosequencing (KRAS)
Oncology Research, University Of Texas/United methodologies. The EML4-ALK translocation was
States Of America, 4Integrative Oncology- Cancer identiÀed using an RT-PCR based method.
Genetics, Bc Cancer Research Center/Canada Results: Mutations in all genes were detected in
tumour samples. The most commonly mutated
Abstract under Embargo - will be presented in a genes were KRAS and TP53. Mutations in
press conference during WCLC 2011. EGFR and BRAF were rare in this sample set.
Overall, mutations were more commonly seen in
adenocarcinoma samples. However, mutations
in TP53 were more often seen in squamous
samples. Mutations in LKB1 were detected in both
adenocarcinoma and squamous samples. Mutation
co-incidences were seen between KRAS, LKB1
and TP53 and between EGFR and TP53. Within potential to target hundreds of transcripts and each
the samples screened, mutations in EGFR, KRAS, transcript may be targeted by numerous miRNAs.
BRAF were exclusive to each other. These mutation Thus, miRNAs represent a broad regulatory
events deÀne molecular subtypes of NSCLC. Whilst mechanism of global gene expression. We
activating V600E mutations were rare in BRAF, hypothesize that deregulation of miRNA expression
we also detected the presence of kinase dead and is an important mechanism in determining
impaired function mutations in a small number of sensitivity/resistance to therapeutic agents. In
samples. The role of these mutations in NSCLC is this study, we demonstrate the application of an
unclear. integrative, multi-dimensional approach to identify
Conclusion: This is the Àrst study to present miRNAs that are associated with chemotherapeutic
mutation coincidence in EGFR, KRAS, TP53, resistance/sensitivity utilizing independent, publicly
LKB1, BRAF and the EML4-ALK translocation in available databases on: miRNA loci copy number
samples from NSCLC patients with adenocarcinoma (CN), miRNA expression, and mRNA expression.
and squamous histologies. Overall, these data Methods: Drug response IC50 data for 23
suggest that mutations in EGFR and KRAS, which chemotherapeutic agents on 73 lung cancer cell
are commonly reported in adenocarcinoma, are lines was obtained from the Wellcome Trust Sanger
rare in squamous cell carcinoma patients, whereas Institute (WTSI) ”Genomics of Drug Sensitivity
mutations in TP53 are more common. Mutation in Cancer” database. Matching Affymetrix SNP
coincidences are seen in both adenocarcinoma and 6.0 microarray data were obtained from the WTSI
squamous cell carcinoma samples. However, in this Cancer Genome Project Data archive (n=67 cell
dataset, these coincidences occur no more often than lines). CN alteration status for all 636 annotated
would be expected by chance given the mutation miRNA genes were correlated with drug response
frequencies detected. by comparing the most resistant and sensitive
Keywords: squamous cell carcinoma, Mutation, cell line tertiles for each drug. The same method
Adenocarcinoma was applied to miRNA expression data (n=254
miRNAs), which were obtained from the Broad
Institute (n= 64 cell lines). CN and expression data
Genetics and Epigenetics Monday, 4 July 2011 14:30-16:00 was integrated to identify miRNAs signiÀcantly
deregulated at both the CN and expression levels.
O07.05 DEREGULATION OF SPECIFIC Putative targeted transcripts of these miRNAs were
MIRNAS CORRELATES WITH compiled using TargetSpy and TargetScan databases.
SYSTEMIC THERAPY RESPONSE IN Only those transcripts identiÀed by both programs,
NON-SMALL CELL LUNG CANCER that were differentially expressed between resistant
Katey S.S. EnÀeld1, Greg L. Stewart1, Larissa A. and sensitive cohorts, and whose expression was
Pikor1, Carlos E. Alvarez2, Stephen Lam1, Raj Chari1, inversely correlated with the expression of the
Wan Lam1 associated miRNA were analyzed. Target gene
1
Integrative Oncology, British Columbia Cancer function analysis was performed using Ingenuity
Research Centre/Canada, 2The Research Institute, Pathways Analysis using mRNA expression data
Nationwide Children’s Hospital/United States Of obtained from Broad Institute (n=68 cell lines).
America Results: Three hundred and seven miRNAs were
identiÀed to be signiÀcantly altered at the CN level
Background: Genetic testing is increasingly being between resistant and sensitive cohorts for at least
used to determine optimal therapy of patients with one drug. Similarly, 172 miRNAs were deregulated
non-small cell lung cancer (NSCLC). The majority at the expression level for at least 1 drug. Six
of studies have focused on sequence mutations miRNAs - miR-10b, miR-193b, miR-203, miR-
and expression changes in protein-coding genes. 328, miR-589, and miR-628 - were signiÀcantly
MicroRNAs (miRNAs) are short non-coding RNA deregulated at both the CN and expression levels
molecules that are 17-25 nucleotides in length. They for at least 1 drug, and correlated with either
regulate gene expression by binding complementary resistance or sensitivity to speciÀc chemotherapeutic
RNA transcripts, and prevent their translation by agents. The functions of the putative mRNA targets
initiating RNA degradation or interfering with correlated with genetic instability that could facilitate
translational machinery. Each miRNA has the drug resistance, and, in some cases, with speciÀc
pathways involved in the drug’s mechanism of and NSCLC, may provide novel biomarkers or
action. chemoprevention strategies for high risk subjects
Conclusion: A method is presented to identify novel with COPD.
predictors of chemotherapeutic agent response for Methods: We generated DNA methylation and
NSCLC. Our in silico discovery provides a better copy number proÀles for NSCLC tumour and
understanding of drug response mechanisms and matched non-malignant lung tissues from smokers
may lead to better predictors of drug response. with (n=10) and without (n=15) COPD, using
Keywords: miRNA, Non-small cell lung cancer, the Illumina InÀnium and Affymetrix SNP 6.0
Chemotherapy response, Data integration arrays, respectively. Methylation proÀles were also
generated for bronchial epithelial cells from small
airways of smokers with COPD alone (n=24), and
Genetics and Epigenetics Monday, 4 July 2011 14:30-16:00 COPD and NSCLC (n=15). Genes that were 1)
differentially methylated between non-malignant
O07.06 CONTRIBUTION OF DNA lung tissue from COPD patients with NSCLC
METHYLATION IN THE DEVELOPMENT compared to similar tissue from patients with
OF LUNG CANCER IN SMOKERS WITH NSCLC alone, 2) additionally altered at the level of
CHRONIC OBSTRUCTIVE PULMONARY gene dosage in COPD tumours compared to tumours
DISEASE from non COPD patients, and 3) differentially
Emily A. Vucic1, Kelsie Thu1, Jennifer Y. Kennett2, methylated in bronchial epithelial cells from COPD
Raj Chari3, Ian M. Wilson1, Don D. Sin4, Stephen patients with NSCLC compared to COPD alone,
Lam5, Wan Lam1 were selected for gene function and pathway
1
Integrative Oncology, British Columbia Cancer analysis.
Research Centre/Canada, 2Integrative Oncology, Results: We identiÀed 544 genes that were
British Columbia Cancer Centre/Canada, 3Genetics, hypermethylated in non-malignant lung parenchyma
Harvard Medical School/United States Of America, tissues and concordantly lost at the DNA level in
4
Faculty Of Medicine, University Of British corresponding tumours from COPD patients, but not
Columbia/Canada, 5British Columbia Cancer in similar tissues from non COPD patients. Of these
Agency/Canada genes, 174 were also hypermethylated in airway
cells of patients with COPD and NSCLC compared
Background: Patients with chronic obstructive to those with COPD alone. These COPD+NSCLC
pulmonary disease (COPD) have an increased risk speciÀc genes corresponded to the PI3K/AKT, aryl
of developing lung cancer. Together these diseases hydrocarbon signalling and retinoic acid mediated
contribute tremendously to mortality and morbidity apoptotic pathways. Our results suggest NSCLC in
worldwide. Our overall goal is to identify molecular COPD patients may develop through unique tumour
pathways associated with the link between COPD promoting and metabolic pathways.
and lung cancer. DNA methylation is highly altered Conclusion: Our preliminary results suggests
in airways of smokers and at sites of chronic NSCLC arising from patients with COPD may
inÁammation. It is also one of the most frequent involve different pathways than those with
and earliest aberrations in lung cancer, associated NSCLC without COPD. Many of these speciÀc
with tumour suppressor gene (TSG) silencing and alterations can be detected in airways of patients
genomic instability. We hypothesize that COPD with COPD+NSCLC using methylation analysis.
related DNA methylation changes constitute early Understanding COPD speciÀc NSCLC molecular
events in TSG inactivation, and in order to inactivate biology may lead to development of targeted
both alleles, a second gene dosage alteration in chemoprevention strategies speciÀc to the NSCLC
tumours may be found at these genes. Furthermore, promoting aspects of COPD.
we hypothesize that genes uniquely inactivated in Keywords: chronic obstructive pulmonary disease,
tissues from COPD patients with non small cell lung epigenetics, COPD related lung cancer, InÁammation
cancer (NSCLC), compared to similar tissues from
patients with NSCLC alone, can be used to identify
molecular pathways causal to lung tumorigenesis in
COPD patients. The detection of these alterations
in small airway epithelium in patients with COPD
Genetics and Epigenetics Monday, 4 July 2011 14:30-16:00 495 has been shown overexpressed in KRAS mutated
adenocarcinoma of the lung but so far the mRNA target
O07.07 MICRORNAS IN LUNG CANCER - is unknown. miR-410 was found enriched in Erlotinib
A FUNCTIONAL GENOMICS APPROACH treated cells, miR-368 was enriched in both Erlotinib
FOR DISCOVERY AND VALIDATION and GeÀtinib treated cells and miR-191 resulted in a
OF NOVEL FACTORS DETERMINING dramatic growth beneÀt independent of Erlotinib or
RESPONSE TO TREATMENT WITH GeÀtinib. miR-191 has been shown overexpressed
EGFR-INHIBITORS. in a number of different types of cancer. We are now
Lukas M. Orre1, Carlos Le Sage2, Reuven Agami2, validating these microRNAs and other, and the next
Janne Lehtiö3 step will be to search for the microRNA targets and a
1
Oncology Pathology, Karolinska Institutet/Sweden, molecular explanation for the biological effects.
2
The Netherlands Cancer Institute/Netherlands, Conclusion: Lung cancer is the leading cause of cancer
3
Oncology And Pathology, Karolinska Institutet/ deaths in the world, reÁecting the need for a better
Sweden understanding of the mechanisms that underlie lung
carcinogenesis. Although focusing on known genes and
Background: The development of rational drug proteins has already yielded new information, unknown
design and molecularly targeted therapies has resulted markers may also lend insight into the biology of lung
in an array of new therapy options recently approved cancer. miRNAs are a class of small noncoding RNA
for treatment of lung cancer (LC) or in clinical trials. genes found to be abnormally expressed in several
However, response to treatment with targeted therapies types of cancer including lung cancer, suggesting that
is restricted to subsets of the LC patients and initial miRNAs play a substantial role in the pathogenesis
response to treatment is often followed by development of human cancers. The research presented here could
of acquired resistance during prolonged administration potentially result in the identiÀcation of miRNAs/
resulting in tumor progression. The aim of this project target proteins/pathways determining the response to
is to Ànd novel components of EGFR signalling treatment with EGFR-inhibitors. The identiÀcation of
and new molecular predictors of treatment response new biomarkers predicting individual tumors response
with EGFR-inhibitors in lung cancer. The focus on to targeted therapy would be a valuable clinical tool for
microRNAs is primarily based on recent Àndings of improvement of lung cancer treatment and hopefully
microRNA deregulation in lung cancer and Àndings patient outcome.
that microRNAs can regulate cellular functions such as Keywords: Functional genomics, EGFR-TKI,
cell proliferation and cell death signalling. microRNA, drug resistance
Methods: Initially functional genomics methods were
used to screen for microRNAs altering the response
to the EGFR inhibitors geÀtinb and Erlotinib. BrieÁy, Session O08: Palliative and Supportive
a miRNA expression library (miR-Lib) containing Care
almost all annotated human miRNAs (Agami, R) was
transduced into U1810 lung cancer cells. After 30 days
Monday, 4 July 2011
of treatment with either Erlotinib or GeÀtinib, deep
sequencing was used to identify miRNAs enriched in
the treated cells compared to untreated control cells. Palliative and Supportive Care Monday, 4 July 2011 14:30-16:00
Enrichment of a speciÀc miRNA after treatment with
a speciÀc inhibitor suggests that expression of that O08.01 CHANGING PREFERENCES FOR
miRNA results in resistance. Selected microRNAs will INFORMATION AND PARTICIPATION
be validated using cell viability assays and cytotoxicity IN THE LAST PHASE OF LIFE: A
assays. After validation of microRNAs affecting the LONGITUDINAL STUDY AMONG
response to EGFR inhibitors, mass spectrometry based NEWLY DIAGNOSED ADVANCED LUNG
proteomics methods will be used to identify speciÀc CANCER PATIENTS
mRNA targets. Koen Pardon1, Reginald Deschepper1, Robert
Results: We have successfully performed all parts of Vander Stichele2, Jan L. Bernheim1, Freddy
the functional genomics experiment, and sequencing Mortier3, Nathalie Bossuyt4, Denis Schallier5, Paul
data revealed several interesting candidates. miR-495 Germonpré6, Daniella Galdermans7, Luc Deliens1
1
was enriched four times in GeÀtinib treated cells. miR- End-of-life Care Research Group, Ghent University
& Vrije Universiteit Brussel/Belgium, 2Heymans change over time in ways they might not expect.
Institute For Pharmacology, Ghent University/ Keywords: Patient-physician communication,
Belgium, 3Bioethics Institute, Ghent University/ palliative care, End-of-life decisions, Advanced
Belgium, 4Department Of Epidemiology, ScientiÀc Lung Cancer
Institute Of Public Health/Belgium, 5Department Of
Medical Oncology, University Hospital Of Brussels/
Belgium, 6Department Of Pulmonary Medicine, Palliative and Supportive Care Monday, 4 July 2011 14:30-16:00
Antwerp University Hospital/Belgium, 7Department
Of Pulmonary Medicine, ZNA Middelheim Hospital/ O08.02 DEPRESSION SHORTENS
Belgium SURVIVAL AND MAY MITIGATE
BENEFICIAL EFFECTS OF A
Background: Objective is to explore changes over CONCURRENT ONCOLOGY
time in the information and participation preferences PALLIATIVE CARE INTERVENTION IN
of newly diagnosed stage IIIb/IV non-small-cell lung LUNG CANCER PATIENTS
cancer patients. Lisa A. Lambert1, Marie Bakitas2, Zhongze Li2, Tor
Methods: Patients were recruited by physicians in Tosteson2, Kathleen Lyons2, James R. Rigas2, Mark
13 hospitals in Flanders, Belgium, and interviewed Hegel2, Tim A. Ahles2
1
every two months until the fourth and every four Department Of Psychiatry, Dartmouth Medical
months until the sixth interview. School/United States Of America, 2Dartmouth
Results: 128 patients were interviewed once, 13 Medical School/United States Of America
six times. The overall rates of wanting information
or participation did not change much over time, Background: Recent randomized control trials
but many individual patients changed their minds. (RCT) of concurrent oncology palliative care
Looking at the Àrst three interviews over a period (COPC) compared to usual oncology care alone have
of four months (N=67), we observed that: 1) demonstrated improved mood, quality of life and
the preferences for information about diagnosis, survival for patients with lung cancer (Temel et al,
prognosis and treatment were stable: practically 2010) and other solid tumors (Bakitas et al, 2009).
all patients wanted this information shortly after In our RCT, the beneÀcial effects of the COPC
diagnosis and kept on wanting it; 2) the preferences intervention (Project ENABLE) on depression and
for information about palliative care and end-of-life survival were evident for the whole study sample
decisions with a possible or certain life-shortening (Bakitas et al, 2009). However, subgroup analyses
effect (ELDs) were unstable: of the patients who of lung cancer participants did not show the same
did not want this information, a quarter changed beneÀt on mood or survival. Since depression has
towards wanting it, and of those who wanted this been associated with shorten survival, we conducted
information, 39% (palliative care) and a quarter analyses on our lung cancer subgroup to investigate
(ELDs) changed towards not wanting it; 3) the this relationship.
preferences for participation in medical decision Methods: Of the 322 participants with newly
making were also unstable: from 50% to 78% of diagnosed solid tumors (breast, gastrointestinal,
patients, depending on the type of decision (in genitourinary and lung), 117 participants had
general, treatment, transfer, end-of-life), changed advanced NSCLC or extensive SCLC (58 control,
their preference towards wanting more or less 59 intervention). We measured depressive symptoms
participation. Changing preferences were associated (Center for Epidemiological Studies Depression
with patients’ quality of life: patients in a worse Scale [CES-D]) at baseline, 1 month and every
physical condition were more likely to persist in 3 months until death or study completion. Lung
wanting information about palliative care and ELDs, cancer subjects were divided into 3 groups based on
and those with more pain were more likely to want baseline CES-D scores: low depressive symptoms
more involvement in medical decisions in general (below study median [CES-D < 12]), “subclinical”
and in transfer decisions as time passed. depressive symptoms (above study median, below
Conclusion: Doctors should ask their advanced lung clinically predictive cut-off [CES-D >12 and < 16])
cancer patients at the beginning of their illness how and clinical depressive symptoms (CES-D > 16).
much information and participation they want, and We evaluated whether baseline depressive symptom
should keep on asking them because preferences do strata predicted median survival using Kaplan-Meier
curves and log rank tests. We applied a longitudinal Palliative and Supportive Care Monday, 4 July 2011 14:30-16:00
regression model with random subject effects to
assess treatment effects on depressive symptoms. O08.03 EXPRESSED WISHES FOR
Finally, we analyzed median CES-D scores at the EUTHANASIA AND INCIDENCE
assessment time point closest to death in lung versus OF END-OF-LIFE DECISIONS IN
non-lung intervention group subjects. We used a ADVANCED LUNG CANCER PATIENTS:
random intercept model with unstructured covariance A PROSPECTIVE STUDY IN FLANDERS,
to determine whether participants with lung cancer BELGIUM
had more depressive symptoms than patients with Koen Pardon1, Reginald Deschepper1, Robert Vander
other solid tumors. Stichele2, Jan L. Bernheim1, Freddy Mortier3, Denis
Results: Based on the strata, median survival time Schallier4, Paul Germonpré5, Daniella Galdermans6,
for participants with lung cancer was signiÀcantly Luc Deliens1
1
different among groups. Participants with low End-of-life Care Research Group, Ghent University
depressive symptoms survived longest with median & Vrije Universiteit Brussel/Belgium, 2Heymans
survival of 13 months. Those with “subclinical” Institute For Pharmacology, Ghent University/
depressive symptoms survived 5.9 months and those Belgium, 3Bioethics Institute, Ghent University/
with clinical depressive symptoms survived 8.1 Belgium, 4Department Of Medical Oncology,
months (p = .016). Longitudinal analysis of treatment University Hospital Of Brussels/Belgium,
5
effects for lung cancer participants showed no Department Of Pulmonary Medicine, Antwerp
signiÀcant difference in CES-D between intervention University Hospital/Belgium, 6Department Of
and control groups. However, intervention Pulmonary Medicine, ZNA Middelheim Hospital/
participants with non-lung cancer diagnoses had Belgium
signiÀcantly lower levels of depressive symptoms at
the assessment point closest to death (Mean CES-D Background: Objective is to explore expressed
= 10.2) compared to the lung cancer subgroup (Mean wishes and requests for euthanasia and the incidence
CES-D = 16.7), which was above depression cut-off of end-of-life decisions with possible or certain
(p = .004). life-shortening effects (ELDs) in stage IIIb/IV lung
Conclusion: Patients with lower baseline depressive cancer patients.
symptoms had longer median survival than those Methods: This is a prospective, longitudinal,
with ‘subclinical’ and clinical levels of depressive observational study of a consecutive sample of
symptoms. At the assessment point closest to death, advanced lung cancer patients who died within
intervention subjects with lung cancer were more 18 months of diagnosis. The pulmonologist or
depressed than subjects with other solid tumors. oncologist and the general practitioner (GP) of
It appears that our COPC intervention had less the patient were asked to Àll in a questionnaire on
effect on depressive symptoms for the lung cancer the medical circumstances surrounding the death,
group than the whole study sample. The signiÀcant immediately after the patient died.
association of baseline ‘subclinical’ and clinical Relevant information was available for 105 of 115
depressive symptoms with survival, combined deaths.
with the lack of intervention effect for participants Results: According to the specialist or GP, 20% of
with lung cancer, suggests the need to develop the patients had expressed a wish for euthanasia,
more robust interventions that speciÀcally target three quarters of these (14.3% of all patients) had
depressive symptoms in this population. made an explicit and repeated request and half of
Keywords: Lung cancer, palliative care, depression, these (7.6% of all patients) received euthanasia.
survival Those who had expressed a wish for euthanasia
but had not made an explicit and repeated request
(5.7% of all patients) did not receive euthanasia.
Patients with a palliative treatment goal at diagnosis
of the advanced cancer, and those who lived longer
were signiÀcantly more likely to express a wish for
euthanasia and to receive euthanasia. Death was
preceded by an ELD in 62.9% of all patients. This
was a non-treatment decision in 14.3%, intensifying
alleviation of symptoms in 39.1% and administration hormones used by the women in the study cohort.
of lethal drugs with the explicit intention to shorten Results: The study cohort included 2320 women
life in 9.5% (euthanasia in 7.6%, physician assisted with NSCLC. The median age at diagnosis was
suicide in 0.0% and ending the patient’s life without 71 years. Forty-seven percent, 36%, and 14% had
request in 1.9%). adenocarcinoma, NSCLC-NOS, squamous cell
Conclusion: Physicians acted with care and did not carcinoma respectively. Thirty-four percent of
perform euthanasia on the basis of an expressed wish patients had stage I & II, 24% had stage III and 38%
only, without explicit and repeated request; however, had stage IV disease. Smoking status was explored
a proportion of explicit and repeated requests were for 1317 patients by chart review. The never smokers
not carried out either because the patient died or (n=163) had signiÀcantly better overall survival
because the treating physician was not aware they (OS) than smokers (p=0.03). In our cohort, 514
had been made. patients were HRT users. The OS of HRT users was
Keywords: Euthanasia, End-of-life decisions signiÀcantly better than non-users (median; 1.35 vs
0.88 years, p<.001). This difference was present with
stages I & II combined (p=.002), stage III (p<.001)
Palliative and Supportive Care Monday, 4 July 2011 14:30-16:00 but not in stage IV NSCLC (p=.19). Type of HRT
used (single estrogen or estrogen progesterone
O08.05 HORMONE REPLACEMENT combination) did not have a signiÀcant effect on OS.
THERAPY AND SURVIVAL OF WOMEN Conclusion: These Àndings suggest that similar to
WITH NON-SMALL-CELL LUNG gender difference women who are HRT users have
CANCER improved survival and this difference is seen only in
Loganathan Kathiravelu1, Grace Musto2, Gary early stage disease indicating that HRT likely alters
Harding3, Gefei Qing4, Ketan Badiani1, Sylvain the biology of the disease.
Lother5, Leigh C. Murphy6, Sri Navaratnam3 Keywords: Hormone Replacement Therapy,
1
Manitoba Insitutie Of Cell Biology, Cancercare survival, Lung cancer, gender
Manitoba/Canada, 2Epidemiology & Cancer
Registry, Cancercare Manitoba/Canada, 3Medical
Oncology And Haematolgoy, Cancercare Manitoba/ Palliative and Supportive Care Monday, 4 July 2011 14:30-16:00
university Of Manitoba/Canada, 4Department
Of Pathology, University Of Manitoba/Canada, O08.06 IMPACT OF HORMONE
5
Medical Oncology And Haematolgoy, Cancercare REPLACEMENT THERAPY (HRT) AND
Manitoba/Canada, 6Manitoba Institute Of Cell TOBACCO USE ON OUTCOMES OF
Biology, Cancercare Manitoba/Canada WOMEN WITH ADVANCED NON SMALL
CELL LUNG CANCER (NSCLC) AT MAYO
Background: Women have a greater risk of CLINIC ARIZONA (MCA)
developing lung cancer, but once they develop the Harshita Paripati1, Amylou C. Dueck2, Julia A. Files3,
disease their clinical outcome is better than men. The Anita P. Mayer3, Helen J. Ross1
1
gender difference is partially due to estrogen thus Hematology/oncology, Mayo Clinic/United States
a similar effect may be expected with exogenous Of America, 2Biostatistics, Mayo Clinic/United
hormone use (HRT). The present study was States Of America, 3Internal Medicine, Mayo Clinic/
undertaken to evaluate the impact of HRT use on United States Of America
clinical outcome of lung cancer and the interaction
with the other prognostic variables. Background: The gender differences in
Methods: All female patients diagnosed with non- susceptibility to tobacco induced carcinogenesis and
small cell lung carcinoma (NSCLC) from January risk of non-small cell lung cancer (NSCLC)have
2000 to December 2007 were identiÀed from the been described in the recent past, but have not been
Manitoba Cancer Registry (MCR) using ICD codes. well-deÀned. It has been suggested that women are
Information on histology, collaborative staging, more susceptible to tobacco-induced carcinogenesis.
smoking status and treatment were also obtained. Recent studies show that estrogen and estrogen
Drug Program Information Network (DPIN); an receptors, speciÀcally ER-ơ may be involved in
administrative data base was used to accurately carcinogenesis. In this study, we analyzed the
capture HRT use, timing, duration and type of effect of tobacco use, menopausal status and use of
hormone replacement therapy (HRT) on survival and America, 2The John Hopkins University/United
outcomes of women with advanced NSCLC. States Of America, 3GTX, Inc./United States Of
Methods: A retrospective review of data from the Lung America
Cancer Registry at Mayo Clinic Arizona (MCA) was
conducted. All analytic female patients with stages III Background: Cancer cachexia causes muscle
and IV NSCLC from 1998-2006 were analyzed for age wasting and leads to decline in physical function.
at diagnosis, type of therapy, outcomes and survival. NSCLC represents greater than 80% of newly
Chart reviews were conducted to obtain speciÀc diagnosed lung cancer with over three quarters
information such as smoking history, menopausal status of patients being diagnosed with Stage III or
and use of hormone replacement therapy. IV disease. At diagnosis, 60% of lung cancer
Results: 381 female patients with advanced (Stages patients have substantial weight loss, increasing
III & IV) NSCLC were identiÀed from 1998-2006. 62 to >80% prior to death from malignancy. Much
patients were excluded due to either incorrect staging, of this weight loss is attributed to muscle wasting
or lack of information regarding treatment and survival. leading to a decline in physical function and other
Of the remaining 319 patients, 95 (30%) patients had detrimental consequences early in the course of
Stage III disease and 224 (70%) patients had Stage a patient’s malignancy. Research has shown that
IV disease. 307 women were post-menopausal, 7 NSCLC patients with weight loss at diagnosis are
women were pre-menopausal and menopausal status less likely to tolerate chemotherapy, have worse
was unknown in the remaining 5 women. 242 women treatment outcomes and shorter overall survival.
(76%) were not on any HRT, and 77 women (24%) This wasting and decline in function may have
were on .HRT Median survival was 8.0 months in the detrimental consequences early in the course of a
patients not on HRT and 11.0 months in the patients on patient’s malignancy, underscoring the importance
HRT (P=0.38). 268 (84%) patients were smokers and of diagnosing and treating this condition at an
51 (16%) patients were non-smokers. Median survival early stage. Published data has shown that a 10%
was 8.0 months in smokers and 14.0 months in non- improvement in physical function is a substantial
smokers (P=0.07). There was no statistically signiÀcant clinically meaningful beneÀt. We conducted a
interaction between smoking status and HRT on overall randomized, double-blind, placebo controlled, multi-
survival (interaction P=0.92). center study to evaluate the effect of GTx-024 on
Conclusion: Our study reveals a trend towards muscle wasting and physical function in patients
poor survival in smokers with NSCLC compared to with cancer cachexia.
non-smokers. There was no statistically signiÀcant Methods: Subjects (n=159) were randomized to oral
difference in overall survival based on use of HRT. GTx-024 (1 or 3 mg) or placebo daily for 16 weeks.
Further studies are needed to evaluate the effect Subjects were males >45 years and postmenopausal
of gender based differences in tumor biology and females, with 2% weight loss in the 6 months prior
determine optimal treatment of women with lung to randomization and diagnosed with either NSCLC,
cancer. colorectal cancer, non-Hodgkin’s lymphoma, chronic
Keywords: hormone replacement therapy (HRT), lymphocytic leukemia or breast cancer. The primary
Non small cell lung cancer (NSCLC), smoker endpoint was change in lean body mass. Secondary
endpoints included QOL and physical function
with clinical beneÀt deÀned as 10% improvement
Palliative and Supportive Care Monday, 4 July 2011 14:30-16:00 in physical function assessed by stair climb power
(responder analysis).
O08.07 GTX-024, A SELECTIVE Results: 103 subjects in the MITT population had
ANDROGEN RECEPTOR MODULATOR stair climb power assessed at baseline and week
(SARM), IMPROVES PHYSICAL 16. GTx-024 treated subjects demonstrated clinical
FUNCTION IN NON-SMALL CELL LUNG beneÀt compared to placebo (P=0.03). Among
CANCER (NSCLC) PATIENTS WITH NSCLC subjects, 28 were included in the physical
CANCER CACHEXIA function analysis. Seventy-eight percent treated with
Shontelle T. Dodson1, Adrian Dobs2, Michael L. GTx-024 responded compared to 30% treated with
Hancock1, Gary Barnette3, Mary A. Johnston1, placebo (P=0.02). Physical function was positively
Mitchell S. Steiner3 correlated with QOL as assessed by the FAACT
1
Medical Affairs, GTX, Inc./United States Of questionnaire further substantiating clinical beneÀt
(Spearman correlation coefÀcient = 0.60, P=0.001). of cardiomyopathy, LVEF was measured by

Conclusion: GTx-024 was well tolerated and echocardiogram or by multiple gated acquisition
showed a statistically signiÀcant and clinically scan every three cycles and in follow-up until death
relevant improvement in physical function in or study discontinuation. Cardiac adverse events
NSCLC subjects. These data provide evidence were graded using the NCI CTCAEv 3.0.
that GTx-024 may play an important role in the Results: Baseline characteristics were similar
management of patients with NSCLC. Further in the amrubicin and topotecan groups: median
research is needed to assess the effect of GTx-024 on age 62 versus 61 years; men 58% versus 60%;
overall survival. ECOG PS score of 0 30% versus 34%; mean
Keywords: muscle wasting, Cachexia, Physical LVEF 62% vs 63%. LVEF (Figure) did not differ
function, GTx-024 signiÀcantly between treatment arms and did
not decline with cumulative doses of amrubicin
exceeding 1000 mg/m2 (Level 4 in Àgure, N=114).
Session O09: SCLC I Grade 3 cardiac adverse events (Table) occurred
in 5.1% (AMR) versus 4.6% (Topo), (P=0.84).
Monday, 4 July 2011
SCLC I Monday, 4 July 2011 14:30-16:00
O09.01 CARDIAC SAFETY OF

AMRUBICIN IN A RANDOMIZED
PHASE 3 TRIAL OF AMRUBICIN
VS TOPOTECAN AS SECOND-LINE
TREATMENT FOR SMALL CELL LUNG
CANCER (SCLC)
David R. Spigel1, Joachim Von Pawel2, Robert Jotte3,
Mark A. Socinski4, Mary E.R. O’Brien5, Richard
Mcnally6, Markus Renschler6
1
Thoracic Oncology, Sarah Cannon Research
Institute/United States Of America, 2Asklepios
Fachkliniken München-Gauting/Germany, 3Us
Oncology/United States Of America, 4Lineberger
Comprehensive Cancer Center/United States Of
America, 5Royal Marsden NHS Foundation Trust/
United Kingdom, 6Celgene Corporation/United
States Of America
Background: Amrubicin is a third-generation

anthracycline and potent topoisomerase II inhibitor.
Prior data suggests that amrubicin has an improved
cardiac safety proÀle compared to Àrst and second
generation anthracyclines. The purpose of this report Conclusion: In this randomized phase III trial
is to evaluate the cardiac safety in the randomized of amrubicin vs topotecan for the second-line
phase III trial (ACT-1) of amrubicin versus topotecan treatment of SCLC, the cardiac safety of amrubicin
for the second-line treatment of patients with SCLC. is comparable to that of topotecan. LVEF remained
Methods: Patients with previously treated SCLC, stable even in patients with cumulative amrubicin
an ECOG PS score 1, and left ventricular ejection dosing >1000 mg/m2. Amrubicin exhibits a safe
fraction (LVEF) 50% were eligible. Patients cardiac proÀle compared with historical results of
received amrubicin 40 mg/m2 IV (n=424) on other anthracyclines.
days 1–3 or topotecan 1.5 mg/m2 IV (n=213) Keywords: amrubicin, SCLC, Anthracycline,
on days 1–5 of a 21-day cycle. To evaluate risk Topotecan
SCLC I Monday, 4 July 2011 14:30-16:00 (such as somnolence [46% all grades] and euphoric
mood [31% all grades]) occurred during and shortly
O09.02 RANDOMIZED PHASE II TRIAL after the Ob infusion. The only Grade 3/4 non-heme
OF THE PAN BCL-2 ANTAGONIST AE with 5% increase in absolute frequency in the
OBATOCLAX (OB) IN COMBINATION Ob arm was somnolence (8 vs 0%). Grade 3/4 febrile
WITH CARBOPLATIN AND ETOPOSIDE neutropenia was rare (5% both arms). Grade 3/4
(CE) VS CE CHEMOTHERAPY ALONE hematologic lab abnormalities were similar for each
IN EXTENSIVE STAGE SMALL CELL arm (CEOb vs CE): anemia (8 vs 15%), neutropenia
CARCINOMA OF THE LUNG (ES-SCLC) (61 vs 58%), and thrombocytopenia (17 vs 10%).
Corey J. Langer1, Istvan Albert2, Peter Kovacs3, L. 74% of the pts on the CEOb arm alive without
Johnetta Blakely4, Gabor Pajkos5, Petar Petrov6, progression after 6 cycles started maintenance
Attila Somfay7, Aleksandra Szczesna8, Petr therapy. EfÀcacy data, including death or progression
Zatloukal9, Andrzej Kazarnowicz10, Mehdi Moezi11, during initial 6 cycles of chemotherapy (Refractory
Marshall Schreeder12, Judy Schnyder13, Mark Rate) are summarized in the table below. Patients
Berger13 with PS 2 at screening did poorly with median OS of
1
Hematology/Oncology, Abramson Cancer Center, 6.0 and 5.8 mos in CEOb and CE arms, respectively.
University Of Pennsylvania/United States Of Conclusion: The CEOb arm demonstrated a trend
America, 2Mátrai Gyógyintézet, Mátraháza/Hungary, for improved ORR, Clinical BeneÀt Rate, PFS, 12
3
Oncology, University Of Debrecen/Hungary, 4The mo and overall survival (OS). Most importantly,
West Clinic/United States Of America, 5Oncology, Ob markedly decreased the rate of refractoriness
Bacs-Kiskun County Hospital/Hungary, 6District to the initial 6 cycles of chemotherapy by 36.5%,
Dispensary For Cancer Diseases With Inpatient suggesting that the observed pre-clinical synergy
Unit/Bulgaria, 7Univ. Of Szeged/Hungary, 8The translates clinically into a reversal of primary
Regional Lung Diseases Hospital/Poland, 9Charles resistance to chemotherapy. OS in PS 0-1 patients
University/Czech Republic, 10Tuberculosis And Lung with ES-SCLC will be evaluated in a Phase III trial
Disease Hospital/Poland, 11Integrated Community comparing CE to CEOb.
Oncology Network/United States Of America,
12 Study ORR Clinical PFS 12 OS OS Refractory
Clearview Cancer Institute/United States Of Arm BeneÀt Month (PS 0-1) Rate (PS
America, 13Gemin X Pharmaceuticals/United States Rate Survival 0-1)
Of America CEOb 64.9% 83.1% 6.0 mos* 45.5% 10.6 mos* 11.9 mos* 25.4%
CE 53.8% 69.2% 5.4 mos* 37.2% 9.9 mos* 10.1 mos* 40.0%
Background: Ob, a pan-BCL-2 antagonist, is One 0.11 0.03 0.08 0.19 0.0506 0.052 0.05
sided p
synergistic in vitro with cisplatin and etoposide (E). value
A Phase I study concluded that a 3-hr Ob infusion in Hazard - - 0.79 - 0.72 0.71 -
combination with carboplatin (C) and E was favored Ratio
over a 24-hr infusion (ASCO 2010, Ab e13531) * Median

Methods: Patients (pts) with chemotherapy-naïve Keyword: small cell carcinoma
ES-SCLC, measurable disease, & PS 0-2 were
randomized to receive six 21-day cycles of CE
(C AUC 5 D1, and E 100 mg/m2 D1-3) or CEOb SCLC I Monday, 4 July 2011 14:30-16:00
(CE plus Ob [30 mg as a 3-hr infusion D1-3]). 73
evaluable pts were planned for each arm. 1° endpoint O09.03 IPILIMUMAB IN COMBINATION
was ORR (conÀrmed CR & PR); 2° endpoints WITH PACLITAXEL AND CARBOPLATIN
included PFS and OS. After completing 6 cycles, AS FIRST-LINE TREATMENT IN
responders received prophylactic cranial irradiation; EXTENSIVE DISEASE-SMALL CELL
pts on CEOb continued Ob as maintenance therapy. LUNG CANCER (ED-SCLC): RESULTS
Results: 165 pts were randomized; 155 pts (77 FROM A PHASE 2 TRIAL
CEOb; 78 CE) received treatment. Median age was Martin Reck1, Igor Bondarenko2, Alexander Luft3,
62 (range 35-80); 56% were male; 31% were PS 0, Piotr Serwatowski4, Fabrice Barlesi5, Raju Chacko6,
60% PS 1, and 9% PS 2. 21% in each arm had brain Martin Sebastian7, Jonathan Siegel8, Jean-Marie
mets. The arms were well balanced with respect to Cuillerot8, Thomas Lynch9
1
baseline demographics. CNS Adverse Events (AEs) Department Of Thoracic Oncology, Hospital
Grosshansdorf/Germany, 2City Clinical Hospital/ (concurrent vs phased vs P/C alone, all grades)
Ukraine, 3Leningrad Regional Clinical Hospital/ pruritus (24% vs 19% vs 5%), rash (36% vs 24%
Russian Federation, 4Oddzial Chemioterapii/ vs 2%), and diarrhea (26% vs 33% vs 16%).
Poland, 5University Of Mediterranée - Assistance Corresponding rates of grade 3/4 events were 0%
Publique Hopitaux De Marseille/France, 6Christian vs 2% vs 0% for pruritus, 5% vs 0% vs 0% for rash,
Medical College/India, 7Department Of Hematology, and 5% vs 10% vs 5% for diarrhea. Hematologic
Oncology And Pneumology, Johannes Gutenberg- abnormalities were similar across 3 arms. Overall
university Medical Center Mainz/Germany, treatment-related grade 3/4 AEs in concurrent,
8
Bristol-Myers Squibb/United States Of America, phased, and P/C alone arms were 43%, 50% and
9
Department Of Oncology, Yale Cancer Center And 30%, respectively. One death in concurrent arm was
Smilow Cancer Hospital/United States Of America reported to be treatment-related.
Conclusion: Phased ipilimumab+P/C, but not
Background: Ipilimumab, a human monoclonal concurrent ipilimumab+P/C, appeared to improve
antibody, augments T-cell activation by inhibiting irPFS, irBORR, and OS, compared to P/C alone.
cytotoxic T-lymphocyte antigen-4. Ipilimumab Ipilimumab did not appear to exacerbate AEs
signiÀcantly improved overall survival (OS) in a observed with P/C alone. AEs seen more frequently
phase 3 study of patients with previously treated in ipilimumab arms were consistent with experience
metastatic melanoma; adverse events (AEs) were from other ipilimumab studies. These data, coupled
managed by drug-speciÀc treatment guidelines (N with those previously presented for NSCLC patients,
Eng J Med 2010;363:711). Ipilimumab may show support further investigation of ipilimumab in SCLC
activity against other advanced cancers. A blinded as Àrst-line treatment. Table. PFS, BORR, and OS in
phase 2 study (CA184-041) assessed ipilimumab ED-SCLC patients
plus paclitaxel/carboplatin (P/C) as Àrst-line
treatment for ED-SCLC or non-small cell lung Concurrent Phased
cancer (NSCLC). Results for ED-SCLC patients are Response Ipilimumab+ P/C Ipilimumab+ P/C Placebo+ P/C
N=43 n=42 n=45
described here. irPFS, median
5.7 (5.2, 6.9) 6.4 (5.3, 7.8) 5.3 (4.7, 5.7)
Methods: One-hundred-thirty patients with mo (95% CI)
previously untreated ED-SCLC were randomized P HR 0.11 0.75 (0.48, 1.19) 0.03* 0.64 (0.40, 1.02)
1:1:1 to receive: concurrent ipilimumab+P/C (4 mWHO-PFS,
median mo 3.9 (2.9, 5.9) 5.2 (4.1, 6.6) 5.2 (4.4, 5.6)
doses of ipilimumab+P/C followed by 2 doses (95% CI)
of placebo+P/C); phased ipilimumab+P/C (2 P HR (95%
0.38 0.93 (0.59, 1.48) 0.37 0.93 (0.59, 1.45)
doses of placebo+P/C followed by 4 doses of CI)
ipilimumab+P/C); or P/C alone (placebo+P/C). irBORR, %
49 (33, 65) 71 (55, 84) 53 (38, 68)
(95% CI)
Ipilimumab (10mg/kg), paclitaxel (175mg/m2), mWHO-
and carboplatin (AUC=6) were administered BORR, % 33 (19, 49) 57 (41, 72) 49 (34, 64)
intravenously every 3 weeks for upto 6 doses. Non- (95% CI)
OS, median
progressors tolerating treatment received ipilimumab mo (95% CI)
9.1 (6.7, 13.0) 12.9 (7.9, 16.5) 9.9 (8.6, 11.7)
(ipilimumab arms), or placebo (P/C alone arm) every P HR (95%
0.41 0.95 (0.59, 1.54) 0.13 0.75 (0.46, 1.23)
12 weeks in a maintenance phase. Key endpoints CI)
included progression-free survival (PFS) and best HR (hazard ratio) values are based on a Cox proportional hazards model,
and P values on a one-sided log-rank test. *Statistically signiÀcant per
overall response rate (BORR) assessed by an IRRC protocol-stipulated Ơ = 0.1. Note that the ED-SCLC cohort was not fully
using modiÀed WHO (mWHO) and immune- powered for formal statistical comparison.
related (ir) response criteria (Clin Cancer Res
2009;15:7412); OS; and safety.
Results: Baseline characteristics of randomized
patients were generally balanced across arms. Table
presents data for irPFS, mWHO-PFS, irBORR,
mWHO-BORR, and OS. Most treatment-related
AEs generally seen with P/C alone, including
fatigue, alopecia, nausea, arthralgia and peripheral
neuropathy, were similar across arms. AEs occurring
more frequently in ipilimumab arms included
SCLC I Monday, 4 July 2011 14:30-16:00 Results: Four eligible trials were identiÀed
and all were available for IPD meta-analysis,
O09.05 CARBOPLATIN- OR CISPLATIN- with a total of 663 patients (329 cisplatin, 334
BASED CHEMOTHERAPY AS FIRST- carboplatin). Baseline characteristics were well
LINE TREATMENT OF SMALL-CELL balanced between arms. Median age was 67 years
LUNG CANCER (SCLC): THE COCIS (27-86) and prevalence of male gender was 78%.
INDIVIDUAL PATIENT DATA META- Performance status (PS) was 0-1 in 72%, 2-3 in
ANALYSIS 28%. 68% of patients had extensive stage, and
Antonio Rossi1, Massimo Di Maio2, Paolo Chiodini3, most of the remaining had poor prognosis limited
Robin Rudd4, Hiroaki Okamoto5, Dimosthenis- stage. With 589 deaths recorded (89%), median
Vassilios Skarlos6, Martin Frueh7, Wendi Qian8, OS was 9.5 months with cisplatin, and 9.5 months
Tomohide Tamura9, Epaminondas Samantas10, Taro with carboplatin (hazard ratio [HR] carboplatin
Shibata11, Francesco Perrone2, Ciro Gallo3, Cesare vs. cisplatin 1.03, 95% conÀdence interval [CI]
Gridelli1, Olga Martelli12, Siow Ming Lee13 0.88–1.22; p = 0.69). For OS there was no evidence
1
Division Of Medical Oncology, S.g. Moscati of treatment difference between cisplatin and
Hospital/Italy, 2Clinical Trials Unit, National Cancer carboplatin according to gender, PS, age or stage.
Institute, “g. Pascale” Foundation/Italy, 3Medical In males, HR of carboplatin vs. cisplatin was 1.02
Statistics, Second University/Italy, 4Department (95% CI 0.85-1.23), while in females HR was 1.06
Of Oncology, St Bartholomew’s Hospital/United (95% CI 0.74-1.51) (treatment by gender interaction
Kingdom, 5Department Of Respirology, Yokohama test p = 0.76). In PS 0-1, HR was 1.02 (95% CI 0.84-
Municipal Citizens Hospital/Japan, 6Metropolitan 1.24), while in PS 2-3 HR was 0.98 (95% CI 0.72-
Hospital, N. Faliro/Greece, 7Medical Oncology, 1.34) (treatment by PS interaction test p = 0.89). In
Kantonsspital/Switzerland, 8Medical Research patients younger than 70 years, HR was 0.99 (95%
Council Clinical Trials Unit/United Kingdom, CI 0.79-1.23), while in elderly patients HR was 1.12
9
National Cancer Center Hospital/Japan, 10Agioi (95% CI 0.87-1.44) (treatment by age interaction
Anargiroi Hospital/Greece, 11JCOG Data Center, test p = 0.53). In limited stage, HR was 0.89 (95%
National Cancer Center/Japan, 12San Giovanni- CI 0.65-1.22), while in extensive stage HR was 1.09
Addolorata Hospital/Italy, 13University College (95% CI 0.90-1.32) (treatment by stage interaction
Hospital/United Kingdom test p = 0.25). Response rate was 67.5% and 65.6%,
with cisplatin and carboplatin, respectively (relative
Background: Platinum-based chemotherapy is risk 0.96, 95% CI 0.82-1.13; p = 0.66). Median
the standard Àrst-line therapy of SCLC. Whether PFS was 5.3 and 5.5 months, for cisplatin and
carboplatin or cisplatin are equally effective in carboplatin, respectively (HR 1.01, 95% CI 0.86–
the treatment of poor prognosis and/or extensive 1.19; p = 0.90). Toxicity proÀle was signiÀcantly
stage SCLC remains controversial. We performed different: hematological toxicity was higher with
an individual patient data (IPD) meta-analysis of carboplatin, and non-hematologic toxicity higher
published randomized trials. with cisplatin.
Methods: In June 2009, a systematic review Conclusion: COCIS is the Àrst IPD meta-analysis
was performed to identify randomized phase III performed to deÀne the optimal treatment of poor
trials comparing cisplatin- vs. carboplatin-based prognosis and/or extensive stage SCLC. No survival
chemotherapy as Àrst-line treatment of SCLC. difference between cisplatin- and carboplatin-based
Primary endpoint of the meta-analysis was overall chemotherapy was reported, and subgroup analysis
survival (OS). IPD (baseline characteristics, treatment, did not suggest signiÀcant interaction with gender,
toxicity and outcome) were obtained via collaborating PS, age or stage. However, the two treatments
with all groups identiÀed by the systematic review. showed a different toxicity proÀle, which should
All statistical analyses were stratiÀed by trial. OS and drive the choice of regimen in the clinical practice.
progression-free survival (PFS) curves were compared Keywords: SCLC, Individual patient data meta-
by log-rank test. Response rate was compared using analysis, Cisplatin, Carboplatin
the Mantel-Haenszel test. Exploratory subgroup
analyses were performed to describe possible
heterogeneity of treatment effect for OS. Interaction
test was also performed.
SCLC I Monday, 4 July 2011 14:30-16:00 IIIa 11,7%, IIIb 66,4%. Mean total GTV was 136 cc ±
14 cc (7,49 - 895 cc). The median delivered TTD was
O09.06 LONG-TERM RESULTS OF 45.0 Gy (6-45 Gy) given in an overall treatment time
CONCURRENT CHEMORADIATION of 34 ± 6.3 days (17-59 days), with an SER of 39 days
USING PET-CT BASED SELECTIVE +/- 17 days (range 7-131), a median MLD of 13,17 Gy
NODAL IRRADIATION FOR STAGE I-III + 3.7 Gy (5.5-22 Gy). PCI was delivered in 88% of
SMALL CELL LUNG CANCER IN 119 cases. 2 patients (1.4%) did not receive the prescribed
PATIENTS. TTD. Isolated nodal failure occurred in 5 patients
Bart Reymen1, Angela Van Baardwijk1, Rinus With a median FU of 44 months, the median overall
Wanders1, Jacques Borger1, Ruud Houben1, Anne- survival was 20 months (95% CI 17.7-22.3 months)
Marie C. Dingemans2, Gerben Bootsma3, Cordula with a 2 year survival of 39%. In univariate analysis
Pitz4, Ragnar Lunde5, Wiel Geraedts6, Philippe the size of the GTV showed a signiÀcant impact on
Lambin1, Dirk De Ruysscher1 overall survival (p=0.009) with a hazard ratio of 1.02
1
Radiation Oncology, MAASTRO Clinic, Grow (95% CI 1-1.04) for death for a 10 cc increase in GTV.
- School For Oncology And Developmental In multivariate Cox regression analysis using GTV,
Biology, Maastricht University Medical Centre/ stage (I/II vs III), PCI (yes/no), SER (30 days vs >
Netherlands, 2Department Of Pulmonology, 30 days, WHO (0/1 vs 2), sex (male vs female), age
Maastricht University Medical Center, Grow - (> 70 yrs vs 70 yrs and LDH (normal vs elevated), the
School For Oncology And Developmental Biology/ only factors showing a signiÀcant inÁuence on OS
Netherlands, 3Pulmonary Diseases, Atrium MC were GTV (p= 0.028), PCI (p< 0.001) and WHO (p=
Parkstad/Netherlands, 4Department Of Pulmonology, 0.01). Median PFS is 14 months (95% CI 12.4-15.6
Laurentius Ziekenhuis/Netherlands, 5Department months). Nodal recurrences occurred in 38 patients.
Of Pulmonology, St. Jansgasthuis/Netherlands, 19 patients had nodal recurrences located out of the
6
Department Of Pulmonology, Orbis MC/ irradiated area, associated with other disease sites in
Netherlands 17 of these patients. Isolated out-of-Àeld nodal failure
occurred in 2 patients (1.7%).
Background: Standard therapy for Stage I-III Conclusion: In this large, homogeneously treated
small cell lung cancer consists of concurrent series of stage I-III SCLC patients, size of the GTV
chemoradiotherapy and accelerated radiotherapy using is shown to be an independent risk factor for stage
CT- based elective nodal irradiation. First results of I-III SCLC. Furthermore, omission of elective
FDG PET-based selective nodal irradiation (SNI) were nodal radiotherapy based on PET-CT is conÀrmed
encouraging. We present the largest series of stage I-III to result in a low number of isolated nodal failures
SCLC irradiated with SNI reported in literature, also with survival results comparable to other series of
investigating the prognostic role of GTV on survival. concurrent chemoradiotherapy using elective nodal
Methods: Analysis on intent-to-treat basis of all irradiation.
patients in our prospectively collected database Keywords: SCLC, PET, Radiochemotherapy, GTV
with stage I-III SCLC referred for concurrent
chemoradiation (WHO-PS 0-2; FEV1/DLCO >30%).
All patients were irradiated using an accelerated SCLC I Monday, 4 July 2011 14:30-16:00
regimen up to 45 Gy in 1.5 Gy fractions twice daily.
Radiotherapy (RT) was started as soon as possible O09.07 IRINOTECAN COMPARED TO
after the start of chemotherapy (carboplatin-etoposide). ETOPOSIDE IN COMBINATION WITH
Profylactic cranial irradiation (PCI) was delivered in PLATINUM ANALOG IN EXTENSIVE
case of non-progression. RT planning was 4D-PETCT DISEASE SMALL CELL LUNG CANCER:
based, only including PET-positive or pathologically SYSTEMATIC REVIEW AND META-
proven disease sites. Overall survival (OS) and ANALYSIS WITH GEOGRAPHIC ORIGIN
progression free survival (PFS) were calculated from SUB-ANALYSIS
diagnosis (Kaplan-Meier method). Joao Paulo S.N. Lima1, Lucas V. Dos Santos1, Emma
Results: 119 patients (69 male, 50 female), median C. Sasse2, Andre D. Sasse2
1
age 66 ± 8.8 years (41-85 years) were included Clinical Oncology, Barretos Cancer Hospital/
from May 23 rd 2004 until June 26th 2009. Stage Brazil, 2Cevon - Center For Evidences In Oncology,
distribution was: IA 0.8%, Ib 2.5%, IIa 4%, IIb 5%, State University Fo Campinas/Brazil
Background: Superiority of irinotecan regimens over Conclusion: The present meta-analysis

etoposide - both combined with platinum analogs - in demonstrated that IP improved OS for both Western
extensive disease small cell lung cancer (ED-SCLC) and Eastern patients. The RR may vary according
has been extensively debated, with contradictory geographical origin of patients. The present Àndings
results in randomized trials worldwide. Ethnic and corroborate the role of ethnic background in cancer
pharmacogenomical issues were hypothesized as major therapy and demands further conÀrmation. These
causes of these divergent Àndings. A systematic review differences must be explored in a pharmacogenomic
was sought to elucidate this confounding scenario. context.
Methods: Randomized controlled trials comparing Keywords: Small cell lung cancer, randomized trial,
Àrst-line irinotecan-platinum doublets (IP) versus meta-analysis, irinotecan
etoposide-platinum doublets (EP) in ED-SCLC
patients were searched in MEDLINE, EMBASE, and
CENTRAL databases, ESMO, ASCO, and IASLC Session O10: Medical Oncology I
meeting proceedings. Meta-analyses were performed
using random-effects model. Subgroup analyses were Monday, 4 July 2011
undertaken comparing the geographical area of study
and interaction test were used to compare subgroups.
The outcomes of interest were overall survival (OS), Medical Oncology I Monday, 4 July 2011 14:30-16:00
progression-free survival (PFS) and response rate (RR).
Results: Seven studies (1967 patients) were included. O10.01 THE EURTAC (EUROPEAN
OS meta-analysis demonstrated superiority of IP over TARCEVA® VS CHEMOTHERAPY)
EP (HR = 0.88; 95% CI 0.81-0.97; P=0.003; I²=0%). STUDY: INTERIM RESULTS OF A
PFS meta-analysis was not feasible due to impending PHASE III RANDOMIZED TRIAL OF
heterogeneity (I²=86%). RR was similar between ERLOTINIB VS CHEMOTHERAPY (CT)
IP and EP groups, absolute rates: IP 52%, EP 50%, IN ADVANCED NON-SMALL-CELL
P-value=0.31. The OS analysis according geographical LUNG CANCER (NSCLC) PATIENTS (P)
area demonstrated that patients around the world WITH EPIDERMAL GROWTH FACTOR
experienced similar beneÀt from IP (table 1). PFS RECEPTOR (EGFR) ACTIVATING
meta-analysis was not feasible due to heterogeneity, not MUTATIONS
caused by geographic differences. RR meta-analysis Radj Gervais1, Rafael Rosell2, Alain Vergnenegre3,
suggests that Asian patients may be more likely to Bartomeu Massuti4, Enriqueta Felip5, Ramon
respond to IP than Western patients (interaction Asian Palmero6, Ramon Garcia-Gomez7, Margarita
versus Western patients P=0.03; table 2). Majem8, Jose Miguel Sanchez Torres9, Rut Porta10,
Manuel Cobo11, Maximo Carreras12, Maria Sanchez-
Table 1: OS Meta- Interaction Ronco13, Enric Carcereny2, Teresa Moran2, Miquel
Patients HR 95% CI P-value
analysis test
Taron2, Marisa Di Seri14, Pilar Garrido15, Amelia
All trials 1967 0.88 [0.81-0.97] 0.003
Insa16, Filippo De Marinis17, Romain Corre18, Isabel
European trials 834 0.84 [0.71-1.00] 0.03 Reference
Bover19, Alfonso Illiano20, Eric Dansin21, Javier
Asian trial 154 0.80 [0.66-0.98 0.05 P=0.73
De Castro22, Michele Milella23, Noemi Reguart24,
US, Canada &
979 0.95 [0.83-1.08] 0.44 P=0.27 Giuseppe Altavilla25, Ulpiano Jimenez26, Mariano
Australian trials
Provencio27, Miguel Angel Moreno28, Josefa
Terrasa29, Jose Munoz Langa30, Javier Valdivia31,
Table 2: RR Meta- Interaction Dolores Isla32, Manuel Domine33, Olivier Molinier34,
Patients OR 95% CI P-value
analysis test Julien Mazieres35, Nathalie Baize36, Rosario Garcia-
All trials 1819 1.19 [0.88-1.62] 0.32 Campelo37, Gilles Robinet38, Delvys Rodriguez39,
European trials 625 0.86 [0.60-1.22] 0.30 Reference Guillermo Lopez-Vivanco40, Vittorio Gebbia41,
Asian trials 215 2.54 [1.36-4.73] 0.40 P=0.02 Dinesh Lalchandani42, Pierre Bombaron43, Reyes
US, Canada & Bernabe44, Alessandra Bearz45, Angel Artal46, Luis
979 1.15 [0.89-1.49] 0.29 P=0.26
Australian trials
Paz Ares47
Asian versus 1
Western trials
1819 P=0.03 Oncology, Centre François Baclesse/France,
2
Oncology, Catalan Institute Of Oncology, Hospital
Germans Trias I Pujol/Spain, 3Hôpital Du Cluzeau/
France, 4Hospital General De Alicante/Spain, Medical Oncology I Monday, 4 July 2011 14:30-16:00
5
Hospital Vall D’Hebron/Spain, 6Catalan Institute Of
Oncology, Hospital Duran I Reynals/Spain, 7Hospital O10.02 UPDATED MEDIAN PFS AND
Gregorio Maranon/Spain, 8Hospital De Sant Pau/ ANALYSIS OF QUALITY OF LIFE
Spain, 9Hospital 12 De Octubre/Spain, 10Catalan (QOL) IN OPTIMAL, A PHASE III,
Institute Of Oncology, Hospital Josep Trueta/Spain, RANDOMIZED, OPEN-LABEL, FIRST
11
Hospital Carlos Haya/Spain, 12F. Hoffmann-la LINE STUDY OF ERLOTINIB VS
Roche Ltd./Switzerland, 13University Of Alcala De CARBOPLATIN/GEMCITABINE IN
Henares/Spain, 14Azienda Policlinico Umberto I/ PATIENTS WITH ADVANCED NON-
Italy, 15Hospital Ramon Y Cajal/Spain, 16Hospital SMALL CELL LUNG CANCER (NSCLC)
Clínico De Valencia/Spain, 17Azienda Ospedaliera WITH EGFR ACTIVATING MUTATIONS
S Camillo Forlanini/Italy, 18Chu Rennes-hopital Caicun Zhou1, Yi-Long Wu2, Gongyan Chen3,
Ponchaillou/France, 19Hospital Son Llatzer/Spain, Jifeng Feng4, Xiaoqing Liu5, Changli Wang6, Shucai
20
Azienda Ospedaliera Monaldi/Italy, 21Centre Oscar Zhang7, Jie Wang8, Songwen Zhou9, Shengxiang
Lambret/France, 22Hospital La Paz/Spain, 23Istituti Ren10, Shun Lu11, Li Zhang12
1
Fisioterapici Hospitalieri, Hospital Regina Elena/ Shanghai Pulmonary Hospital, Tongji University/
Italy, 24Oncology, Hospital Clinic/Spain, 25Aou China, 2Guangdong Lung Cancer Institute,
Policlinico G. Martino/Italy, 26Oncology, Hospital Guangdong Academy Of Medical Sciences &
De La Princesa/Spain, 27Oncology, Hospital Puerta Guangdong General Hospital/China, 3The Cancer
De Hierro/Spain, 28Oncology, Complejo Hospitalario Hospital Of Harbin Medical University, Harbin
De Jaen/Spain, 29Hospital Son Dureta/Spain, Medical University/China, 4Tumor Medical, Jiangsu
30
Hospital Universitario Dr Peset/Spain, 31Hospital Province Cancer Hospital/China, 5Tumor Medical,
Virgen De Las Nieves/Spain, 32Hospital Lozano 307 Hospital Of The Academy Of Military Medical
Blesa/Spain, 33Oncology, Fundacion Jimenez- Sciences/China, 6Tianjin Cancer Hospital/China,
Diaz/Spain, 34Le Mans Regional Hospital/France, 7
Tumor Medical, Bejiing Chest Hospital/China,
35 8
Thoracic Oncology Disease, Toulouse Universitary Department Of Thoracic Oncology, Beijing Cancer
Hospital/France, 36Centre Hospitalaire Universitaire Hospital And Institute/China, 9Tongji University
Angers/France, 37Hospital Teresa Herrera/Spain, AfÀliated Shanghai Pulmonary Hospital/China,
38 10
Centre Hospitalier Universitaire Morvan/ Medical Oncology, Tongji University AfÀliated
France, 39Hospital Insular De Gran Canaria/ Shanghai Pulmonary Hospital/China, 11Shanghai
Spain, 40Hospital De Cruces De Barakaldo/Spain, Chest Hospital, Jiaotong University/China, 12Tumor
41
Medical Oncology, “La Maddalena” Hospital/ Medical, Sun Yat-Sen University Cancer Center
Italy, 42Hospital Universitario La Candelaria/ (SYSUCC)/China
Spain, 43Centre Hospitaliere Emile Muller, Hôpital
Sur Mulhouse/France, 44Hospital Nuestra Señora Background: OPTIMAL demonstrated superiority
De Valme/Spain, 45Cro Di Aviano/Italy, 46Hospital of erlotinib (E) vs carboplatin/gemcitabine (G/C) in
Miguel Servet/Spain, 47University Hospital - Virgen terms of progression free survival (PFS), objective
Del Rocio/Spain response rate (ORR) and tolerability in 1st line
advanced NSCLC patients with EGFR activating
Abstract under Embargo - will be presented in a mutations. We update PFS data and Àrstly report the
press conference during WCLC 2011. pre-planned analyses of patients’ quality of life (QoL).
Methods: Chemonaïve pts with EGFR Act Mut+
advanced NSCLC, ECOG PS 0–2 and measurable
disease were randomized to E (150mg/d, until
unacceptable toxicity or progressive disease), or G/C
(G [1000mg/m2, d1, 8] + C [AUC 5, d1], q 3 wks for
up to 4 cycles), and stratiÀed by histology, smoking
status and mutation type (n=165). Primary endpoint
was PFS. Secondary endpoints including ORR, OS,
QoL (FACT-L, TOL, LCS) and safety. Median PFS
is updated, the QoL questionnaire was administered
at randomization and once every 6 weeks until PD.
Clinically relevant improvement during the study doublet chemotherapy, but head-to-head data for
was predeÀned as patient with clinically relevant these agents are limited. In particular, efÀcacy of these
improvement one or more times during the study. agents in EGFR wild type (WT) NSCLC is of interest,
Results: 165 were randomized and 154 included in as patients with EGFR mutation-positive (MUT+)
the study population (82 E; 72 G/C). In the primary NSCLC are increasingly likely to receive erlotinib
analysis, PFS was signiÀcantly prolonged with E Àrst line. The open-label, phase III TITAN study was
vs G/C: mPFS of 13.1 vs 4.6, HR 0.16; p<0.0001 designed to assess the efÀcacy and tolerability of
(data reported in ESMO 2010). By the cut-off date second-line erlotinib versus chemotherapy (docetaxel
of Jan 7, 2011, an updated analysis showed median or pemetrexed) in advanced NSCLC.
PFS of 13.7 vs 4.6 months, respectively, HR 0.164, p Methods: A total of 2590 patients with untreated,
<0.0001). 128 patients with a baseline and at least one advanced NSCLC received up to 4 cycles of Àrst-
post-baseline QoL assessment were included for QoL line platinum-based chemotherapy in the run-in
analysis (74 E; 54 G/C).Compared with G/C group, phase. Those with controlled disease were offered
E had a clinically relevant improvement in QoL, as entry into SATURN (phase III study of maintenance
assessed by scores on the FACT-L ( 73% vs 29.6 %; erlotinib), while those with disease progression (PD)
OR 6.9; 95% CI 3.07–15.48; p<0.0001) and by scores were offered entry into TITAN. Patients entering
on LCS (75.7% vs 31.5%; OR 6.77; 95% CI 3.04– TITAN (n=424) were randomised (1:1) to receive
15.05; p<0.0001), and by scored on the TOI ( 71.6% erlotinib 150mg/day or chemotherapy (docetaxel or
vs 24.1%, OR 7.79; 95% CI 3.44–17.66; p<0.0001). pemetrexed, at investigators’ discretion; standard
Conclusion: Erlotinib demonstrated improved PFS and regimens), until unacceptable toxicity or conÀrmed
QoL over G/C, with a more favorable tolerability proÀle. PD. Overall survival (OS) was the primary endpoint,
Keywords: erlotinib, Quality of Life, Non-small cell secondary endpoints included progression-free
lung cancer, EGFR mutations survival (PFS), safety and biomarker analyses.
Methodology for biomarker sampling and analysis
was as reported for SATURN (Cappuzzo et al. 2010).
Medical Oncology I Monday, 4 July 2011 14:30-16:00 Results: The full analysis population comprised 203
patients in the erlotinib arm and 221 for chemotherapy
O10.03 EFFICACY OF SECOND-LINE (116 for docetaxel and 105 for pemetrexed). The erlotinib
ERLOTINIB VERSUS CHEMOTHERAPY arm had a greater percentage of males and current
RELATIVE TO BIOMARKER STATUS IN smokers and a lower incidence of adenocarcinoma
THE PHASE III GLOBAL TITAN STUDY versus the chemotherapy arm. No signiÀcant difference
IN ADVANCED NON-SMALL-CELL LUNG in OS or PFS was seen between arms: HR=0.96 for OS
CANCER (NSCLC) (95% CI 0.78–1.19; log-rank p=0.73) and HR=1.19
Tudor-Eliade Ciuleanu1, Lilia Stelmakh2, Saulius for PFS (95% CI 0.97–1.46; log-rank p=0.09). The
Cicenas3, Skaidrius Miliauskas4, Alexandru biomarker analyses results for OS and PFS are shown
Grigorescu5, Carina Hillenbach6, Hrefna in the table. For patients with conÀrmed EGFR WT
Johannsdottir7, Barbara Klughammer8, Emilo disease (n=149), erlotinib and chemotherapy were
Esteban Gonzalez9 equally effective as second-line therapy, HR=1.25 (95%
1
Oncology, Institute Of Oncology Ion Chiricuta/ CI 0.88–1.78, p=0.2030) for PFS and HR=0.85 (95% CI
Romania, 2St Petersburg State Medical Pavlov 0.59–1.22, p=0.3725) for OS.
University/Russian Federation, 3Institution Of
Oncology Vilnius University/Lithuania, 4Hospital Of
Lithuanian University Of Health Sciences Kaunas
Clinics/Lithuania, 5Institute Of Oncology Bucharest/
Romania, 6Department Of Statistics, F. Hoffmann-la
Roche Ltd/Switzerland, 7Clinical Science, F. Hoffmann-
La Roche Ltd/Switzerland, 8F. Hoffmann-La Roche Ltd/
Switzerland, 9Hospital Universitario C Asturias/Spain
Background: Erlotinib, docetaxel and pemetrexed

are approved for patients with advanced NSCLC
whose disease progresses after Àrst-line platinum
Conclusion: Erlotinib provided similar efÀcacy for the enrollment. Randomized patients received
outcomes to chemotherapy in second-line advanced either geÀtinib 250 mg per oral every day or
NSCLC, and was as effective as chemotherapy in pemetrexed 500 mg/m2 iv day 1 with vitamin
patients with conÀrmed EGFR WT disease. B12 and folic acid supplement every 21 days. The
Keywords: erlotinib, Biomarkers, Second-line, Non- primary end point was progress-free survival (PFS).
small cell lung cancer Results: One hundred thirty-Àve patients were
randomly assigned with being stratiÀed with
performance status (0-1 vs. 2) and gender. Overall
Medical Oncology I Monday, 4 July 2011 14:30-16:00 response rates were 30.1% and 14.9% (P < 0.001) for
geÀtinib and pemetrexed, respectively. The primary
O10.04 RANDOMIZED PHASE III TRIAL endpoint of PFS was met with 9.4 months for
OF GEFITINIB OR PEMETREXED geÀtinib versus 2.9 months for pemetrexed, which
AS SECOND-LINE TREATMENT was signiÀcantly different (P = 0.010). The median
IN PATIENTS WITH NON-SMALL overall survival has not been reached yet in both
CELL LUNG CANCER PREVIOUSLY groups. The 1-year survival rate for geÀtinib and
TREATED WITH PLATINUM-BASED pemetrexed arm was 73.6% and 70.5% (P = 0.89),
CHEMOTHERAPY (KCSG-LU08-01) respectively. The further analyses of EGFR mutation
Myung-Ju Ahn1, Jong-Mu Sun1, Ki Hyeong Lee2, Jin status, post-study treatment and adverse events will
Seok Ahn1, Sang-We Kim3, Young Joo Min4, Hwan be presented.
Jung Yun5, Hoon-Kyo Kim6, Hong-Suk Song7, Yeul Conclusion: GeÀtinib showed superior efÀcacy
Hong Kim8, Bong Seog Kim9, In Gyu Hwang10, to pemetrexed as second-line therapy in clinically
Keehyun Lee11, In Sook Woo12, Hun Mo Ryoo13, selected NSCLC patients in Korea. Considering
Kyung-Hee Lee14, Hyeon Gyu Yi15, Joungsoon sequence of salvage therapy, geÀtinib would be
Jang10, Jung Hye Kwon16, Byung-Su Kim17, Keunchil preferable to pemetrexed in enriched NSCLC
Park1 patients.
1
Internal Medicine, Samsung Medical Center/Korea, Keywords: Salvage therapy, Pemetrexed, geÀtinib,
2
Internal Medicine, Chunbuk National University phase III
Hospital/Korea, 3Asan Medical Center/Korea, 4Ulsan
University Hospital/Korea, 5Chungnam National
University Hospital/Korea, 6The Catholic University Medical Oncology I Monday, 4 July 2011 14:30-16:00
Of Korea St. Vincent’s Hospital/Korea, 7Kemyung
University Dongsan Medical Center/Korea, O10.06 A RANDOMIZED, DOUBLE-
8
Korea University Anam Hospital/Korea, 9Seoul BLIND PHASE III STUDY OF ICOTINIB
Veterans Hospital/Korea, 10Chung-Ang University VERSUS GEFITINIB IN PATIENTS
Hospital/Korea, 11Bucheon St. Mary’s Hospital/ WITH ADVANCED NON-SMALL CELL
Korea, 12Yeouido St. Mary’s Hospital/Korea, LUNG CANCER (NSCLC) PREVIOUSLY
13
Daegu Catholic University Medical Center/Korea, TREATED WITH CHEMOTHERAPY
14
Yeungnam Univeristy Medical Center/Korea, 15Inha (ICOGEN)
University Hospital/Korea, 16Hallym University Yan Sun1, Yankai Shi1, Li Zhang2, Xiaoqing Liu3,
Kangdong Sacred Heart Hospital/Korea, 17Seoul Caicun Zhou4, Li Zhang5, Dong Wang6, Qiang Li7,
National University Boramae Medical Center/Korea Shucai Zhang8, Shukui Qin9, Chunhong Hu10, Yiping
Zhang11, Fenlai Tan12
1
Background: We try to compare the efÀcacy of Internal Medicine, Cancer Hospital, Chinese
geÀtinib versus pemetrexed as second-line therapy Academy Of Medical Sciences/China, 2Internal
in never-smokers with advanced pulmonary Medicine, Sun Yat-sen University Cancer Center
adenocarcinoma previously treated with platinum- (SYSUCC)/China, 3Pulmonary Oncology, 307
based chemotherapy. Hospital Of The Academy Of Military Medical
Methods: Eligible patients had a performance status Sciences/China, 4Oncology, Shanghai Pulmonary
0 to 2, previous treatment with one prior platinum- Hospital, Tongji University/China, 5Pulmonary
based regimen, pulmonary adenocarcinoma, and Medicine, Perking Union Medical Hospital/China,
6
never-smoking state. Epidermal growth factor Oncology, Third AfÀliated Hospital, He Third
receptor (EGFR) mutation status was not considered Military Medical University Of People’s Liberation
Army/China, 7Pulmonary Medicine, Changhai among which 27 (40.9%) were in Ic and 39 (59.1%)
Hospital, The Second Military Medical University/ were in Ge. The ORR and PFS in both Ic and Ge
China, 8Oncology, Bejiing Chest Hospital/China, groups demonstrated signiÀcant differences between
9
Pla Cancer Centre, Nanjing Bayi Hospital/China, pts with mutations (M) and pts with the wild type
10
Oncology, 2nd Xiangya Hospital/China, 11Internal gene (W). In the Ic group, M vs. W was 59.3%
Medicine, Zhejiang Cancer Hospital/China, 12R & D (16/27) vs. 5.1% (2/39) for ORR and 198 d vs. 70 d
Center, Zhejiang Betapharma/China for PFS. In the Ge group it was 52.6% (20/39) vs.
3.7% (1/27) for ORR and 158 d vs. 76 d for PFS.
Background: Icotinib (ComanaTM) is a potent and Conclusion: This study demonstrated that Icotinib
selective inhibitor targeting the tyrosine kinase provides similar efÀcacy to GeÀnib, but with better
domain of epidermal growth factor receptor (EGFR). tolerability, in NSCLC patients previously treated
Of 88 kinases proÀled, Icotinib (Ic) powerfully with one or two chemotherapy agents.
inhibited EGFR and its 3 mutants, with no Keywords: EGFR-TKI, icotinib, NSCLC, phase III
meaningful inhibition of the rest of kinases tested. trial
Ic was found to have signiÀcant clinical activity
in patients with NSCLC in early phase trials. This
study was designed to show that Ic is not inferior to Medical Oncology I Monday, 4 July 2011 14:30-16:00
GeÀtinib (Ge).
Methods: Patients (Pts) with NSCLC progressed O10.07 OVERALL SURVIVAL (OS)
after one or two lines of chemotherapies were RESULTS OF A RANDOMIZED PHASE 2
randomized to receive Ic (125mg Tid) or Ge (250mg TRIAL OF PF299804 VERSUS ERLOTINIB
Qd). The primary endpoint was progression-free IN PATIENTS WITH ADVANCED NON-
survival (PFS). The second endpoints included SMALL CELL LUNG CANCER (NSCLC)
overall survival (OS), overall response rate (ORR), AFTER FAILURE OF CHEMOTHERAPY
time to progression (TTP), quality of life (QOL) Michael Boyer1, Fiona H. Blackhall2, Carlos H.
and tolerability. Exploratory endpoints included Barrios3, Richard C. Frank4, Deo Seog Heo5,
association of efÀcacy with EGFR gene mutation, Keunchil Park6, Rafael Rosell7, Denis C. Talbot8,
which was examined by DsX Scorpion ARMS. Ian C. Taylor9, Jane Liang10, Alicyn K. Campbell11,
Results: From Feb 2009 to Nov 2010, 399 patients Joseph O’Connell9, Suresh Ramalingam12
1
were randomized to receive either Ic (200) or Ge Medical Oncology, Sydney Cancer Centre/Australia,
2
(199). Baseline characteristics were well balanced Medical Oncology, The Christie NHS Foundation
between the two arms . Ic demonstrated 35 day Trust/United Kingdom, 3Medicine, Pucrs School
(d) median PFS extension compared to Ge (Ic vs. Of Medicine/Brazil, 4Oncology, Norwalk Hospital/
Ge: 137 d vs. 102 d, HR 0.84, 95% CI 0.67-1.05), United States Of America, 5Internal Medicine,
reaching the primary objective of non-inferiority. Seoul National University Hospital/Korea, 6Div Of
In per-protocol set, median TTP in Ic (154 d) was Hem/onc, Dept Of Medicine, Samsung Med Ctr,
signiÀcantly longer than Ge (109 d) (P=0.04). Sungkyunkwan University School Of Medicine/
With 49.4% maturity, OS was similar between Ic Korea, 7Medical Oncology, Catalan Institute Of
and Ge groups (median OS was 504 d and 531 d, Oncology/Spain, 8Medical Oncology, Oxford
respectively). Further follow-up of OS is ongoing. Oncology Centre/United Kingdom, 9Oncology, PÀzer
Furthermore, ORR (Ic vs. Ge: 27.6% vs. 27.2%), Oncology/United States Of America, 10Clinical
DCR (75.4% vs. 74.9%), TTP (156 d vs. 111 d ) and Statistics At Oncology Business Unit, PÀzer
QoL (101.4± 9.6 vs. 103.0± 19.1) were comparable Oncology/United States Of America, 11Clinical
between Ic and Ge groups. Adverse response rate in Development And Medical Affairs, PÀzer Oncology/
Ic group was 60.5%, which was signiÀcantly lower United States Of America, 12Hematology And
than that in Ge group (70.4%) (P=0.04). SpeciÀcally, Medical Oncology, Winship Cancer Institute Of
39.5% pts in Ic developed rash compared to 49.2% Emory University/United States Of America
in Ge; 18.5% pts in Ic had diarrhea compared to
27.6% in Ge (P=0.03); 8.0% pts in Ic had elevated Background: PF299804 is a potent, irreversible
aminotransferase level compared to 12.6% in Ge. inhibitor of human epidermal growth factor receptors
EGFR gene mutational analysis was performed for (EGFR)/HER-1, -2, and -4, with superior antitumor
132 pts. Mutations were identiÀed in 66 pts (50%), activity over reversible EGFR tyrosine kinase
inhibitors (TKIs) in geÀtinib- and erlotinib-sensitive treatment discontinuation was uncommon in both arms.
and -resistant preclinical models. The current A phase 3 study of PF299804 vs erlotinib for second-/
randomized trial assessed PF299804 vs erlotinib in third-line therapy of advanced NSCLC is planned.
patients with NSCLC after chemotherapy failure. 1. Ramalingam SS et al. ESMO 2010; abstr 365PD
Methods: Eligible patients (any histology, ECOG Keywords: PF-00299804, Overall survival, Non-
performance status [PS] 0–2, no prior HER-directed small cell lung cancer, EGFR TKI
therapy, 1 or 2 prior chemotherapy regimens,
available tumor tissue) were randomized 1:1 to oral A revised/updated abstract may be included in
PF299804 45 mg or erlotinib 150 mg once daily the Late Breaking Abstract Supplement, available
and treated until progression/toxicity. The primary at the 14th World Conference on Lung Cancer.
endpoint was progression-free survival (PFS);
secondary endpoints included OS, objective response
rate (ORR) per RECIST, safety, and patient-reported Session O11: Medical Oncology V
outcomes (PRO).
Results: 188 patients were randomized: median Monday, 4 July 2011
age 61 years, 88% PS 0/1, 41% female, 65%
adenocarcinoma, 25% East Asian, 21% non-smoker,
16% EGFR mutation, 16% KRAS mutation. Medical Oncology V Monday, 4 July 2011 14:30-16:00
Baseline characteristics were balanced between
arms except for PS 2 (PF299804, n=20; erlotinib, O11.01 QUALITY OF LIFE IN ADVANCED
n=3), EGFR mutation (PF299804, n=19; erlotinib, NON-SMALL CELL LUNG CANCER,
n=11), and >1 prior chemotherapy regimen EFFECTS OF CISPLATIN DOSE AND
(PF299804, n=38; erlotinib, n=27). Tumor genotype CARBOPLATIN IN COMBINATION
ascertainment rates were high (KRAS, 78%; EGFR, WITH GEMCITABINE: RESULTS
81%). All but 3 patients were followed up until FROM BTOG2, A BRITISH THORACIC
disease progression or death. PFS was signiÀcantly ONCOLOGY GROUP PHASE III TRIAL IN
longer with PF299804 vs erlotinib overall (median 1363 PATIENTS
12.4 vs 8.3 weeks; hazard ratio [HR]=0.70, Lucinda Billingham1, Piers Gaunt2, Hugh Jarrett2,
P=0.030), with beneÀts across several subgroups David Dunlop3, Joyce Thompson4, Kenneth J.
including adenocarcinoma, non-adenocarcinoma and O’byrne5, Muthu Kumar6, Geraldine Skailes7,
EGFR wild type. At the time of this submission 65 Marianne Nicolson8, Riyaz Shah9, Pauline Leonard10,
deaths had been reported on PF299804 and 73 on A Chetiyawardana11, Paula Wells12, Conrad
erlotinib, and the median OS was 9.64 months for Lewanski13, Penella Woll14, Barbara Crosse15,
PF299804 and 7.53 months for erlotinib (HR=0.841; Michelle Hill16, David Ferry17
1
P=0.31). Frequent treatment-related adverse events School Of Health & Population Sciences, University
(TRAEs) for PF299804 vs erlotinib (overall/grade Of Birmingham/United Kingdom, 2CRCTU,
3 or 4) were: diarrhea (73%/12% vs 49%/3%), University Of Birmingham/United Kingdom,
3
acneiform dermatitis (65%/11% vs 57%/6%), Medical Oncology, Beatson West Of Scotland
stomatitis (29%/1% vs 12%/1%), decreased appetite Cancer Centre/United Kingdom, 4Birmingham
(25%/1% vs 22%/0), paronychia (26%/3% vs Heartlands Hospital/United Kingdom, 5Oncology,
9%/1%), dry skin (24%/1% vs 15%/1%), fatigue St James’s Hospital/Ireland, 6Derby Royal Hospital/
(18%/2% vs 20%/1%) and nausea (17%/2% vs United Kingdom, 7Royal Preston Hospital/
16%/1%). 10 patients discontinued due to TRAEs: 7 United Kingdom, 8Aberdeen Royal InÀrmary/
receiving PF299804 and 3 receiving erlotinib. United Kingdom, 9Kent Oncology Centre/United
Conclusion: PF299804 was associated with a Kingdom, 10Whittington Hospital/United Kingdom,
11
signiÀcant improvement in PFS, a trend towards Manor Hospital/United Kingdom, 12Whipps Cross
superior OS and improvement in lung cancer Hospital/United Kingdom, 13Oncology, Imperial
symptoms1 compared with the selective reversible College Healthcare/United Kingdom, 14University
EGFR TKI erlotinib in advanced NSCLC. OS Of ShefÀeld/United Kingdom, 15HuddersÀeld
for relevant clinical and molecular subsets will be Royal InÀrmary/United Kingdom, 16University Of
presented. Common EGFR TKI AEs were more Birmingham/United Kingdom, 17Oncology, New
frequent with PF299804 than with erlotinib but Cross Hospital/United Kingdom
Background: The standard of care for advanced non- quality-adjusted life months were 6.1 on GC80, 5.6
small cell lung cancer (NSCLC) is platinum-based on GC50 and 6.1 on GCb6.
chemotherapy but the optimal dose of cisplatin and Conclusion: Although higher doses of cisplatin (80
comparison with carboplatin is uncertain. Given the mg/m2) are thought detrimental to QoL compared
median survival time of these patients is 8-12 months, to 50 mg/m2 we found minimal differences but a
it is important to understand the impact of such noteworthy problem in delayed neuropathy. Also,
treatment choices on patients’ quality of life (QoL). the belief that carboplatin produces superior QoL
The BTOG2 trial is a large phase III randomised compared to cisplatin at either dose is not obvious.
trial comparing three treatment arms: gemcitabine Importantly carboplatin treatment may not palliate
(1250mg/m2 day 1 and day8) with either cisplatin dysponea as well as cisplatin. Adjusting for QoL does
80mg/m2 (GC80), cisplatin 50mg/m2 (GC50) or not change the conclusions from the primary survival
carboplatin AUC6 (GCb6). Treatment was given for analysis. As the largest QoL study in advanced
a maximum of four 21-day cycles. Primary outcome NSCLC, these data will provide valuable information
is survival time but due to stage of disease and nature on immediate and long-term effects of treatments, thus
of treatment, QoL was recognised as an important aiding clinicians and patients in their decisions.
outcome. The BTOG2 trial was innovative in aiming Keywords: Quality of Life, Cisplatin, BTOG2,
to collect QoL data on all trial patients and is the Advanced NSCLC
largest study to date addressing this issue in NSCLC.
Methods: QoL was measured using standard, A revised/updated abstract may be included in
validated questionnaires. The EORTC QLQ-C30 the Late Breaking Abstract Supplement, available
and lung cancer speciÀc module LC13 provide a at the 14th World Conference on Lung Cancer.
descriptive proÀle of patients’ quality of life and
the EQ-5D provides a valuation of patients’ health
state. The timing of assessments was at each cycle of Medical Oncology V Monday, 4 July 2011 14:30-16:00
chemotherapy and each follow-up visit. Descriptive
analysis was used to compare the treatment groups O11.02 CLASS III ȕ-TUBULIN,
in terms of change over time for the 27 different HISTOPATHOLOGY AND QUALITY
measures. EQ-5D measures are combined with OF LIFE IN ADVANCED NSCLC
survival data using the integrated quality-survival PATIENTS RANDOMIZED IN A LARGE
product to provide mean quality-adjusted life months MULTICENTER PHASE III TRIAL
(QALM) for each treatment arm. Adam Vilmar1, Eric Santoni-Rugiu2, Jens B.
Results: Of the 1363 randomised patients, 97% Sorensen3
1
completed at least one QoL assessment, returning Oncology, Unversity Hospital Of Copenhagen/
a total of 8023 questionnaires with a median Denmark, 2Department Of Pathology, Copenhagen
of 6 forms per patient and maximum of 34. University Hospital/Denmark, 3Department Of
Questionnaire completion rates at baseline and Oncology, Finsen Centre, National University
during treatment were 92% and 89% respectively. Hospital/Denmark
At pre-randomisation, the mean global heath status
score and EQ-5D utility score were 62% and 0.66 Background: Platinum based doublets are the
and this is reasonably balanced across the treatment cornerstone of treatment in advanced non-small cell
groups. On initiation of treatment, patients in all lung cancer (NSCLC) and often include vinorelbine
three treatment arms had improved pain, cough, or taxanes. A valid, predictive biomarker is greatly
haemoptysis, insomnia, appetite loss and emotional needed in order to select chemotherapy sensitive
functioning with associated improvements in global patients for these microtubule interfering agents.
measures of QoL but these beneÀts generally fell Class III b-tubulin (TUBB3) has been demonstrated
away after completion of chemotherapy (12+ of value in NSCLC but evidence is not uniform.
weeks). GC50 performed better in terms of the Accordingly, we explored the predictive role
functioning scores and in terms of fatigue, nausea of TUBB3 in patients with advanced NSCLC.
and vomiting whilst GCb6 performed worst for Furthermore, histopathological variations and quality
dyspnoea. All treatments had a deleterious effect of life (QOL) was correlated to biomarker status.
on peripheral neuropathy with the post-treatment Methods: 443 patients with advanced NSCLC
toxicity momentum markedly worse for GC80. Mean were enrolled in a phase III trial and randomized to
triplet chemotherapy or standard doublet regimen. symptom burden and impact on quality of life in
Immunohistochemical evaluation for TUBB3-status advanced non small cell lung cancer (NSCLC)
was mainly performed on bioptic material and patients.
correlated to response rates (RR), progression free Methods: Patients with advanced (stage IIIB/
survival (PFS), overall survival (OS), QOL and toxicity. IV) NSCLC in France (n= 613) and Germany
Results: 261 (58.9%) patients had representative (n=600) were recruited into an observational cross-
tissue samples for TUBB3 evaluation. No signiÀcant sectional study. Of these, 837 patients consented
differences were found in RR, PFS or OS according to complete questionnaires at a single timepoint.
to TUBB3-status. Patients with TUBB3-negative The study period extended from Jul-Oct 2010.
(neg) adenocarcinomas had a signiÀcantly prolonged Patient reported symptoms using the Lung Cancer
PFS and OS when compared to the opposite Symptom Scale (LCSS), which assesses six lung
subgroup (7.87 versus (vs) 6.83 months, P = 0.035 cancer symptoms including fatigue, loss of appetite,
& 14.17 vs 11.17 months, P = 0.018, respectively). shortness of breath, cough, pain and blood in
Multivariate analysis revealed a hazard ratio of 1.55 sputum. Each of these symptoms is scored on a
(95% CI 1.04-2.31, P = 0.032) for patients with 0-100 visual analogue scale. An average symptom
TUBB3 adenocarcinoma positivity. Concerning burden index was calculated as a mean of the six
QOL, in the adenocarcinoma subgroup, patients with symptom scores. Quality of life was assessed using
TUBB3-neg tumors showed a mean decline from the Functional Assessment of Cancer Therapy- Lung
baseline of -18.25 points (95% CI - 4.28 - -32.22, p = (FACT-L), which is a validated lung cancer speciÀc
0.013) as compared to -3.86 (95% CI -7.0-15.52, P = questionnaire. Items on the FACT-L are rated on a
0.5) for patients with positive tumors. 5-point Likert Scale ranging from 0 (not at all) to
Conclusion: TUBB3 was found of predictive 4 (very much). The total FACT-L score can range
value in patients with advanced NSCLC and from 0-136. Higher scores indicate higher severity
adenocarcinomas in the largest randomized of symptoms on the LCSS and a better quality of
population published to date. TUBB3 may be life on the FACT-L. Correlation between the total
clinically implementated in conjunction with other FACT-L score and LCSS symptom burden index
biomarkers, but QOL information should be recorded was assessed. A multivariate regression analysis was
during validation, as prophylactic intervention may performed with FACT-L total score as the dependent
be needed in speciÀc subgroups at risk of toxicity. variable and LCSS individual symptom scores
Keyword: NSCLC, predictive markers, Class III as predictors. Age, gender, stage and Karnofsky
beta-tubulin, microtubule interfering agents scores for performance status were used as control
variables.
A revised/updated abstract may be included in Results: Majority of the patients were male (67%),
the Late Breaking Abstract Supplement, available Caucasian (93%) with an average age of 63 years
at the 14th World Conference on Lung Cancer. (median= 64 years). Approximately 45% of the
patients were current smokers and 40% were ex-
smokers. Fifty two percent of the patients were on
Medical Oncology V Monday, 4 July 2011 14:30-16:00 Àrst line therapy and remaining 48% were on second
or later line therapies. The proportion of patients
O11.03 ADVANCED LUNG CANCER that reported scores greater than zero for each of
SYMPTOM BURDEN AND IMPACT ON the lung cancer symptoms was: Fatigue (98%),
PATIENT QUALITY OF LIFE loss of appetite (98%), shortness of breath (94%),
Shrividya Iyer1, Gavin Taylor-Stokes2, Adam cough (93%), pain (90%) and blood in sputum
Roughley2 (70%). The average (SD) symptom burden index
1
Global Outcomes Research, PÀzer Oncology/United was 41.2 (22.3). The mean± SD severity scores on
States Of America, 2Adelphi Real World/United individual symptoms were: fatigue (53.9±26.5), loss
Kingdom of appetite (53.1±27.9), cough (41.4±30.9), shortness
of breath (42.9± 29.5), pain (37.2± 30.6) and blood
Background: Patients with advanced lung cancer in sputum (19.4±27.9). The average (SD) FACT-L
experience disease symptoms that could have score was 71.4(19). A signiÀcant negative correlation
signiÀcant impact on their quality of life. The main was found between LCSS symptom burden
objective of our study was to assess patient reported index and FACT-L scores (Ư= -0.67; p<0.001).
Fatigue (ơ =-0.123; p<0.001), loss of appetite (ơ=- topics on a 5-point Likert scale which evaluated
0.173;p<0.001), pain (ơ=-0.148; p<0.001) , shortness the importance of each item. Demographic
of breath (ơ = -0.118; p<0.001), stage IV (ơ= -3.70; characteristics, clinical factors, and support group
p<0.05) and performance status (ơ = 0.117;p<0.05) content preferences were assessed.
were found to be signiÀcant predictors of lung cancer Results: There were 4402 respondents to the
speciÀc quality of life. invitation to participate, and 3728 patients
Conclusion: Fatigue, loss of appetite, shortness of and caregivers elected to participate (85%).
breath and pain have a signiÀcant negative impact Characteristics included for all 3728 patients: 70%
on patient reported disease speciÀc quality of life women, mean age 58 (range 20-89). For the 233
in advanced NSCLC patients. Future treatments patients with lung cancer, 66.5% were women and
which alleviate these symptoms may lead to positive the mean age was 62; 35.5% had advanced disease.
beneÀts in quality of life in advanced NSCLC For the whole group, the four most common cancers
patients. were breast 45%, prostate 15%, lung 6%, and
Keywords: Quality of Life, lung cancer symptoms, colorectal 5%. 90% of participants were patients and
Patient Reported Outcomes 10% were caregivers. 80% of participants rated all
26 topics. The table below shows rankings by the
top 2 categories (the percent ranking each topic as
Medical Oncology V Monday, 4 July 2011 14:30-16:00 “Very Important” or “Important”) of the 10 highest
rated topics for patients with lung cancer and for all
O11.05 AN EVIDENCE BASED patients.
ASSESSMENT OF 3728 PATIENTS
CONCERNING TOPICS FOR TOPICS (Top 10 LUNG CANCER ALL PATIENTS
SUPPORT GROUP DISCUSSION AND rated of 26) PATIENTS (N=3728): Very
PRESENTATION AMONG PATIENTS (n=233): Very Important+Important /
Important+Important / (Ranking)
WITH LUNG CANCER. DO PATIENTS (Ranking)
WITH LUNG CANCER DIFFER FROM Side effects and 95.4% (1) 93.5% (2)
THOSE WITH OTHER CANCERS? their prevention
Richard J. Gralla1, Kathleen D. Morse1, Cynthia Cancer treatment 94.5.% (2) 95.0% (1)
N. Rittenberg1, Judith A. Petersen2, Kenda Burg2, choices
Beverly J. Davis2, C Sison3, L M. Rosen3, Martin Making decisions 92.2% (3) 90.1% (4)
about care
Lesser3
1 Living with a 91.7% (4) 91.4% (3)
Medical Oncology, Hofstra North Shore - LIJ cancer diagnosis
School Of Medicine/United States Of America, Pain and its 91.6% (5) 79.9% (13)
2
Nexcura/United States Of America, 3Feinstein control
Institute For Medical Research/United States Of Cancer-related 91.3% (6) 84.4% (11)
America fatigue
Dealing with 91.2% (7) 85.8% (6)
Background: Cancer support groups are now anxiety /
depression
available at most cancer centers, although this can
Uncertainty of 89.3% (8) 84.9% (8)
differ depending on the location of the treatment cancer
center. Even though there is increasing demand Stress and stress 88.0% (9) 85.1% (7)
among patients and families for support groups, little management
data exist outlining which topics patients and their Talking with 87.7% (10) 88.5% (5)
caregivers consider as most important for support medical
professionals
group discussion and presentation. We conducted
a large web-based anonymous survey to determine
preferences of patients and caregivers for cancer Conclusion: 1) This is the largest survey of patients
support groups. and caregivers concerning support groups for both
Methods: The established patient base of patients with lung cancer and for a more general
NexCura®, a web-based information resource, was cancer population. 2) Patients with lung cancer
used to survey registered patients and caregivers ranked most topics in a similar manner to the general
in this on-line assessment. Participants ranked 26 cancer population; however, topics dealing with pain
and fatigue were more highly ranked by those with improved progression-free survival (PFS) and
lung cancer. 3) Physical and psychological issues the Àrst maintenance study with a pemetrexed-
are the most highly ranked issues by lung cancer containing induction regimen.
patients and families. 4) These results should guide Methods: Following four 21-day cycles of
the content of support groups to meet the needs of pemetrexed-cisplatin (N=939), patients with disease
patients and caregivers. control of advanced nonsquamous NSCLC were
Keywords: Support Groups, Quality of Life, PROs randomized 2:1 to pemetrexed 500 mg/m2 plus BSC
or placebo plus BSC every 21 days until disease
progression or unacceptable toxicity (N=539).
Medical Oncology V Monday, 4 July 2011 14:30-16:00 Patients in both groups were fully supplemented with
folic acid and Vitamin B12. Toxicity was assessed
O11.06 SAFETY, RESOURCE USE, using CTCAE. Resource use was summarized for
AND QUALITY OF LIFE (QOL) all patients enrolled in the induction phase and for
RESULTS FROM PARAMOUNT: A all randomized patients by treatment group. Both
PHASE III STUDY OF MAINTENANCE toxicity and resource use were compared using
PEMETREXED PLUS BEST SUPPORTIVE Fisher’s exact test. Patients completed the EuroQol
CARE (BSC) VERSUS PLACEBO PLUS 5-dimensional scale (EQ-5D), a standardized
BSC IMMEDIATELY FOLLOWING instrument to measure health outcome, at each visit.
INDUCTION TREATMENT WITH Mean UK population-based index and Visual Analog
PEMETREXED-CISPLATIN FOR Scale (VAS) scores were calculated and changes
ADVANCED NONSQUAMOUS NON- from baseline during induction and maintenance
SMALL CELL LUNG CANCER (NSCLC) were analyzed using a paired t-test; additionally,
Cesare Gridelli1, Filippo De Marinis2, Jean-Louis treatment group differences during maintenance were
Pujol3, Martin Reck4, Rodryg Ramlau5, Barbara analyzed using a mixed-effects analysis of variance
Parente6, Thierry Pieters7, Gary Middleton8, model.
Katherine Winfree9, Symantha Melemed10, Results: The induction safety results are presented
Annamaria H. Zimmermann10, William John10, Julie elsewhere. Safety of single-agent maintenance
Beyrer9, Nadia Chouaki11, Carla Visseren-Grul12, pemetrexed in PARAMOUNT was similar to the
Luis Paz Ares13 Àrst maintenance phase III study (Ciuleanu et al.
1
Division Of Medical Oncology, S. Giuseppe Moscati Lancet. 2009;374:1432–1440). Overall, 23.4% of
Hospital/Italy, 2Oncological Pulmonary Unit 1st, San pemetrexed-treated patients completed >10 cycles
Camillo-forlanini, High Specialization Hospitals/ (4 induction plus 6 maintenance cycles) compared
Italy, 3Hopital Arnaud De Villeneuve, Montpellier with 13.9% of placebo-treated patients (p=0.009).
Academic Hospital/France, 4Krankenhaus No difference in drug-related Grade 3/4/5 toxicities
Grosshansdorf/Germany, 5Oncology, Wielkopolskie was observed with long-term pemetrexed exposures,
Centrum Pulmonologii I Torakochirurgii, except neutropenia (>10 cycles, 8.3% versus 10
Poznan University Of Medical Sciences/Poland, cycles, 2.2%; p=0.015), which did not translate into
6
Pulmonology, Centro Hospitalar De Vila Nova De increased infections (1.2% and 2.9%, respectively;
Gaia/espinho Epe/Portugal, 7Oncology, Cliniques p=0.691). Resource use was similar between
Universitaires Saint-luc/Belgium, 8Royal Surrey induction and maintenance, although anti-emetic use
County Hospital Nhs Trust, St. Luke’s Cancer was higher in induction (66.7%) than maintenance
Centre/United Kingdom, 9Oncology, Eli Lilly And (34.7%). During maintenance, transfusions
Company/United States Of America, 10Eli Lilly (13.4% versus 5.0%; p=0.003) and concomitant
And Company/United States Of America, 11Eli Lilly use of granulocyte colony-stimulating factor or
And Company, Suresnes/France, 12Eli Lilly And granulocyte-macrophage colony-stimulating factor
Company, The Netherlands/Netherlands, 13University (5.3% versus 0.0%; p<0.001) and anti-infectives
Hospital - Virgen Del Rocio/Spain (25.3% versus 16.7%; p=0.028) were greater in
pemetrexed-treated versus placebo-treated patients.
Background: PARAMOUNT is the second phase The overall rate of hospitalizations was similar
III, randomized, double-blind, placebo-controlled between treatment groups. During induction,
study of single-agent maintenance pemetrexed overall EQ-5D compliance was 79.4%. Statistically
in which maintenance pemetrexed signiÀcantly signiÀcant but not clinically relevant differences in
change from baseline were observed in index scores Background: Afatinib is a novel, irreversible,
at Cycles 3 and 4 during induction. No signiÀcant ErbB-family blocker and has activity against the
VAS changes were observed. During maintenance, EGFR T790M mutation, the frequent mechanism of
most EQ-5D assessments were completed: acquired resistance to erlotinib or geÀtinib in non-
pemetrexed, 84.3%; placebo, 80.9%. At the small cell lung cancer (NSCLC). A randomized,
postdiscontinuation visit, where the most worsening placebo-controlled Phase III trial of afatinib was
could be anticipated, 43.9% of pemetrexed-treated undertaken in NSCLC patients who had previously
patients and 44.3% of placebo-treated patients progressed on erlotinib or geÀtinib. Progression-free
completed the EQ-5D. The most common reason survival (PFS) and overall survival (OS) from this
for missing assessments was failure to administer trial have been previously reported (Miller VA, et
questionnaire. No clinically relevant within-group or al., 2010). There was a three-fold increase in median
treatment differences in index or VAS scores were PFS (1.1–3.3 months, P<0.0001). However, no effect
observed. on OS was noted (hazard ratio [HR]=1.001; through
Conclusion: Long-term use of pemetrexed January, 2011). Reported here are the patient-
continuation maintenance until disease progression reported symptom and Health-related Quality of Life
was well-tolerated with a safety proÀle similar to (HRQoL) results from this trial.
that in previous single-agent pemetrexed studies. Methods: 585 patients with lung adenocarcinoma
Resource use corresponded to toxicities typically (stage IIIb/IV), who had progressed after
observed with pemetrexed, and overall resource use chemotherapy (one to two lines) and 12 weeks of
was low. Increased anti-emetic use in induction was erlotinib or geÀtinib, were randomized (2:1) to receive
likely due to cisplatin. The EQ-5D results suggest either afatinib or placebo plus best supportive care
that patients can tolerate long-term maintenance (BSC). Symptom and HRQoL beneÀt were measured
pemetrexed treatment without signiÀcant decreases using the European Organisation for Research
in Qol. and Treatment of Cancer (EORTC) questionnaires
Keywords: Paramount, Pemetrexed, maintenance, (QLQ-C30/ LC13) at baseline, Weeks 2, 4, 6 and
Quality of Life 8, and then every 4 weeks, at treatment end, and
Àrst follow up. NSCLC-related symptoms (cough,
dyspnoea and pain) using the EORTC instrument were
Medical Oncology V Monday, 4 July 2011 14:30-16:00 pre-speciÀed using three pre-planned analyses. First,
the percentages of patients improved by 10 points
O11.07 SYMPTOM AND HEALTH- (EORTC transformed score), at any time during the
RELATED QUALITY OF LIFE BENEFIT study, who had worsened (by 10 points at any time
OF AFATINIB (BIBW 2992) IN ADVANCED without any improvement), and who were stable (not
NSCLC PATIENTS PREVIOUSLY improved or worsened), were determined. Second,
TREATED WITH ERLOTINIB the change in EORTC scores over time was estimated
OR GEFITINIB: RESULTS OF A using a mixed-effects growth curve model with the
RANDOMIZED PHASE III TRIAL (LUX- average proÀle over time for each endpoint described
LUNG 1) by a piecewise linear model adjusted for baseline
Vera Hirsh1, Jacques Cadranel2, Julie Cong3, Diane performance status and gender. Third, the time to
Fairclough4, Henrik Finnern5, Robert Lorence3, deterioration (Àrst 10-point worsening in EORTC
Vincent A. Miller6, Mike Palmer7, James Chih-Hsin scores) was analyzed using a stratiÀed log-rank test.
Yang8 Results: Compared to placebo, a signiÀcantly higher
1
The Montreal Chest Institute, Mcgill University proportion of afatinib-treated patients showed a
Health Center/Canada, 2Hopital Tenon/France, 10-point improvement in the three pre-speciÀed
3
Boehringer Ingelheim Pharmaceuticals/United symptoms of cough (46% vs. 25%; P<0.0001),
States Of America, 4University Of Colorado/United dyspnoea (51% vs. 36%; P=0.0006) and pain (50%
States Of America, 5Boehringer Ingelheim/Germany, vs. 32%; P<0.0001). Compared to placebo, afatinib
6
Memorial Sloan-Kettering Cancer Center/United also signiÀcantly improved mean scores over time for
States Of America, 7Keele University/United cough (Mean difference –6.99; P<0.0001), dyspnoea
Kingdom, 8National Taiwan University Hospital/ (Mean difference –2.68; P=0.0161) and pain (Mean
Taiwan difference –4.02; P=0.0056), signiÀcantly delayed the
time to deterioration for cough (HR=0.60; P<0.001);
and showed trends in delaying dyspnoea (HR=0.84; Background: Adenocarcinoma of the lung in
P=0.170) and pain (HR=0.88; P=0.287). Afatinib’s never-smokers is a distinct clinical entity. However,
beneÀt on dyspnoea and pain symptoms appeared whether any such difference exists between
greater in patients with worse baseline performance squamous cell carcinoma (SqCC) patients by
status (1–2 compared to 0). Consistent with afatinib’s smoking status is unknown.
tolerability proÀle, a higher proportion of afatinib- Methods: Retrospective analysis of SqCC patients
treated patients compared to placebo-treated patients according to smoking status from three cancer
showed a signiÀcant (P<0.05) worsening of EORTC registries (US, Japan, Korea). Kaplan-Meier survival
scores for diarrhoea, sore mouth, dysphagia and analysis was used to compare survival differences.
appetite. However, compared to placebo, afatinib Cox proportional hazards regression was used to
signiÀcantly (P<0.05) improved global HRQoL, identify independent prognostic factors.
physical functioning and fatigue. Results: 10,196 SqCC patients including 818 (8.0%)
Conclusion: In the LUX-Lung 1 trial, the addition of who were never-smokers were analyzed. 10.1% of
afatinib to BSC signiÀcantly improved not only PFS, Asian SqCC patients compared to 4.5% of US SqCC
but also NSCLC-related symptoms, global HRQoL patients were never-smokers. Never-smokers with
and physical functioning. SqCC were signiÀcant older than ever-smokers with
Keywords: Afatinib, QOL, Non-small cell lung SqCC (71 years vs. 69 years; p < 0.0001) and is
cancer, Phase IIb/III independent of region: Asia (p < 0.0001) and US (p
= 0.0383). Overall survival (OS) of never-smokers
with SqCC was signiÀcant worse than ever-smokers
Session O12: Epidemiology I with SqCC (11 months vs. 13 months; p = 0.0059).
Asian SqCC never-smokers had signiÀcant worse
Monday, 4 July 2011 OS than Asian SqCC ever-smokers (10 months vs.
14 months; HR = 1.172; p = 0.0008). Furthermore,
male SqCC never-smokers had signiÀcant worse OS
Epidemiology I Monday, 4 July 2011 14:30-16:00 than male SqCC ever-smokers (10 months vs. 13
months; HR = 1.165; p = 0.0040) and is independent
O12.01 NEVER-SMOKERS WITH of country of origin. Cox proportional hazards
SQUAMOUS CELL CARCINOMA OF THE analysis among Asian male SqCC patients revealed
LUNG: A DISTINCT CLINICAL ENTITY never-smoking status was found to be a signiÀcant
AMONG MALE ASIAN PATIENTS? A unfavorable prognostic factor versus ever-smoker
COMBINATION ANALYSIS OF THREE (HR = 1.126; p = 0.0498).
CANCER REGISTRIES FROM ASIA AND Conclusion: Epidemiologic study revealed
THE UNITED STATES OF AMERICA differences in the age of diagnosis of survival
Sai-Hong I. Ou1, Tomoya Kawaguchi2, Myung-Ju outcome between Asian male SqCC lung patients
Ahn3, Jeeyun Lee3, Atsuhisa Tamura4, Ryusei Saito5, according to smoking status indicating potential
Yosihito Maruyama6, Yun-Hee Park3, Jin-Seok difference in etiologies of SqCC among Asian male
Ahn3, Argyrios Ziogas7, Jason A. Zell1, Akihide patients by smoking status.
Matsumura2, Keunchil Park8 Keywords: squamous cell carcinoma in never-
1
Department Of Internal Medicine, Chao Family, smokers, ethnicity
Comprehensive Cancer Center/United States Of
America, 2Internal Medicine, National Hospital
Organization Kinki-chuo Chest Medical Center/ Epidemiology I Monday, 4 July 2011 14:30-16:00
Japan, 3Medicine, Samsung Medical Center/Korea,
4
National Hospital Organization Tokyo Hospital/ O12.02 GENOTYPING NON-SMALL CELL
Japan, 5National Hospital Organization Nishigunma LUNG CANCER (NSCLC) IN LATIN
Hospital/Japan, 6Research Group Of Statistical AMERICAN (LATAM) PATIENTS
Sciences, Osaka Prefecture University/Japan, Oscar Arrieta1, Andrés F. Cardona2, Aly G. Lopez3,
7
Epidemiology, Unviersity Of California Irvine/ Guillermo F. Bramuglia4, Alma D. Campos Parra1,
United States Of America, 8Div. Of Hem/Onc, Dept. Silvia J. Serrano5, Marcelo Castro6, Elena Aréchaga1,
Of Medicine, Samsung Med CTR, Sungkyunkwan Edgar Amorin7, Ricardo Kirchuk8, Mauricio Cuello9,
University School Of Medicine/Korea José R. Borbolla10, Rafael Rosell11
1
Subunidad De Investigación, Instituto Nacional De
Cancerologia/Mexico, 2Oncología Clinica, Grupo De
Oncologia Clinica Y Traslacional/Colombia, 3Centro
De Diágnostico Molecular/Peru, 4Catedra De
Farmacologia, Facultad De Farmacia Y Bioquimica,
Uba-Fundacion Investigar/Argentina, 5Fundación
Para La Investigación Clínica Y Molecular Aplicada
Del Cáncer/Colombia, 6Fundación Investigar/
Argentina, 7Instituto Nacional De Enfermedades
Neoplásicas/Peru, 8Instituto De Oncología Angel
Roffo/Argentina, 9Departamento Básico De
Medicina, Hospital De Clínicas Udelar/Uruguay,
10
Boehringer Ingelheim/Mexico, 11Hospital Germans
Trias I Pujol, Catalan Institute Of Oncology/Spain
Background: Epidermal Growth Factor Receptor
(EGFR) and K-Ras are key pathways in NSCLC;
mutations in these genes determine a subgroup of
patients with different prognosis and therapeutic Conclusion: Our Àndings add to a growing body of
approach. It has been shown that the frequency of evidence which points to the genetic heterogeneity of
mutations varies between different ethnic groups. the EGFR pathway in NSCLC among different ethnic
Our group previously reported a high response rate groups; LATAM NSCLC patients were signiÀcantly
in non-selected Mexican patients with refractory more likely to harbor activating EGFR mutations as
advanced NSCLC treated with erlotinib. Up to now compared with Caucasian population. K-Ras mutations
EGFR and K-Ras mutation frequencies have not appears be less frequent. This data highlights the need
been described in the LATAM population. for these differences to be taken into account in the
Methods: EGFR and K-Ras mutation analyses design of future trials. This work was partially funded
were performed in archived tissues from 933 by Astrazeneca and Boehringer Ingelheim Oncology
LATAM patients from 4 different countries, using Investigator Initiated Study 1200.142.
DNA sequencing or Therascreen (Qiagen, United Keyword: Epidermal Growth Factor Receptor
Kingdom) Real Time-PCR-kit. (EGFR), Non Small Cell Lung Cancer (NSCLC),
Results: EGFR mutations were evaluable in 933 K-Ras, Latin American
patients (México 295; Colombia 254; Argentina
183 and Perú 201), including 530 women (56.8%)
with a mean age of 60.6 years (SD ± 12.1); 42.7% Epidemiology I Monday, 4 July 2011 14:30-16:00
were current smokers, and 50.2% were former or
non-smokers; smoking history was not available in O12.03 IMPACT OF HIV INFECTION ON
6.9%. 35.2% patients had activating mutations in the SURVIVAL IN LUNG CANCER
EGFR, 49.5% with Ex19 deletion; 47.4% with the Ramesh Rengan1, Nandita Mitra2, Kaijun Liao3, Ian
in-frame L858R mutation, 0.009% with Ex18, and Frank4, Katrina Armstrong3, Anil Vachani5
1
2.1% had complex mutations; 20.7% patients had Radiation Oncology, University Of Pennsylvania/
K-Ras mutation of 318 tissues evaluated (Table 1). United States Of America, 2Center For Clinical
The sensitivity mutations showed association with: Epidemeiology And Biostatistics, University Of
female gender (p =0.024), non-smoker status (p Pennsylvania/United States Of America, 3General
=0.01), adenocarcinoma histology (p <0.001), and Internal Medicine, University Of Pennsylvania/
lack of K-Ras mutation (p =0.006). Among these United States Of America, 4Internal Medicine,
patients, 55 received treatment with either erlotinib University Of Pennsylvania/United States Of
or geÀtinib; response rates were as follows: 3/55 America, 5Division Of Pulmonary Medicine,
(5.5%) complete response, 25/55 (45.5%) partial University Of Pennsylvania/United States Of
response, 25/55 (45.5) stable disease, 2/55 (3.6) America
progression.
Background: It has been previously reported
that lung cancer patients with HIV have a poorer
prognosis than those that are non-HIV infected. The study is limited by small patient numbers, potential
purpose of this project was to examine the SEER- imbalance between groups in unmeasured covariates
Medicare registry to determine the impact of HIV and that the SEER-Medicare database only captures
infection on overall survival in lung cancer. patients who are over 65. Although these results
Methods: Patients with a diagnosis of lung cancer are hypothesis generating, these data represent the
with or without HIV infection were analyzed for largest comparative analysis of survival with lung
overall survival by querying the SEER-Medicare cancer in HIV infected individuals that the authors
lung database from 2000-2005. HIV infected are aware of and would suggest that HIV status
individuals were identiÀed by having either of the should not impact treatment decisions in lung cancer
two ICD 9 codes V08 or 042 (HIV group). The patients.
control group was identiÀed as any individual in the Keywords: Lung cancer, HIV, AIDS
database without either of the HIV codes. A stage by
stage and overall Kaplan-Meier survival analysis was
performed comparing the HIV infected group with Epidemiology I Monday, 4 July 2011 14:30-16:00
the control group. Cox models with propensity score
adjustment were used to account for any imbalances O12.05 NEIGHBORHOOD–
betweent groups in measured covariates such as LEVEL SOCIOECONOMIC (SES)
stage, race, median income, sex, and comorbidities. DETERMINANTS NEGATIVELY IMPACT
Results: A total of 372 patients were identiÀed in TREATMENT DECISIONS AMONG NON-
the HIV group and 85259 patients were identiÀed SMALL CELL LUNG CANCER PATIENTS
for the control group; stage I/II: 110 patients in the IN THE SOUTHEASTERN UNITED
HIV group and 20862 patients in the control group; STATES
stage IIIA/IIIB: 118 patients in the HIV group and Marybeth M. Joshi1, Loretta Erhunmwunsee2, Debbi
26960 patients in the control group; stage IV 144 H. Conlon2, David H. Harpole2
1
patients in the HIV group and 37437 in the control Surgery, Duke University Medical Center/United
group. The median survival of the overall population States Of America, 2Surgery, Duke University/United
was 6 months for the control group and 7 months States Of America
for HIV group (p=0.17). For stage I/II patients, the
median survival for the control group was 36 months Background: Lung cancer is increasing throughout
for the control group and 42 months for the HIV the world. The Southeastern United States is a
group (p=0.37). For stage IIIA/IIIB, the median fair representation of the developing world with
survival was 7 months for the control group and signiÀcant health and SES disparities and 42% of
4.5 months for the HIV group (p=0.03). For stage the nation’s extreme poor. While there has been a
IV patients, the median survival was 3 months for reduction in lung cancer through tobacco control
both the control group and the HIV group (p=0.98). measures in most of North America, the Southeastern
After using propensity scores to adjust for potential United States is burdened by an increasing incidence
confounders, there was no difference in survival in smoking, lung cancer and disease mortality rates.
between the two groups (hazard ratio 1.035, 95% CI Technological advances in the treatment of lung
0.92-1.16). cancer have been made, but these advances are often
Conclusion: In contrast to previous reports, we cost prohibitive and may in fact exacerbate existing
found no signiÀcant survival difference between disparities.
HIV infected individuals and controls with lung Methods: A consecutive, prospective cohort of
cancer. On a stage for stage basis, only HIV infected NSCLC patients treated within a single health
individuals with stage IIIA/IIIB disease had a poorer system from 1995-2007 had SES determinants
survival. Although this may be a reÁection of greater (median household income; poverty; high school;
tumor virulence in HIV patients, this is unlikely college education) abstracted from corresponding
as there was no signiÀcant difference identiÀed in 2000 census tract (neighborhood) data. Variables
any other stage grouping. Stage III disease requires were divided into quintiles and statistical
an aggressive regimen of combination therapy comparisons were performed using the highest
with chemotherapy, radiation, and surgery, and the and lowest 20th percentiles. Categorical data are
poorer outcome may be a reÁection of HIV patients presented as percentages and compared by Pearson’s
being treated with a less aggressive approach. This X2. Continuous data are presented as medians and
compared by the Wilcoxon test. Survival was deÀned A revised/updated abstract may be included in
as time between initial diagnosis and date of cancer- the Late Breaking Abstract Supplement, available
speciÀc death or last follow-up and was determined at the 14th World Conference on Lung Cancer.
utilizing the Kaplan-Meier method. Any difference
in survival between groups was assessed using
the log-rank test; signiÀcant univariate associates Epidemiology I Monday, 4 July 2011 14:30-16:00
were assessed for independence using Cox logistic
regression modeling. O12.06 COMMON VARIATION IN NF-
Results: There were 4712 NSCLC patients (median ɤB PATHWAY GENES AND RISK OF
follow-up of 32.1 mos.; Clinical Stage 1-2, n=1723; SMOKING-ASSOCIATED LUNG CANCER
Stage 3-4, n=2989). Early stage patients realized Brenda Diergaarde1, Yan Du2, Shama Buch2,
similar resection and survival rates irrespective of Marjorie Romkes2, Pamela Hershberger2, Joel
median household income, poverty or education. In Weissfeld2, Jill Siegfried2
1
contrast, living in areas of lower education, income Epidemiology, University Of Pittsburgh - University
and higher poverty negatively impacts survival Of Pittsburgh Cancer Institute/United States Of
and chemotherapy delivery in those with advanced America, 2University Of Pittsburgh - University Of
disease (Table 1). Moreover, this difference persisted Pittsburgh Cancer Institute/United States Of America
even when corrected for Medicare eligibility
(p<0.0001). Table 1. SES Variables in Advanced- Background: Cigarette smoking elicits airway
stage Subjects inÁammation in all of those who smoke and is the
major cause of lung cancer. However, 4 out of 5
Variable Survival Chemotherapy Delivery smokers never develop lung cancer and lung cancer
p<0.0001 Median Survival occurs in never smokers as well. The reasons for
High School
Low (68.1%) 7.97 mo. p<0.0001 this are currently unclear but genetic factors likely
Education
High (89.7%) 11.17 mo.
play an important role. Nuclear factor-kappa B
p=0.046 Median Survival
College (NF-kB) signaling plays a key role in inÁammation
Low (10.2%) 8.2 mo. p=0.0075
Education and has been shown to underlie smoking-associated
High (39.5%) 10.43 mo.
p<0.0001 Median Survival pulmonary inÁammation and lung carcinogenesis.
Median
Household
Low ($30,757%) 8.07
p<0.0001
Functionally relevant polymorphisms in genes
mo. High ($52,614%) that encode key components of the NF-kB
Income
11.23 mo.
signaling pathway may well inÁuence risk of
p=0.0002 Median Survival
Poverty Low (5.3%) 11.07 mo. p<0.0001
smoking-associated lung cancer by modifying the
High (17.5%) 7.67 mo. inÁammatory response.
Methods: We examined associations between
Conclusion: Although these patients received initial 24 single nucleotide polymorphisms (SNPs) in
care within a comprehensive cancer center with NFKB1, NFKB2, RELA, RELB and REL (all these
a multi-disciplinary thoracic oncology program, genes encode NF-kB transcription factor subunits)
data indicate that neighborhood SES signiÀcantly and risk of lung cancer in a large case-control
impacts treatment decisions among patients with study. The study population consisted of 639 lung
advanced lung cancer. This appears independent of cancer cases and 936 controls; all participants were
insurance accessibility and a result of access to care Caucasian and current or former cigarette smokers
due to travel, treatment time, and cost restrictions. who had smoked at least 10 pack-years. Genotyping
In contrast, resection requires a limited and Ànite was conducted using Sequenom iPLEX Gold assay.
treatment course and we observed no difference Deviation from Hardy-Weinberg equilibrium was
in resection rates or survival among early stage evaluated with the exact method. Associations
subjects residing in high poverty or less educated between alleles and genotypes and lung cancer
neighborhoods. Currently, we are investigating the risk were examined using Pearson Chi-square test
role of comorbid status and access to care within this and Cochran-Armitage trend test, respectively. Per
dataset to further understand disparities in treatment (minor) allele odds ratios (OR) and corresponding
decisions. 95% conÀdence intervals (95% CI) were also
Keywords: Non-small cell lung cancer, calculated for each SNP.
socioeconomic factors, health care disparities Results: Four SNPs in NFKB1 were statistically
signiÀcantly associated with lung cancer risk in Background: The presence of certain mutations
our study population. The minor alleles of these in the Epidermal Growth Factor Receptor (EGFR)
SNPs were associated with a decreased risk of lung predicts that a patient with advanced non-small
cancer (rs3821958, OR: 0.82, 95%CI: 0.71-0.95, cell lung cancer (NSCLC) will respond better
Ptrend= 0.01; rs1609798, OR: 0.84, 95%CI: 0.72- to Tyrosine Kinase Inhibitors (TKIs) than to
0.99, Ptrend=0.04; rs3755867, OR: 0.83, 95%CI: platinum-based chemotherapy. Previous studies
0.71-0.97, Ptrend= 0.02; and rs1801, OR: 0.82, with Caucasian patients have shown the prevalence
95%CI: 0.70-0.96, Ptrend=0.01). No statistically of EGFR mutation to be around 10-15%. The
signiÀcant associations were observed for the other aim of the REASON study is to determine the
examined SNPs. epidemiology of EGFR mutation in advanced
Conclusion: NFKB1 encodes the precursor protein NSCLC patients (p) in Spain (all histologies),
p105, which contains an inhibitor of NF-kB (IkB)- and to better understand the clinical factors
like C-terminal portion and functions as NF-kB (gender, smoking habits, tumour histology) that
inhibitor. Proteasome-mediated processing of p105 may be associated with EGFR mutations, in a
produces the NF-kB transcription factor subunit representative sample of advanced NSCLC p.
p50. This is the Àrst study to report associations Methods: All newly diagnosed advanced NSCLC
between polymorphisms in NF-kB pathway genes p in 39 Spanish centers nationwide were included
and lung cancer risk. Our results suggest that prospectively for a 6-month period. Patient’s
common variation in NFKB1 may modify smoking- characteristics were recorded from clinical records
associated risk of lung cancer. (Funded by the (gender, smoking status, tumour histology, sample
University of Pittsburgh Cancer Institute SPORE in type –tumour biopsy, cytology, etc-). Mutation
Lung Cancer, NCI P50 CA90440) testing was performed on available tumour samples,
Keywords: nuclear factor-kappa B signaling, mainly through two central laboratories (using RT-
Polymorphisms, lung cancer risk PCR-based methodologies), or on-site where EGFR
mutation testing was customary.
Results: 1050 p have been included by February
Epidemiology I Monday, 4 July 2011 14:30-16:00 2011. As of data cutoff in December 2010, data
from 714 p have been analyzed. 711 were of
O12.07 EPIDEMIOLOGICAL STUDY TO Caucasian ethnicity. 76.2% p were men, 39.2%
EVALUATE THE PREVALENCE OF EGFR were smokers, 45.9% ex-smokers, and 14.9%
MUTATIONS IN PATIENTS WITH NEWLY never-smokers. Median age was 66 years (range
DIAGNOSED LOCALLY ADVANCED 25-90). 22.7% p had squamous-cell carcinoma,
OR METASTATIC NSCLC (STAGE IIIB/ 69.2% had non-squamous histology (57.6%
IV NON-SMALL CELL LUNG CANCER): adenocarcinoma, 2.2% bronchoalveolar, 9.4%
SPANISH REASON large-cell carcinoma, 1.7% adenosquamous
Bartomeu Massuti1, Emilo Esteban Gonzalez2, carcinoma, and 4.4% non-speciÀed). Mutation
Margarita Majem3, M. Teresa Martínez Aguillo4, analysis was not feasible in 61 p (8.5%) due either
Natividad Martínez Banaclocha5, Cristina Martí to sample unavailability (6.0%) or inadequacy
Blanco6, Manuel Domine7, Lorenzo Gómez- (2.5%) for mutation testing.
Aldaravi8, Oscar Juan Vidal9, Carmen Gonzalez-
Arenas10 Exon 19 deletion and exon 21 L858R point
1
Servicio De Oncología, Hospital General mutation were analyzed in 653 samples. Mutation
Universitario De Alicante/Spain, 2Hospital rate was 10.7% (82.7% exon 19 del and 17.1%
Universitario Central De Asturias/Spain, 3Hospital exon 21 L858R).
De La Santa Creu I Sant Pau/Spain, 4Hospital De
Navarra/Spain, 5Hospital General Universitario Mutation rates according to clinical features are
De Elche/Spain, 6Hospital Sant Joan De Reus/ summarized in table 1.
Spain, 7Fundación Jiménez-Díaz/Spain, 8Complejo
Hospitalario Universitario De Albacete/Spain,
9
Hospital Arnau De Vilanova De Valencia/Spain,
10
Medical, Astrazeneca/Spain
Patients Patients Session O13: Clinical Cases and Clinical

% of clinical
with
available
with EGFR
Mut (Exon
% of
mutations
factor within Decisions I
mutated
tumor 19 del, and 95%
patients and
sample L858R) CI
95% CI
(N=653) (N=70)
Monday, 4 July 2011
5.8 41.4 (29.8-
Gender Men 503 29
(3.9-8.2) 53.9)
27.3 58.6 (46.2-
Women 150 41 Clinical Cases and Clinical Decisions I Monday, 4 July 2011 14:30-
(20.4-35.2) 70.2)
Smoking 4.1 (2.0- 16:00
Current Smoker 242 10 15.1 (7.5-26.1)
Status 7.5)
Ex-smoker 301 21
7.0 31.9 (20.9-
(4.4-10.5) 44.4) O13.01 LUNG CANCER COMPLICATING
37.6 53.0 (40.3- LUNG TRANSPLANTATION: INCIDENCE
Never-smoker 93 35
(27.8-48.3) 65.4) AND OUTCOME – A SINGLE CENTER
Missing 17 4
EXPERIENCE
Tumor 14.9 81.4 (70.3-
Type
Adenocarcinoma 383 57
(11.5-18.8) 89.7) Mir Alireza Hoda, Victoria Augustin, Bahil Ghanim,
Bronchioloalveolar
16 3
18.7
4.3 (0.9-12.0)
Peter Jaksch, Mai-Britt Ernst, Clemens Aigner,
adenocarcinoma (4.1-45.6)
Gyoergi Lang, Shahrokh Taghavi, Walter Klepetko
Large-Cell 5.1
carcinoma
59 3
(1.1-14.1)
4.3 (0.9-12.0) Division Of Thoracic Surgery, Medical University
Adenosquamous Vienna/Austria
11 0
carcinoma
Squamous-Cell 2.8
carcinoma
145 4
(0.8-6.9)
5.7 (1.6-14.0) Background: Long-term immunosuppression,
12.0 longer survival times and underlying end-stage
NOS 25 3 4.3 (0.9-12.0)
(2.5-31.2) pulmonary disease might be important contributing
Missing 14 0
factors for the development of lung cancer in
lung transplant patients. Aim of the study was to
Exons 18 through 21 were analyzed in 401 samples. determine the incidence and outcome of lung cancer
Mutation rate was 16.5% (62.1% exon 19 del, 18.2% in a single center cohort of lung transplant recipients.
exon 21, 10.6% exon 18, and 9.1% exon 20). Methods: We retrospectively reviewed the records
Updated full results will be provided at the of 962 consecutive patients who underwent lung
Conference. transplantation between 1989 and 2009 at our
Conclusion: The estimated prevalence of sensitizing institution to identify patients diagnosed with
EGFR mutations (Exon 19 del, exon 21 L858R) in a bronchogenic carcinoma. Records were reviewed for
representative sample of newly diagnosed advanced demographics, lung transplant characteristics and
NSCLC patients in Spain (all histologies) agrees outcome.
with previous data obtained in caucasian patients. Results: 10 patients were identiÀed with an
Whenever a sample is available, EGFR mutation unexpected lung cancer in the explanted lungs and
testing is feasible in over 95% of cases, and may 10 patients with lung cancer developing after lung
therefore become routine clinical practice. Around transplantation. 6 women and 14 men with mean
3% of squamous-cell carcinomas show EGFR age 55 ± 14 years (range 19-69 years) received 8
mutations, which is about the same rate as other single lung transplants (70 %) and 12 bilateral lung
clinically relevant mutations. transplant (30%). Mean follow up was 2405 ± 1052
Keywords: Spain, Epidemiology, EGFR mutations, (range 672-4346) days. The underlying diagnoses
NSCLC for transplantation were pulmonary Àbrosis (4
cases), COPD (11 cases), cystic Àbrosis (2 cases),
A revised/updated abstract may be included in alpha1-antitrypsin-deÀciency, Histiocytosis X
the Late Breaking Abstract Supplement, available and hypersensitivity pneumonitis. 18 cases were
at the 14th World Conference on Lung Cancer. identiÀed as non-small cell lung cancer of which
12 had been adenocarcinoma, 6 squamous cell
carcinoma while 1 patient was diagnosed with a
low differentiated neuroendocrine carcinoma and
another patient with a carcinoid of the lung. In
patients developing lung cancer after transplantation
6 cancers occurred in the native lung and 4 in the
transplanted lung. Mean time from transplantation to and deemed necessary to receive immediate cancer
diagnosis of lung cancer was 1859 ± 809 (range 264- chemotherapy were included. As advanced lung
2797) days. Late stage lung cancer (IIIB-IV) was adenocarcinoma was diagnosed, pemetrexed
diagnosed in 7 patients, 3 patients were diagnosed in (500 mg/m2) combined carboplatin (AUC 5) was
early stage disease (Ia-IIb). Median overall survival administered after one week folic acid supplement.
after detection of lung cancer was 198 days (SE Patients’ characteristics, ECOG performance
144, range 0-2800 days). One-year and three-years status (PS) prior to hospitalization, reasons of ICU
survival after lung cancer diagnosis were 34% and admission, APACHE II score on ICU admission,
11%, respectively. In patients with unexpected length of ICU and hospital stay, chemotherapy
lung cancer in the explanted lungs all neoplasms response, drug adverse effects, and ICU mortality
were detected in early stages (stage I, T1A and were examined.
T1B). Recurrence of tumor was not found in any Results: Nine patients were admitted to the ICU with
of these patients. One patient died 6 months after newly diagnosed advanced lung adenocarcinoma .
transplantation, all other 9 patients are still alive. Two of them did not receive any chemotherapy and
Conclusion: Unexpected lung cancer in explanted 7 patients received chemotherapy with pemetrexed
lungs, with an incidence of 1,03 % in all our patients combined carboplatin. One with septic shock, 1 with
, is found in an early stage and does not affect pulmonary tumor embolism, 2 with brain metastasis,
survival. In the case of diagnosis of lung cancer after and 3 with respiratory failure admitted for ICU
lung transplantation, rapid progression to locally care. These patients did not receive intubation with
advanced disease or metastatic disease is common, mechanical ventilator support but Àve of them
limiting therapeutic options. needed non-invasive positive pressure ventilator to
Keywords: Lung cancer, lung transplantation, treat. The PS statuses prior to hospitalization were
immunosuppression 0 to 1. The mean of APACHE II scores at the time
of chemotherapy were 22. The average of ICU stay
was 12.4 days and hospital stay was 24.2 days. Five
Clinical Cases and Clinical Decisions I Monday, 4 July 2011 14:30- of them (71.4%) had partial response after Àrst dose
16:00 of chemotherapy. One patient (14.3%) developed
fatigue, one patient (14.3%) has grade 2 mucositis
O13.02 OUTCOME IN CRITICALLY ILL and one (14.3%) has grade 4 neutropenia. Overall,
LUNG ADENOCARCINOMA PATIENTS one patients (14.3%) died in the ICU due to febrile
RECEIVING CHEMOTHERAPY neutropenia and pneumonia with septic shock.
WITH PEMETREXED COMBINED Conclusion: Chemotherapy in the ICU for lung
CARBOPLATIN IN THE INTENSIVE cancer patients can be considered if the critical
CARE UNIT illness related to malignancy. Chemotherapy
Chung-Yu Chen1, Kuan-Yu Chen2, Chong-Jen Yu2, with pemetrexed combined carboplatin for lung
Pan Chyr Yang3 adenocarcinoma may be a choice as higher response
1
Internal Medicine, National Taiwan University rate and less hematologic effect than other cytotoxic
Hospital Yun-lin Branch/Taiwan, 2Pulmonary And agents.
Critical Care Medicine, National Taiwan University Keywords: lung adenocarcinoma, Pemetrexed,
Hospital/Taiwan, 3National Taiwan University Carboplatin, Critical care
College Of Medicine/Taiwan
Background: The decision to start chemotherapy the Late Breaking Abstract Supplement, available
in critically ill cancer patients is extremely complex at the 14th World Conference on Lung Cancer.
in the intensive care unit (ICU). Therefore,
this study evaluated the outcomes and the
complications in critically ill cancer patients with
lung adenocarcinoma receiving chemotherapy with
pemetrexed combined carboplatin in the ICU.
Methods: From January 2010 to February 2011, all
patients admitted to the ICU for organ failures due
to newly diagnosed, untreated lung adenocarcinoma
Clinical Cases and Clinical Decisions I Monday, 4 July 2011 14:30- 15% of febrile neutropenia, 15% esophagitis and
16:00 9% pneumonitis). There were no treatment related
deaths. Median weight loss during treatment was
O13.03 CHEMORADIOTHERAPY FOR 5% (0-17%). At a median follow up of 24 months
RECURRENT NSCLC; RETROSPECTIVE (1.5-82), median progression free survival was 25
DATABASE ANALYSIS OF TWO LARGE months, median survival was not reached. Time
CANCER CENTERS. to subsequent progression was not associated with
Dawn Ng1, Patricia Moretto2, Glenwood D. Goss2, patient baseline or treatment characteristics.
Garth Nicholas2, Scott Laurie2, Alex Sun3, Natasha
Leighl1, Robert Macrae4, Jair Bar2
1
Medical Oncology, University Health Network/
Princess Margaret Hospital/Canada, 2Medical
Oncology, The Ottawa Hospital Cancer Center/
Canada, 3Radiation Oncology, University Health
Network/Princess Margaret Hospital/Canada,
4
Radiation Oncology, The Ottawa Hospital Cancer
Center/Canada
Conclusion: The standard treatment for regional
Background: Recurrence of NSCLC is commonly recurrence of NSCLC is palliative chemotherapy.
considered incurable, and is approached similarly However, selected patients with locally advanced
to metastatic disease. However, local or regional recurrent NSCLC might beneÀt from concomitant
recurrence can potentially be treated with curative chemoradiotherapy, with a long-term survival
intent. We set out to study the outcomes of comparable to patients who present initially with
recurrent NSCLC patients that were treated by Stage III disease.
chemoradiotherapy with a curative intent. Keywords: NSCLC, recurrence, chemo-radiotherapy
Methods: Computerized databases of NSCLC
patients of The Ottawa Hospital Cancer Center
(TOHCC; 2000-2009) and Princess Margaret Clinical Cases and Clinical Decisions I Monday, 4 July 2011 14:30-
Hospital (PMH; 1999-2007) Cancer Center were 16:00
systematically screened for patients with recurrent
NSCLC that were treated with curative intent O13.05 VERTEBRAL COLLAPSE
combined chemoradiotherapy. Patients were AFTER COMBINED MODALITY FOR
included if they underwent initial curative surgery LOCALLY ADVANCED LUNG CANCER.
and no more than three years later, had subsequent METASTASES, OSTEOPOROSIS OR
radiologic diagnosis of regional recurrence and were COMPLICATION OF THERAPY? A
treated with chemoradiotherapy with curative intent REPORT OF 4 CASES.
(N=30 patients, 28 and 2, of 5791 and 2225 screened Laurence M.M. Crombag1, Ellen Van Reij2, Erik C.
from TOHCC and PMH respectively). Phernambucq2, Suresh Senan2, Pieter E. Postmus1
1
Results: Median age was 65 (range 49-79), 38% Pulmonary Diseases, Vrije Universiteit Medical
were males. Median interval from primary surgery Centre/Netherlands, 2Radiation Oncology, Vrije
to recurrence was 16 months (range 6-34), and was Universiteit Medical Centre/Netherlands
conÀrmed by biopsy in 62%. Stage was IIIA in 23
patients, IIIB in 6 and IIB (T3, N0) in one patient. Background: The standard treatment for patients
Median number of involved sites (N stations and/ presenting with unresectable lung cancer stage
or lung lobes) was 3 (1-5). A median of 66 Gy III and a good performance score is combined
was given (26-66 Gy) in 33 fractions (10-35). chemotherapy with thoracic radiation therapy. This
Most common chemotherapy regimens delivered approach results in 5-year survival rates for both
were cisplatin-vinorelbine q3weekly (41%), small-cell (SCLC) and non-small-cell lung cancer
weekly carboplatin-paclitaxel (21%) and cisplatin- (NSCLC) patients of 10-20%. One reason for the
etoposide (SWOG regimen, 12%). A median of 6 poor outcome is disseminated disease becoming
weeks of treatments were concurrent (0-10). 44% symptomatic during follow-up. A common mode
of patients suffered grade 3-4 toxicities (including of disease relapse are skeletal metastases which
result in pain and pathological fractures. However, Clinical Cases and Clinical Decisions I Monday, 4 July 2011 14:30-
treatment-induced bone toxicity can also manifest as 16:00
bone fractures.
Methods: Extensive analysis was performed in 4 O13.06 PERIPHERAL SKIN EDEMA
patients initially treated with combined radio- and AS UNUSUAL TOXICITY IN THREE
chemotherapy for locally advanced lung cancer who PATIENTS (PTS) TREATED WITH
developed back pain due to fracture(s) of vertebra(e) PEMETREXED ALONE OR IN
17 months after completing therapy (median, COMBINATION WITH CISPLATIN
range 0,5-48 months). Plain X-ray, computed (CDDP) IN ADVANCED NON SMALL
tomography, dual-energy X-ray absorptiometry, CELL LUNG CARCINOMA (NSCLC).
magnetic resonance imaging, FDG-positron emission Domenico Galetta, Nicola Silvestris, Annamaria
tomography and/or radionuclide scintigraphy Catino, Giuseppe Colucci
were performed to detect the underlying cause. In Medical Oncology, Giovanni Paolo Ii Oncology
one patient histology of the vertebral column was Institute/Italy
obtained. Mean and maximal radiation dose to the
affected vertebral bodies in the radiation Àeld were Background: To date, pemetrexed is one of
calculated. the most widely used drugs in the treatment of
Results: We studied the features of 4 patients (4 pts with NSCLC and non squamous histology.
female, median age 64,5 y (59-68 y), 3 NSCLC, This administration is usually associated with a
1 SCLC) who presented with back pain after favourable toxicity proÀle. Recently, a series of
completing chemo-radiotherapy for lung cancer 14 pts with peripheral skin edema related to the
(concurrent in 3, sequential in 1) to a total dose administration of pemetrexed has been reported
of 50, 60, 62 en 66 Gy, respectively. Radiologic (D’Angelo S.P. et al J. Thor Oncol 2011,6:624-626).
imaging revealed vertebral collapse. None of the Main relevant aspects of this clinical picture were
patients had signs of metastatic disease at FDG-PET similar to Áuid retention, mainly localized to the end
scan or radionuclide scintigraphy. In 3 patients DXA of the lower limbs ranging from ankle swelling to
scan revealed osteopenia. One patient underwent pitting edema with overlying skin erythema.
vertebroplasty and histology obtained revealed no Methods: In our Institution within the last Àve
malignancy. In all patients affected vertebrae were years, 3 of 120 consecutive NSCLC pts, observed
near the treated planning target volume (PTV) and in and treated with pemetrexed, showed a peripheral
one patient, the PTV incorporated multiple vertebrae. skin edema. Two pts (A and B) received pemetrexed
One patient had besides one vertebrae near PTV as Àrst-line treatment, at the dosage of 500 mg/m2
also several fractured lumbar vertebrae outside the in combination with cisplatin 75 mg/m2 , and in the
radiation Àelds. The median mean and maximal third case (C) the drug was administered as single
radiation dose to the affected vertebral bodies were agent as second line treatment at the same dose. All
48,1 Gy (29,7 - 53,3 Gy) and 59,3 Gy (47,3 – 68,3 subjects were Caucasian with an ECOG performance
Gy) respectively. The median follow-up since the status of 0-1 in the absence of relevant comorbidities.
onset of the back pain complaints was 14 months Results: Pts A (59 years old) - He developed skin
(10.5-27 months). All patients are still without signs edema to bilateral lower extremities after the 4th
of disease progression cycle of therapy without hematological toxicity.
Conclusion: Although metastatic disease is an Edema was initially treated with topical steroids
important cause for collapsed vertebral bodies in with a signiÀcant worsening of the condition after
lung cancer patients, other benign or treatment- the 5th cycle. Dermatological advice interpreted
related aetiologies must be considered as well. All this picture as erysipelas and started antibiotic
our patients were postmenopausal females and it is therapy with macrolides in combination with
unclear if these collapses could be prevented by the systemic steroids obtaining a slight improvement
use of bisphosphonates. of clinical picture. Sixth cycle, administered on a
Keywords: vertebral collapse, Lung cancer, reduced dose to 75%, was associated with a Áare
combined modality treatment of edema. Discontinuation of pemetrexed was
decided. A clinical complete regression occurred
within one month. Pts B (65 years old) - He showed
dermatologic toxicity after 2nd cycle although with a
lower intensity. Systemic steroid therapy improved therapy. Nine years earlier, at the age of 73, she had
clinical picture even if the patient progressed after been treated with cyclophosphamide, doxorubicin,
the 4th cycle and crossed to a second line therapy etoposide and PCI, for a SCLC in the left upper lobe,
with complete resolution of clinical symptoms resulting in CR. Second primary lung tumor (SPLT)
after twenty days. Pts C (66 years old) - In this pts, in long-term survivors of SCLC is a well-known
we observed the onset of edema to the limbs after entity and it has been stated that especially these
the 3rd cycle with bilateral signs of erythema. The patients are at very high risk of developing a SPLT.
vascular echodoppler analysis did not show phlebitis In SCLC patients the SPLT is most frequent NSCLC.
episodes. Treatment with diuretics was ineffective SCLC after SCLC has been found but will often be
and, after the 4th cycle, a 75% dose reduction of considered as a late recurrence of the primary SCLC.
pemetrexed was decided without any improvement. In this patient the “recurrence” was very late and the
Subsequently, steroid systemic therapy was started radiological picture much more that of a primary lung
with a further dose reduction up to 50% with clinical cancer with spiculae and its pattern of nodal spread.
improvement and disappearance of the skin picture. Therefore it is unlikely on clinical grounds that this
Conclusion: Our expertise and the literature data second primary is a late metastasis that remained
suggest that skin edema could be considered a new dormant for almost nine years. For these reasons we
side effect of pemetrexed. The treatment of choice decided to compare DNA of both tumors by CGH.
appears the reduction of dosage of pemetrexed Methods: Tissue from both episodes was analysed
combined with systemic steroids. Treatment by array CGH. DNA was isolated from formalin
discontinuation should be considered only in non Àxed parafÀn (FFPE) embedded samples.
responsive pts. Results: The chromosomal alterations were
Keywords: Advanced NSCLC, Peripheral skin essentially different between the two samples.
edema, Pemetrexed Conclusion: The results of array CGH make it very
unlikely that the second tumour is a metastases of the
Àrst. Sofar we know this is the Àrst reported patient
Clinical Cases and Clinical Decisions I Monday, 4 July 2011 14:30- with deÀnitive proof of being in long-term remission
16:00 after chemotherapy and developing very late during
follow-up a 2nd primary SCLC.
O13.07 AN 82-YEAR OLD WOMAN Keyword: Small cell, array CGH, second primary
WITH SMALL CELL LUNG CANCER:
LATE RELAPSE AT 9 YEARS OR A NEW
PRIMARY? Session O14: Molecular Pathology:
Martijn R. Groenendijk1, Erik Thunnissen2, Bauke NSCLC Subtyping
Ylstra3, Mark A. Van De Wiel4, Paul P. Eijk1, M. A.
Paul5, Egbert F. Smit6, Pieter E. Postmus7
1
Pulm Diseases, VUMC/Netherlands, 2Pathology,
VUMC/Netherlands, 3Pathology, VU University
Medical Center/Netherlands, 4VUMC/Netherlands, Molecular Pathology: NSCLC Subtyping Tuesday, 5 July 2011 10:30-
5
Department Of Thoracic Surgery, VU University 12:00
Medical Center/Netherlands, 6Pulmonary Diseases,
Vrije Universiteit Medical Centre/Netherlands, O14.01 IS LARGE CELL CARCINOMA
7
Department Of Pulmonary Diseases, VU University OF THE LUNG A REAL ENTITY?
Medical Center/Netherlands AN IMMUNOHISTOCHEMICAL
PERSPECTIVE
Background: A 82 years old lady was diagnosed Giulio Rossi1, Mattia Barbareschi2, Mauro Papotti3,
with a mass in the right upper lobe with lymph nodes Paolo Graziano4, Giuseppe Pelosi5, Maria Cecilia
in mediastinum and supraclavicular. FDG-PET Mengoli1, Alberto Cavazza6
1
was positive with a small mass adjacent to the R Azienda Policlinico, Section Of Pathologic
adrenal. Biopsy revealed SCLC. She was treated with Anatomy/Italy, 2Unit Of Surgical Pathology &
carboplatin-etoposide resulting in PR. Shortly after Laboratory Of Molecular Pathology, S. Chiara
chemotherapy was stopped, multiple brain metastases Hospital/Italy, 3University Of Turin At San Luigi
became symptomatic for which she refused further Hospital/Italy, 4Division Of Pathology Of The
Forlanini Hospital/Italy, 5National Cancer Institute Results: Overall, there were 104 males and 17
And University Of Milan/Italy, 6Unit Of Pathologic females, with a mean age of 66 years. Tumor size
Anatomy, Hospital St. Maria Nuova/Italy ranged from 1 to 13 cm (mean, 4 cm). Tumors
were generally in stage I (55%) and II (36%),
Background: Large cell carcinoma (LCC) is an lymphnode involvement was noted in 29% and 67%
“undifferentiated non-small-cell carcinoma that were peripherally-located. Forty-seven cases were
lacks the cytologic and architectural features of classiÀed as large cell neuroendocrine carcinoma
small cell carcinoma and glandular or squamous (LCNEC) (39%), 24 as basaloid carcinoma (BC)
differentiation”, then not signiÀcantly differing from (20%), 22 as clear cell carcinoma (CCC) (18%),
the deÀnition of poorly-differentiated non-small-cell 6 as LCC with rhabdoid features (RC) (5%), 2
lung cancer (NSCLC). The advent of histology-based as lymphoepithelioma-like carcinoma (LELC)
therapies have considerably changed the pathologists’ (2%) and 22 were entirely undifferentiated (16%).
perspectives, requiring immunostains aimed at ImmunoproÀle of the different types of LCC are
NSCLC subtyping in routine practice. The concept of summarized in Figure 1.
LCC is thus challenged by immunomarkers, basically Conclusion: When applying a selective panel
evidencing squamous cell, adenocarcinoma or of immunohistochemical stains, LCC appears as
neuroendocrine differentiation. a waste-basket of tumors with different lineage.
Methods: One-hundred-twenty-one surgically- Undifferentiated type, CCC, RC are most commonly
resected LCC were collected. Cases were reviewed variants of poorly-differentiated adenocarcinomas.
according to the 2004-WHO classiÀcation and tested LELC and BC should be considered as poorly-
for immunoexpression with markers of glandular differentiated variants of squamous cell
(TTF-1 [clone, 8G7G3/1], cytokeratin 7 [CK7] carcinomas. LCNEC is a true poorly-differentiated
[OV-TL12/30]), squamous (p63 [A4A], CK5/6 neuroendocrine carcinoma. Immunostains in
[D5/16B4]) and neuroendocrine (chromogranin LCC is a diagnostic tool highlighting tumor
[DAK-A3], synaptophysin [polyclonal], CD56 differentiation and is essential for proper patients
[123C3]) differentiation. When tumor cells presented management. In a future lung cancer classiÀcation,
an heterogeneous expression of markers of different it should be considered the relevant diagnostic role
lineages, TTF-1 and p63 were considered ab initio of immunohistochemistry and the possibility to
the master markers and some basic rules were eliminate the LCC category.
established, as follows: 1- any TTF-1 positivity Keywords: large cell carcinoma,
excluded squamous cell differentiation even in immunohistochemistry, TTF-1
presence of staining for p63 and CK5/6; 2- strong
and diffuse immunostaining for squamous markers
excluded NE differentiation; 3- a minimal expression Molecular Pathology: NSCLC Subtyping Tuesday, 5 July 2011 10:30-
for NE markers in single tumor cells did not 12:00
excluded squamous or glandular differentiation; 4-
neuroendocrine LCC can be positive for TTF-1. O14.02 A TWO-HIT MINIMALIST
DIAGNOSTIC ALGORITHM BASED
ON P40 (DELTANP63) AND TTF-1
IMMUNOSTAINING UPON SMALL
BIOPSY/CELLBLOCK SAMPLES FOR
DIFFERENTIATING MAIN SUBTYPES OF
NON-SMALL CELL LUNG CANCER AND
SPARING MATERIAL
Giuseppe Pelosi1, Alessandra Fabbri1, Giulio Rossi2,
Patrick Maisonneuve3, Angelica Sonzogni4, Enrica
Bresaola4, Ugo Pastorino5, Mauro Papotti6
1
Department Of Pathology And Laboratory
Medicine, National Cancer Institute And University
Of Milan School Of Medicine/Italy, 2Azienda
Policlinico, Section Of Pathologic Anatomy/Italy,
3
Division Of Epidemiology And Biostatistics,
European Institute Of Oncology/Italy, 4European phenotype TTF1-/p40+ if the latter was 50% or less.
Institute Of Oncology/Italy, 5National Cancer SC with the proÀle TTF1-/p40- was consistent with
Institute/Italy, 6Department Of Clinical And the presence of glandular differentiation.
Biological Science, University Of Turin/Italy
Background: The diagnostic assessment of non- Molecular Pathology: NSCLC Subtyping Tuesday, 5 July 2011 10:30-
small cell lung cancer (NSCLC) on biopsy or 12:00
cellblock samples may be demanding by morphology
alone. As precise typing and sparing material O14.03 ACCURACY OF HISTOLOGICAL
for further testing are compulsory, a minimalist NON-SMALL CELL LUNG CARCINOMA
algorithm approach by immunohistochemistry (IHC) SUBTYPING IN DIAGNOSTIC LUNG
is warranted as diagnostic adjunct to morphology. BIOPSIES: THERE IS NEED FOR
Methods: Forty-six consecutive small biopsies UNIFORM GUIDELINES
and cellblocks and paired surgical specimens (as Spasenija Savic1, Katharina Glatz2, Keith M. Kerr3,
gold standard) from 30 adenocarcinomas (AD), 10 Andrew G. Nicholson4, Masayuki Noguchi5, Helmut
squamous carcinomas (SQC), 5 adenosquamous H. Popper6, Yasushi Yatabe7, William D. Travis8,
carcinomas (ADSQ) and one sarcomatoid Lukas Bubendorf9
1
carcinoma (SC) were IHC-evaluated for TTF- Pathology, University Hospital Basel/Switzerland,
2
1 (clones 8G7G3/1 and SPT24) and p63 [clone Institute For Pathology, University Hospital Basel/
4A4 recognizing all known isotypes of p63 and a Switzerland, 3Pathology, Aberdeen University
rabbit anti-human polyclonal anti-p40 recognizing Medical School/United Kingdom, 4Department Of
non-transactivating (non-TA), truncated or deltaN Histopathology, Royal Brompton Hospital, National
isoforms only]. Hierarchic clustering approach and Heart And Lung Institute Division Of Imperial
the area under the curve (AUC)-receiver operating College School Of Medicine/United Kingdom,
5
characteristic (ROC) analysis were used in the study. Pathology, Institute Of Basic Medical Sciences,
Results: Unsupervised clustering of surgical University Of Tsukuba/Japan, 6Pathology, Medical
specimens and biopsies showed a nonrandom and University/Austria, 7Aichi Cancer Center Hospital/
overlapping distribution of the relevant markers, Japan, 8Memorial Sloan-kettering Cancer Center/
which closely correlated with each other and the United States Of America, 9Departement Of
diverse tumor categories, as also conÀrmed by Pathology, University Hospital Basel/Switzerland
mosaic plot analysis. There were no differences in
AUC-ROC curves for each marker between any two Background: The accurate stratiÀcation of non-
samples. Diagnostic combinations were TTF1+/ small cell lung carcinoma (NSCLC) in lung
p40- or TTF1-/p40- for AD; TTF1-/p40+ (p40 more biopsies has become crucially important for therapy
than 50%) for SQC; and TTF1+/p40+ or TTF1-/ decisions. Treatment has signiÀcantly changed
p40+ (p40 less than 50%) for ADSQ. The only case especially for squamous cell carcinoma (SCC) and
of SC lacked TTF1 and p40, this indicating glandular adenocarcinoma (AC). The WHO classiÀcation of
cell lineage and absence of squamous differentiation. lung cancers and the data supporting the clinical
Forty-three out of 46 (93%) lesions were correctly importance of this distinction are based on light
classiÀed by IHC on biopsy/cellblock by using these microscopy alone. However, immunohistochemistry
two markers compared to 40/46 (87%) by revised (IHC) can further reÀne the diagnosis where
morphology and to 36/46 (78%) by original site morphological criteria for a deÀnitive diagnosis
pathologists, with a diagnostic accuracy being 98% of SCC or AC are not met. The aim of this study
for SQC and sarcomatoid carcinoma, and 96% for was to test the level of agreement for histological
AD and ADSQ. subtyping of NSCLC in diagnostic lung biopsies
Conclusion: This two-hit, IHC-based model of among internationally known experts in pulmonary
TTF1 and p40 on biopsy/cellblock was effective pathology (IEPP), pathologists with special interest
to correctly forecast most cases of lung cancer. in pulmonary pathology (SIPP) and all-round
Negativity for p40 excluded all SQC and paved pathologists (AP).
the way to AD diagnosis also in event of TTF1 Methods: We selected 15 diagnostic lung biopsies
negativity. Dual adenosquamous differentiation was including four AC, one SCC, one combined small
highlighted by coexisting p40 and TTF-1 or the cell carcinoma (SCLC) with component of SCC,
four NSCLC, not otherwise speciÀed (NOS), three Molecular Pathology: NSCLC Subtyping Tuesday, 5 July 2011 10:30-
NSCLC, favor AC, one carcinoid and one NSCLC 12:00
with neuroendocrine features. Histological subtyping
was performed according to the WHO 2004 criteria. O14.05 OPTIMAL COMBINATION OF
When the morphological criteria for a speciÀc MARKERS FOR SUBCLASSIFICATION
subtype were not met, we considered IHC results and OF POORLY DIFFERENTIATED NON-
made a diagnosis according to the recently published SMALL CELL LUNG CARCINOMA
recommendations of the international association for Hyo Sup Shim
the study of lung cancer/American thoracic society/ Pathology, Ewha Womans University/Korea
European respiratory society (J. Thorac Oncol. 2011
Feb;6(2):244-85). Study participants could view a Background: Recently, some studies have been
virtual slide of the HE staining and representative reported on the optimal immunohistochemical
images of alcian blue PAS and immunohistochemical markers for subclassiÀcation of non-small
stainings (TTF-1, CK 7, CK 5/6, p63 in all cases; cell lung carcinoma (NSCLC). Main pitfall in
neuroendocrine markers in selected cases) Five subclassiÀcation of NSCLC is small specimen with
IEPP, 27 SIPP and 56 AP examined the cases and poorly differentiated (PD) area. In this study, we
completed the online questionnaire (). added newly proposed markers (e.g. SOX2, napsin
Results: IEPP reached full agreement in the A) to conventional markers (p63, TTF-1, CK5/6,
diagnosis of SCC, combined SCLC with component and CK7) and evaluated optimal combination for
of SCC and the carcinoid. SIPP and AP reached an subtyping of NSCLC, primarily focusing on the PD
agreement of 96% and 91%, 70% and 34% and 78% area.
and 41%, respectively for these cancers. Agreement Methods: Two hundred eleven resected NSCLCs
was lowest in the AC biopsies with no signiÀcant were classiÀed based on histologic Àndings. After
difference between the IEPP, SIPP and AP (60%, histologic review, only PD areas were taken and
69% and 59%, respectively). In the remaining tissue microarrays were constructed to simulate
NSCLC (NSCLC, NOS; NSCLC, favor AC and small biopsy conditions. The tissue microarrays
NSCLC with neuroendocrine features) 33% of IEPP included 36 adenocarcinomas, 38 squamous cell
agreed with the diagnosis, which was signiÀcantly carcinomas, and 8 large cell carcinomas. All
higher compared to 20% and 15% in SIPP and AP, specimens were stained with TTF-1, napsin A, CK7,
respectively. None of the IEPP required IHC in the p63, CK5/6, and SOX-2.
SCC biopsy compared to 56% and 77% of SIPP Results: p63 was both sensitive and speciÀc for
and AP, respectively. In AC most of the pathologist PD squamous cell carcinoma (sensitivity 92%,
would have ordered IHC (IEPP: 75%; SIPP: 87%; speciÀcity 93%, positive predictive value 92%, and
AP: 96%). negative predictive value 93%). A combination of
Conclusion: With the exception of AC expert p63 and CK5/6 slightly increased the sensitivity
pathologists are more accurate in histological (95%), however decreased the speciÀcity (91%)
subtyping of NSCLC. There is substantial for PD squamous cell carcinoma. TTF-1 was a
disagreement on how to classify NSCLC depending speciÀc marker (100%) for PD adenocarcinoma as
on IHC results. Although according to the WHO AC well known, but showed lower sensitivity (53%).
and SCC are diagnosed by morphological criteria TTF-1 combined with with napsin A increased the
most pathologists rely their diagnosis on additional sensitivity (75%). CK7 was sensitive (92%) but
IHC stains. This study demonstrates the need for not speciÀc marker (76%) for PD adenocarcinoma.
uniform guidelines and education in histological SOX2 was speciÀc (100%) but not sensitive
NSCLC subtyping in order to be able to make marker (53%) for PD squamous cell carcinoma.
appropriate treatment decisions. Combinations of theses markers did not greatly
Keywords: Histological subtyping, increase the diagnostic performance.
immunohistochemistry, Non-small Cell Lung Conclusion: A simple combination of p63, TTF-1,
Carcinoma and naspin A can be enough for the subclassiÀcation
of poorly differentiaed NSCLC.
Keywords: Non-small Cell Lung Carcinoma,
subclassiÀcation, immunohistochemistry
Molecular Pathology: NSCLC Subtyping Tuesday, 5 July 2011 10:30- Keywords: EGFR mutation, squamous cell
12:00 carcinoma, non-small-cell lung cancer (NSCLC),
SmartAmp2
O14.06 SIGNIFICANCE OF EPIDERMAL
GROWTH FACTOR RECEPTOR GENE A revised/updated abstract may be included in
MUTATIONAL ANALYSIS IN SQUAMOUS the Late Breaking Abstract Supplement, available
CELL LUNG CARCINOMA at the 14th World Conference on Lung Cancer.
Kimihiro Shimizu1, Yohei Miyamae1, Junko Hirato2,
Seiichi Kakegawa1, Tetsuhiro Nakano1, Masayuki
Sugano1, Jun Atsumi1, Izumi Takeyoshi1 Molecular Pathology: NSCLC Subtyping Tuesday, 5 July 2011 10:30-
1
Department Of Thoracic And Visceral Organ 12:00
Surgery, Gunma Univerity Graduate School Pf
Medicine/Japan, 2Department Of Pathology, Gunma O14.07 DISTINCTION BETWEEN
Univerity Graduate School PF Medicine/Japan PULMONARY ADENOCARCINOMA
AND SQUAMOUS CELL CARCINOMA
Background: Epidermal growth factor receptor ON BIOPSIES. A MOLECULAR
(EGFR) gene mutations have been reported to PATHOLOGIC ANALYSIS
be clinically signiÀcant in non small cell lung Erik Thunnissen1, Evan Boers2, Katrien Grunberg1,
cancer (NSCLC). However, because most previous Danielle Heideman1, Dirk J. Kuik3, Arnold
studies focused only on adenocarcinomas, EGFR Noorduijn4, Matthijs Oosterhout Van5, Divera Pronk1,
mutations in other histotypes are poorly investigated. Cornelis A. Seldenrijk5, Hannie Sietsma6, Egbert F.
Here, we evaluated the frequency of EGFR gene Smit7, Robertjan Suylen Van8, Jan Thusen Von Der9,
mutations in squamous cell carcinoma (SCC) and its Anne Wiersma10, Bart Vrugt11
1
clinicopathological features. Pathology, VUMC/Netherlands, 2Zwolle/
Methods: In total, 89 frozen tumor specimens that Netherlands, 3Epidemiology And Biotatistics, VUMC/
had been Àrst diagnosed as SCC, were examined Netherlands, 4Pathologie/Netherlands, 5Pathology,
for EGFR mutations in exons 19 and 21 using Antonius ZHS/Netherlands, 6Pathology, UMCG/
direct sequencing, PNA-enriched sequencing, Netherlands, 7Pulmonary Diseases, Vrije Universiteit
and SmartAmp2. Additionally, pathological Medical Centre/Netherlands, 8AZM/Netherlands,
9
investigation, including immunostaining for p63 and AMC/Netherlands, 10Alysis/Netherlands, 11MZH/
TTF-1, alcian blue staining and EGFR mutation- Netherlands
speciÀc immunohistochemistry in mutation-positive
samples was also performed. Background: For treatment purposes distinction
Results: The frequency of EGFR mutations was between squamous cell carcinomas (SqCC) and
5.6% (5/89); all mutations were deletions in EGFR adenocarcinomas (AdC), is important. In the past
exon 19. Immunohistological investigation of these EGFR and KRAS mutations are occasionally
samples revealed that two of Àve were positive for detected in squamous cell carcinomas. In these
p63 and TTF-1 staining, and showed production studies immunohistochemistry has not been used
of mucin, as evidenced by alcian blue staining. for diagnosis. The aim of this study is to examine
Consequently, three of the samples were considered the diagnostic accuracy on lung cancer biopsies for
to be true SCC at the Ànal pathological diagnosis, the distinction between AdC and SqCC and relate
while the remaining two samples were revised to these to immunohistochemical and KRAS and EGFR
adenosquamous carcinoma and adenocarcinoma. The mutation analysis.
Ànal frequency of the EGFR mutations in true SCC Methods: An interobserver study was performed
was 3.4% (3/87). on prospectively collected biopsies obtained by
Conclusion: In conclusion, EGFR mutations were bronchoscopy or transthoracic needle biopsy. The
found in a small, but signiÀcant, number of SCC diagnosis was correlated with immunohistochemical
tumor samples and thus EGFR mutational analysis (IHC) analysis for markers of adeno (TTF1 and/or mucin
was useful in the accurate diagnosis of SCC. Our data positivity) and squamous cell differentiation (P63 ,
demonstrate that EGFR mutational analysis should CK5/6) as well as KRAS and EGFR mutation analysis.
be performed not only in adenocarcinoma, but also in Results: 11 observers independently read H&E
SCC to allow an accurate diagnosis and treatment. stained slides of 110 prospectively collected cases,
resulting in a kappa score of 0.55 ± 0.10. H&E based that NSCLC cells expressing certain markers (CD44,
consensus diagnosis ( 8/11 readings concordant), CD 133 and ALDH 1) have stem cell properties. We
showed high concordancy between H&E and aimed to investigate the expression of three cancer
IHC markers. In All cases with EGFR and KRAS stem cell markers (CD44, CD133, ALDH 1) in
mutations immunohistochemical adenocarcinoma NSCLC and evaluated their prognostic values for
differentiation was shown. In 2 of 26 cases with a postoperative relapse and correlation with histological
consensus diagnosis of SqCC a KRAS mutation was subtypes.
present. In poorly differentiated NSCLC a squamoid Methods: Tumours were obtained from 102 patients
appearance is present in some biopsies leading to the with stage 1 NSCLC (both Adenocarcinoma and
erroneous impression of squamous differentiation SCC) who underwent surgical resection (1999-2008).
on H&E and subsequent diagnosis of squamous cell Sequentially sampled parafÀn sections were immuno-
carcinoma, while additional stains indicate adeno- probed with antibodies for CD44standard, CD133 and
differentiation (TTF1+ and/or mucin+; p63-) . ALDH 1 followed by reaction with DAB-conjugated
Conclusion: In the diagnostic workup of secondary antibodies. All slides were scored by
non-small cell lung carcinoma on biopsies an independent pathologist in a blinded manner.
immunohistochemical analysis is a useful adjunct Statistical analysis was conducted where correlations
for reliable molecular pathologic classiÀcation. With between CSC biomarker expression, histological
this diagnostic approach the search for EGFR and subtypes and cancer recurrence rates was performed.
KRAS mutation analysis may be limited to the non- Cumulative risks for developing recurrence of lung
squamous NSCLC group. cancer after curative treatment of primary tumours
Keywords: Adenocarcinoma, squamous cell was calculated using the Kaplan-Meier method and
carcinoma, mutation analysis, immunohistochemistry was compared between the groups using the log-rank
test.
Results: 102 pts with age range of 42-84 (median 68)
Session O15: Cancer Stem Cells and underwent radical surgery and were pathologically
miRNA staged as WHO stage1A (64) or 1B (38). Median
follow up was 60 months (10-108) where follow up
data was unavailable for 2 patients. Within the patient
population 39% had relapsed; 31% had distant and 8%
locoregional relapses where within these relaspses,
Cancer Stem Cells and miRNA Tuesday, 5 July 2011 10:30-12:00 17/63 (23%) were Stage 1A and 22/37(59%) stage
1B. Analysis demonstrated a higher expression of
O15.01 EVALUATION OF RELATIONSHIP CD44 in Squamous Cell Carcinoma (SCC) than
OF CANCER STEM CELL MARKERS Adenocarcinoma (ACA). Within the 102 stained
AND RISK OF RECURRENCE IN EARLY sections, 53% in SCC vs. 24% in ACA were positive
STAGE NON SMALL CELL LUNG for CD44 (p=0.005) with 61% of positive SCC
CANCER demonstrating high expression (>20% positive cells/
Muhammad Alamgeer1, Tracy Brown2, Beena section) versus 21% of ACA tumours. Slightly higher
Kumar3, Gavin M. Wright4, Matthew Conron4, expression of ALDH 1 was noted in SCC compared
Prudence Russell4, Zoe Wainer4, Elizabeth Blake3, to ACA, but the difference did not reach statistical
Vinod Ganju3 signiÀcance. None of the markers individually
1
Medical Oncology, Monash Medical Centre/ predicted risk of relapse. A majority of relapsed
Australia, 2Monash University/Australia, 3Monash cases (69%; 27/39) were associated with positive
Medical Centre/Australia, 4St Vincent’s Hospital/ ALDH1 expression but this did not reach statistical
Australia signiÀcance. However, in stage 1B subpopulation,
ALDH1 positivity was associated with signiÀcantly
Background: Current cancer treatment failure is higher relapse rate (72% vs 40% p=0.02). Concurrent
due to a small population of slow-growing and drug dual immuno-localisation of stem cell markers is
resistant cells known as cancer stem cells (CSCs). currently on-going.
Unlimited self-renewal and exclusive tumerogenicity Conclusion: The predictive role of stem cell markers
are hypothesized to be the properties of stem cells in early NSCLC treated with potentially curative
responsible for relapse. In Vitro studies have proved surgery was investigated. The difference in CD44
expression between ACA and SCC suggests that the and malignant adult stem cell populations. In this
positive cells identiÀed were not homogeneous stem study we set out to determine if ALDH+ cells from
cells but instead were differentiated. If a relationship different lung cancers all had properties of CSCs,
between stem cell biomarker expression and patient whether the ALDH+ CSCs from different tumors
prognosis can be derived it is necessary to identify exhibited molecular differences, and whether CSCs
additional epitopes other than CD44 and CD133, used different ALDH isozymes for the ALDH+
although ALDH1 appears to be a potential indicator phenotype.
of stem cell sub-populations. Methods: We isolated ALDH+ cell populations
from 12 non-small cell lung cancer (NSCLC) lines
A revised/updated abstract may be included in representing the spectrum of NSCLC oncogenotypes
the Late Breaking Abstract Supplement, available using the Áow cytometry based AldeÁuor kit and
at the 14th World Conference on Lung Cancer. compared their mRNA transcript expression to bulk
ALDH- cell populations by Illumina microarray
analysis and their clonogenic phenotypes. Common
Cancer Stem Cells and miRNA Tuesday, 5 July 2011 10:30-12:00 gene differences across cell line ALDH+ and ALDH-
cell fractions were conÀrmed by qPCR and Western
O15.02 ALDEHYDE DEHYDROGENASE blot analysis. Lentiviral shRNA gene knockdown
1A3 IS A FUNCTIONAL BIOMARKER and over expression constructs were employed
AND THERAPEUTIC TARGET FOR to assay for gene function on cancer “stemness”
LUNG CANCER STEM CELLS. including the measure of cell clonogenicity,
James P. Sullivan1, Chunli Shao1, Luc Girard1, proliferation, expression of stem cell markers,
Alexander Augustyn1, Carmen Behrens2, Ignacio I. and tumorigenicity. Illumina genome wide mRNA
Wistuba3, John D. Minna4 expression data on 182 clinically annotated resected
1
Hamon Center For Therapeutic Oncology Research, lung adenocarcinomas were analyzed for ALDH
University Of Texas Southwestern Medical Center/ isozyme expression levels and survival.
United States Of America, 2Thorasic Head And Results: ALDH+ compared to ALDH- tumor cells
Neck Medical Oncology, University Of Texas MD from the same NSCLC demonstrated signiÀcant
Anderson Cancer Center/United States Of America, differences in clonogenicity conÀrming the biologic
3
Pathology, University Of Texas MD Anderson importance of the ALDH+ subset within each tumor.
Cancer Center/United States Of America, 4Hamon Genome wide analysis of ALDH+ and ALDH- cells
Center For Therapeutic Oncology Research, Internal revealed that the ALDH+ subpopulations varied
Medicine, Pharmacology, University Of Texas dramatically in mRNA expression patterns between
Southwestern Medical Center/United States Of different NSCLCs, however ALDH1A1, ALDH1A3
America or both were observed to be commonly upregulated
in ALDH+ cells from different NSCLCs. qRT-PCR
Background: Many lung cancers are believed to and immunoblotting studies conÀrmed ALDH1A3
be driven by a subpopulation of stem-like tumor to be more commonly upregulated in ALDH+
cells (termed cancer stem cells or CSCs) that cells. shRNA mediated knockdown of ALDH1A3
are deÀned by their capacity for self-renewal, or ALDH1A1 in NSCLCs was associated with a
high tumorigenicity and clonogenicity (Sullivan, signiÀcant reduction in ALDH activity, proliferation,
Cancer Metastasis Rev. 2010;29:61-72). Because and clonogenicity indicating speciÀc ALDH
of these attributes, a cure will likely depend on isozymes are required for NSCLC cell survival
the total eradication of lung CSCs, which are and growth. Finally, elevated ALDH1A3 transcript
also hypothesized to be resistant to conventional expression in resected lung adenocarcinomas was
chemotherapy. Our group has recently identiÀed associated with impaired cancer free patient survival.
and characterized a population of lung CSCs in both Conclusion: We have found that ALDH+
lung cancer cell lines and patient tumor samples subpopulations isolated from NSCLCs exhibit
by their elevated aldehyde dehydrogenase activity dramatically different mRNA expression proÀles.
(Sullivan, Cancer Res. 2010;70:9937-48.). Aldehyde We also found that ALDH1A3 and ALDH1A1
dehydrogenases (ALDH) are a family of intracellular are the predominant ALDH isozymes responsible
enzymes that participate in the detoxiÀcation, for ALDH+ activity. shRNA knockdown studies
differentiation and drug resistance of many normal showed that continued expression of ALDH1A3
or ALDH1A1 is required for NSCLC ALDH+ restricted Adeno-Cre viruses: Ad5-CC10-Cre, Ad5-
activity and tumor cell growth. Finally, ALDH1A3 SPC-Cre and Ad5-CGRP-Cre. By restricting Trp53
NSCLC activity may be a prognostic biomarker. and Rb1 deletion to deÀned lung epithelial cells,
Thus, ALDH1A1 and ALDH1A3 are important new we show that both cells expressing NE and AT2
biomarkers and potential therapeutic targets for cell markers are capable of initiating SCLC in vivo,
eliminating lung CSCs. although NE cells do so at a much higher frequency.
(Supported by IASLC Fellowship, NCI U24 Conversely, loss of Trp53 and Rb1 in Clara cells did
CA126608, and SPORE P50CA70907) not cause efÀcient lung tumor formation.
Keywords: Cancer stem cells, Aldehyde
dehydrogenase Conclusion: These results highlight the effects of
inactivation of Trp53 and Rb1 in distinct subsets of
lung epithelium in the adult mouse and demonstrate
Cancer Stem Cells and miRNA Tuesday, 5 July 2011 10:30-12:00 for the Àrst time, that NE cells are by far the most
efÀcient to serve as the cell of origin of SCLC.
O15.03 CELL OF ORIGIN OF SMALL Moreover, the technology reported here, will prove
CELL LUNG CANCER: INACTIVATION useful in identifying the cell of origin of different
OF TRP53 AND RB1 IN DISTINCT CELL lung cancer types.
TYPES OF ADULT MOUSE LUNG
Kate Sutherland1, Natalie Proost1, Inge Brouns2, Dirk Keywords: Cell of origin, Small cell lung cancer
Adriaensen2, Ji-Ying Song3, Anton Berns1
1
Division Of Molecular Genetics, Netherlands
Cancer Institute/Netherlands, 2Department Of Cancer Stem Cells and miRNA Tuesday, 5 July 2011 10:30-12:00
Veterinary Sciences, University Of Antwerp/Belgium,
3
Department Of Experimental Animal Pathology, O15.05 AN ARF/EGFR CROSS-TALK
Netherlands Cancer Institute/Netherlands CONTROLS THE GROWTH OF LUNG
ADENOCARCINOMA CELLS
Background: Lung cancer is the most common Peggy Ozenne1, Delphine Dayde1, Pascal Perron1,
cause of cancer related mortality worldwide. Céline Barrial1, Elisabeth Brambilla1, Beatrice
Uncovering the identity of the cell type(s) that give Eymin1, Sylvie Gazzeri2
1
rise to both lung cancer subtypes and elucidating Institut Albert Bonniot, Inserm U823/France,
2
the genetic and molecular changes associated with Institut Albert Bonniot Bp170, Inserm U823/France
their transformation is of critical importance. This
knowledge will help focus intervention strategies on Background: The Epidermal Growth Factor
eliminating the cancer propagating cells that most Receptor (EGFR) is a tyrosine kinase (TK) that
likely retain many of the characteristics of its cell of mainly mediates proliferative and survival signals.
origin. Somatic mutations in the EGFR TK domain plays a
Methods: To determine whether a speciÀc cellular critical role in the development and treatment of lung
compartment in the lung exhibits cancer-initiating adenocarcinoma. These kinase domain mutations
properties, we have established a new strategy of in EGFR are generally referred to as activating
inducing mouse lung cancer by directly inactivating mutations as they seem to result in the increased
tumor suppressor genes in a small, well-deÀned activity of the receptor, leading to hyperactivation of
population of cells. We have constructed a series of downstream pro-survival pathways. The ARF tumor
Adeno-Cre vectors that permit cell-type-restricted suppressor is at the crossroad of oncogenic and
switching of oncogenes and tumor suppressor genes genotoxic pathways and plays a strong protective
in Clara cells, Alveolar type 2 (AT2) cells and role against lung cancer development. Based on
neuroendocrine (NE) cells, respectively. recent data showing that ARF expression is strongly
Results: Using Rosa26R-LacZ and mT/mG reporter reduced in almost all lung tumors with EGFR
animals we show that the cell-type-restricted Adeno- activating mutations, we postulated that ARF is part
Cre viruses exhibit high speciÀcity to the distinct of a failsafe mechanism protecting cells against
target cell populations. To gain insight into the target untimely or excessive mitotic signals induced by
cell for transformation in SCLC, we infected Trp53F/ EGFR signaling.
F;Rb1F/F conditional animals with our cell-type- Methods: Expression of human ARF was induced
(expression vectors) or abolished (siRNA) in Medicine, Vancouver General Hospital/Canada,

4
H3255 and H1975 cell lines derived from lung Princess Margaret Hospital/Canada, 5Hamon
adenocarcinoma and expressing the L858R missence Center For Therapeutic Oncology Research,
activating mutation of EGFR. Cell growth and University Of Texas/United States Of America,
6
apoptosis were studied after methylen blue and National Human Genome Research Institute,
active caspase 3 staining respectively. SpeciÀc National Institutes Of Health/United States Of
siRNAs and pharmacological inhibitors were used America
to characterize the signaling pathway controlled
by ARF. EGFR L858R encoding vector or siRNA Background: NF-ƩB signaling is essential for lung
against EGFR L858R were used to study the role of cancer development and is activated in over 60%
EGFR L858R on ARF expression. of lung cancers. However, the genetic mechanisms
Results: We demonstrate that ARF inhibits the responsible for its activation remain largely
growth of lung tumor cells expressing the EGFR unknown. IKBKB (also known as IKK-ơ/IKK-2)
L858R activating mutation by inducing apoptosis. activates NF-ƩB which enables the transcription of a
In these cells, expression of ARF promotes the myriad of genes involved in tumorigenesis, making
nuclear accumulation of phospho-Stat3Tyr705 as IKBKB critical in NF-ƩB signaling. IKBKB is a
well as the downregulation of the anti-apoptotic substrate of the KEAP1-CUL3-RBX1 E3 ubiquitin
bcl-2 protein. Pharmacological inhibition of Stat3 ligase complex, thus implicating this complex in
prevents both bcl-2 repression and apoptosis induced the regulation of NF-ƩB signaling. We investigated
by ARF, indicating that ARF triggers apoptosis of complex component gene disruption as a novel
EGFR L858R mutant cells by a Stat3-dependent genetic mechanism of NF-ƩB activation in lung
inhibition of bcl-2 expression. In turn we show cancer. We hypothesize that genetic disruption of
that the EGFR-L858R mutant downregulates the KEAP1, CUL3 and RBX1 occurs frequently in
expression of the ARF protein, thereby counteracting lung tumors and may be ultimately responsible for
the antiproliferative effect of ARF. IKBKB accumulation and stimulation of NF-ƩB
Conclusion: These results identify for the Àrst time activity. Furthermore, disruption of any one E3
an original link between ARF and the EGFR L858R ubiquitin ligase complex is likely to be sufÀcient to
activating mutant and suggest that loss of ARF and result in tumorigenic NF-ƩB activation through the
activation of EGFR cooperate to induce lung tumor loss of complex function.
formation. Methods: Genomes of 644 NSCLC tumors and
Keywords: EGFR, INK4/ARF, apoptosis, Lung 90 NSCLC cell lines were analyzed for gene
cancer dosage status of the individual E3 ligase complex
components and IKBKB. Gene expression levels
A revised/updated abstract may be included in of the complex components, IKBKB and NF-ƩB
the Late Breaking Abstract Supplement, available target genes were assessed in 35 adenocarcinomas
at the 14th World Conference on Lung Cancer. (AC) and 13 squamous cell carcinomas (SCC),
each with matched non-malignant tissues. Genes
were classiÀed as over or under expressed if the
Cancer Stem Cells and miRNA Tuesday, 5 July 2011 10:30-12:00 fold change between tumor and matched non-
malignant tissues was greater or less than 2 fold.
O15.06 KEAP1/CULLIN-3/RING BOX IKBKB protein expression levels were assessed
PROTEIN-1 E3 UBIQUITIN LIGASE in tumors and cell lines with and without complex
COMPLEX DISRUPTION IS A NOVEL or IKBKB genetic disruption. The importance of
GENETIC MECHANISM OF NF-țB IKBKB expression to the lung cancer phenotype was
ACTIVATION IN LUNG CANCER measured by pharmacological inhibition in NSCLC
Larissa A. Pikor1, Kelsie Thu1, Raj Chari2, Ian M. cell lines.
Wilson1, Calum E. Macaulay1, John C. English3, Results: We observed strikingly high frequencies of
Ming S. Tsao4, Adi F. Gazdar5, Stephen Lam1, genetic disruption (42%) of the E3 ligase complex
William W. Lockwood6, Wan Lam1 and IKBKB in non-small cell lung carcinomas
1
Integrative Oncology, BC Cancer Research Centre/ (NSCLC) and aberrant expression in 63% of samples
Canada, 2Genetics, Harvard Medical School/United examined. While both ACs and SCCs showed
States Of America, 3Pathology And Laboratory complex disruption, the patterns of gene disruption
differed between subtypes; KEAP1 loss was more 188) have been linked to different subtypes of lung
prevalent in AC whereas CUL3 loss and IKBKB cancer (LC). In other cancers, such as glioblastoma,
gain occurred more frequently in SCC, suggesting breast, and prostate was demonstrated that altered
that complex disruption in these NSCLC subtypes miRNA expression may be a key modiÀer of their
is achieved through different mechanisms. NSCLC sensitivity to chemo/radiotherapy (CT and RT).
samples with complex component disruption Recently, several miRNAs were linked to cisplatin
showed elevated protein expression levels of responsiveness of Non-small cell lung carcinoma
IKBKB and overexpression of NF-ƩB target genes, (NSCLC) but role of miRNAs in regulating RT
demonstrating the effect of complex disruption sensitivity in NSCLC and small cell lung carcinoma
on NF-ƩB activity. Pharmacological inhibition (SCLC) is yet unclear. However such analyses
of IKBKB proved detrimental to cell viability, are warranted as it may indicate miRNAs with RT
highlighting the functional signiÀcance of complex response prediction capacity. Here we report that
disruption. low miR-214 expression may act as such predictor in
Conclusion: Our analysis revealed gene dosage NSCLC but not in SCLC.
alteration is a prominent mechanism that disrupts Methods: miRNAs expression level in 6NSCLC
each component of the KEAP1-CUL3-RBX1 E3 (H23, H1299, A549, H157, H661, U1810) and
ubiquitin ligase complex and its NF-ƩB stimulating 6SCSLC (H69, H82, U1285, U1690, U1906,
substrate, IKBKB in a subtype speciÀc pattern. U2020) cell lines was performed using miRNA
Multiple component disruption of this complex Genechips Array (Affymetrix). The cell lines were
sensitizes cells to IKBKB inhibition and represents divided into RT resistant and sensitive groups based
a novel mechanism driving aberrant NF-ƩB pathway on their SF2 values (Resistant 3 Sensitive) in
activation in NSCLC. clonogenic survival. Microarray data was validated
Keywords: NFkB signaling, IKBKB, KEAP1/ by qPCR using TaqMan® MicroRNA Assays
CUL3/RBX1 E3 Ubiquitin ligase, genetic disruption (Applied Biosystems).NSCLC radiosensitive
(RS) H23 cell line was transfected with miR-214
mimics (Dharmacon) to overexpress miR-214. To
Cancer Stem Cells and miRNA Tuesday, 5 July 2011 10:30-12:00 irradiate cells with 8 Gy a Co60 source was used.
The apoptotic cells were measured by assessing
O15.07 MIR-214 OVEREXPRESSION the percentage of cells with fragmented, condensed
PROTECTS NSCLC AGAINST nuclei after DAPI staining and active caspase3
RADIOTHERAPY-INDUCED CELL analyzed by FACS. The Akt-p and MAPKp38
DEATH BY CAUSING IMPAIRED expression was analyzed by western blot.
APOPTOTIC SIGNALLING Results: miRNAs microarray analysis revealed
Nadeem Shahzad Akbar1, Hogir Salim2, Dali certain candidate miRNAs with RT sensitivity
Zong3, Kristina Viktorsson3, Ali Moshfegh2, Rolf predicting capacity in NSCLC and SCLC subtypes,
Lewensohn3, Boris Zhivotovsky4 respectively, namely, miR-214, miR-1827 in
1
Institute Of Environmental Medicine, Institute Of NSCLC and miR-324-5p in SCLC. Data suggested
Environmental Medicine, Division Of Toxicology, that low expression of miR-214 may confer RT
Karolinska Institutet,/Sweden, 2Department Of sensitivity of NSCLC as miR-214 was signiÀcantly
Oncology-Pathology, Karolinska Biomics Center, less expressed in RT sensitive cell lines, H23 and
Department Of Oncology-Pathology, Karolinska H1299, compared to RT-resistant NSCLCs, U1810,
Institutet,/Sweden, 3Department Of Oncology- H661, H157 and A549. MiR-214 expression was
pathology, Karolinska Biomics Center, Department conÀrmed by qPCR. Subsequently, role of miR-214
Of Oncology-Pathology, Karolinska Institutet,/ was analyzed in radiosensitivity of RS H23 cells,
Sweden, 4Institute Of Environmental Medicine, transfected with miR214 mimics. When miR-214
Division Of Toxicology, Karolinska Institutet,/ transfectedH23 cells were analyzed for their RT
Sweden response, a signiÀcant increase in cell survival was
observed. Given that proper activation of apoptotic
Background: MicroRNAs (miRNAs) are recognized signaling may confer radiosensitivity, H23 cells
to regulate initiation, promotion and progression of became protected from RT induced apoptosis
carcinogenesis. More recently altered microRNA with miR-214 expression. Control and scramble-
signatures (e.g., miR-15, miR-21, let-7, and miR- expressed cell showed 3times more condensed nuclei
4
and 4times higher caspase3 activity as compared Pathology, The University Of Texas MD Anderson
with H23 overexpressing mir-214. Further analysis Cancer Center/United States Of America, 5Dept. Of
was focused on survival signaling kinases, namely Biostatistics, Vanderbilt University Medical Center/
Akt and MAPKp38, aiming to reveal if increased United States Of America, 6Emory University/
signaling through these kinases contributes to United States Of America, 7Div. Of Pulmonary And
miR-214 protective character against RT-induced Critical Care, David Geffen School Of Medicine
cell death. MAPKp38 expression was signiÀcantly At Ucla/United States Of America, 8Hematology
enhanced in cell lines overexpressing mir-214 but we Oncology, Vanderbilt Ingram Cancer Center/
were not able to detect any notable difference in Akt United States Of America, 9The Sidney Kimmel
level with or without mir-214 suggesting that may be Comprehensive Cancer Center At Johns Hopkins,
Akt expression is not being inÁuenced by mir-214 Johns Hopkins University/United States Of America,
10
particularly in H23 NSCLC cell line. Div. Of Hematology/oncology, University Of
Conclusion: we demonstrated that high level of Texas Southwestern Medical Center/United States
miR-214 protects NSCLC cells against RT-induced Of America, 11MofÀtt Cancer Center/United
cell death by blocking caspase-3-mediated apoptosis, States Of America, 12Thoracic And Head & Neck
implicating a role for low miR-214 expression as a Medical Oncology, University Of Texas M.D.
marker of RT sensitive NSCLC phenotype. Anderson Cancer Center/United States Of America,
13
Keyword: miRNA, lung cancer, small cell lung Hematology/oncology, Medical University Of
cancer, non-small cell lung cancer, radiotherapy. South Carolina/United States Of America, 14Bldg.
10 - Magnuson Cc Rm 12n226, National Cancer
A revised/updated abstract may be included in Institute/United States Of America, 15Div. Of Medical
the Late Breaking Abstract Supplement, available Oncology, University Of Colorado Cancer Center/
at the 14th World Conference on Lung Cancer. United States Of America, 16University Of Texas
Southwestern Medical Center/United States Of
America, 17Div. Of Medical Oncology, University Of
Session O16: Biomarkers II Colorado Denver School Of Medicine/United States
Of America
Background: The ability to detect driver mutations
including EGFR and EML4-ALK in tumor
Biomarkers II Tuesday, 5 July 2011 10:30-12:00 specimens from patients with ACL and administer
agents targeting the molecular alterations is
O16.01 CLINICAL CHARACTERISTICS revolutionizing the management of patients with
OF PLANNED 1000 PATIENTS WITH ACL. Multiplexed assays are available to detect
ADENOCARCINOMA OF LUNG these different driver mutations in adenocarcinoma
(ACL) UNDERGOING GENOMIC specimens at diagnosis and are enlarging the
CHARACTERIZATION IN THE US LUNG numbers of candidates who can be effectively treated
CANCER MUTATION CONSORTIUM with targeted agents. Therefore, we created the
(LCMC) LCMC to determine the frequency of 10 different
Bruce E. Johnson1, Mark G. Kris2, David genetic alterations from 1000 advanced stage ACL
Kwiatkowski1, A. J. Iafrate3, Ignacio I. Wistuba4, patients, to compare the presence of the alterations
Yu Shyr5, Jeff Engelman3, Fadlo R. Khuri6, Steven with clinical features, with other alterations, and
Dubinett7, William Pao8, Charles Rudin9, Joan with clinical outcome, and to give the information to
Schiller10, Eric B. Haura11, George Blumenschein12, clinicians for their ongoing care and future research.
George Simon13, Giuseppe Giaccone14, Elizabeth Methods: The 14 member LCMC have recruited
Koehler5, Kelly Kugler15, John D. Minna16, Paul patients with ACL and tested the DNA from their
Bunn17 ACL in CLIA laboratories for KRAS, EGFR,
1
Medical Oncology, Dana-farber Cancer Institute/ HER2, BRAF, PIK3CA, AKT1, and NRAS using
United States Of America, 2Department Of Medicine, standard multiplexed assays and Áuorescence in situ
Memorial Sloan-kettering Cancer Center/United hybridization (FISH) for ALK rearrangements and
States Of America, 3Cancer Center, Massaschusetts MET ampliÀcations (genetic alterations). All had
General Hospital/United States Of America, advanced stage (IIIB/IV) and performance status
0-2 with available tissue. This abstract focuses on Biomarkers II Tuesday, 5 July 2011 10:30-12:00
genetic alterations detected by multiplexed assay,
with FISH results reported in a separate abstract. O16.02 PROTEIN BIOMARKER PANEL
Results: To date, 911 patients have been registered ACCURATELY RESOLVES NON-
with about 80 enrolling per month. Each of the MALIGNANT NODULES IDENTIFIED
institutions has enrolled a median of 65 patients THROUGH LOW-DOSE HELICAL CT
(range 3 to 238) from 02/10 to 02/11. Multiplexed SCANNING
assays have been completed and reported for 420 Charles Birse1, Robet J. Lagier2, Robert N. Bruce1,
patients; among these patients, a genetic alteration Jennifer L. Tomic1, Steve M. Ruben2, Thomas J.
has been detected in more than 50%. The median Lenk1, Aaron O. Bungum3, Eric S. Edell3, James R.
age of the full evaluable patient population (n=808) Jett4, Fabien Maldonado3
1
is 61 (IQR 52 - 68), with 479 (59.3%) women. Two Product Development, Celera/United States Of
patients (0.2%) had no systemic therapy at the time America, 2Research, Celera/United States Of
of enrollment, 195 (24.1%) had a single course of America, 3Pulmonology, Mayo Clinic/United States
chemotherapy, and 302 (37.4%) had two or more Of America, 4Oncology, National Jewish Health/
treatment regimens (the information on the rest of United States Of America
the patients is not yet reported). 237 patients (29.3%)
are never smokers, 438 (54.2%) are former smokers, Background: Concerns remain regarding the low
and 66 (8.2%) are current smokers (8.3% of patients speciÀcity of CT scanning and the resulting cost
have yet to report the data). The 216 patients with and morbidity associated with biopsy or resection
genetic alterations by multiplexed assay had a of benign pulmonary nodules. In the CT arm of the
median age of 62 (IQR 53 – 68.5), compared to a National Lung Screening Trial (NLST), solitary
median age of 59 (IQR 48.5 – 67) among patients nodules that turned out not to be cancerous were
without genetic alterations (p=0.0328). Gender and detected in about 25% of the subjects. Lung cancer
smoking history did not show signiÀcant association biomarkers may serve as a useful complement to
with mutation status; with the complete dataset, imaging, serving as a simple, cost-effective means
signiÀcant associations may emerge. The relationship of further clarifying the diagnosis in patients
of each clinical feature to genetic alteration will be with suspicious pulmonary nodules identiÀed by
further presented. radiologic imaging.
Conclusion: We detected a driver mutation in more Methods: 6 biomarkers were assayed in serum
than 50% of the DNA from ACL. The results of collected from subjects with non-small cell lung
EGFR mutation testing are now used by treating cancer (NSCLC) and appropriately matched controls.
physicians to select erlotinib as initial treatment 548 specimens collected from 3 independent sites
according to NCCN, ASCO, and ESMO guidelines. were employed in the study. Samples were randomly
Patients with other driver mutations are being divided into a training set (NSCLC n=108, controls
offered participation in LCMC-linked clinical trials n= 157) and a testing set (NSCLC n=122, controls
testing agents targeting the mutation identiÀed, e.g. n=161) and used to develop a split-point algorithm
crizotinib with EML4-ALK. At half of LCMC sites, for lung cancer detection. Subsequently, performance
multiplexed testing for all mutations is now routine of the algorithm was evaluated in an independent
practice of pathology departments for patients with plasma-based validation study undertaken in a
ACL. cohort of lung cancer subjects (n=50) and controls
Keywords: lung neoplasm, genomic changes, (n=50) matched for age, gender and smoking history.
Epidermal growth factor receptor, EML4-ALK Controls included subjects with non-malignant
pulmonary nodules (n=21).
Results: The 6-marker split point model identiÀed
cancer cases with good accuracy in training
(AUC=0.86) and testing (AUC=0.89) datasets.
All stages of cancer were well resolved: stage
I 69% (n=98), stage II = 82% (n=45), stage III
= 79% (n=48) stage IV = 77% (n=39); at 88%
speciÀcity. Application of the model to data from the
independent cohort revealed that the algorithm again
identiÀed the malignant cases accurately AUC=0.83 were found on rebiopsy of patients with prior EGFR-
(sensitivity= 70% at speciÀcity=94%). 19/21 non- mutant ADC who developed acquired resistance to
malignant nodules within the control population erlotinib.
were correctly classiÀed. The panel of 6 biomarkers Results: Of 82 SCLC, 2 (2.4%) harbored EGFR,
described in these studies accurately identiÀes lung 1 (1.2%) KRAS, and 1 (1.2%) PIK3CA mutations.
cancer cases in both serum and plasma. Both EGFR-mutations occurred in SCLC that
Conclusion: This panel of 6 biomarkers shows were preceded by ADC harboring the same EGFR
promise in differentiating benign from malignant mutation (exon 19 deletion, L858R), and the lone
pulmonary nodules. While additional studies are KRAS mutation (G12V) occurred in combined
clearly required, these preliminary results suggest SCLC. Overall, all EGFR/KRAS mutations were
that this test may serve as a valuable adjunctive tool restricted to SCLC associated with either prior or
to imaging, providing a rapid, cost-effective means combined ADC (3/10; 30%) whereas none occurred
of prioritizing cases for more invasive biopsy. in pure SCLC (0/71) (p=0.0014). In contrast to
Keywords: biomarker, NSCLC, nodule SCLC, pure LCNEC harbored KRAS mutations in
7 of 51 (14%; 95% CI 4%-23%) cases (p=0.0017).
Similar to ADC in smokers, KRAS mutations in
Biomarkers II Tuesday, 5 July 2011 10:30-12:00 LCNEC were predominantly smoking-related G-T or
G-C transversions (5/7; 71%).
O16.03 ANALYSIS OF EGFR AND Conclusion: EGFR and KRAS mutations are
KRAS MUTATIONS IN SMALL CELL extremely rare in SCLC and are restricted to SCLC
CARCINOMA AND LARGE CELL associated with ADC either as unusual form of
NEUROENDOCRINE CARCINOMA OF ADC progression or as de-novo combined SCLC/
LUNG. ADC. In particular, two of our cases reÁect the rare,
Natasha Rekhtman1, Angela Marchetti1, Christopher recently described phenomenon of clonal evolution
Lau1, Andre L. Moreira1, William D. Travis1, of ADC to SCLC in the setting of erlotinib therapy.
Maureen Zakowski1, Maria Catherine Pietanza2, SigniÀcant rate of KRAS mutations in LCNEC is
Gregory J. Riely3, Mark G. Kris3, Marc Ladanyi1 a novel Ànding which suggests a histogenetic link
1
Pathology, Memorial Sloan-Kettering Cancer between a subset of LCNEC and ADC.
Center/United States Of America, 2Medicine/ Keyword: EGFR KRAS SCLC LCNEC
Thoracic Oncology Service, Memorial Sloan-
Kettering Cancer Center/United States Of America,
3
Medicine, Memorial Sloan-Kettering Cancer Biomarkers II Tuesday, 5 July 2011 10:30-12:00
Center/United States Of America
O16.05 TWO YEAR RESULTS OF LC-
Background: EGFR and KRAS mutations occur MAP: AN INSTITUTIONAL PROGRAM
in ~20% and ~30% of lung adenocarcinoma (ADC) TO ROUTINELY PROFILE TUMOR
in North America, respectively. The prevalence and SPECIMENS FOR THE PRESENCE
signiÀcance of mutations in these and other key OF MUTATIONS IN TARGETABLE
signaling molecules in high-grade neuroendocrine PATHWAYS IN ALL PATIENTS WITH
carcinomas of lung is not well established. NON-SMALL CELL LUNG CANCERS
Methods: A total of 132 high-grade neuroendocrine Mark G. Kris1, Maria E. Arcila2, Chris Lau2, Natasha
carcinomas were analyzed for hot-spot point Rekhtman2, Edyta Brzostowski2, Michelle Pilloff1,
mutations EGFR, KRAS, AKT1, BRAF, HER2, Gregory J. Riely1, Valerie Rusch3, Suresh Jhanwar2,
MEK1, and PIK3CA by Sequenom mass Alex Lash4, Maureen Zakowski2, Marc Ladanyi2
1
spectrometry genotyping and EGFR Exon 19 Medicine, Memorial Sloan-Kettering Cancer
deletions by standard methods. Included were small Center/United States Of America, 2Pathology,
cell lung carcinomas (SCLC) (n=81) and large cell Memorial Sloan-Kettering Cancer Center/United
neuroendocrine carcinomas (LCNEC) (n=51). SCLC States Of America, 3Thoracic Surgery, Memorial
specimens included resections (n=40), Àne needle Sloan-Kettering Cancer Center/United States Of
aspirates (n=36) and small biopsies (n=5), and all America, 4Sloan-Kettering Institute, Memorial Sloan-
LCNEC specimens were resections. Eight SCLC Kettering Cancer Center/United States Of America
were combined with non-SCLC, and two SCLC
Background: Mutated oncogenes underlie the individuals with EGFR and HER2 mutations and
behavior of lung cancers and can serve as targets to identify patients appropriate for clinical trials of
for therapy. Determining the presence of these investigational targeted therapies. Supported by P01
molecular abnormalities can direct the care of CA129243 and the Chandler Fund.
individual patients and aid research. To acquire and Keywords: Driver Mutation, EGFR,
use this information in as many patients as feasible, Adenocarcinoma, Mutation ProÀling
in January 2009 our multidisciplinary Disease
Management Team began a program within the
Department of Pathology to prospectively detect Biomarkers II Tuesday, 5 July 2011 10:30-12:00
the presence of mutations in EGFR, KRAS, BRAF,
HER2, PIK3CA, MEK1, and AKT1 and EML4- O16.06 PROGNOSTIC IMPLICATIONS
ALK re-arrangements in all patients diagnosed with OF DRIVER MUTATIONS IN SMOKERS
non-small cell lung cancer with sufÀcient tissue AND NEVER SMOKERS WITH LUNG
for testing. We named this effort the Lung Cancer ADENOCARCINOMA
Mutation Analysis Project (LC-MAP). Paul K. Paik1, Melissa Johnson1, Sandra P.
Methods: Patients sign an institutional consent to D’Angelo1, Camelia S. Sima2, Mark G. Kris1,
permit the use of previously obtained (“leftover”) Gregory J. Riely1
1
tissue for mutation proÀling after standard diagnostic Medicine, Memorial Sloan-Kettering Cancer
studies are completed. In the Department of Center/United States Of America, 2Epidemiology
Pathology, we use PCR-based testing for EGFR exon And Biostatistics, Memorial Sloan-Kettering Cancer
19 deletions and HER2 insertions. An additional 91 Center/United States Of America
mutations in 7 genes were assayed in a multiplexed
mass-spectrometry-based system (Sequenom™). Background: We previously demonstrated a dose-
EML4-ALK re-arrangements are determined by dependent relationship between smoking history and
ALK FISH. survival in patients with stage IIIB/IV non-small
Results: 1231 patients have entered. For those cell lung cancer (NSCLC), with never-smokers
genotyped with adenocarcinoma (n=896) and living 50% longer than smokers (Janjigian et. al.,
histologies other than squamous cell (n=49), a driver Cancer 2010). This relationship was independent of
mutation was found in 56% of the tumor specimens age, performance status, and gender on multivariate
(95% CI 52 to 59%). Mutations detected include analysis. We hypothesized that smoking-dependent
282 KRAS (30%), 186 EGFR (20%), 23 EML4- differences in the distribution of driver mutations
ALK (7%), 12 HER2 (5%), 11 PIK3CA (1%), 10 determined differences in prognosis between these
BRAF (1%), 2 MEK1 (0.2%), and 1 AKT1 (0.1%). two subgroups.
For persons with squamous tumors, mutations Methods: We reviewed 301 consecutive never
were detected in 3% of specimens (95% CI 0.3 to smokers and 373 consecutive smokers with lung
10%). This information lead to the use of the EGFR adenocarcinoma who underwent testing for EGFR
tyrosine kinase inhibitor erlotinib in 78 patients with and KRAS mutations and rearrangements in ALK
EGFR sensitizing mutations. 46 others were entered between May 2009 and May 2010. KRAS mutations,
on clinical trials testing agents targeting the speciÀc EGFR exon 19 deletions, and exon 21 L858R
molecular abnormality detected. mutations were identiÀed by standard methods. ALK
Conclusion: 1) Determining the presence of rearrangements were identiÀed through FISH and
actionable mutations in patients with lung cancer conÀrmed by PCR. Clinical outcomes and patient
can be made part of the routine evaluation of tumor characteristics were collected. Survival probabilities
specimens within a department of clinical pathology. were estimated using the Kaplan-Meier method.
2) We detected a “known” driver mutation in Group comparison was performed with log-rank tests
one of the 8 genes assessed in tumors from 56% and Cox proportional hazards methods.
of patients with adenocarcinoma and histologies Results: EGFR mutations were present in 111 (37%)
other than squamous cell. 3) We identiÀed a driver never smokers vs. 54 (14%) smokers (p<.0001);
mutation in any the 8 genes assayed in only 3% of KRAS mutations were present in 12 (4%) never
specimens from patients with squamous tumors. 4) smokers vs. 158 (43%) smokers (p<.0001); and
The mutational data obtained can be used to select ALK rearrangements were present in 35 (12%) never
available drugs (erlotinib, geÀtinib, trastuzumab) for smokers vs. 9 (2%) smokers (p<.0001). Median
survival for advanced stage (IIIB/IV) never smokers Biomarkers II Tuesday, 5 July 2011 10:30-12:00
vs. smokers was 53.4 months (95% CI: 43.8-NR) vs.
24.8 months (95% CI: 18.6-49.9 months) (p<.001). O16.07 MOLECULAR
Among never smokers with advanced disease, CHARACTERISTICS OF THE “OTHER
median OS was as follows: EGFR 36.6 months LUNG CANCERS” - NOT SMALL CELL,
(95% CI 18.8-NR), KRAS 10.4 months (95% CI: ADENOCARCINOMA OR SQUAMOUS
5.4-NR), and ALK rearrangements 62.9 months CELL CARCINOMA
(95% CI: 43.8-NR). Multivariate analysis (stage, Jamie E. Chaft1, Natasha Rekhtman2, Maria E.
performance status, mutation, age) found signiÀcant Arcila2, Marc Ladanyi2, Gregory J. Riely1, Alex
survival differences between never smokers with Lash3, Edyta Brzostowski2, Michelle Pilloff1, Suresh
EGFR mutations vs. KRAS mutations (HR for death Jhanwar2, Maureen Zakowski2, Valerie Rusch4, Mark
4.2 95% CI: 1.11-15.63, favoring EGFR) and EGFR G. Kris1
1
mutations vs. ALK rearrangements (HR for death Medicine, Memorial Sloan-Kettering Cancer
0.31, 95% CI: 0.1-0.94, favoring ALK). Conversely, Center/United States Of America, 2Pathology,
within a given genotype, no signiÀcant survival Memorial Sloan-Kettering Cancer Center/United
differences were present when categorized by States Of America, 3Sloan-Kettering Institute,
smoking history, as below: Memorial Sloan-Kettering Cancer Center/United
States Of America, 4Thoracic Surgery, Memorial
Overall Survival in Advanced Stage Patients by Smoking Sloan-Kettering Cancer Center/United States Of
History and Genotype America
Median OS
Genotype (months) 95% CI (months) p
Background: When assigning therapy, clinicians
EGFR mutation
have historically classiÀed lung cancer as either
Smoker NR 29.9-NR 0.21
small cell or non-small cell lung cancer (NSCLC)
Never-smoker 36.6 18.8-NR
despite the detailed observations recorded by
KRAS mutation
pathologists. With the increasing evidence that
Smoker 17.8 12.7-34 0.95
histology is predictive of therapeutic outcomes,
better characterization of lung cancer that is not
ALK rearrangement
clearly deÀned small cell lung cancer (SCLC),
Smoker 35.4 35.4-NR 0.86
adenocarcinoma (ADC), or squamous cell carcinoma
NR, not reached
(SQCC) is needed. The role of genotyping these
“other lung cancers” has not been systematically
evaluated.
Conclusion: The prognostic impact of smoking Methods: Evaluation of an institutional database
history is genotype-driven. Never smokers and created as part of the Lung Cancer Molecular
smokers with lung adenocarcinomas are not Analysis Project (LC-MAP) with routine assessment
homogeneous subgroups. Each is made up of a of histology and assessment of driver mutations
unique distribution of driver mutations. These driver in EGFR, KRAS, BRAF, HER2, PIK3CA, AKT1,
mutations, including EGFR and KRAS mutations NRAS, MEK1, MAP2K1, and EML4-ALK (Kris,
and rearrangements in ALK, are associated with Proc ASCO, 2010).
different prognoses that do not vary by smoking Results: Between 1/1/2009 – 12/31/2010, 1210
history. Integration of these two factors determines patients with lung cancer signed informed consent
the overall prognosis of never smokers and smokers and had sufÀcient tissue for analysis. 49 of 1210
with lung adenocarcinomas. (4%, CI 3-5%) were other lung cancers. Of these 49,
Keywords: never smoker, EGFR, Kras, 12 were large cell carcinomas (LCC), 9 were large
Adenocarcinoma cell neuroendocrine carcinomas (LCNEC), 14 were
pleomorphic/sarcomatoid carcinomas (pleo), 4 were
NSCLC, not otherwise speciÀed (NOS) and 10 had
combined histologies. To date molecular results are
available on 42 patients and driver mutations were
found in 17/42 (40%, 95% CI 27-56%). There was
1 EGFR mutation in a patient with adenosquamous
carcinoma (AS). 14 patients had KRAS mutations, Ottawa Hospital / University Of Ottawa/Canada,
12
3 with NOS, 6 pleo, 2 AS, 1 LCC, 1 LCNEC and 1 Ottawa Hospital Regional Cancer Centre/
mixed with LCNEC and ADC components. There Canada, 13University De Laval/Canada, 14Dalhousie
was 1 PIK3CA mutation in a patient with a LCNEC University/Canada, 15Department Of Pathology,
and 1 BRAF mutation in a patient with LCC. 25 University Health Network, Princess Margaret
patients had no mutations identiÀed and 7 have Hospital And University Of Toronto/Canada
results pending.
Conclusion: We have shown that mutations occur Background: Accurate lung cancer risk prediction
in ~40% of the “other lung cancers” with rare models are useful for individuals, clinicians,
histologies. While the frequency and epidemiology public health ofÀcials and health administrators.
of mutations in adenocarcinoma of the lung has The relationship between pulmonary function
been well deÀned with >50% of cases harboring an and lung cancer is unclear, and past studies of sex
identiÀable driver mutation, the less common lung differences have been inconsistent. The current study
cancer histologies are under studied. These Àndings investigates the relationship between spirometric
support the molecular testing of “other lung cancers” data and lung cancer, assessing differences by sex.
which is now routine at our institution. Support: NIH Methods: The current study analyzes baseline
T32 CA009207, P01 CA129243, RC2 CA148394. data from the Pan-Canadian Early Detection
Keywords: Non-small cell lung cancer, molecular of Lung Cancer Study, which has the objective
mutations to evaluate a new multi-modal early detection
strategy that integrates risk modeling, spirometry,
autoÁuorescence bronchoscopy and blood
Session O17: Non Invasive Early biomarkers with computed tomography for early
Detection Methods detection of lung cancer. Multivariable logistic
regression models were used to evaluate the
independent relationship between lung cancer and
percent predicted forced expiratory volume in 1
second (FEV1%), percent predicted forced vital
Non Invasive Early Detection Methods Tuesday, 5 July 2011 10:30- capacity (FVC%), and FEV1/FVC ratio, and their
12:00 interactions with sex. Likelihood ratio tests (LRT)
were used to evaluate the contribution of spirometric
O17.01 PULMONARY FUNCTION AS A data and interaction terms to models. The receiver
PREDICTOR OF LUNG CANCER RISK operator characteristic area under the curve (ROC
Martin C. Tammemagi1, Stephen Lam2, Wan C. Tan3, AUC) assessed predictive discrimination. The
Don D. Sin2, Annette M. Mcwilliams4, Sukhinder Hosmer-Lemeshow goodness-of-Àt statistic and
Atkar-khattra5, Alain Tremblay6, Geoffrey Liu7, calibration plots were used to assess calibration.
Heidi Roberts8, Kamyar Soghrati9, Serge Puksa10, Results: At baseline screening 61 lung cancers
John R. GofÀn10, Kayvan Amjadi11, Glenwood D. were detected in 2532 screenees. A full model was
Goss12, Garth Nicholas12, Simon Martel13, Francis prepared including lung cancer risk factors: age,
Laberge13, Michael Johnston14, Ming S. Tsao15 education, family history of lung cancer, body mass
1
Community Health Sciences, Brock University/ index, current smoking status, age at starting regular
Canada, 2Department Of Integrative Oncology, smoking, computed tomography examination of
British Columbia Cancer Agency/Canada, 3Ubc the chest in the last three years, sex, FEV1% and
James Hogg Research Centre/Canada, 4Department sex*FEV1% interaction. The LRT p-value for the
Of Integrative Onocology, British Columbia Cancer interaction term was 0.076, and for FEV1% and
Research Centre/Canada, 5British Columbia the interaction term was 0.002. The relationship
Cancer Agency/Canada, 6University Of Calgary/ between FEV1% and lung cancer risk by sex is
Canada, 7Medical Oncology And Hematology, depicted in Figure 1. Compared to women, the risk
Princess Margaret Hospital/Canada, 8Joint for men climbs much more rapidly as the FEV1%
Department Of Medical Imaging, Women’s College decreases below 80. The ROC AUCs for the full
Hospital/Canada, 9Princess Margaret Hospital/ model and the reduced model excluding FEV1%
Canada, 10Juravinski Cancer Centre/Canada, and the interaction term were 0.726 and 0.675.
11
Respirology:interventional Pulmonology, The The difference, 0.0515 (p = 0.094), is sizeable,
representing 10.3% of the distance between a conclusive or in-conclusive non-surgical workup

random and perfect classiÀcation. The Hosmer- will reduce the resection rate for benign disease in test
Lemeshow goodness-of-Àt test p-values for the positive participants of a lung cancer screening program.
full and reduced models were 0.781 and 0.965, Methods: (18)F-Fluorodeoxyglucose-positron
suggesting that both models were well calibrated. emission tomography (PET) scans were made
in 220 test positives. Nodules were classiÀed as
positive, indeterminate or negative based on visual
comparison with background activity. Gold standard
for a positive PET was the presence of cancer in the
resection specimen, or the detection of cancer during
> 2 years follow-up. Sensitivity, speciÀcity, positive
predictive value (PPV) and negative predictive
value (NPV) were calculated and 95% ConÀdence
Intervals (CI) constructed.
Results: The sensitivity of PET to detect cancer was
84.2% (95%CI: 77.6-90.7%), the speciÀcity 75.2%
(95%CI: 67.1-83.3), the PPV 78.9% (95%CI: 71.8-
86.0) and the NPV 81.2% (95%CI: 73.6-88.8). The
resection rate for benign disease was 23%, but 55% of
them had clinical consequences. A pre-operative PET
Conclusion: These Àndings indicate that low after an in-conclusive non-surgical work-up reduced
FEV1% is strongly associated with increased risk the resection rate for benign disease by 11%, at the
of lung cancer and that the effect is greater in males expense of missing 12% lung cancer cases. A pre-
than in females. Inclusion of FEV1% and FEV1%- operative PET after a conclusive non-surgical work-up
sex interaction in the model substantially improved reduced the resection rate for benign disease by 78%
predictive discrimination. at the expense of missing 3% lung cancer cases.
Keyword: spirometry, pulmonary function, FEV1, Conclusion: A pre-operative PET scan after
lung cancer risk an inconclusive non-surgical work-up is not
recommended because of the very low NPV, but after
a conclusive non-surgical work-up the resection of
Non Invasive Early Detection Methods Tuesday, 5 July 2011 10:30- benign disease can be decreased by 72%.
12:00 Keywords: Positron-emission Tomography,
Pulmonary nodule, Thoracic surgery, Lung cancer
O17.02 THE ROLE OF THE FDG-PET
SCAN IN THE NELSON LUNG CANCER
SCREENING TRIAL Non Invasive Early Detection Methods Tuesday, 5 July 2011 10:30-
Susan V. Westeinde1, Harry J. De Koning2, Frederik 12:00
B. Thunnissen3, Matthijs Oudkerk1, Harry J.M.
Groen4, Jan-Willem J. Lammers5, Carla Weenink4, O17.03 CT SCREENING OF LUNG
Rene Vernhout1, Kristiaan Nackaerts6, Willem Mali7 CANCER BRINGS FORWARD EARLY
1
Pulmonary Medicine, Erasmus MC/Netherlands, DISEASE. THE DANISH LUNG CANCER
2
Public Health, Erasmus MC/Netherlands, SCREENING TRIAL (DLCST): STATUS
3
Pathology, Vumc/Netherlands, 4Pulmonary AFTER FIVE YEARS OF CT SCREENING.
Medicine, Umc Groningen/Netherlands, 5Pulmonary Zaigham Saghir1, Asger Dirksen2, Haseem G.
Medicine, UMC Utrecht/Netherlands, 6Respiratory Ashraf3, Philip Tønnesen2, Karen S. Bach2, Hanne
Medicine, University Hospital Gasthuisberg/ Hansen4, Birgit G. Skov4, Niels Seersholm2, Jann
Belgium, 7Radiology, UMC Utrecht/Netherlands Mortensen5, Paul F. Clementsen2, Klaus R. Larsen4,
Martin Døssing6, John Brodersen7, Hanne Thorsen7,
Background: In computer tomography (CT) lung Klaus Kofoed5, Jesper H. Pedersen5
1
cancer screening up to 30% of all resections are Department Of Respiratory Medicine, Gentofte
performed for benign disease. The purpose of this University Hospital/Denmark, 2Gentofte University
study is to to investigate if a pre-operative PET after Hospital/Denmark, 3Akershus University Hospital/
Norway, 4Bispebjerg University Hospital/Denmark, Non Invasive Early Detection Methods Tuesday, 5 July 2011 10:30-
5
Rigshospitalet/Denmark, 6Nordsjællands University 12:00
Hospital/Denmark, 7University Of Copenhagen/
Denmark O17.05 PRELIMINARY FIVE-YEAR
RESULTS FROM A RANDOMIZED
Background: The effects of low dose CT STUDY OF LUNG CANCER SCREENING
screening on true disease stage-shift, mortality and WITH SPIRAL CT (THE DANTE TRIAL)
overdiagnosis are unclear. We present lung cancer Maurizio V. Infante1, Silvio Cavuto2, Fabio R.
Àndings and mortality at end of screening in the Lutman3, Giorgio Brambilla3, Giuseppe Chiesa4,
randomised Danish Lung Cancer Screening Trial Eliseo Passera4, Enzo Angeli5, Maurizio Chiarenza6,
(DLCST). Giuseppe Aranzulla7, Umberto Cariboni1, Valentina
Methods: 4,104 men and women, healthy heavy Errico1, Edoardo Bottoni1, Emanuele Voulaz1, Marco
smokers/former smokers were randomised to annual Alloisio1, Daniel Solomon1, Anna Destro8, Massimo
low dose CT screening or no screening for Àve Roncalli8, Armando Santoro9, Gianluigi Ravasi1
1
years (baseline and four incidence rounds). Two Thoracic And General Surgery Dept., Istituto
experienced chest radiologists read all CT scans Clinico Humanitas/Italy, 2Italian Association For
and registered the location, size and morphology of The Fight Against Cancer/Italy, 3Radiology Dept,
nodules. Nodules with a diameter between 5 and 15 Istituto Clinico Humanitas/Italy, 4Thoracic Surgery
mm without benign characteristics were rescanned Dept, Humanitas-Gavazzeni/Italy, 5Radiology Dept,
after three months. Volume-doubling-time (VDT) Humanitas-Gavazzeni/Italy, 6Medical Oncology
was used to measure growth rate. Growing nodules Dept, Humanitas-Catania Oncology Centre/Italy,
7
(>25% increase in volume) and nodules larger than Radiology Dept, Humanitas-Catania Oncology
15 mm were referred for diagnostic workup. In the Centre/Italy, 8Pathology Dept, Istituto Clinico
control group, lung cancers were diagnosed and Humanitas/Italy, 9Medical Oncology Dept, Istituto
treated outside the study by usual clinical practice. Clinico Humanitas/Italy
Results: The participation rates were high in both
groups (screen: 95.5%; control 93.0%; p<0.001). Background: It is hoped that screening for lung
2.5% of screening tests were positive, and after cancer with spiral CT may decrease lung cancer
diagnostic workup 1.8% were classiÀed as false mortality, but encouraging results have only
positive Àndings (non-malignant). Lung cancer been obtained in uncontrolled studies. Recently,
detection rate was 0.8% at baseline and mean the National Lung Screening Trial investigators
annual detection rate was 0.6% at incidence rounds announced that screening by LDCT signiÀcantly
(p=0.492). SigniÀcantly more lung cancers were reduced lung cancer mortality as compared with
diagnosed in the screening group as compared to screening by chest X-rays. The purpose of our study
the control group (68 vs.24, p<0.001), and more was to explore the effect of screening with low-
were low stage (57 vs.10 stage I-IIIA NSCLC and dose spiral CT (LDCT) on lung cancer mortality
limited stage SCLC, p<0.001), whereas frequencies in comparison with no screening in a high-risk
of high stage were the same (11 vs.14 stage IIIB-IV population. Secondary endpoints were incidence,
NSCLC and extensive stage SCLC, p=0.640). This stage and resectability.
indicates no absolute stage-shift and some degree Methods: Male subjects, aged 60-75, smokers
of overdiagnosis. At end of screening, 60 were of 20+ pack-years were randomized to screening
deceased in the screening group and 42 in the control with low-dose spiral CT or control. All participants
group (p=0.072). 15 and 10 died of lung cancer, underwent a baseline, once-only chest X-ray (CXR)
respectively (p=0.923). and sputum cytology examination in order to
Conclusion: CT screening of lung cancer brings increase accrual. Screening-arm subjects also had a
forward early disease, and at this point no absolute LDCT upon accrual, which was to be repeated every
stage-shift or reduction in mortality was observed. year for four additional years, while controls had a
SigniÀcantly more lung cancers were diagnosed yearly interview and basic medical examination, with
in the screening group indicating some degree of further testing only in case of suspicious symptoms.
overdiagnosis. Results: Starting March 2001 through to February
Keywords: mortality, Stage-shift, Lung cancer, CT 2006, 2811 subjects were randomized and 2472 were
screening actually enrolled (LDCT 1276, control 1196). As of
December 2010, active follow-up was 13541 person- size, nodule location, gender, age, distance from the
years (LDCT 7097, Ctrl 6444). LDCT subjects had pleura, and smoking history. Statistical analyses were
a signiÀcantly higher probability of undergoing an performed by the Kaplan-Meier method.
invasive 2nd line investigation following a screening Results: The results showed that 1267 newly
CT than control arm subjects following medical developed nodules had been identiÀed in 825
interview and testing on demand. Lung cancer screenees (825/9754, 8.5%) (356 females, and 469
was detected in 92 (7.2%) LDCT patients and 58 males; mean age 64 years, range, 44-84 years). As
(4.8%) controls (p<0.005), with signiÀcantly more of February 24, 2011, the outcome of 1153 of the
patients with Stage I disease and signiÀcantly less 1267 newly developed nodules had been determined:
cases detected due to intercurrent symptoms in the 9 nodules had been diagnosed as cancer (2 as
screening arm (p<0.005). The absolute number adenocarcinoma, 3 as squamous cell carcinoma, 2
of lung cancer cases with stage II-IV disease was as small cell carcinoma, 2 as a pulmonary metastasis
virtually the same as in the control arm (42 vs. 45, by prostate cancer and by esophageal cancer,
p=1.0). Resectability rates were similar in both respectively), 3 nodules as inÁammation, 1 nodule
groups. Focused effect size measures on lung cancer as bronchiolitis obliterans organizing pneumonia,
mortality (i.e. mortality rates) are under evaluation. 453 nodules (453/1153, 39%) had disappeared, 256
Conclusion: Five-year results of the DANTE trial nodules (256/1153, 22%) had shrunk, and 431 nodules
still suggest that the beneÀt of lung cancer screening (431/1153, 37%) were stable. The median follow-up
by spiral CT is small in patients over 60 as compared period of the screenees whose nodules were stable or
with clinical surveillance only. Screening for lung had shrunk was 29 months (range, 3-67). The results
cancer should continue to remain investigational. according to whether the screenees were smokers
Collateral studies are needed to improve patient showed that 87 nodules (87/1153, 8%) had developed
selection and outcomes. in female smokers and 458 nodules (458/1153, 40%)
Keywords: Lung cancer, Early Detection, Spiral CT, had developed in female non-smokers, while 454
Randomized controlled trial nodules (454/1153, 39%) had developed in male
smokers and 154 nodules (154/1153, 13%) had
developed in male non-smokers. There were 240
Non Invasive Early Detection Methods Tuesday, 5 July 2011 10:30- pure ground-glass nodules (GGNs), and their mean
12:00 size was 6 mm (range, 1.5-27). There were 77 mixed
GGNs (GGNs with a solid component), and their
O17.06 NEWLY DEVELOPED NODULES mean size was 6.4 mm (range, 2.5-24.5). There were
DURING FOLLOW-UP AFTER BASELINE 836 solid nodules, and their mean size was 4.8 mm
CT LUNG CANCER SCREENING OR (range, 1.5-35). A multivariate analysis is in progress.
DURING REPEAT CT SCREENING Conclusion: As of February 24, 2011, 99.2%
Ryutaro Kakinuma1, Masahiro Kaneko2, Takaaki (1144/1153) of the newly developed nodules in our
Tsuchida2, Masahiko Kusumoto2, Hisao Asamura2, cohort during follow-up after baseline CT lung cancer
Yukio Muramatsu1, Noriyuki Moriyama1 screening or during repeat CT screening were false-
1
Screening Technology And Development Division, positive. Risk-based follow-up criteria should be
National Cancer Center, Research Center For established.
Cancer Prevention And Screening/Japan, 2National Keyword: CT, screening, early detection, newly
Cancer Center Hospital/Japan developed nodule
Background: To evaluate newly developed nodules

detected during follow-up after baseline CT lung cancer Non Invasive Early Detection Methods Tuesday, 5 July 2011 10:30-
screening or during repeat CT screening. 12:00
Methods: Between February 2004 and March 2010,
9754 people were enrolled in our observational CT O17.07 CT SCREENING FOR LUNG
lung cancer screening study. Screenees in whom newly CANCER: THE IMPLICATION OF LUNG
developed nodules had been detected during that BIOPSY RECOMMENDATIONS
period were identiÀed from the nodule database. The Ute Wagnetz1, Ravi Menezes2, Scott Boerner2,
following information was retrieved from the database: Narinder Paul2, Dirk Wagnetz3, Shaf Keshavjee2,
types of change in size, nodule consistency, nodule Heidi Roberts4
1
Nuklearmedizinische Praxis Am Schwabentor/ Session O18: New Image Guided
Germany, 2University Health Network/Canada, Approaches For Tumor Characterization
3
Thoracic Surgery, Universitaetsklinik/Germany, and Prediction Of Therapy Outcome in
4
Joint Department Of Medical Imaging, Women’s NSCLC
College Hospital/Canada
Background: The purpose of our study was to Tuesday, 5 July 2011

address the implication of invasive diagnostic
procedures recommended from a lung cancer
screening protocol; in particular to assess how many New Image Guided Approaches For Tumor Characterization and
invasive procedures were recommended for benign Prediction Of Therapy Outcome in NSCLC Tuesday, 5 July 2011 10:30-
nodules. 12:00
Methods: Between 2003 and 2009, 4782 high-risk
smokers were enrolled in a lung cancer screening O18.01 FDG-PET BASED
study. A helical low-dose computed tomography CHEMOTHERAPY SELECTION FOR
(LDCT) of the chest was performed using 120 kVp, METASTATIC NON-SMALL CELL LUNG
40-60 mA and a collimation of 1 mm or 1.25 mm. The CANCER
morphological features targeted were parenchymal Keith Eaton1, Renato G. Martins1, Katherine A.
nodules; indication for biopsy was made based on the Guthrie2, Kari Stricker1, Antoine Leblond3, Laurie L.
diagnostic algorithm provided by the International Carr4, Jon Umlauf3, Hubert Vesselle3
1
Early Lung Cancer Action Program (I-ELCAP). We Medical Oncology, University Of Washington/
recorded the time point of biopsy recommendation United States Of America, 2Fred Hutchinson
(baseline, follow-up), the morphology and size, Cancer Research Center/United States Of America,
3
growth, the types of diagnostic procedures including Radiology, University Of Washington/United States
complication rate, and the Ànal pathology. Of America, 4University Of Colorado/United States
Results: A total of 128 diagnostic biopsies were Of America
recommended for suspicious nodules, 127 were
performed: 110 percutaneous CT-guided Àne-needle- Background: Several groups have demonstrated that
aspiration biopsies (FNAB), 9 diagnostic resections the change in the primary tumor FDG uptake by PET
by video-assisted thoracoscopic surgery (VATS), 7 after a single cycle of platinum-based chemotherapy
bronchoscopies and 1 ultrasound guided biopsy of a predicted which advanced stage NSCLC patients had
supraclavicular lymph node. Of the 110 FNABs, 24 longer progression-free and overall survival (PFS
had unsatisfactory results; 13 underwent secondary and OS) after administration of the entire multi-cycle
diagnostic VATS resection. The indication for biopsy chemotherapy regimen. Non-responders by early
was made based on morphology in 48% (62/128), PET were highly unlikely to respond by CT RECIST
growth on follow-up in 40% (51/128) and in 12% and had statistically signiÀcantly lower median PFS
(15/128) for new nodules; 61 nodules were smooth and OS.
or lobulated solid, 17 spiculated, 7 cavitary, 27 part- Methods: We are conducting a prospective clinical
solid and 12 non-solid. In total 104/124 (84%) were trial to test the hypothesis that FDG-PET could be
true positive for malignancy, 20/124 (16%) were used to select optimal chemotherapy. Chemotherapy
false positive; in 4 cases Ànal result is pending. The naïve patients with metastatic NSCLC and a
overall false positive rate was 0.42% (20/4782); baseline FDG PET receive carboplatin (AUC=6)
11.6% (16/128) FNAB and 3.6% (5/128) VATS were and paclitaxel (175mg/m2) (CP) chemotherapy
recommended for benign nodules. on day 1 and repeat FDG-PET on day 18. Using a
Conclusion: Recommended biopsy procedures previously validated measure of response, namely
for screen-detected suspicious pulmonary nodules a decrease in the SUVmax of > 20% in the primary
resulted in a low intervention rate for benign lesion, PET-responding patients are continued on CP
nodules. The rate of false positive invasive chemotherapy for a total of 4 cycles. Patients who
procedures is minimal when adhering to a follow up do not respond by PET are switched to alternate
protocol that relies on morphology and growth. docetaxel (75mg/m2 d8) and gemcitabine (1000mg/
Keywords: computed tomography, lung nodules, m2 d1,8) (DG) for three additional cycles. The
Screening, false positives primary outcome is the CT RECIST response rate to
the alternate DG chemotherapy. Secondary endpoints New Image Guided Approaches For Tumor Characterization and
include PFS and OS. Prediction Of Therapy Outcome in NSCLC Tuesday, 5 July 2011 10:30-
Results: The study planned for a total of 45 12:00
evaluable patients. To date, 40 patients have
sufÀcient data for analysis. Of these, 16 (40%) met O18.02 EFFECTS OF THE ANTI-
the FDG-PET criteria for response after a single ANGIOGENIC DRUG BEVACIZUMAB
cycle of CP. The primary endpoint was the response ON TUMOR PERFUSION AND
rate in PET non-responders switched to alternate DG DRUG DELIVERY OF 11C-LABELED
chemotherapy. To date, only one non-responding DOCETAXEL IN NON-SMALL CELL
patient had a RECIST response, and the study goal LUNG CANCER (NSCLC) PATIENTS:
of 3 or more responding patients has not been met. IMPLICATIONS FOR SCHEDULING OF
Overall, 28 (70%) patients have died, 27 with disease ANTI-ANGIOGENIC AGENTS
progression. Another 7 (18%) patients had disease Astrid A. Van Der Veldt1, Mark Lubberink1,
progression but remained alive at last contact. Idris Bahce2, Maudy Walraven3, Michiel P. De
The rates of OS and PFS showed no signiÀcant Boer4, Henri N. Greuter1, N. H. Hendrikse1, Jonas
variability according to early PET response (p=0.94 Eriksson1, Albert D. Windhorst1, Pieter E. Postmus2,
and p=0.60, respectively). Henk M. Verheul3, Erik H. Serne4, Adriaan A.
Conclusion: This is the Àrst trial in solid tumor Lammertsma1, Egbert F. Smit2
1
oncology that utilizes early FDG- PET response Nuclear Medicine & Pet Research, VU University
data to select subsequent chemotherapy. Previous Medical Center/Netherlands, 2Pulmonary Diseases,
work suggested that non-responders by early PET VU University Medical Center/Netherlands,
3
are unlikely to beneÀt from the continuation of the Medical Oncology, VU University Medical Center/
same chemotherapy and have inferior PFS and OS. Netherlands, 4Internal Medicine, VU University
This work demonstrates that although changing Medical Center/Netherlands
chemotherapy in the event of non-response by PET
did not lead to CT RECIST responses, patients Background: Current strategies combining anti-
who switched chemotherapy had similar PFS and angiogenic drugs with chemotherapy provide clinical
OS to those who initially responded by PET. It is beneÀt in patients with advanced-stage NSCLC
possible that the change in chemotherapy directed cancer. It has been hypothesized that pre-treatment
by PET was responsible for these results. This with anti-angiogenic drugs may transiently normalize
trial demonstrates the feasibility of this FDG-PET abnormal tumor vasculature and contribute to
response based adaptive approach that could be improved delivery of subsequent chemotherapy
tested in a randomized clinical trial. (Nat Med 2001;7:987-9). The purpose of this study
Keywords: FDG-PET, NSCLC, adaptive therapy, was to investigate this concept in NSCLC patients
personalized therapy using a perfusion tracer ([15O]H2O), radiolabeled
chemotherapy ([11C]docetaxel) and positron emission
A revised/updated abstract may be included in tomography (PET) before and after a single infusion
the Late Breaking Abstract Supplement, available of bevacizumab.
at the 14th World Conference on Lung Cancer. Methods: Ten NSCLC patients were included.
Patients underwent dynamic PET scans with [15O]
H2O and [11C]docetaxel before, and at 5 hours
and 4 days after IV bevacizumab administration
(15 mg·kg-1). An additional [15O]H2O scan
was performed at 2 hours. Systemic effects of
bevacizumab were investigated by assessing:
(1) plasma levels of vascular endothelial growth
factor (VEGF) using ELISA kits, (2) blood
pressure, (3) cardiac output using [15O]H2O, and (4)
microcirculation in the skin using capillaroscopy.
Results: Two hours after bevacizumab
administration, tumor perfusion did not change
(Wilcoxon Signed Ranks test, P=0.89). At 5 hours,
however, both tumor perfusion and the net inÁux rate

constant of [11C]docetaxel decreased signiÀcantly
(P<0.05 for both). These changes persisted until day
4 (P<0.01 for both). Changes in tumor parameters
were accompanied by a rapid decrease in circulating
VEGF at 3 hours (P<0.05) and a decline in cardiac
output at 4 days (P=0.05). The other systemic
parameters remained unchanged.
Conclusion: A single dose of bevacizumab induces a
rapid and signiÀcant decline in tumor perfusion and
[11C]docetaxel delivery in NSCLC tumors. These
rapid changes in tumor parameters are not due to
changes in cardiovascular parameters. The Àndings
of the present study highlight the importance of drug
scheduling for enhancing drug delivery to tumors
and advocate further studies to optimize scheduling
of anti-angiogenic drugs. Methods: 1. Diagnosing malignant pulmonary
Keywords: bevacizumab, Tumor angiogenesis, nodules PET and DWI were carried out
Non-small cell lung cancer, Positron Emission prospectively in 192 patients with 232 pulmonary
tomography nodules/masses before surgery. FDG uptake of each
lesion was quantitatively measured by a contrast
ratio of standard uptake value (SUV-CR) between
New Image Guided Approaches For Tumor Characterization and the lesions and contralateral lung. Diffusion of water
Prediction Of Therapy Outcome in NSCLC Tuesday, 5 July 2011 10:30- molecule in each lesion was quantitatively measured
12:00 by a minimum ADC (ADC-min). The diagnostic
results were compared between the two modalities.
O18.03 DIFFUSION-WEIGHTED 2. N staging of NSCLC Both FDG-PET CT and
MAGNETIC RESONANCE IMAGING DWI were prospectively used in 169 patients before
FOR DIAGNOSING MALIGNANT surgical intervention for NSCLC to examine 1558
PULMONARY NODULES AND NODAL lymph node stations. The diagnostic results were
STAGING OF NON-SMALL CELL compared between the two modalities.
LUNG CANCER. COMPARISON WITH Results: 1. Diagnosing malignant pulmonary
POSITRON EMISSION TOMOGRAPHY nodules The receiver operating characteristics curve
Takeshi Mori1, Hiroaki Nomori2, Yasuomi Ohba1, showed cutoff values of the ADC-min and the SUV-
Kentaro Yoshimoto1, Koei Ikeda1, Makoto Suzuki1 CR for benign/malignant discrimination to be 1.1
1
Thoracic Surgery, Kumamoto University/Japan, x 10-3 mm2/s and 0.37, respectively. DWI and PET
2
General Thoracic Surgery, Keio University School showed sensitivities of 0.7 and 0.72 and speciÀcities
Of Medicine/Japan of 0.95 and 0.73, respectively. While there was no
signiÀcant difference in sensitivity between the
Background: Recent developments of diffusion- two methods, DWI showed a signiÀcantly higher
weighted magnetic resonance imaging (DWI) speciÀcity than PET due to fewer false-positives
make it possible to image malignant tumors due to for active inÁammatory lesions (p=0.004). The
provide tissue contrast based on difference in the ADC-min and SUV-CR values showed a signiÀcant
diffusion of water molecules among tissues, which reverse correlation (r=-0.445, p<0.001). 2. N staging
can be measured by apparent diffusion coefÀcient of NSCLC The accuracy of N staging in the 169
(ADC) value. The aim of this study is to examine patients was 0.89 with DWI, which was signiÀcantly
the usefulness of 1) diffusion-weighted magnetic higher than the value of 0.80 obtained with PET-CT
resonance imaging (DWI) for benign/malignant (P=0.003), because of less overstaging in the former.
discrimination of pulmonary nodules/masses and Among the 1558 lymph node stations examined
2) nodal (N) staging of non-small cell lung cancer pathologically, 56 had metastases, and the other 1309
(NSCLC) compared with 18F-Áuorodeoxyglucose did not. Although there was no signiÀcant difference
(FDG) positron emission tomography (PET). in the diagnosis of the 56 metastatic lymph node
stations between the 2 methods, DWI was more LN metastasis in patients with a solid proportion
accurate for diagnosing the 1309 non-metastatic 50%. Sensitivity, speciÀcity, accuracy, positive and
stations than PET-CT because of fewer false-positive negative predictive values of FDG-PET/CT for nodal
results (P=0.001). staging on per-patient basis were 14.3%, 87.1%,
Conclusion: DWI may be able to be used in place 82.4%, 7.1%, and 93.6%. Those of CT were 14.3%,
of FDG-PET for diagnosing malignant pulmonary 95.1%, 89.8%, 16.7%, and 94.1%. There were no
nodules and N staging of NSCLC with fewer false- signiÀcant differences in diagnostic accuracy between
positive results compared with FDG-PET. FDG-PET/CT and CT for nodal staging (P>0.05). On
Keywords: N stage of NSCLC, Lung cancer, per-nodal-station basis, sensitivity, speciÀcity, and
benign/malignant discrimination, diffusion weighted accuracy of FDG-PET/CT were 16.7%, 95.6%, and
magnetic resonance imaging 93.8%. Those of CT were 16.7%, 99.0%, and 97.2%.
CT showed signiÀcantly higher accuracy than FDG-
PET/CT (P<0.001). Between cases with and without
New Image Guided Approaches For Tumor Characterization and LN metastasis, there was a signiÀcant difference in
Prediction Of Therapy Outcome in NSCLC Tuesday, 5 July 2011 10:30- solid proportion (P<0.05) and marginal difference in
12:00 central location (P=0.065).
Conclusion: FDG-PET/CT shows very low
O18.05 IS FDG-PET/CT NECESSARY IN sensitivity and has little additional value compared
DIAGNOSING NODAL METASTASIS to CT in nodal staging of T1 NSCLCs manifesting as
OF T1 NON-SMALL CELL LUNG subsolid nodules. The solid proportion was the only
CANCER MANIFESTING AS SUBSOLID signiÀcant different feature between patients with or
NODULES? without LN metastasis.
Chang Min Park1, Sang Min Lee1, Jin Mo Goo1, Keywords: T1 NSCLC manifesting as subsolid
Kwang Gi Kim2 nodule, PET/CT, CT, LN staging
1
Department Of Radiology, Seoul National
University Hospital/Korea, 2Department Of A revised/updated abstract may be included in
Biomedical Engineering, National Cancer Center/ the Late Breaking Abstract Supplement, available
Korea at the 14th World Conference on Lung Cancer.
Background: The diagnostic value of FDG-PET/

CT for LN staging in nonsmall cell lung cancer New Image Guided Approaches For Tumor Characterization and
manifesting as subsolid nodule has not been evaluated Prediction Of Therapy Outcome in NSCLC Tuesday, 5 July 2011 10:30-
yet. The purpose of our study was to retrospectively 12:00
evaluate and compare the diagnostic accuracy of
FDG-PET/CT and chest CT for LN staging in T1 O18.06 PET SUVMAX IN STAGE I
NSCLCs manifesting as subsolid nodules. We also LUNG ADENOCARCINOMA (LAC) IS
investigated the predictive factors for LN metastasis A PREDICTOR OF RECURRENCE,
in T1 subsolid NSCLCs among FDG-PET/CT and CT CORRELATES WITH THE NEW
features. IASLC/ATS/ERS HISTOLOGICAL
Methods: From January 2005 to March 2010, 5912 CLASSIFICATION, AND FURTHER
patients were diagnosed with NSCLC in our hospital. STRATIFIES PROGNOSIS IN
Among them, 108 patients with pathologically- INTERMEDIATE-GRADE ACINAR /
proven T1 NSCLCs manifesting as subsolid nodules PAPILLARY SUBTYPE
with lymph node (LN) staging were included in this Kyuichi Kadota1, Christos Colovos2, Kei Suzuki2, E
study. Diagnostic accuracies of FDG-PET/CT and C. Zabor2, Camelia S. Sima2, Nabil P. Rizk2, Valerie
CT for nodal staging were evaluated on per-patient W. Rusch2, William D. Travis2, Prasad S. Adusumilli2
1
and per-nodal-station basis and compared. SUVmax Department Of Pathology And Surgery, Memorial
and CT features of primary tumors were evaluated to Sloan-kettering Cancer Center/United States Of
investigate predictive factors for nodal metastasis. America, 2Memorial Sloan-Kettering Cancer Center/
Results: Of the 108 patients, all tumors were United States Of America
adenocarcinoma pathologically, and nodal metastases Background: Our aims were to investigate whether
were found in only 7 patients (6.5%). There was no preoperative PET SUVmax in stage I LAC can:
(a) predict recurrence, (b) correlate with the new Session O19: Medical Oncology II
IASLC/ATS/ERS histological classiÀcation, and (c)
help further stratify the intermediate grade acinar / Tuesday, 5 July 2011
papillary predominant morphology patients, the most
prevalent subgroup.
Methods: Stage I LAC patients who had SUV values Medical Oncology II Tuesday, 5 July 2011 10:30-12:00
available (n=222, 1999 to 2005) were classiÀed
according to the IASLC/ATS/ERS classiÀcation: low- O19.01 APRICOT-L: A BIOMARKER
grade: lepidic (LPD), intermediate-grade: acinar (ACI), BASED PHASE II RANDOMIZED
and papillary (PAP), and high-grade: micropapillary PLACEBO- CONTROLLED STUDY OF
(MIP) and solid (SOL). Median SUVmax (3.0) was APRICOXIB IN COMBINATION WITH
used to categorize the cohort into high and low. Log- ERLOTINIB IN NON-SMALL CELL LUNG
rank tests and Cox proportional hazards models were CANCER (NSCLC) PATIENTS
used to analyze the association between PET SUVmax, Barbara J. Gitlitz1, Eric D. Bernstein2, George P.
morphology, and time to recurrence (TTR). Keogh3, Edgardo S. Santos4, Gregory Otterson5,
Results: The IASLC/ATS/ERS histological Ginger Milne6, Mary C. Syto7, S.L. Zaknoen7
1
classiÀcation identiÀed: low-grade, 89% 5-year Medicine, University Of Southern California Keck
recurrence free probability (RFP) (LPD, n=16); School Of Medicine/United States Of America,
2
intermediate-grade, 86% 5-year RFP (PAP, n=63 Providence Medical Center/United States Of
and ACI, n=118); and high-grade, 71% 5-year RFP America, 3Charleston Hematology Oncology
(SOL, n=22 and MIP, n=3) (p=0.039). Patients Associates Pa/United States Of America, 4University
with high SUVmax showed signiÀcantly shorter Of Miami/sylvester Comprehensive Cancer Center/
TTR compared to patients with low SUVmax United States Of America, 5Ohio State University
(78% vs. 92% 5-year RFP, p=0.012). SUVmax Medical Center - Arthur G. James Cancer Hospital
was signiÀcantly associated with histologic And Richard J. Solove Research Institute/United
grade (p<0.001, Figure 1A). Furthermore, in the States Of America, 6Vanderbilt University/United
intermediate-grade, the most common group, patients States Of America, 7Tragara Pharmaceuticals, Inc./
with high SUVmax had signiÀcantly shorter TTR United States Of America
compared to patients with low SUVmax (79% vs.
93% 5-year RFP, p=0.031, Figure 1B). The ability Background: Apricoxib is a once-daily, oral,
of SUVmax to predict recurrence is signiÀcant potent and selective inhibitor of COX-2. The
even after adjusting for histologic grade (p=0.033). COX-2 pathway plays a key role in tumor growth,
angiogenesis and resistance to therapy. Combinations
of a COX-2 inhibitor and EGFR inhibitors are
of interest in NSCLC because COX-2 signaling
activates the Erk/MAPK pathway. In a Phase I study
apricoxib and erlotinib were found to be safe and
demonstrated a disease control rate of 60%. The
recommended Phase II dose was based on decreases
in PGE-M; a urinary marker for tumoral COX-2
activity. Thus, this Phase II trial used decreases in
PGE-M to select patients for randomization.
Methods: Pts with IIIB or IV NSCLC that had a
Conclusion: In stage I LAC, pre-operative PET 50% decrease from baseline PGE-M after a 5-day
SUVmax predicts recurrence, correlates with open-label run in of apricoxib were randomized.
the IASLC/ATS/ERS classiÀcation, and, most Pts were treated with erlotinib 150 mg PO daily
importantly, helps further stratify prognosis among and apricoxib/placebo 400mg PO daily. Pts must
most prevalent acinar and papillary morphology. have failed a prior platinum-based regimen for IIIB
Keywords: lung, Adenocarcinoma, Histological or IV disease and have measureable disease. The
classiÀcation, PET primary objective was a 40% improvement in time to
progression over the placebo arm.
Results: 176 patients entered run-in and 120/176
1
(73%) were randomized in a 2:1 (active: placebo) Catalan Institue Of Oncology, Hospital Germans
fashion (82% of patients had at least a 50% drop). Trias & Pujol/Spain, 2Hospital Germans Trias
Characteristics: Sex: M/F: 67/53; age range 36- I Pujol/Spain, 3Hospital Vall D’Hebron/Spain,
4
87 yrs.; 95% ECOG PS 0 or 1 and 5%, PS2. Most Hospital 12 De Octubre/Spain, 5Fox Chase Cancer
common adverse events of any grade included; Center/United States Of America, 6Merck & Co.,
diarrhea (55%), rash (54%), fatigue (38%) and nausea Inc/United States Of America, 7OfÀce Of The Chief
(33%). More patients on the active combination arm Medical OfÀcer, Merck & Co., Inc./United States Of
discontinued due to adverse events (7% vs 21%). America, 8Vanderbilt-Ingram Cancer Center/United
In an analysis based on a pre speciÀed subgroup, States Of America
patients in the 65 age group demonstrated statistically
signiÀcant clinical beneÀt in all efÀcacy measures. Background: The insulin-like growth factor
receptor 1 (IGF-1R) is a receptor tyrosine kinase that
ITT N=114 P value 65 N=65 P value HR promotes cell proliferation and is over expressed in
DCR 46% vs 51% NS 35% vs 60% 0.018 non-small cell lung cancer (NSCLC). Dalotuzumab
Median TTP 2.1 vs 1.8 0.97 1.4 vs 2.7 0.018 HR 0.5 (MK-0646) is a humanized IgG1 monoclonal
(months) (NA, 0.9) antibody that binds to and inhibits the function of
Median OS 5.6 vs 5.9 0.83 3.8 vs 8.5 0.025 HR 0.4 IGF-1R, inhibits tumor growth, and enhances the
(months) (NA,0.9)
anti-tumor activity of erlotinib in murine xenograft
models of NSCLC. This phase IIa study was
Conclusion: This study is the Àrst randomized designed to evaluate the effect of dalotuzumab
placebo controlled trial to demonstrate a clinical combined with erlotinib on progression-free survival
beneÀt in a biomarker selected population of (PFS) in patients with recurrent NSCLC.
NSCLC patients using urinary PGE-M. Safety of this Methods: Patients with stage IIIb/IV NSCLC who
combination is acceptable in this patient population previously failed at least 1, but no more than 2,
with patients > 65 years on active drug experiencing prior chemotherapy regimens were randomized 1:1
more study discontinuations due to adverse events. to an intravenous dalotuzumab 10 mg/kg/wk + oral
Although the overall ITT showed no beneÀt, in erlotinib 150 mg/day arm or an erlotinib-only control
patients aged 65 or younger DCR, TTP and OS was arm. Patients in the erlotinib control arm were
signiÀcantly improved with the active combination. eligible for crossover to the dalotuzumab + erlotinib
A Phase III deÀnitive trial is planned arm upon disease progression. The primary study
Keywords: biomarker, COX2 endpoint was PFS. Secondary endpoints included
overall survival (OS), response rate (complete
A revised/updated abstract may be included in response + partial response), safety, and tolerability.
the Late Breaking Abstract Supplement, available IGF-1R expression in peripheral blood mononuclear
at the 14th World Conference on Lung Cancer. cells was assessed before and after therapy.
Results: Between December, 2007 and September,
2010, 75 patients were enrolled and randomized
Medical Oncology II Tuesday, 5 July 2011 10:30-12:00 to the dalotuzumab arm (37 patients, median age
62 yrs, 73% male) or the control arm (38 patients,
O19.02 AN OPEN LABEL, RANDOMIZED median age 59 yrs, 74% male). All patients were
PH II STUDY EVALUATING included in efÀcacy and safety analyses. Baseline
DALOTUZUMAB COMBINED WITH patient characteristics were well balanced between
ERLOTINIB IN PATIENTS WITH the dalotuzumab and control arms. One objective
NON-SMALL CELL LUNG CANCER response was observed in each of the two study
FOLLOWING FAILURE OF PRIOR arms. Median PFS was increased slightly in the
CHEMOTHERAPY dalotuzumab arm, but OS decreased. Patients in
Rafael Rosell1, Teresa Moran2, Enriqueta Felip3, the dalotuzumab arm experienced more Grade
Jose Miguel Sanchez Torres4, Hossein Borghaei5, 3-5 adverse events and study-drug related serious
Shanghong Guan6, Holly Brown6, Timothy adverse events (primarily hyperglycemia). Higher
Fitzgerald6, Jason Clark6, Sriram Sathyanarayanan6, tumor IGF-1R expression at baseline was not
Mark Ayers6, James Hardwick7, Brian Lu6, Li Yan6, associated with improved clinical outcome.
David Johnson8 Conclusion: Dalotuzumab 10 mg/kg weekly +
erlotinib 150 mg daily is well-tolerated in patients Background: Met is associated with a poor outcome
with advanced NSCLC but did not increase in many cancers, including NSCLC. Met activation
PFS, OS or response rate. Further development is a mechanism of resistance to EGFR inhibition,
of this combination therapy for NSCLC is not supporting dual inhibition of Met/EGFR. MetMAb is
recommended. a monovalent monoclonal antibody that speciÀcally
binds the Met receptor.
Methods: MetMAb plus erlotinib (ME) was
compared with placebo plus erlotinib (PE) in patients
with 2nd/3rd line NSCLC in a global, randomized,
double-blind Phase II study (OAM4558g). Tissue
collection was mandatory to assess c-Met IHC
expression levels (Met Dx). The co-primary
Keywords: IGF-1R, IGF1R, dalotuzumab, MK- endpoints were PFS in the Met Dx+ population and
0646 ITT population. Additional endpoints included safety
and OS. Met Dx- patients were removed from the
ME group after the initial unblinding.
Medical Oncology II Tuesday, 5 July 2011 10:30-12:00 Results: Patients with NSCLC (n=128) were
randomized in a 1:1 ratio to receive ME or PE.
O19.03 FINAL EFFICACY RESULTS Baseline characteristics were well balanced between
FROM A RANDOMIZED PHASE II STUDY groups. 95% of tissue was evaluable for c-Met IHC,
(OAM4558G) EVALUATING METMAB 88% for EGFR and KRAS mutations, and 75%
OR PLACEBO IN COMBINATION WITH for MET FISH. Met Dx+ NSCLC, associated with
ERLOTINIB IN ADVANCED NSCLC a worse outcome (OS HR 2.52, PE cohort), was
David Spigel1, Thomas Ervin2, Rodryg Ramlau3, present in 54% of patients. After a median follow up
Davey B. Daniel4, Jerome Goldschmidt5, George of 9.9 months, a total of 99 PFS and 70 OS events
Blumenschein6, Maciej Krzakowski7, Gilles have occurred. ME resulted in a statistically and
Robinet8, Christelle Clement-Duchene9, Fabrice clinically signiÀcant improvement in both PFS and
Barlesi10, Ramaswamy Govindan11, Taral Patel12, OS in the Met Dx+ group. An OS beneÀt from ME
Sergey Orlov13, Michael S. Wertheim14, Jiping Zha15, was observed in MET FISH+ NSCLC as well as
Ajay Pandita16, Wei Yu16, Robert Yauch16, Premal in FISH-/IHC+; removing data from patients with
Patel16, Amy Peterson17 EGFR mutation did not alter the results. Selective
1
Sarah Cannon Research Institute And Tennessee beneÀt of ME was not observed in other subgroups.
Oncology, PLLC, Sarah Cannon Research Institute And Erlotinib-related toxicities were comparable between
Tennessee Oncology, PLLC/United States Of America, treatment groups.
2
Florida Cancer Specialists/United States Of America,
3
Wielkopolskie Centrum Chorob Pluc I Gruzlicy, Posnan Median
University Of Medical Sciences/Poland, 4Chattanooga (months)
Oncology Hematology Associates/United States Of Population n PFS HR OS HR PE ME 95% CI p
America, 5Blue Ridge Cancer Centre/United States 1.5 3.0 0.26-0.85 0.01
c-Met IHC+ 65 0.47
Of America, 6University Of Texas M.D. Anderson 0.37 4.6 12.6 0.20-0.71 0.002
Cancer Center/United States Of America, 7The Maria MET FISH+ 0.15-1.49 0.19
(³5 copies) 19 0.47 2.4 12.6
Sklodowska-Curie Institute Of Oncology/Poland, 8Centre
FISH-/IHC+ 37 0.44 3.6 7.1 0.17-1.15 0.09
Hospitalier Universitaire Morvan/France, 9Chu Nancy
FISH-/IHC+/ 0.22-1.59 0.29
Service De Pneumologie/France, 10AP-HM University EGFR wt 32 0.59 3.6 7.1
Of Mediterranée/France, 11Washington University *c-Met IHC- 56 3.02 9.2 5.5 1.13-8.11 0.021
School Of Medicine/United States Of America, 12Mid *ITT 128 1.09 8.2 7.1 0.62, 1.91 0.76
Ohio Onc/Hem, Inc/United States Of America, 13St
Petersbury Pavlov State Medical University/Russian *Initial data cut.
Federation, 14Hematology/Oncology Associates/United Conclusion: Greater than half the patient population
States Of America, 15Crown Bio Science/United States Of had Met Dx+ NSCLC, which was associated with
America, 16Genentech/United States Of America, 17ECD, a worse outcome. Addition of MetMAb to erlotinib
Genentech/United States Of America signiÀcantly improved PFS and OS in these patients,
resulting in a near 3-fold reduction in the risk of 3-21). All were hospitalized and 3 died. Flare was
death. This beneÀt was not exclusive to EGFR associated with a preceding shorter initial time to
mutation or MET FISH+ and was observed in FISH-/ progression on TKI (Figure 1), median 9 vs. 15
IHC+ patients, suggesting that c-MET IHC is a more months, p=0.002 (Wilcoxon) and the presence of
sensitive predictor of beneÀt from MetMAb. pleural or CNS disease (p=0.03, 0.01). There was no
Keywords: c-Met IHC, NSCLC, cMet, MetMAb association between disease Áare and presence of an
acquired T790M mutation.
Medical Oncology II Tuesday, 5 July 2011 10:30-12:00
O19.05 DISEASE FLARE AFTER

TYROSINE KINASE INHIBITOR
DISCONTINUATION IN PATIENTS WITH
EGFR-MUTANT LUNG CANCER AND
ACQUIRED RESISTANCE
Jamie E. Chaft1, Geoffrey R. Oxnard1, Vincent A.
Miller1, Mark G. Kris1, Camelia S. Sima2, Gregory J.
Riely1
1
Medicine, Memorial Sloan-Kettering Cancer
Center/United States Of America, 2Epidemiology
And Biostatistics, Memorial Sloan-Kettering Cancer
Conclusion: In patients with EGFR-mutant lung
Background: Treatment of oncogene-addicted cancer with acquired resistance to EGFR TKI,
malignant neoplasms with targeted kinase inhibitors discontinuation of erlotinib or geÀtinib prior to
is biologically and clinically different than treatment initiation of an alternative treatment is associated
with cytotoxic chemotherapy. We have observed with a clinically signiÀcant risk of accelerated
that some patients with acquired resistance to disease progression. This risk is correlated with a
EGFR tyrosine kinase inhibitors (TKI) (initial shorter period of initial disease control on TKI and
response followed by RECIST disease progression) with pleural or CNS involvement. Further work is
have accelerated progression of disease after merited to discover other clinical and molecular
discontinuation of EGFR TKI. The risk of a serious characteristics that predict this phenomenon. Future
disease Áare after discontinuing erlotinib or geÀtinib clinical trials targeting this patient population should
in EGFR-mutant lung cancer despite acquired eliminate or minimize protocol-mandated washout
resistance has not been systematically evaluated. periods. Funded by NIH T32 CA009207, P01
Methods: We identiÀed patients with EGFR- CA129243
mutant lung adenocarcinoma enrolled in 6 trials Keywords: EGFR mutatant, acquired resistance,
for treatment of acquired resistance in which TKI erlotinib, geÀtinib
discontinuation for at least 7 days was mandated
prior to treatment on trial. Disease Áare was deÀned
as symptomatic progression of disease leading to Medical Oncology II Tuesday, 5 July 2011 10:30-12:00
hospitalization or death during the washout period.
All patients met consensus criteria for acquired O19.06 LUX-LUNG 4: A PHASE II TRIAL
resistance (Jackman, JCO, 2010). OF AFATINIB (BIBW 2992) IN ADVANCED
Results: 61 patients were eligible. Baseline EGFR NSCLC PATIENTS PREVIOUSLY
mutations were exon 19 deletions (41), L858R (19) TREATED WITH ERLOTINIB OR
and 1 patient with E709A & G791A. The median GEFITINIB
time on TKI before discontinuation was 19 months Shinji Atagi1, Nobuyuki Katakami2, Toyoaki Hida3,
(range 7-78). 14 patients (23%; 95% CI 14-35%) Koichi Goto4, Takeshi Horai5, Akira Inoue6, Akiko
experienced a disease Áare after discontinuation of Sarashina7, Yoko Seki7, Robert Lorence8, Mehdi
geÀtinib or erlotinib. The median time to disease Shahidi9, Nobuyuki Yamamoto10
1
Áare from discontinuation of TKI was 8 days (range Department Of Thoracic Oncology, Kinki - Chuo
Chest Medical Center/Japan, 2Kobe City Medical assessment. The median duration of response to
Center General Hospital/Japan, 3Aichi Cancer afatinib was 12 and 16 months, by independent
Center Hospital/Japan, 4Cancer Center Hospital review and investigator assessment, respectively.
East/Japan, 5Cancer Institute Hospital/Japan, Median progression-free survival (PFS) was 4.6
6
Tohoku University/Japan, 7Nippon Boehringer months. Two patients had primary tumour T790M
Ingelheim/Japan, 8Boehringer Ingelheim mutations; one, harbouring L858R+T790M, had a
Pharmaceuticals/United States Of America, long stable disease (308 days). At data cut-off, the
9
Boehringer Ingelheim/United Kingdom, 10Shizuoka 25th percentile of overall survival was 10.6 months.
Cancer Center/Japan Common adverse events included diarrhoea, rash/
acne, stomatitis, nail effects and decreased appetite.
Background: There is an unmet medical need in Trough plasma concentrations of afatinib were rather
non-small cell lung cancer (NSCLC) patients after stable throughout courses 1–2, indicating that the
failure of erlotinib or geÀtinib [Àrst-generation, pharmacokinetics of afatinib did not change during
reversible EGFR tyrosine kinase inhibitor (TKIs)], multiple administrations.
particularly in patients with T790M EGFR Conclusion: This LUX-Lung 4 trial demonstrated
mutations, the most common mechanism of acquired that afatinib had clinically meaningful efÀcacy
resistance. Afatinib, an irreversible erbB family (including 8.2% overall response rate, 67% DCR
blocker, has a spectrum of preclinical activity that >8 weeks and 4.6-month median PFS) in spite of
includes activity against T790M. Afatinib was tested investigating a patient population expected to have
in this Phase II study (LUX-Lung 4) in patients acquired resistance to Àrst-generation EGFR TKIs.
enriched for acquired resistance to Àrst-generation Keywords: NSCLC, BIBW 2992, Phase II, LUX-
EGFR TKIs. Lung 4
Methods: Patients in Japan with Stage IIIB/IV
NSCLC (ECOG performance status of 0–1) who
had radiographic conÀrmed progression after 1–2 Medical Oncology II Tuesday, 5 July 2011 10:30-12:00
lines of chemotherapy and 12 weeks of erlotinib
or geÀtinib received 50 mg afatinib orally once O19.07 ACTIVITY AND TOLERABILITY
daily. The primary endpoint was objective tumour OF COMBINED EGFR TARGETING
response. Primary tumour tissue and/or serum were WITH AFATINIB (BIBW 2992) AND
tested for EGFR mutations just before administration CETUXIMAB IN T790M+ NSCLC
of afatinib. Three trough plasma concentrations were PATIENTS
investigated from each patient in treatment courses Leora Horn1, Harry J.M. Groen2, Egbert F. Smit3,
1 and 2. Yelena Y. Janjigian4, Yali Fu5, Fei Wang5, Mehdi
Results: Of 62 patients, 77% were female, 69% had Shahidi6, Louis Denis7, William Pao8
1
never smoked, 47% had a performance status of 0, Department Of Medicine, Vanderbilt University
and the median age was 65 years. Ninety percent Medical Center/United States Of America,
2
of patients had their primary tumour and/or serum, University Medical Center Groningen/Netherlands,
3
just before administration of afatinib, tested for Vrije University Medical Center Groningen/
EGFR mutations by local or central laboratories. Of Netherlands, 4Memorial Sloan-Kettering Cancer
these patients, 73% were EGFR mutation positive. Center/United States Of America, 5Boehringer
11%, 79% and 10% had received prior erlotinib, Ingelheim Pharmaceuticals Inc/United States Of
geÀtinib or both, respectively. 65% had achieved America, 6Boehringer Ingelheim/United Kingdom,
7
prior response to erlotinib or geÀtinib. The median Boehringer Ingelheim/Germany, 8Vanderbilt
duration of prior erlotinib or geÀtinib was 58 weeks. University/United States Of America
There was typically a short interval (median 3
weeks) between stopping prior erlotinib or geÀtinib Background: Acquired resistance (AR) after initial
and starting afatinib. For assessment of efÀcacy to beneÀt to erlotinib or geÀtinib is associated with a
afatinib, independent review revealed conÀrmed second site exon 20 EGFR T790M mutation (M)
partial responses (PRs) in 8.2% of patients and a in >50% of cases. To date, there are no effective
67% disease control rate (DCR) for at least 8 weeks. targeted therapies for NSCLC patients who develop
Similar rates of PR (13%) and disease control T790M-mediated AR. Preclinical data suggest that
(72% for >8 weeks) were noted by investigator afatinib, a potent ErbB family blocker, is active
1
in T790M M cell lines such as H1975. Combined Center For Lung Cancer, National Cancer Center,
EGFR targeting with afatinib and cetuximab Republic Of Korea/Korea, 2Cancer Biostatistics
has induced near complete responses in T790M Branch, National Cancer Center, Republic Of Korea/
transgenic murine models. This is the Àrst clinical Korea
study to assess safety and preliminary efÀcacy of this
combination in NSCLC patients. Background: Sleeve lobectomy has been introduced
Methods: Eligible NSCLC patients with clinically as an alternative procedure for the patients whose
deÀned AR (Jackman D. J Clin Oncol 2010; 28:357) pulmonary reserves are inadequate to tolerate
received oral afatinib (A) 40 mg daily with escalating pneumonectomy for lung cancer. However,
dose cohorts of biweekly cetuximab (C) and at 250 and sleeve lobectomy could lead severe anastomotic
500 mg/m2. Patients receiving the recommended Phase complications such as Àstulas and stenosis.
II dose (RP2D) were evaluated for objective response. Wedge bronchoplastic lobectomy has been
Acquisition of tumour tissue for detection of T790M at proposed as an alternative procedure to reduce these
or after emergence of AR was mandated. complications. The objective of this study was to
Results: 28 patients were treated, 24 received the evaluate the feasibility, safety and oncologic results
predeÀned maximum dose = RP2D: A 40 mg + C of wedge bronchoplastic lobectomy.
500 mg/m2. No dose-limiting toxicity was observed. Methods: We retrospectively reviewed the medical
The common adverse events were grade 1/2 rash records of 191 patients who underwent wedge
(29%/46%) and diarrhoea (46%/21%), respectively bronchoplastic lobectomy and mediastinal lymph
and three (12.5%) patients had grade 3 rash. Disease node dissection from 2001 to 2009. Bronchoscopic
control was observed in all patients enrolled at RP2D follow-up was performed in 95 patients.
(tumour size reduction up to 76%, treatment duration up
to 6+ months so far). ConÀrmed partial responses (PRs)
were seen in 8/22 (36%, 95% CI: 0.17–0.59) evaluable
patients, including 4/13 (29%) conÀrmed PRs in
T790M+ NSCLC. Enrollment continues in an 80-patient
expansion cohort meeting strict criteria for AR.
Conclusion: Combined EGFR targeting with
afatinib and cetuximab is tolerable at RP2D and
shows encouraging clinical activity following AR
to prior erlotinib or geÀtinib, including T790M+
NSCLC. Updated safety and efÀcacy including data Results: There were 174 male patients with a mean
from the expansion cohort will be presented. age of 61.8 ± 8.2 years. The median follow-up
Keywords: EGFR targeting, Afatinib, BIBW 2992, duration was 28 months. Nine patients showed severe
Non-small cell lung cancer postoperative complications such as bronchopleural
Àstula (n=3), necrosis at bronchoplasty site (n=1) or
total obstruction (n=5). Operative mortality was 7
Session O20: Surgery - Techniques (3.7%). Local recurrence was reported in 17 (8.9%)
patients and regional recurrence was reported in 12
Tuesday, 5 July 2011 patients. The 5-year overall survival was 62.8%. The
5-year overall survival was 68.6% in N0, 64.4% in
N1 and 52.6% in N2 (p=0.09). The 5-year overall
Surgery - Techniques Tuesday, 5 July 2011 10:30-12:00 freedom from local recurrence and locoregioanl
recurrence were 85.3% and 78.9%, respectively and
O20.01 WEDGE BRONCHOPLASTIC these were not different according to nodal status.
LOBECTOMY FOR NON-SMALL CELL Multivariate analysis showed that positive N1 and
LUNG CANCER AS AN ALTERNATIVE N2 node (p=0.036 and p=0.042, respectively) were
TO SLEEVE LOBECTOMY the risk factors for overall survival after wedge
Seong Yong Park1, Hyun-Sung Lee1, Hee-Jin Jang1, bronchoplastic lobectomy.
Jungnam Joo2, Bin Hwangbo1, Hee Seok Lee1, Geon Risk factors for overall survival after wedge
Kook Lee1, Moon Soo Kim1, Jong Mog Lee1, Jay il bronchoplastic lobectomy using Cox proportional
Zo1 hazard model
Multivariate
Univariate analysis
analysis
75 robotic lobectomy cases by a single surgeon
HR (95% CI) p value HR (95% CI) p value are reviewed. Each step, from port placement
Age 1.039 (0.998~1.082) 0.062 … … to exctraction of the specimen is analyzed with
Gender
2.112 (0.511~8.727) 0.302 … …
discussion of potential pitfalls at each step.
(male vs female) Results: The Àrst 75 robotic lobectomies by a single
Preoperative
chemotherapy
1.628 (0.723~3.662) 0.239 … … surgeon are reviewed. The procedure is broken
T stage down into 7 steps: 1. Patient positioning and port
T2 (vs T1) 1.802 (0.777~4.176) 0.170 … … placement. 2. Early dissection. 3. Identifying and
T3 (vs T1) 1.630 (0.602~4.417) 0.337 … … dividing lobar veins and arteries. 4. Completion of
T4 (vs T1) 2.256 (0.658~7.732) 0.196 … … Àssure. 5. Dividing the bronchus and extraction of
Nodal status (N stage) the specimen. 6. Lymph node dissection. 7. Pain
N1 (vs N0) 2.203 (1.019~4.763) 0.045 … … management and control of air leaks. Each step has
N2 (vs N0) 2.241 (0.958~5.244) 0.063 … …
its own set of problems which will vary depending
Resection margin 2.311
(above the dysplasia)
0.509 (0.123~2.105) 0.351
(1.057~5.051)
0.036 on the target lobe. Having a plan for each lobe and
Concomitant 2.426 understanding the potential problems at each step
1.710 (0.724~4.042) 0.221 0.042
pulmonary angioplasty (1.032~5.701) signiÀcantly reduces the conversion rate and the
Severe bronchial
0.622 (0.085~4.531) 0.639 … … operating room time.
complications
Conclusion: Robotic approach to lobectomy offers a
Postoperative 1.778
1.600 (0.884~2.897) 0.120 0.059 number of advantages over the VATS approach. The
chemotherapy (0.978~3.233)
Postoperative
0.606 (0.226~2.377) 0.734 … …
robotic procedure is however a signiÀcant departure
radiotherapy from standard surgical techniques and requires
the development of new set of skills. The robotic
Conclusion: Wedge bronchoplastic lobectomy approach has a unique set of potential problems
for lung cancer is a feasible procedure without that must be understood and anticipated in order to
compromising the oncological principles. It could minimize conversion and reduce operating room
be chosen as the Àrst choice as an appropriate time.
alternative to sleeve lobectomy and pneumonectomy Keywords: lobectomy, Davinci, Robotic
regardless of nodal status.
Keywords: Survival analysis, bronchoplastic A revised/updated abstract may be included in
procedure the Late Breaking Abstract Supplement, available
at the 14th World Conference on Lung Cancer. Surgery - Techniques Tuesday, 5 July 2011 10:30-12:00
O20.03 USEFULNESS OF ECG-GATED

Surgery - Techniques Tuesday, 5 July 2011 10:30-12:00 MULTI DETECTION COMPUTED
TOMOGRAPHY (MDCT) FOR
O20.02 HOW TO DO A ROBOTIC EVALUATION OF CARDIOVASCULAR
LOBECTOMY INVASION IN THORACIC MASS
Arthur T. Martella, Jane Upson Masanori Tsuchida1, Takehisa Hashimoto1, Hirohiko
Surgery, University Of Pennsylvania/United States Shinohara1, Hiroyuki Ishikawa2
1
Of America Thoracic And Cardiovascular Surgery, Niigata
University Graduate School Of Medical And Dental
Background: Robotic lobectomy is an alternative Sciences/Japan, 2Radiology, Niigata University
approach to minimally invasive lobectomy that Graduate School Of Medical And Dental Sciences/
offers some advantages over the traditional VATS Japan
approach. It is, however, new technology with its
own set of limitations and technical difÀculties. Background: One of the newest CT application
Methods: We examine the evolution of the steps technologies is cardiac synchronized image
involved in performing a Totally Endoscopic reconstruction. ECG synchronized technique on
Lobectomy with the DaVinci Robot. The Àrst multi-slice CT provide the thinner and faster scan
than that of the single detector CT within one breath- adjacent cardiovascular structures. ECG-gated
hold. To determine the feasibility and usefulness of MDCT can provide additional information and
ECG-gated Multi Detection Computed Tomography improve the accuracy of preoperative staging for
(MDCT) for evaluating cardiovascular invasion of a predicting cardiovascular invasion of a thoracic mass
thoracic mass, the sliding motion between the mass by evaluating
and adjacent structures were determined by this Keywords: ECG-gated MDCT, Cardiovascular
technology. invasion, Thoracic mass
Methods: Twenty-Àve patients with regular sinus
rhythm (20 males and 5 females, mean age 57 years)
were included in this study. They all had thoracic Surgery - Techniques Tuesday, 5 July 2011 10:30-12:00
masses with equivocal cardiovascular invasion on
regular chest CT scan that was surgically conÀrmed. O20.05 PHOTODYNAMIC THERAPY
The pathologic diagnoses were thymoma in 12, FOR NSCLC: A SINGLE INSTITUTION 12
thymic cancer in 2, lung cancer in 6, and other YEAR REVIEW
thoracic tumor in 5. The evaluated cardiovascular Patrick Ross, Susan Moffat-Bruce, Megan
structures on the ECG-gated MDCT were as follows: Hendershot, Edmund Kassis, Krista Maxey, John
aorta in 19, main pulmonary artery (MPA) in 10, Wilson
pericardium in 6, atrium in 4, superior vena cava Thoracic Surgery, Ohio State University/United
(SVC) and brochiocephalic vein (BCV) in 8. Two States Of America
radiologists independently reviewed the ECG-gated
MDCT to evaluate invasion based on the presence Background: Photodynamic therapy (PDT) is an
or absence of sliding motion between the mass and endoluminal treatment which can be utilized for
adjacent structures. The results were compared to the bronchogenic carcinoma. A unique combination
surgical results. of a photosensitizing drug and an activating non
Results: The ECG-gated MDCT images showed thermal laser light (630nm), PDT can treat malignant
the presence of sliding motion in 39 structures in lesions throughout the tracheo bronchial tree. PDT
25 patients, which were surgically conÀrmed as was initially conceived as therapy for palliation
not being invaded except one case of BCV. The of symptoms in advanced NSCLC. Control of
ECG-gated MDCT revealed the absence of sliding hemoptysis and relief of airway obstruction are
motion in 8 structures (two aortic arch, three MPA, common indications. This series evaluates the
one pericardium, one atrium, and three SVC and outcomes at a comprehensive cancer center where
BCA in 8 patients). These structures were surgically PDT has been incorporated into curative and
conÀrmed as tumor invasion, except for one distal palliative therapy for early and advanced NSCLC.
aortic arch in one patient, which were falsely Methods: A retrospective review of medical records
diagnosed as being invaded. The pericardium, and the cancer registry database was performed
cardiac chambers, and MPA usually showed for all cancer patients treated with PDT at our
excellent sliding motion between the thoracic mass institution between 1998 and 2010. The cohort of
when there was no adhesion. Absent or minimal NSCLC patients comprising this study were selected
motion of the distal aortic arch caused the absence from this population. All patients received 2mg/kg
of sliding motion on the ECG-gated MDCT. intravenously of Photofrin as the photosensitizing
drug. Dosimetry was 200 joules/cm for Àrst light
application. Initial light application occurred 48
hours after drug injection. Bronchoscopy for tumor
debridement was performed 48 hours after each light
application. Subsequent photosensitizing injections
were separated by at least 4 weeks.
Results: We treated 681 patients with PDT during
the study interval. There were 411 patients with
bronchogenic carcinoma; 381 patients had NSCLC
and formed the cohort for analysis. There were
Conclusion: The presence of sliding motion may 255 males (67%) and 126 females (33%).The
indicate that thoracic mass does not invade into average age was 61.8 years. The histology was
squamous cell in 53%, adenocarcinoma in 10% and Background: Accurate prediction of functional loss
undifferentiated NSCLC in 37%. The stages were after lung resection (PPO FEV1 and PPO DLCO),
Stage I 18%, Stage II 10%, Stage III 43%, Stage by regional lung perfusion together with spirometry,
IV 23%. The indications for PDT were as follows: is well established. A non-invasive, non-radiation
Curative 7%, Induction 29%, Symptom Control Vibration Response Imaging (VRIxp) device has
44%, Palliation 20%. All patients received 200 J/ been developed that analyzes lung sounds and
cm for the Àrst light application; 345 (90%) received calculates quantitative regional acoustic energy.
a second application and 27% received 3 or more A multi-center study is underway to corroborate
light applications following a single photosensitizing preliminary single-center results that quantitative
drug injection. The majority (331) of patients had a lung sound measurements are comparable to
single course of therapy; 10 patients had 3 or more quantitative lung perfusion for estimating PPO and
courses of injection and light application. There predicting perioperative risk.
were 4 severe photosensitivity reactions. There were Methods: Currently, 120 patients have been enrolled
no perforations of the airway. Tracheobronchial in the study at 6 USA sites; 95 patients met eligibility
strictures occurred in 2 patients; both patients for inclusion in this preliminary analysis. All subjects
required dilation. The 30 day mortality was 16% and underwent pulmonary function tests, quantitative
90 day mortality was 18% reÁecting the advanced perfusion scans and VRIxp testing before resection
stage of the cohort. Aggregate survival analysis (84 lobectomies, 12 pneumonectomies) for non-
showed 60% 1 year, 30% 2 years, 20% 3 years , 16% small cell lung cancer or other intra-thoracic
4 years, and 12% 5years. malignancies. PPO values were calculated by
Conclusion: PDT has been incorporated into the subtracting the percent functional uptake (perfusion)
management of all stages of NSCLC as deÀnitive or percent acoustic energy (VRI) of the lung
therapy and for control of symptoms. PDT for segments to be resected from the total number of
NSCLC of the central airways is associated with low segments in that lung; calculations were compared
morbidity and mortality. Photosensitivity reactions for both methods at baseline.
are infrequent with proper patient education. Results: High correlation was found between the
Multiple courses of PDT can be performed without predictions based on VRI values and those based
additional risk. Importantly, PDT can be used on perfusion (r=0.98 for PPO FEV1% and 0.99 for
successfully in combination with other therapeutic PPO DLCO%). Agreement rate between the two
modalities including, external beam radiation, methods was 92% for PPO FEV1% and 87% for
brachytherapy, chemotherapy and surgical resection. PPO DLCO%; 96% (91/95) of the estimations were
Keyword: photodynamic therapy within 10%. For PPO FEV1% estimations (Table)
there was 100% agreement for the 16 estimations of
high surgical risk (PPO FEV1 <=40%). There was
Surgery - Techniques Tuesday, 5 July 2011 10:30-12:00 good agreement between the two methods by the
Bland-Altman plot (-6.1% to 8.3% for PPO FEV1%;
O20.06 ESTIMATING POSTOPERATIVE mean difference 1.1%±7.2% and -4.9% to 6.8%
LUNG FUNCTION AND SURGICAL for PPO DLCO%; mean difference 0.96%±5.9%).
RISK OF LUNG RESECTION BY Actual FEV1% of 62%±13% (4.6±2 months post-
QUANTITATIVE BREATH SOUND op) was compared to PPO predictions in 20 patients:
MEASUREMENTS 54%±13% and 55±16% based on perfusion and
Frank C. Detterbeck1, Merav Gat2, Daniel Miller3, VRI, respectively. VRI predictions correlated better
Seth Force3, Cynthia Chin4, Hiran C. Fernando5, than perfusion with actual values (r=0.7 and 0.6).
Joshua R. Sonett6, Rodolfo C. Morice7 Actual post-op DLCO% was 58%±20% compared
1
Department Of Surgery (Thoracic), Yale University School to 50%±18% and 49±16% for VRI and perfusion,
Of Medicine/United States Of America, 2Deep Breeze Ltd/ respectively. VRI had higher correlation than
Israel, 3Emory University/United States Of America, 4Mt. perfusion (r=0.8 and 0.7).
Sinai School Of Medicine/United States Of America, 5Dept. Conclusion: Predictions based on lung function
Cardiothoracic Surgery, Boston Medical Center/United testing and quantitative breath sound measurements
States Of America, 6Columbia University Medical Center/ demonstrated high correlations with quantitative
United States Of America, 7The University Of Texas MD perfusion estimations and corroborate previously
Anderson Cancer Center/United States Of America published results. Given its simplicity of operation,
lack of radiation and the non-invasive nature of patients had p-N3. We will report the investigation
VRIxp testing, it could be a good alternative to of the prognoses of left non small cell lung cancer
quantitative perfusion scans in preoperative lung (NSCLC) patients who underwent initially our
resection assessment. extended bilateral mediastinal dissection, focused on
the patients with N2 and N3 disease. According to
Table 1. Distribution of PPO FEV1% Estimations the macroscopic dissection procedure, dissection of
Calculated by Perfusion and by VRI Quantitative the lymphatics from the lungs to the supraclavicular
Lung Sound Measurements lymph nodes was performed by sequential
removal of the related organs. We systematically
Perfusion PPO compared and reviewed the route of lymphatic
VRI PPO <40% 40-60% 60-80% >80% Total communications to the contra lateral side with the
<40% 16 2 0 0 18 anatomical signiÀcance of left-to-right lymphatic
40-60% 0 34 3 0 37 communications in the bilateral mediastinal lymph
60-80% 0 2 30 0 32 nodes.
>80% 0 0 1 7 8 Results: The overall 5-year survival rate Kaplan-
Total 16 38 34 7 95 Meier method, including operative deaths and deaths
% agreement 100% 89% 88% 100% due to unrelated diseases, was 48.4% in p-N2 left
lung cancer patients. With respect to the p-N3 factor,
% agreement for all distribution ranges = 92% the 5-year survival rate was 49.9% in p-N3±26.7%in
(87/95) N3 (neck lymph node metastases case) .
Keyword: Pulmonary function Conclusion: We found various lymphatic
communications such as between the left and right
A revised/updated abstract may be included in mediastinal lymph nodes and around the trachea in
the Late Breaking Abstract Supplement, available terms of clinical and anatomical status. The overall
at the 14th World Conference on Lung Cancer. 5-year survival rate was 48.4% in p-N2, 49.9% in
p-N3±, and 26.7% in N3³ left lung cancer patients.
Our results suggest the importance of the dissection
Surgery - Techniques Tuesday, 5 July 2011 10:30-12:00 of the bilateral mediastinal lymph nodes by median
sternotomy.
O20.07 SYSTEMATIC BILATERAL Keywords: Median Sternotomy, ND3, bilateral
MEDIASTINAL NODAL DISSECTION mediastinal lymph nodes
FOR N2,N3 LEFT LUNG CANCER
THROUGH MEDIAN STERNOTOMY A revised/updated abstract may be included in
Shingo Ikeda, Toshiya Yokota, Tatsuhiro Hoshino, the Late Breaking Abstract Supplement, available
Masashi Mikubo, Masahito Naitoh, Enjo Hata at the 14th World Conference on Lung Cancer.
Surgical Department Of Respiratory, Mitsui
Memorial Hospital/Japan
Background: Patients with p-N2, N3 cases have a

poor prognosis, and lung operation is not normally
indicated. We have performed bilateral mediastinal
lymph node dissection by median sternotomy
to resect lung cancer and dissect the bilateral
mediastinal lymph nodes. However, some studies
have examined the communication between the left
and right tracts in lung cancer cases, we anatomically
analyzed this technique, and conÀrmed its clinical
result.
Methods: We have performed this operation in 265
patients with primary left lung cancer excluding
small cell carcinoma and stageIV since 1987. 43out
of 265 patients had p-N2 lymph node metastases, 33
Session O21: Nursing I month assessment. Factors signiÀcantly associated

with successful quitting were baseline readiness to
Tuesday, 5 July 2011 quit and a need for hospitalization during cancer
treatment. Those who quit had signiÀcantly lower
distress scores and higher SCQoL self-control
Nursing I Tuesday, 5 July 2011 10:30-12:00 domain scores at 12 months than non-quitters.
Conclusion: Patients still smoking when diagnosed
O21.01 A PROSPECTIVE COHORT with a curable cancer are highly-addicted smokers
STUDY OF CURRENT AND RECENT EX- who require intensive support to quit. Those who do
SMOKERS OFFERED ENROLMENT IN quit report less distress and a greater sense of self-
A SMOKING CESSATION PROGRAM control. Population measures to stop people starting
FOLLOWING DIAGNOSIS OF A smoking are essential.
POTENTIALLY CURABLE CANCER Keywords: Smoking, quitting, supportive care
Linda Mileshkin1, Ingrid Plueckhahn2, Deborah
Cruickshank2, Leonid Churilov3 A revised/updated abstract may be included in
1
Division Of Cancer Medicine, Peter MacCallum the Late Breaking Abstract Supplement, available
Cancer Centre/Australia, 2Peter MacCallum Cancer at the 14th World Conference on Lung Cancer.
Centre/Australia, 3Florey Neuroscience Institutes/
Australia
Nursing I Tuesday, 5 July 2011 10:30-12:00
Background: There is good evidence that people
treated for curable cancers have better survival rates O21.02 BREATHE EASY: A
if they quit smoking. A cancer diagnosis provides a PILOT PROJECT FOR DYSPNEA
“teachable moment” when healthcare providers can MANAGEMENT IN LUNG CANCER
offer smoking-cessation treatment. This prospective PATIENTS
single-arm study aimed to assess the impact of a Lida Ahmadi1, Tracey Das Gupta2, Tammy Lilien3,
tailored smoking-cessation intervention for cancer Magdalene Winterhoff2, Leslie Gibson3, Anita
patients. Chakraborty2, Giovanna Sirianni2, Jeff Myers2, Yee
Methods: Eligible patients had recently diagnosed C. Ung4
1
curable cancer, were planned for or were Radiation Oncology, Odette Cancer Centre/Canada,
2
receiving treatment with curative intent and were Odette Cancer Centre/Canada, 3Sunnybrook Health
current smokers or recent quitters (<30days). Sciences Centre/Canada, 4Dept Radiation Oncology,
The intervention involved an initial face-to-face Odette Cancer Centre/Canada
motivational interview and regular follow-up by
a trained quit counsellor nurse. Free nicotine- Background: Dyspnea is the subjective experience
replacement therapy and/or access to other of breathing discomfort and is present in 60-70%
appropriate pharmacotherapy was provided. Quit of lung cancer patients. It is a distressing symptom
rate was measured by self-report with biochemical which is often inadequately evaluated and managed
conÀrmation, and patient distress and quality of in lung cancer patients. A nursing led initiative
life using the distress thermometer and smoking- was piloted to screen, evaluate and educate lung
cessation quality of life questionnaire (SCQoL) cancer patients at a regional cancer centre involving
respectively. The primary end-point was the a multidisciplinary and interprofessional team
prolonged abstinence rate at 12 months. consisting of nurses, occupational therapist, social
Results: A pragmatic sample of 71 patients (61% worker, palliative care physicians and lung cancer
male) with a mean age of 54 (range 27-71) was oncologists. This pilot project used the Edmonton
accrued. Forty-one pts (58%) had a smoking-related Symptom Assessment System (ESAS) to screen
cancer with 27 (38%) employed and 24 (34%) living patients for dyspnea and then depending on the
with another smoker. Most patients were heavily severity, the patients were offered educational
addicted and had started smoking at a mean 16 materials, enrollment in a breathing exercise class or
years (range 7-25). The prolonged abstinence rate opiod narcotics for symptom control.
at 12 months was 24% (95%CI 14-36%) with 37% Methods: Lung cancer patients seen in the outpatient
having not smoked in the 7 days prior to the 12 department of a regional cancer centre are screened
using ESAS evaluating symptoms of pain, fatigue, Nursing I Tuesday, 5 July 2011 10:30-12:00
nausea, depression, anxiety, drowsiness, appetite,
overall well being and dyspnea. The ESAS is a 10 O21.03 AN INTER-PROFESSIONAL
point score that rates the severity of each symptom MODEL OF CARE TO IMPROVE
from 0 to 10. The severity can be divided into low SURGICAL OUTCOMES IN
(scores of 1-3), moderate (scores of 4-6) and severe THORACIC ONCOLOGY OR “BETTER
(scores of 7-10). Any patient who rates a dyspnea PREPARATION EQUALS IMPROVED
score of 4 or higher is immediately identiÀed and PATIENT OUTCOME”
then evaluated by an oncology nurse to verify Chantal Bornais1, Christine Blais1, L. Murphy2, P.
the severity of the dyspnea. The patient is then Chamberland3
1
evaluated by the oncologist and the ESAS scores Integrated Cancer Program, The Ottawa Hospital/
reviewed. Any reversible or medically treatable Canada, 2Social Work, The Ottawa Hospital/Canada,
3
causes of dyspnea are evaluated by the oncologist Physiotherapy, The Ottawa Hospital/Canada
and appropriate care given according to the
etiology of the dyspnea. In addition the oncologist Background: In January 2007, the Thoracic Cancer
evaluates the need for any intervention with opiods Assessment Clinic (CAC) in Ottawa, Canada,
for symptom control. If patients are started on opened with a mandate to provide rapid assessment,
opiods the oncology nurse contacts the patient diagnostic services and initiation of treatment to
by telephone within 48-72 hours to evaluate the patients with suspected or newly diagnosed lung
effectiveness of the intervention. The oncology nurse cancer. Since its inception, the CAC has developed
further evaluates the patients using a qualitative many new methods of caring for lung cancer patients
questionnaire and then discusses with the patient any with the intention to provide as much information
educational material on dyspnea management and as is available to patients regarding the cancer care
also offers enrollment to the Breathe Easy dyspnea system; including diagnostic processes, treatment
class. Patients are asked to complete the EORTC and support. The previous model of care involved
QLQ QC30 questionnaire prior to the class. At the eligible surgical patients having all the pre-operative
Breathe Easy class, participants are taught breathing preparation in a pre-admission unit (PAU) that
exercises as well as other techniques to manage services all surgical areas within a large urban
their dyspnea. About 4-6 weeks after the class, teaching hospital. With this model, lung cancer
participants are contacted again to repeat the ESAS, patients were reporting feeling unprepared for
EORTC QLQ QC30, Canadian Problem Checklist surgery and recovery. Indeed, feedback from the in-
and a satisfaction survey. patient staff substantiated this viewpoint as patients
Results: This is an ongoing pilot study. Qualitative were not participating fully in their recovery with
data on patient acceptance of the Breathe Easy class discharge delays occurring in some cases.
is encouraging. ESAS and EORTC QLQ QC30 data Methods: To address this issue, the CAC staff has
have been collected on the Àrst 12 patients enrolled developed a teaching session that replaces the PAU
on the Breath Easy class. Followup reevaluation teaching. The newly developed session provides an
scores will be updated. inter-professional focus involving nursing, social work,
Conclusion: This nursing led initiative on dyspnea physiotherapy, anaesthesia and thoracic surgeons to
management has enhanced interprofessional maximize patient comprehension and involvement in
collaboration among health care professionals caring the preparatory and recovery phases of surgical care.
for lung cancer patients. The Breathe Easy class is Results: The initial goal of increasing patient
feasible and has had good patient satisfaction. It knowledge and thereby reducing anxiety levels
is hoped the active screening and intervention for regarding upcoming surgery was achieved. More
symptoms of dyspnea will enhance the care of our importantly, many other unplanned beneÀts also
lung cancer patients and decrease the need for these became apparent. Feedback received from patients
patients to be seen in emergency care. and their support systems including family and
Keywords: dyspnea, Lung cancer, breathing friends both pre-operatively and post operatively
exercises indicates the value of this session beyond the needs
of the patient. Assessment of potential discharge
planning issues at time of teaching has evolved as an
important added beneÀt from this session.
Conclusion: Although initially designed based on Results: A total of 44 evaluable patients were
health care team expectations for patient recovery enrolled in the study. Twenty patients were women
and observed patient struggles during preparation and 24 were men. Forty patients had lung cancer, 37
for, and recovery from surgery, the pre-operative non small cell lung cancer and four small cell lung
teaching session continues to evolve. The session is cancer histology. Two patients had a diagnosis of
now reÁective of the needs of patients as dictated by esophageal cancer and two had pancreatic cancer.
the patient population and their support systems. Eighteen patients had locally advanced cancers
Keywords: pre-operative teaching, Interprofessional and 26 had advanced cancers. All but one patient
care received chemotherapy. The median score for the
baseline KPS was 80 with a range of 50-90, the
median baseline score for the LCSS item was 47
Nursing I Tuesday, 5 July 2011 10:30-12:00 with a range of 0-100 and the SF-36 baseline score
median was 35 with a range of 0-90. When the
O21.05 COMPARISON OF PERFORMANCE KPS and SF-36 scores were analyzed, there was a
STATUS AS RATED BY PATIENTS USING positive correlation of 0.50 with a signiÀcant Wald
WEB-BASED QUALITY OF LIFE TOOLS test p-value < 0.0001. The KPS and LCSS Normal
AND KARNOFSKY PERFORMANCE Activity scores correlated negatively with a score of
STATUS RATINGS AS DETERMINED BY A -0.39 with a signiÀcant Wald test p-value of 0.01.
HEALTHCARE PROVIDER Conclusion: Patient reported performance status
Paula A. Caron, Ellen Parker, Jiang Gui, Mark Carey, on the SF-36 Health Survey via web-based tools
Ian Williams, Konstantin H. Dragnev, James R. Rigas correlated positively with KPS as rated by a health
Thoracic Oncology, Dartmouth Hitchcock Medical care provider during clinic visits. However, the KPS
Center/United States Of America and normal activity score on the LCCS correlated
negatively. The disparity between patient responses
Background: Performance status is a crucial to the question, “How much has your illness
variable considered when patients are enrolled affected your ability to carry out normal activities?”
in clinical trials. Multiple patient administered and observer rating of the KPS raises questions
validated tools exist to measure quality of life and about routine use of the KPS to determine patient
functional status. The Karnofsky Performance Status functioning. A web based patient completed rating
(KPS) scale is a clinician driven tool to measure tool such as the SF-36 or LCSS may provide more
performance status. Patient performance status is accurate measurements of a patient’s performance
usually based on the KPS rather than a patient’s self status than subjective rating by a healthcare provider.
rating using a validated tool. Keywords: Karnofsky Performance Scale (KPS),
Methods: Patients enrolled in a pilot web-based SF-36, Lung Cancer Symptom Scale (LCSS),
study of cancer patients with anemia receiving performance status
growth factor support completed four web-based
assessment tools using a PC tablet. The study tools
were completed at time of enrollment for a baseline Nursing I Tuesday, 5 July 2011 10:30-12:00
score and every three to four weeks while the patient
was on study. For the purpose of this analysis, the O21.06 CHEMOTHERAPY REVIEW BY
physical functioning health domain score from each SPECIALIST LUNG CANCER NURSES
entry date of the SF-36 Health Survey, and the score Rachel Thomas, Sarah Compton
for each entry of the normal activity question of the Medical Oncology, Guy’s And St Thomas’ NHS
Lung Cancer Symptom Scale (LCSS) was compared Foundation Trust/United Kingdom
to the KPS score . Each completion date of the SF-
36 and the LCSS was considered a data point for Background: With appropriate training and
comparison with the corresponding KPS score for competencies nurses can review patients receiving
that date. Medical records were reviewed to obtain chemotherapy. This utilises nurse and doctor skills
KPS scores corresponding to dates the LCSS and more efÀciently and provides opportunities to
SF-36 were completed on-line by patients. A linear improve the quality of patient care. A patient survey
mixed effect model was employed to account for identiÀed dissatisfaction with the oncology service
variation introduced by patients’ multiple visits. at Guy’s hospital. SpeciÀcally, it highlighted a lack
of pro-active support, assessment and monitoring potential of facilitating communication, maintaining

of patients following the Àrst cycle of treatment. In continuity of care and improving overall outcomes as
addition patients were waiting between 60 and 90 patients travel through their experiences enrolled in
minutes to see the oncologist. clinical trials.
Methods: Following a service review and discussion Methods: This presentation will describe the
with medical staff and senior management, a importance of optimal patient management in a
CNS-led clinic was proposed to address the issues clinical trial in order to improve outcomes for lung
identiÀed by the survey. Nurses will have completed cancer patients. Obtaining unique data related to how
a chemotherapy course and have competencies in a patient’s personal experience in conducting a trial
running a nurse-led clinic. Initially the clinic will affects his outcome, is very useful. The important
include patients receiving the oral and intravenous roles/responsibilities of the clinical research team
agents, erlotinib, vinorelbine and cisplatin. The CNS members will be described.
carries out consent, a pre-treatment consultation Results: The invaluable collaborative relationship
talk and all treatment reviews. The oncologist sees between the research team and the IPO in ensuring
the patient following scans and also if they meet the continuity for a complex treatment plan will be
toxicity speciÀc indications for doctor review. outlined.
Results: Patients undergo a comprehensive holistic Conclusion: In conclusion, the potential beneÀts of
assessment in the new clinic. Waiting time have been the involvement of the research team and IPO in the
reduced. The clinic runs in parallel to the oncologist conduct of clinical trials for lung cancer patients will
clinic who are available for support. The weekly be presented. Future directions will be proposed.
clinic is run by one of two nurses, providing cover
for leave and sickness.
Conclusion: The new clinic provides a high quality Session O22: Technology and Models
nurse-led service with continuity of care and less
waiting for patients. Nurses are more likely to Tuesday, 5 July 2011
perform a comprehensive protocol-led and holistic
review. Doctor time is released to see challenging
and clinical trial patients. Future plans include Technology and Models Tuesday, 5 July 2011 10:30-12:00
an audit of the new service, expansion into other
treatment areas with additional clinics and nurse O22.01 BLOOD-BORNE CANCER CELLS
prescribing. IN PULMONARY VEINS IN SURGICAL
Keyword: Nurse Led On Treat Patient Clinic NON-SMALL CELL LUNG CANCER
(NSCLC)
Samer Alchab1, Stephane Vignes2, Elisabeth
Nursing I Tuesday, 5 July 2011 10:30-12:00 Memba1, Bernard Bazelly2, Jalal Assouad2, Valerie
Gounant2, Jean-François Bernaudin1, Dominique H.
O21.07 CLINICAL RESEARCH TEAM Grunenwald3
AND “ADVANCED PRACTICE NURSE” 1
Histology And Tumor Biology, Er2upmc Hôpital
COLLABORATION: IMPROVING Tenon Paris France/France, 2Thoracic Surgery,
OUTCOMES THROUGH OPTIMAL Hopital Tenon./France, 3Thoracic Surgery, Hopital
MANAGEMENT. Tenon. University Of Paris Vi/France
Penny Chipman, Carol Burnett
Department Oncology, Clinical Research Program, Background: Patients with NSCLC have a high risk
Mcgill University/Canada of relapse even after complete surgical resection.
The presence of cancer cells in the pulmonary
Background: Lung cancer care teams face venous blood draining the tumour may be a potential
signiÀcant challenges in supporting patients and their primary source of haematogenous dissemination
families throughout the rapid and often short illness even at the time of surgery.
trajectory of lung cancer patients. The important Methods: A consecutive series of 16 patients with
collaborative role between the clinical research completely resected primary NSCLC, was studied.
team and the advanced practice nurse, known as Blood samples were collected on EDTA from the
”InÀrmier(e)Pivot (IPO)” in Quebec, Canada, has the pulmonary vein draining the tumor after vessel ligation.
Within 2 hours, blood mononuclear cells were collected Background: Mitosis is a highly complex series
after Ficoll gradient centrifugation and cancer cells of events that requires careful coordination to
were selected after incubation with anti-CD326EpCAM navigate successfully. Protein phosphorylation
microBeads and magnetic isolation [MACS Cell by a small number of kinases, in particular by the
isolation Technology (Milteny Biotec France)]. Aurora, CDK1-cyclinB and Polo-like kinase 1 (Plk1)
Cytospins of the cells obtained either without ( n:10) enzymes, orchestrates almost every step of mitosis,
or after (n:6) magnetic isolation were immunolabelled from entry to cytokinesis. However, these enzymes
with anti CK antibody [Pan-Cytokeratin Mouse are also frequently dysregulated in many human
Monoclonal Antibody NovocastraTM] for epithelial cancers, including cancers of the lung. To discover
characterization. Preliminary experiments have more about the respective functions of Aurora A,
been done using A549 cell line and peripheral blood Aurora B and Plk kinases, we mapped mitotic
mononuclear cells from donors. phosphorylation sites to these kinases through the
Results: Pulmonary venous blood sampling then combined use of quantitative phosphoproteomics
isolation by Ficoll-Hypaque allowed to collect (20 and selective targeting of kinase activities by
± 10) ml of blood and (37 ±10) x106 mononuclear small molecule inhibitors. This work uncovers
cells or (1.8 x106) cells/ml. Using the magnetic new functional roles and establishes new substrate
isolation technique, it was possible to recover an recognition motifs for these kinases, and provides
average of 10 cytokeratinplus cancer cells per 20 an analytical template for further use in dissecting
x106 mononuclear cells or per 15 ml of blood. kinase signaling events in other areas of systems
Cytokeratinplus cells were detected in respectively biology and translational biomedical research.
7/10 and 6/6 patients without or after magnetic Methods: To scan mitotic cells for substrates
isolation. Detection of cancer cells without magnetic of the Aurora A, Aurora B, and Plk enzymes,
isolation which was a laborious and tedious method we quantitatively determined differences in the
was obtained in 70% of the patients, while after phosphorylation status of proteins from mitotically
isolation 100% of the samples contained cancer cells. arrested HeLa cells treated with respective kinase
This last method provided the necessary sensitivity inhibitors by SILAC, in which control (light)
for the detection and isolation of very small numbers cells were treated with Taxol and MG132, while
of circulating tumor cells. kinase-inhibited (heavy) cells were treated with
Conclusion: This work has enabled us to develop a Taxol, MG132 and either MLN8054, AZD1152,
method for collecting tumor cells in the pulmonary or BI2536 (selective small molecules that target
venous blood draining NSCLC at time of surgery. Aurora A, Aurora B, and Plk enzyme activities).
The results show that it is an important phenomenon Heavy and light cells were mixed, lysed, digested,
found in 81.25% of patients. This method allows and processed for phosphorylation by strong cation
to study more thoroughly the characteristics of exchange (SCX) chromatography, followed by TiO2
circulating cancer cells in NSCLC. treatment to enrich for phosphorylation and analysis
Keywords: NSCLC, cancer cells by LC-Orbitrap MS/MS.
Results: Over the course of eight separate SILAC
experiments we sequenced a total of almost 900,000
Technology and Models Tuesday, 5 July 2011 10:30-12:00 redundant phosphopeptides on 6061 mitotic proteins.
Using clustering methods we were able to connect
O22.02 QUANTITATIVE PROTEOMICS 127 sites on 101 proteins to Aurora kinase A activity,
IDENTIFIES NOVEL SUBSTRATES 165 sites on 127 proteins to Aurora kinase B activity,
OF THE AURORA AND POLO-LIKE and 486 sites on 334 proteins to Plk activity. Each
KINASES of these datasets was interrogated separately for
Arminja N. Kettenbach1, Devin K. Schweppe2, motifs, revealing both previously described but also
Konstantin H. Dragnev3, James R. Rigas3, Scott A. undescribed linear substrate sequence elements that
Gerber1 were sufÀcient for enzyme targeting in cells. In
1
Norris Cotton Cancer Center, Dartmouth Medical addition, we were able to observe cross-regulation
School/United States Of America, 2Genetics, of Aurora kinase A and Plk kinase activities on
Dartmouth Medical School/United States Of substrates of the cognate kinases, conÀrming
America, 3Thoracic Oncology, Dartmouth Hitchcock previous reports of these relationships and
Medical Center/United States Of America expanding our view of the biological role that this
cross-regulation effects in mitosis. We were able to assay data was combined. By this combination, 30
demonstrate that several of these candidate substrates hypermethylated and down-regulated genes, and 22
were efÀciently phosphorylated by puriÀed kinase hypomethylated and up-regulated genes were selected.
in vitro, supporting the likelihood of our candidate The gene expression level and DNA methylation
kinase assignment as correct. Using bioinformatic pattern were conÀrmed by semi-quantitative RT-PCR
tools, we discover a highly interconnected network and pyrosequencing, respectively.
of centrosomal, spindle-associated and kinetochore- Results: By these validations, we selected 5 hyper-
associated proteins that are targets of these kinases. methylated and down-regulated genes, and 1
Finally, we found that a single, speciÀc Aurora kinase hypo-methylated and up-regulated gene. We could
A phosphorylation site on the mitotic protein NuMA1 identify speciÀc CpG sites of the promoter of those
appears essential for proper spindle localization of the 6 genes that showed apparent differences of DNA
protein and for the spindle bipolarity of HeLa cells. methylation between normal lung and SCC. In
Collectively, these data advance our understanding of addition, with the aid of pyrosequencing, we could
the essential role these kinase families in mitosis, and obtain the data reÁecting the quantitative differences
reveal candidate mechanisms by which these enzymes of DNA methylation of speciÀc promoter regions
regulate cell division. between normal lung and SCC. These 6 genes were
Conclusion: Our technology-driven approach has proven to be actually regulated by DNA methylation
allowed us to connect oncogenic kinase activities by conÀrming the recovery of their DNA
with phosphorylation sites in lung cancer cells. methylation pattern and gene expression level using
Keywords: plk1, aurora, proteomics, kinase a demethylating agent. The DNA methylation pattern
of the CYTL1 promoter region was signiÀcantly
different between early and advanced stages of SCC.
Technology and Models Tuesday, 5 July 2011 10:30-12:00 Conclusion: we combined the whole genome DNA
methylation pattern and the gene expression proÀle
O22.04 GENOME-WIDE ANALYSIS OF speciÀc to SCC of the lung. Through this study,
DNA METHYLATION AND THE GENE we proved this method is very effective in Ànding
EXPRESSION CHANGE IN LUNG genes regulated by DNA methylation and we found
CANCER 6 genes (CCDC37, CYTL1, CDO1, SLIT2, LMO3
Hae Won Lee, Yong Jae Kwon, Moon-Chul Kang, and SERPINB5) in SCC of the lung which is highly
Heejong Baek, Jong Ho Park related to smoking. Hypermethylation process occurs
Department Of Thoracic Surgery, Korea Cancer in the early period of carcinogenesis and is reversible
Center Hospital/Korea by demethylating agent. So cancer related genes
overexpressed by hypermethylation are supposed to
Background: The recent DNA methylation studies be reversible or controllable. We hope that this result
on cancers have revealed the necessity of proÀling an can contribute to the development of a new method
entire human genome, and not to restrict the proÀling for the early detection and prevention of lung cancer.
to speciÀc regions of the human genome. It has been Keywords: DNA methylation, whole genome
suggested that genome-wide DNA methylation analysis analysis, Microarray
enables us to identify the genes that are regulated by
DNA methylation in carcinogenesis of lung cancer.
Methods: We used a total of 50 tissue samples from Technology and Models Tuesday, 5 July 2011 10:30-12:00
50 lung cancer patients who underwent surgery at
Korea Cancer Center Hospital without preoperative O22.05 NEUROENDOCRINE
treatment. The histology of all the specimens was TRANSCRIPTION FACTOR ASCL1
squamous cell carcinoma. The mean age of patients DEFINES MULTIPLE PROGENITORS
was 62.6 years (42-82) and 48 persons (96%) had IN THE LUNG DURING THE
the history of smoking. We used another 21 samples DEVELOPMENT AND REPAIR
for the microarray, 3 samples for the whole genome Ilona Linnoila1, Yan Li2
1
DNA methylation assay and 30 samples for semi- Exp. Pathology Section, Ccbb, Nci, Nih/United
quantitative RT-PCR and pyrosequencing. The clinical States Of America, 2Nci, Nih/United States Of
information was obtained from the medical records. America
Microarray data and whole genome DNA methylation
Background: Pulmonary neuroendocrine cells given naphthalene (300mg/kg of body weight)

(PNECs) are a minor subpopulation in the airway intraperitoneally and examined after 1-5 days. In
epithelium. However, up to one third of lung cancers this model naphthalene kills Clara cells, which is
display neuroendocrine (NE) features, ranging from followed by their rapid regeneration and a transient
less aggressive carcinoids to the highly virulent PNEC hyperplasia by day 5.The experiment
small cell lung cancers. While PNECs possess a self- revealed increased contribution of Ascl1 lineage
renewal function, their role in lung development or cells to PNECs, while a portion of regenarating
carcinogenesis remains unclear. We have previously airway epithelial cells was also derived from Ascl-
shown that Ascl1, a proneural basic helix-loop-helix expressing progenitor cells.
transcription factor, is critical for the development Conclusion: The proneural transcription factor
of PNECs. The expression of Ascl1 is also tightly Ascl1-deÀned cellular lineage contributes to the
linked to the NE phenotype in lung cancer. On the formation of PNECs as well as to the various known
other hand, little is known about the differentiation progenitor populations of epithelial (non-NE) cells
potential of Ascl1 lineage in the lung. Aim We which include Clara, Type II and potentially ciliated
investigated the descendants of Ascl1-deÀned cells during embryonic lung development and injury
cellular lineage during lung development and injury repair. Further studies are needed to determine the
repair. role of Ascl1 lineage descendants in carcinogenesis.
Methods: We used immunohistochemistry and Keywords: Ascl1, progenitor, lung, Neuroendocrine
genetically engineered mice.
Results: During mouse embryogenesis pulmonary
Ascl1 positive cells became Àrst evident on Technology and Models Tuesday, 5 July 2011 10:30-12:00
embryonic day (E)12.5, while the markers CGRP,
CC10, ơ-tubulin and SPC for mature PNECs, O22.06 SAMPLE HANDLING AND
epithelial airway (Clara and ciliated) and alveolar PROCESSING ARE CRITICAL FACTORS
Type II cells, respectively, were all detected later INFLUENCING THE RESULTS OF
(E17.5). Ascl1-GIC (Development 2007:135:285- WHOLE GENOME GENE EXPRESSION
293) mice were crossed with R26R-stop-lacZ PROFILING IN LUNG CANCER TISSUES
reporter mice, to reveal Ascl1-deÀned cells and Maxim B. Freidin1, Neesa Bhudia1, Eric Lim2,
their descendants that expressed Cre recombinase Andrew G. Nicholson2, Sanjay Popat3, William O.
and stained blue with X-Gal. The number of blue Cookson1, Miriam F. Moffatt1
1
cells increased dramatically with age both along National Heat And Lung Institute, Imperial College
the airways and in the alveolar compartment, far London/United Kingdom, 2Academic Department Of
exceeding the number of any PNEC populations. Thoracic Surgery, Royal Brompton Hospital/United
Using in vivo lineage tracing with inducible Cre Kingdom, 3Royal Marsden Hospital/United Kingdom
recombinase (Ascl1-CreERTM;R26R-stop-lacZ),
we followed the cell fate of Ascl1-expressing Background: Lung cancer is the leading cause
precursors after administering tamoxifen at of cancer death worldwide. Gene expression
different developmental points. Ascl1 lineage cells proÀling can allow the identiÀcation of subgroups
contributed, in time dependent manner, to several of cancer allowing early prediction of disease
diverse phenotypes identiÀed by histology and progression and survival. The quality of biological
immunohistochemistry. The cells expressing Ascl1 at samples and their handling may strongly inÁuence
E9.5 gave rise to PNECs, Clara, ciliated and alveolar global gene expression, but these factors have not
Type II cells during lung maturation. Interestingly, been controlled for in many reported studies. We
Ascl1-expressing progenitor cells also gave rise to therefore set out to investigate systematic changes
neural ganglion cells adjacent to embryonic airways. in gene expression that may occur between surgical
In contrast, the lineage of the cells expressing Ascl1 resection, routine processing in the histopathology
on E11.5 was only traced to airway lining cells, department, frozen storage, and long term archiving
but not alveolar Type II pneumocytes. In order to in FFPE blocks.
study the fate of Ascl1 lineage descendants during Methods: Lung carcinoma tissue samples were
injury repair, adult Ascl1-GIC;R26R-stop-lac-Z or obtained from six patients undergoing resection of
Ascl1-CreERTM;R26R-stop-lacZ mice that received primary tumours. Genome-wide gene expression was
four doses of tamoxifen prior to treatment, were established at 5 time points (T1= at thoracotomy,
preserved in RNAlater; T2 = immediately after Session O23: Tri- and Biomodality

tumour resection, preserved in RNAlater; T3 =
~30 minutes interval between removal of specimen Wednesday, 6 July 2011
and its transition to histopathology department,
preserved in RNAlater; T4 = ~30 minutes interval
between removal of specimen and its transition to Tri- and Biomodality Wednesday, 6 July 2011 14:30-16:00
histopathology department, snap-frozen; T5 = 1
week storage at -80C (after snap freezing) using O23.01 PRE-OPERATIVE
Illumina HumanWG-6 v2.0 Expression Bead-Chip. CHEMOTHERAPY IMPROVES SURVIVAL
In addition, genome-wide gene expression was also AND REDUCES RECURRENCE IN
examined for samples from standard formalin-Àxed OPERABLE NON-SMALL CELL LUNG
and parafÀn embedded blocks (FFPE) for each CANCER: PRELIMINARY RESULTS OF
patient. A SYSTEMATIC REVIEW AND META-
Results: Sampling immediately after resection ANALYSIS OF INDIVIDUAL PATIENT
closely represented the tissue obtained in situ, with DATA FROM 13 RANDOMISED TRIALS
only 193 (1%) of genes differing more than two- Sarah Burdett1, Larysa H. Rydzewska1, Jayne F.
fold between T1 and T2. Delaying tissue harvest Tierney1, Jean-Pierre Pignon On Behalf Of The
for an average transition time of 30 minutes from Nsclc Meta-Analyses Collaborative Group2
1
the operating theatre had a signiÀcant impact on Meta-analysis Group, MRC Clinical Trials Unit/
gene expression proÀles with approximately 25% to United Kingdom, 2Gustave-Roussy Institute/France
33% of genes differing between T1 and T3-T5 time
points. We found many genes previously identiÀed Background: Results from two previous individual
as lung cancer biomarkers that were altered in this patient data (IPD) meta-analyses found that giving
period. Examination of FFPE specimens showed chemotherapy (CT) after either surgery or surgery
minimal correlation with fresh samples. Two big plus radiotherapy (RT) improves survival in patients
clusters of differentially expressed genes were with non-small cell lung cancer (NSCLC). However,
identiÀed which distinguish T1/T2 time points from giving CT prior to surgery may increase resectability
later ones. Top genes in these clusters are those and eradicate micro-metastases. Pre-operative CT
recognised to be important for the inÁammatory may also be given to a broader range of patients and
response (TNF, IL18, NFKB), cellular growth and be better tolerated.
proliferation (MAPK, PDGF), cell death and tissue Methods: We conducted a systematic search for
development (FOS, OSM, IL6, Cyclin A). Pathway randomised controlled trials (RCTs) followed by the
analysis revealed “InÁammatory Response” and central collection, checking and analysis of updated
“Cell-to-Cell Interaction and Signalling” among individual patient data (IPD). For each outcome,
the top biological processes appearing in transition results from individual RCTs were combined using
between T1/T2 and dated samples. the Àxed-effect model. We pre-speciÀed analyses to
Conclusion: Sample handling and processing are explore any variation in effect by trial and patient
critical factors when conducting and interpreting characteristics.
results for Lung Cancer gene expression proÀling. Results: We identiÀed 18 RCTs, but data are
Genes affected by sample handling are of functional unavailable for two and are awaited for a further
importance of lung cancer development Tissue three of these. Therefore, we currently have IPD
collection for gene expression analysis immediately from 13 trials and 2094 patients; 81% of all patients
after lung resection with conservation in RNAlater is randomised. Nine trials gave all chemotherapy pre-
an optimal strategy for gene expression proÀling. operatively and four trials used pre and some post-
Keywords: gene expression, FFPE, specimen operative CT. Seven trials also used post-operative
handling, Lung cancer RT in both arms. Platinum-based chemotherapy
was used in all but one trial (of docetaxel). 80%
of patients were male, 57% were aged 65 years or
younger and 86% had a performance status of 0 or
1. 6% of the patients had clinical stage Ia disease,
44% had stage Ib, 26% had stage II and 24%, stage
III. 52% had squamous tumours and 28% had
adenocarcinomas. The results show a signiÀcant Oncology, University Of Maryland/United States

beneÀt of pre-operative CT on survival (HR=0.88, Of America, 4St. Joseph’s Hospital/United States
95% CI 0.79-0.98, p=0.025), representing an Of America, 5Department Of Surgery, University
absolute improvement of 5% at 5 years (from 35% Of Maryland/United States Of America, 6Radiation
to 40%). There was no clear evidence of a difference Oncology, Medical College Of Wisconsin/United
in this effect by the CT regimen or scheduling, the States Of America, 7Radiation Oncology, University
number of drugs, the platinum agent used or whether Of California, San Francisco/United States Of
post-operative RT was given. Also, there was no America, 8Tt Southwestern Medical Center/United
good evidence that any patient subgroup deÀned by States Of America
age, sex, performance status or histology beneÀted
more or less from pre-operative CT. Similarly, Background: Multimodality therapy has curative
neither the relative nor absolute beneÀts differed potential in patients presenting with stage III non
by clinical stage. Recurrence data were available small cell lung cancer. Mediastinal clearance after
from 12 trials (2035 patients) and were analysed at induction chemoradiation has been associated with
a landmark time of 6 months from randomisation to superior outcomes and may serve as an important
the Àrst event. The results show a signiÀcant beneÀt intermediate marker for efÀcacy. RTOG 0229 is
of pre-operative CT on time to local recurrence a phase II trimodality trial designed to evaluate
(HR=0.83, 95% CI 0.70-1.00, p=0.048), time mediastinal clearance rates following induction
to distant recurrence (HR=0.67, 95% CI 0.57- concurrent chemotherapy with full dose RT.
0.80, p<0.000003), and recurrence-free survival Methods: Patients with stage III NSCLC
(HR=0.86, 95% CI 0.77-0.96, p=0.007). Based on (pathologically proven N2 or N3) were eligible.
8 trials, there was no clear evidence of increased or All patients were deemed to be candidates for
decreased complete resection rate with pre-operative trimodality therapy prior to the initiation of
CT. IPD from the remaining trials will be included therapy. Participating surgeons were required to
and results updated. demonstrate expertise in surgery after chemoXRT
Conclusion: These preliminary results demonstrate and adhere to speciÀc guidelines regarding surgical
that pre-operative CT signiÀcantly reduces local procedure and postoperative management. Induction
and distant recurrence and improves recurrence-free chemotherapy consisted of weekly CBDCA
survival and overall survival in NSCLC. Absolute (AUC =2.0) and paclitaxel 50 mg/m2. Concurrent
and relative effects are similar to those seen for radiation was prescribed with 50.4 Gy delivered
post-operative CT, necessitating a formal indirect to the mediastinum and primary tumor and boost
comparison of the IPD meta-analyses of pre and of 10.8 Gy to all gross disease (total dose of 61.2
post-operative CT. Gy to known disease). The mediastinum was
Keywords: Non-small cell lung cancer, pathologically reassessed prior to or at the time of
Chemotherapy, Surgery, meta-analysis resection. Consolidation chemotherapy was delivered
to patients who had not progressed (CBDCA AUC
=6, paclitaxel 200 mg/m2 q 21d x 2 cycles). The
Tri- and Biomodality Wednesday, 6 July 2011 14:30-16:00 primary endpoint of the study was mediastinal nodal
sterilization (MNS), with secondary endpoints that
O23.02 RTOG 0229:A PHASE II TRIAL included 2 year overall survival, and post operative
OF CONCURRENT CHEMOTHERAPY morbidity/mortality.
AND FULL DOSE RADIOTHERAPY Results: 60 patients were accrued, 57 were eligible.
FOLLOWED BY SURGICAL RESECTION Median age for the entire cohort was 59. Sixty-one
AND CONSOLIDATIVE THERAPY FOR percent of patients were male, 77% had ECOG
LOCALLY ADVANCED NON SMALL performance status of 0. Ninety-eight percent of
CELL CARCINOMA OF THE LUNG patients had N2 disease documented by pathologic
Martin J. Edelman1, Rebecca Paulus2, Mohan assessment of their mediastinum (N3: 2%). The
Suntharalingam3, Mark Krasna4, Whitney Burrows5, histology included 51% adenocarcinoma, 19%
Elizabeth M. Gore6, Sue S. Yom7, Hak Choy8 squamous cell carcinoma, and 28% NSCLC-NOS.
1
Greenebaum Cancer Center, University Of Ninety-Àve percent of patients received radiation
Maryland/United States Of America, 2Rtog Statistical per protocol; 91% received chemotherapy as
OfÀce/United States Of America, 3Radiation per protocol, (49% with protocol mandated dose
modiÀcations). The Grade 3/4 toxicities included: Of Medical Oncology, University Of Colorado
hematologic 35%, gastrointestinal 14%, and Denver/United States Of America, 4Department
pulmonary 23%. Thirty-six patients underwent Of Pathology And Neuropathology, University
resection. There was a 14% (5/37) incidence of grade Hospital Essen/Germany, 5Thoracic Surgery,
3 postoperative pulmonary complications. There Ruhrlanclinic/Germany, 6Institute Of Pathology
was one 30 day, post-operative grade 5 toxicity And Neuropathology, University Hospital Essen,
(3%). Forty-three patients (75%) were evaluable University Of Duisburg-essen/Germany, 7Thoracic
for the primary endpoint. Twenty-seven out of 43 Surgery, University Of Freiburg/Germany,
8
evaluable patients (63%) achieved the primary Radiotherapy Unit, Institut Gustave Roussy/France
endpoint of MNS (p=0.05). With a median follow-
up of 24 months for all patients, the 2 year overall Background: TM approaches including induction
survival was 54% (median OS 27 months), and 2 (IND) chemotherapy (CTx), radiotherapy (RTx)
year progression free survival was 33% (median PFS and surgery (S) for selected pts with LAD stage III
13 months). The 2 year OS was 67% for those who NSCLC are a valid strategy in the management to
achieved mediastinal nodal clearance, and 54% for achieve LTS (Eberhardt et al, JCO 1998, Albain
those with residual nodal disease. et al, Lancet 2009). Here we have performed
Conclusion: This multi-institutional trial conÀrms exploratory analysis of our sequential trimodality
the safety of neoadjuvant concurrent chemoradiation trials performed between 1991 and 2002 to identify
with full dose radiotherapy and the ability of this subgroups either with increased or reduced LTS to
approach to sterilize mediastinal nodal disease. The generate hypotheses to prospectively stratify our pt
low surgical morbidity and mortality is likely a result population in future clinical trials with TM.
of the requirement for proven surgical expertise Methods: From 1/91 till 2/2002 four seqential
and adherence to speciÀc management protocols. clinical trials were performed at the West German
These results support the contention that tri-modality Tumor Centre plus selective thoracic/academic
therapy remains a viable option for selected stage III centers in Germany/Europe: 1) JCO1 was based on
NSCLC pts. This project was supported by RTOG IND CTx (cisplatin/etoposide=PE) plus concurrent
grant U10 CA21661, and CCOP grant U10 CA37422 (cc) CTx/RTx followed by S (Eberhardt, JCO
from the National Cancer Institute (NCI). 1998) 2) CISTAXOL was based on cisplatinum/
Keywords: mediastinal sterilization, Stage III, paclitaxel=PT IND plus cc CTx/RTx plus surgery or
trimodality therapy deÀnitive CTx/RTx-boost to 65 Gy (Gauler, (WCLC
Seoul) JTO 2009) 3) CISTAXOL/EPO was based
on the same protocol prophylactically supported
Tri- and Biomodality Wednesday, 6 July 2011 14:30-16:00 by epoetin alpha 4) KREBSHILFE1/JCO2 was a
randomized trial based on cisplatin/etoposide=PE
O23.03 COMPETING RISKS ANALYSIS IND plus cc CTx/RTc plus S supplemented by PCI
AND LONG-TERM SURVIVAL (LTS) and compared to local treatment alone (S + RTx) -
OF PATIENTS (PTS) WITH LOCALLY only pts from the TM arm are included here in this
ADVANCED (LAD) STAGE III NON- investigation (Poettgen, JCO 2007). All patients
SMALL-CELL LUNG CANCER signed informed consent and trials were submitted to
(NSCLC) TREATED ON SEQUENTIAL the ethics committee of each participating institution.
TRIMODALITY (TM) TRIALS Results: From 2/91 till 2/02 243 pts were accrued
Wilfried Eberhardt1, Rodrigo Hepp2, Thomas C. to the four sequential trials: 94 pts JCO1, 64 pts
Gauler1, Daniel C. Christoph3, Andreas-Claudius CISTAXOL, 30 pts CISTAXOL/EPO and 55 pts
Hoffmann1, Dirk Theegarten4, Stefan Welter5, Kurt KREBSHILFE1/JCO2. LTS follow-up (F-UP) was
W. Schmid6, Jeremias Wohlschlaeger4, Bernward performed 2/11 to collect information on pts survival
Passlick7, Cécile Le Péchoux8, Georgios Stamatis5, and disease/comorbidity status. Pts characteristics:
Martin Stuschke2, Christoph Poettgen2 m 187 f 56; age median 56 range 28-71 ; stages IIB
1
Department Of Medicine (cancer Research), West 6 (UICC5; IIIA UICC6) IIIA 139 IIIB 98; induction
German Tumor Center, University Hospital Essen/ PE 149 induction PT 94. Complete/R0-res: 122 (50,2
Germany, 2Department Of Radiotherapy, West %); no R0: 121; med S of pts still alive at last FUP
German Cancer Center, University Hospital Essen/ 112 months (m). med OS (m), 5y-OS, 10y-OS, 15y-
Germany, 3Department Of Medicine, Division OS (%): all pts: 23 m 24.7 19.5 9.9 IIB/IIIA: 25 m
2
27.5 19.8 10.8; IIIB: 22 m 20.5 19.1 8.6 log-rank Department Of Biostatistics, Brown University/
p = NS. ADC: IND PE 38 m 32.0 15.2 11.4 ; IND United States Of America, 3Greenebaum Cancer
PT 24 m 11.1 11.1 log-rank 0.04. SCC: IND PE 21 Center, University Of Maryland/United States
m 20.0 15.7 4.6; IND PT 43 m 45.5 41.7 log-rank Of America, 4Radiology/Nuclear Medicine,
0.0075. IND PE: ADC 26 m 32.0 15.2 11.4 ; SCC 21 Washington University/United States Of America,
5
m 19.9 15.7 4.6 log-rank p = NS; induction PT: SCC Acrin Headquarters/United States Of America,
6
23 m 45.5 41.7 ; ADC 24 m 11.1 11.1 log-rank p = Department Of Radiation Oncology, Washington
0,0021. Age: less 50 yrs 26 m 27.9 27.9 23.2 greater/ University/United States Of America, 7Radiology,
equal 50 yrs 23 m 23.6 16.7 3.1 log-rank p = 0.057. Wake Forest University/United States Of America
Stage, N-status, T-status and gender did not reveal
signiÀcant impact on LTS. Treatment-dependant Background: ACRIN 6668/RTOG 0235 is a
subgoups: R0-res: 38 m 40.5 32.5 17.0 ; no R0 18 prospective trial rigorously assessing the utility of
m, 8.5 6.2 log-rank p = 0.01. Competing risks: all pre- and post-chemoradiotherapy FDG-PET scan
events post 5-yrs were either 1) comorbidity-related for Stage III NSCLC. This trial allowed a variety
(vascular, pulmonary) 2) second cancers 3) second- of chemoradiotherapy regimens (physicians’
primaries ; not any late relapse could be conÀrmed. preference). We analyzed the effect of the choice of
Brain relapse was observed predominantly before 5 chemotherapy regimen and other potential prognostic
yrs post diagnosis. factors for outcomes.
Conclusion: Mature 10-y F-UP of stage III pts put Methods: A total of 251 patients were accrued to
on TM conÀrms excellent LTS/cure rate of selected this study, of whom 235 were eligible. A subset of
subgroups of pts with IIIA and IIIB. Interestingly, 128 of these patients received a ‘standard’ concurrent
our exploratory analysis reveals signiÀcant chemoradiotherapy regimen; either Carboplatin/
interaction between induction therapy (PE vs PT) paclitaxel/RT (Group A) or Etoposide/cisplatin/
and histopathology: on PT induction SCC have RT (Group B), and were evaluable for follow-up.
excellent whereas ADC reveal poor prognosis. 213 patients received XRT (mean dose: 63.9 Gy;
This effect was not observed with PE induction. SD: 10.5 Gy). Analysis was performed for overall
Furthermore, age less than 50 yrs at diagnosis survival, with emphasis on the effects of choice of
seems to implicate better LTS. 1) as a consequence chemotherapy and radiotherapy dose.
this Ànding will have to be prospectively analysed/ Results: For all 128 patients analyzed for the
validated in the ongoing randomized ESPATUE chemotherapy question, the 2-year overall survival
trial (KREBSHILFE2) 2) Further improvement was 44.5% (95% CI: 36.0%, 53.4%). Survival rates
of LTS has to address and aggressively manage were 42.2% and 51.8% for Group A and Group B,
comorbidities and second primary/second cancer respectively. The log-rank test showed that overall
risk. Brain metastases remain an issue in the time survival was not different between two groups (p=0.99).
period prior to 5 years post diagnosis. Within this population, radiotherapy dose was marginally
Keywords: Surgery, Stage III, combined modality, signiÀcant as a factor associated with survival (p=0.066).
lung cancer, non-small-cell When analyzed for the entire evaluable population of
patients with radiotherapy data (N=213), radiotherapy
dose became highly signiÀcant (p<.0001). The results
Tri- and Biomodality Wednesday, 6 July 2011 14:30-16:00 suggest that the hazard rate for death decrease by 1.9%
for each 1 Gy increase in radiotherapy dose.
O23.05 IS THERE AN OPTIMAL Conclusion: Carboplatin/paclitaxel or etoposide/
CONCURRENT CHEMO-RT cisplatin as concurrent chemotherapy during
REGIMEN FOR STAGE III NSCLC? -- deÀnitive radiotherapy has similar outcomes.
PRELIMINARY ANALYSIS OF ACRIN Radiotherapy dose appears to be a more important
6668/RTOG 0235 factor than choice of doublet concurrent
Mitchell Machtay1, Fenghai Duan2, Jeremy chemotherapy regimen. ACRIN receives funding
Gorelick2, Bradley Snyder2, Martin J. Edelman3, from the National Cancer Institute through the
Barry Siegel4, Irene Mahon5, Jeffrey Bradley6, grant U01 CA079778, and RTOG receives funding
Caroline Chiles7 through grant CA21661.
1
Radiation Oncology, Case Western Reserve Keywords: chemoradiotherapy, Non-small Cell
University/Hospitals/United States Of America, Lung Carcinoma, Stage III
Tri- and Biomodality Wednesday, 6 July 2011 14:30-16:00 Conclusion: High-dose cisplatin containing
chemotherapy concurrently combined with
O23.06 REVIEW OF PUBLISHED radiotherapy did not result in better overall survival
TREATMENT RESULTS AND compared to low dose cisplatin RCT regimens for
TOXICITY OF CONCURRENT locally advanced NSCLC. The series with the best
RADIOCHEMOTHERAPY SCHEMES IN overall survival rates and a favorable toxicity proÀle
LOCALLY ADVANCED NSCLC was combining high-dose radiotherapy and low-dose
Caro Koning1, Sanne Wouterse1, Joost Daams2, José monochemotherapy consisting of daily cisplatin.
Belderbos3, Lon Uitterhoeve1 Keyword: locally advanced NSCLC
1
Radiation Oncology, Amc/Netherlands,
2
Medical Library, Academic Medical Center/ A revised/updated abstract may be included in
Netherlands, 3Department Of Radiation Oncology, the Late Breaking Abstract Supplement, available
The Netherlands Cancer Institute - Antoni Van at the 14th World Conference on Lung Cancer.
Leeuwenhoek Hospital/Netherlands
Background: After two meta-analyses reporting Tri- and Biomodality Wednesday, 6 July 2011 14:30-16:00
the superiority of concurrent above sequential
Radiochemotherapy (RCT) for locally advanced O23.07 RESULTS OF A PHASE II TRIAL
NSCLC in 2010, the question which concurrent RCT ON INDIVIDUALIZED RADIATION
combination to prefer, is still unanswered. DOSE-ESCALATION BASED ON
Methods: A systematic review was performed to NORMAL TISSUE CONSTRAINTS IN
determine which concurrent RCT regimen (mono- CONCURRENT CHEMO-RADIATION
versus polychemotherapy, high-dose versus low- FOR STAGE III NON-SMALL CELL LUNG
dose schemes) yields superior results. The databases CANCER (NSCLC) (NCT00572325 TRIAL)
of Pubmed, Ovid-Medline, Ovid-Embase and Angela Van Baardwijk1, Bart Reymen1, Rinus
the Cochrane library were searched for full text Wanders1, Jacques Borger1, Anne-Marie C.
publications between January 1992 and December Dingemans2, Gerben Bootsma3, Cordula Pitz4,
2009 on the use of concurrent RCT only, in phase II Ragnar Lunde5, Wiel Geraedts6, Frank Peters7,
and phase III studies including at least 50 patients Philippe Lambin1, Dirk De Ruysscher1
1
per treated group. Data on treatment results in terms Radiation Oncology, MAASTRO Clinic, Grow
of overall survival and toxicity were collected. - School For Oncology And Developmental
Results: Seventeen articles were included in this Biology, Maastricht University Medical Centre/
analysis. In 11 manuscripts cisplatin containing Netherlands, 2Department Of Pulmonology,
chemotherapy was applied, in eight patient Grow - School For Oncology And Developmental
series as monochemotherapy and in four as Biology, Maastricht University Medical Centre/
polychemotherapy. In six studies high-dose and in Netherlands, 3Department Of Pulmonology,
six series low-dose cisplatin was used as part of the Atrium Mc Parkstad/Netherlands, 4Department Of
RCT. In six reports carboplatin was the treatment of Pulmonology, Laurentius Ziekenhuis/Netherlands,
5
choice. Total radiotherapy (RT) doses varied from Department Of Pulmonology, St. Jansgasthuis/
45 Gy to 70.2 Gy, fraction doses from 1.8 Gy to 2.75 Netherlands, 6Department Of Pulmonology, Orbis
Gy. Concurrent carboplatin did not yield improved Mc/Netherlands, 7Department Of Medical Oncology,
overall survival compared to RT only. One of the Orbis Mc/Netherlands
series using daily low-dose cisplatin combined with
high-dose RT resulted in the highest 2- and 3- year Background: Concurrent chemo-radiation
overall survival of 56 % and 29%, respectively. and radiation dose-escalation are strategies to
Acute toxicity of this daily cisplatin regimen improve overall survival (OS) in locally advanced
consisted mainly of grade > 3 esophagitis (17%), and NSCLC. Previously, we have shown the efÀcacy
nausea and vomiting (6%). High-dose concurrent of individualized radical radiotherapy/sequential
cisplatin resulted in considerably higher incidences chemo-radiation by individualized dose-escalation
of haematological toxicities and caused higher to the limits of normal tissues (van Baardwijk et al,
incidences of and more severe nausea and vomiting J Clin Oncol 2010). Here, we report the results of a
complaints. phase II trial investigating individualized radiation
dose-escalation in concurrent chemo-radiation. prescription in concurrent chemo-radiation based on

Methods: Patients with stage III NSCLC Àt for normal tissue constraints is feasible, even in patients
concurrent chemo-radiation (WHO-PS 0-2; FEV1 with large tumor volumes and multi-level N2/3
and DLCO >30%) were included. All patients were disease, with acceptable severe late toxicity (<7%)
irradiated using an individualized prescribed total and promising results with a 2yr OS of 51.5%.
tumor dose (TTD) based on normal tissue dose Keyword: NSCLC, chemoradiation, dose-escalation,
constraints: maximal mean lung dose (MLD) 19 Gy, individualized
maximal spinal cord dose 54 Gy and maximal dose
to the brachial plexus 66 Gy. A TTD between 51 and
69 Gy was delivered in 1.5 Gy fractions twice daily Session O24: Surgery - Outcomes
up to 45 Gy, followed by once daily fractions of 2
Gy. Radiotherapy (RT) was started at the 2nd course Wednesday, 6 July 2011
of chemotherapy (cisplatin-vinorelbine or cisplatin-
etoposide). RT planning was 4D-PET-CT based. OS
and Progression Free Survival (PFS) were calculated Surgery - Outcomes Wednesday, 6 July 2011 14:30-16:00
from date of diagnosis (Kaplan-Meier method).
Toxicity was scored according to CTCAEv3.0. The O24.01 ADENOSQUAMOUS CARCINOMA
trial (NCT00572325) was approved by the required OF THE LUNG: SURGICAL RESULTS
authorities. COMPARED WITH SQUAMOUS CELL
Results: 150 patients (97 males and 53 females, AND ADENOCARCINOMA
median age 63.2 years) were included from April 1st Hajime Maeda1, Akihide Matsumura2, Tetsushi
2006 till December 31st 2009. Stage distribution: IIB Suito3, Tsutomu Kawabata4, Osamu Kawashima5,
0.7%, IIIA 34.7%, IIIB 64.6%, including 7 patients Takehiro Watanabe6, Kan Okabayashi7, Ichiro
(9.7%) with recurrent disease after surgery. Median Kubota8
1
total GTV (±SD, range) was rather large: 73.9 ± 91.3 General Thoracic Surgery, National Hospital
cc (3.7-518.9 cc). Median TTD was 65.0 ± 5.9 Gy Organization Toneyama Hospital/Japan, 2National
(51-69.0 Gy) given in an overall treatment time of Hospital Organization Kinki-Chuo Chest Medical
35 days (equals a classical scheme of 74 Gy in 37 Center/Japan, 3National Hospital Organization
fractions QD in 7.4 weeks). The median MLD was Ibaraki-Higashi Hospital/Japan, 4National Hospital
16.3 ± 3.7 Gy (4.4-21.0 Gy). Six patients (4.0%) Organization Okinawa Hospital/Japan, 5National
did not complete radiotherapy (3 due to toxicity, Hospital Organization Nishi-Gunma Hospital/
3 patient’s wish). Severe acute toxicity (grade 3, Japan, 6Nishi-Niigata Chuo National Hospital/
n=51, 34.0%) consisted mainly of grade 3 dysphagia Japan, 7National Hospital Organization Fukuoka-
during RT (n=36; 24.0%) and 1 month after RT (n=9, Higashi Medical Center/Japan, 8National Hospital
6.0%). Pulmonary complaints were less frequent: Organization Minami-Kyushu Hospital/Japan
grade 3 and 4 dyspnea resp. 4 and 1 patient (2.7%
and 0.7%) and grade 3 cough in 13 patients (8.7%). Background: Adenosquamous carcinoma of the
With regard to late toxicity 6 patients (4%) had grade lung (ASC) is a relatively rare tumor. Some studies
3 dysphagia (eg. stenosis/ulcus), 3 patients (2%) have suggested that ASC is more aggressive than
a thoracic empyema/Àstula and 1 patient died of a adenocarcinoma (AC) or squamous cell carcinoma
radiationpneumonitis (0.7%). Five patients (3.3%) (SC). The purpose of the present study was to test
died within 3 months after start of RT (pulmonary the hypothesis that ASC exhibits distinct clinical
causes, n=2; sepsis, n=1; cardiomyopathy, n=1; behavior from AC and SC of the lung in the setting
unknown cause, n=1). With a median FU of 29.4 of a multi-institutional cohort study.
months (95%CI 26.1-32.6 months), the median OS Methods: This retrospective cohort study used a
was 24.2 months (95%CI 18.9-29.6 months, 2yr OS prospective database produced by the Japan National
51.5%) and the median PFS 16.5 months (95%CI Hospital Organization Study Group for Lung Cancer
11.9-21.1 months). Eighty-six patients (57.6%) over a 19-year period (operations from 1975 to 2003,
showed recurrent disease: 20 (13.4%) local and/or follow-up data until March 2010). There were 17,129
regional recurrence, 40 (26.7%) distant metastasis cases that underwent operation during that period
and 26 (17.3%) a combination of both as Àrst event. for various kinds of primary malignant lung tumors.
Conclusion: Applying an individualized dose When a sample from a tumor comprises at least 20%
each of SC and AC, the condition is classiÀed as Surgery - Outcomes Wednesday, 6 July 2011 14:30-16:00
ASC. Pathologic staging was done according to the
6th edition of the International Union Against Cancer O24.02 TIME TRENDS OF SURGICAL
(UICC) TNM classiÀcation of malignant tumours. OUTCOME AND DISTRIBUTION OF
Results: We identiÀed 351 patients with ASC CLINICOPATHOLOGIC FACTORS IN
(2.0%), 9,469 with AC (55.3%), and 6,183 with PATIENTS WITH PATHOLOGICAL
SC (36.6%). SigniÀcantly more patients with ASC STAGE I NON-SMALL CELL LUNG
presented with T2 or T3 compared with patients CANCER OVER THE LAST THREE
with AC (49.9% vs 37.7% and 16.5% vs 7.9% DECADES
respectively, p<0.0001). SigniÀcantly more patients Jung-Jyh Hung, Wen-Hu Hsu, Yu-Chung Wu
with ASC presented with N2 (27.6%) compared Department Of Surgery, Taipei Veterans General
with patients with AC (21.9%, p=0.0004) and SC Hospital/Taiwan
(19.0%, p=0.0002). Consequently, in pathologic
stage distribution signiÀcantly more patients with Background: The seventh edition of the TNM
ASC presented with stage IIIA (29.9%) compared classiÀcation for lung cancer has been published in
with patients with AC (21.5%, p<0.0001) and SC 2009. The aim of this study is to evaluate time trends
(21.6%, p=0.0061). Kaplan-Meier survival curves of surgical outcome and clinicopathologic factors in
for p-stage IA tumors indicated that ASC has the patients with pathological stage I non-small cell lung
least favorable survival. The 5-year survival rates cancer (NSCLC) according to the seventh edition of
were 75.2% for AC, 67.8% for SC, and 50.0% for the TNM classiÀcation.
ASC. There were statistical differences between Methods: We retrospectively reviewed the
the three groups (p<0.0001). The survival curves clinicopathologic characteristics of 1,424 patients
for p-stage IB tumors also indicated that ASC has with resected stage I NSCLC from Taipei Veterans
the least favorable survival. The 5-year survival General Hospital between January 1980 and
rates were 54.1% for AC, 50.2% for SC, and December 2008, during the three periods of 1980-
38.5% for ASC. There were statistical differences 1990, 1991-2000, and 2001-2008. The overall
between AC and SC (p=0.0030) and between survival and distribution of clinicopathologic
AC and ASC (p=0.0154). The survival curves for characteristics were analyzed.
p-stage IIB tumors also indicated that ASC has the Results: The number of patients during the 3 periods
least favorable survival. The 5-year survival rates was 267 (18.8%), 540 (37.9%) and 617 (43.3%),
were 34.3% for AC, 39.8% for SC, and 27.4% for respectively. The 5-year overall survival rates during
ASC. There were statistical differences between the three periods improved signiÀcantly: 52.3, 58.3,
SC and ASC (p=0.0278) and between AC and and 68.2%, respectively (P < 0.001) (Figure 1).
ASC (p=0.0444). The survival curves for p-stage Surgical mortality (within 30 days after surgery)
IIIA tumors also indicated that ASC has the least rate during each period was 2.6, 2.6, and 1.1%,
favorable survival. The 5-year survival rates were signiÀcantly decreased in the last period (P = 0.021).
18.1% for AC, 21.3% for SC, and 10.9% for ASC. The percentage of female patients increased during
There was statistical difference between AC and each period: 15.4, 24.4, and 35.7%, respectively (P
ASC (p=0.0169). < 0.001). The percentage of adenocarcinoma also
Conclusion: Adenosquamous carcinoma (ASC) of increased during each period: 50.6, 54.6 and 76.5%,
the lung is more aggressive than adenocarcinoma respectively (P < 0.001). Tumor size during each
(AC) or squamous cell carcinoma (SC). The period was 3.2, 3.2 and 2.7 cm, tending to be smaller
decreased survival of patients with early-stage ASC when diagnosed in the last period (P < 0.001).
compared with single histology AC and SC suggests The number of mediastinal lymph nodes dissected
a role of clinical trial for adjuvant chemotherapy. increased during each period: 11.4, 16.6 and 20.6,
Keywords: adenosquamous carcinoma, Surgery, respectively (P < 0.001). The number of mediastinal
Prognosis lymph node stations dissected also increased during
each period: 3.0, 4.2 and 5.3, respectively (P <
0.001). The overall survival in subgroups of patients
with squamous cell carcinoma and those undergoing
pneumonectomy did not improve over time.
score for choice of approach (VATS versus open) was

constructed from clinical and tumor characteristics
(age, gender, histology, performance status, tumor
location, and T1 versus T2). Overall survival, disease-
free survival and second primary cancers were
compared using Cox proportional hazards regression
with 5 strata based on propensity scores
Results: 752 patients (66 VATS and 686 open) were
analyzed. Results are shown in Table 1. The median
Conclusion: The surgical outcome in patients of survival for the open lobectomy group was 8.4 years
stage I NSCLC improved signiÀcantly during the last while the median survival for the VATS lobectomy
three decades. The prevalence of female gender and groups was not achieved at the time of the analysis,
adenocarcinoma signiÀcantly increased over time, p=0.36.
while tumor size at diagnosis tended to be smaller. Table 1. Long-term Outcomes
However, no survival improvement was identiÀed
in patients with squamous cell carcinoma and those VATS
Open Lobectomy
undergoing pneumonectomy. Lobectomy
(n=686)
Keywords: Non-small cell lung cancer, time trend, (n=66)
5-year survival 5-year survival (95%
surgical outcome, survival HR P
(95% CI) CI)
Overall 71.6%
65.9% (63.3%-69.7%) 1.22 0.36
Survival (61.3%-83.6%)
Surgery - Outcomes Wednesday, 6 July 2011 14:30-16:00 Disease-
75.2%
Free 69.2% (65.4%-73.3%) 1.19 0.55
(63.5%-89.1%)
O24.03 SURVIVAL, RECURRENCE Survival
AND SECOND PRIMARIES AFTER Local
Disease- 89.4%
VIDEO-ASSISTED (VATS) LOBECTOMY free (81.0%-98.7%)
92.6% (90.3%-95.0%) 0.65 0.38
COMPARED TO OPEN LOBECTOMY Survival
FOR THE TREATMENT OF NON-SMALL New 87.8%
81.7% (78.3%-85.3%) 1.71 0.17
CELL LUNG CANCER Primary (79.6%-96.8%)
Walter J. Scott1, Mark S. Allen2, Gail Darling3, Bryan
Meyers4, Paul Decker2, Joe Putnam5 Conclusion: These data support the assertion that
1
Thoracic Surgery, Fox Chase Cancer Center/United VATS lobectomy provides comparable oncologic
States Of America, 2Mayo Clinic/United States Of outcomes to those achieved with open lobectomy.
America, 3University Of Toronto/Canada, 4Washington Keyword: non-small cell lung cancer, VATS,
Univeristy Of St Louis/United States Of America, lobectomy, randomized trial
5
Vanderbilt Univeristy/United States Of America
Background: Many reports describe a lower
morbidity, mortality and length of stay after VATS Surgery - Outcomes Wednesday, 6 July 2011 14:30-16:00
lobectomy, but skeptics have challenged the
oncologic effectiveness of the minimally invasive O24.05 JAPANESE LUNG CANCER
approach. This secondary analysis of a multicenter, REGISTRY STUDY OF 11663 SURGICAL
randomized trial compares long term oncologic CASES IN 2004: DEMOGRAPHIC AND
endpoints between patients receiving either an open PROGNOSIS CHANGES OVER DECADE
or VATS lobectomy Noriyoshi Sawabata1, Etsuo Miyaoka1, Hisao
Methods: Prospectively collected and audited data Asamura2, Yoichi Nakanishi2, Kenji Eguchi2, Masaki
were analyzed from 964 patients who underwent Mori2, Hiroaki Nomori2, Yoshitaka Fujii2, Meinoshin
lobectomy, segmentectomy or bilobectomy as part Okumura2, Kohei Yokoi2
1
of a randomized, multicenter clinical trial. While the Genetral Thoracic Surgery Osaka University
surgical intervention was not the primary focus of Graduate School Of Medicine, Japanese Joint
the trial, the surgical approach was captured and this Committee For Lung Cancer Registration/Japan,
2
allows an analysis of the impact of approach on the Japanese Joint Committee For Lung Cancer
oncologic effectiveness of the surgery. A propensity Registration/Japan
Background: The Japan Lung Cancer Society, the Conclusion: In Japanese cases of lung cancer
Japanese Association for Chest Surgery, and the surgery, demographics, surgical results, and stage-
Japanese Respiratory Society jointly established speciÀc prognoses changed over the 10-year study
the Japanese Joint Committee for Lung Cancer period, while 5-year survival rate for surgical cases
Registration (JJCLCR), which has regularly improved to 69.6% in 2004.
conducted lung cancer registries for surgical cases in Keywords: Lung cancer, Surgery, Registry, Japan
5-year periods. We analyzed data obtained in these
registries to reveal the most recent surgical outcomes
and trends related to lung cancer surgery in Japan. Surgery - Outcomes Wednesday, 6 July 2011 14:30-16:00
Methods: Using data from the registry conducted
in 2010 for cases of surgery performed in 2004, O24.06 A RANDOMIZED CLINICAL
demographics, surgical results, and stage-speciÀc TRIAL OF PREOPERATIVE
prognoses were analyzed. In addition, in order to NEOADJUVANT CHEMOTHERAPY
comprehend alterations of those parameters over a FOLLOWED BY SURGERY IN THE
decade, data from the Japanese nationwide registries TREATMENT OF STAGE III NON-SMALL
in 1994 and 1999 are also presented. CELL LUNG CANCER BASED ON
Results: In cases of lung cancer that underwent MOLECULAR STAGING
surgery in Japan, demographics and stage-speciÀc Qinghua Zhou
prognoses changed in the decade studied. In that Tianjin Lung Cancer Institute, Tianjin Medical
time period, the percentages for female patients, University General Hospital/China
adenocarcinoma, small-sized tumors (<2 cm), stage
I or II diseases, and aged patients increased, whereas Background: To explore the feasibility and
the rate of surgery-related deaths decreased to only toxicity of pre-operative neoadjuvant chemotherapy
0.8%. With those changes, the 5-YSR in 2004 of followed by surgery in the treatment of stage
all lung cancer patients who underwent surgery III NSCLC and to evaluate its effects on tumor
was (n=11663, 7369 males, mean age 66.7 years) response, resection rate, tumor downstaging, and
69.6%. The 5-year survival rates by c-stage and survival rate based on detection of Muc-1 mRNA
p-stage were as follow: IA (n=6295,4978), 82.0% expression.
and 86.8%; IB (n=2339, 2552), 66.8% and 73.9%; Methods: From Jan. 1990 to Jan. 2006, 624
IIA (n=819, 941), 54.5% and 61.6%; IIB (n=648, patients were randomly devided into group A
848), 46.4% and 49.8%; IIIA (n=1216, 1804), 42.8% (preoperative neoadjuvant chemo-therapy group)
and 40.9%; IIIB (n=90, 106), 40.3% and 27.8%; and and group B (control group, without neoadjuvant
IV (n=256, 434), 31.4% and 27.9%, respectively. chemotherapy). Group A had 314 patients and
Furthermore, the prognoses of all cases and cases group B had 310 cases. Expression of Muc-1
in each stage improved over the decade (Table). mRNA was detected in all the 624 patients before
and after neoadjuvant chemo-therapy in Group
A and before operation in Group B by RT-PCR.
The patients in group A were give 2 cycles of
neoadjuvant chemotherapy, and operations were
performed in 4 weeks after Ànishing the last
chemotherapy. The regimens included Gem‹DDP
in 214 cases and NVB‹DDP in 100 cases .
The patients in group B were Àrstly operated.
All the 624 patients were given postoperative
chemotherapy with GP or NP regimen for 3-4
cycles after operation.Thoracic radiation therapy of
45-50Gy was given in the patients with N2 disease
both in group A and group B.
Results: The tumor response to induction
chemotherapy was 75.16…(236-314) in group A.
The tumor downstaging was 41.08…(129-314).
The histological complete response was 14.65…
(46-314). The resection rate was 94.90… in group lobectomy for patients with non-small cell lung
A, and 90.65… in group B.The positive rate of cancer (NSCLC) in an attempt to stratify potential
Muc-1 mRNA expression was 28.98% and 5.73% differences in long-term survival outcomes.
in peripheral blood samples in Group A beforeand Methods: We established a multi-institutional
after induction chemotherapy, respectively..The registry for 4138 patients with NSCLC who
positive rate of Muc-1 mRNA expression was underwent lobectomy between January 2000
24.84% in Group B. No signiÀcant differences of and December 2007 from eight institutions in
blood loss, operative complications and mortality the People’s Republic of China. Age, gender,
were observed between the group A and group histological type and tumor staging based on the
B (P>0.05). The 1-, 3-, 5- and 10-year survival latest TNM classiÀcation were entered into a non-
rates were 78.30%, 51.46 %, 27.31 % and 20.35 parsimonious multivariable logistic regression
% in group A, and 64.53%,40.54%, 14.19 % and model. The predicted probability derived from the
12.64 % in group B respectively. The 1-, 3-, 5- logistic equation was used as the propensity score
and 10-year survival rates of the patients without for each individual. Based on similar propensity
micrometastasis were 89.62 %, 67.46 %, 39.61 scores, we matched 1356 of the 1584 patients
%and 31.75 % in group A, and 77.23%, 54.34 %, who underwent VATS lobectomy with 1356 of the
24.89 % and 20.87 % in group B respectively. The 2554 patients who underwent open lobectomy and
long-term survival rates in group A both with and compared their long-term survival outcomes.
without micrometastasis were remarkably higher Results: The mean age of the 2712 matched
than that in group B (P<0.01). patients was 59 (S.D. = 11) years. After
Conclusion: The results demonstrate that the pre- propensity-matching, VATS and open lobectomy
operative neo-adjuvant chemotherapy is safe patients were similar in regards to important
and effective. It is helpful to decrease the tumor prognostic variables. Four prognostic factors
staging, to eradicate micrometastasis in peripheral were independently associated with improved
blood , to increase the resection rate of the tumor, survival in the multivariate analysis: gender (p =
and to improve the long-term survival rate and life 0.001), histological type (p < 0.001), pathological
qualities of patients with stage NSCLC. staging (p < 0.001) and operation type (lobectomy/
Keywords: Lung cancer, neoadjuvant sleeve resection versus pneumonectomy (p =
chemotherapy, micrometastasis, Randomized 0.044). Patients who underwent VATS versus open
clinical trial lobectomy had similar long-term survival (p =
0.101).
A revised/updated abstract may be included in Conclusion: The current propensity score
the Late Breaking Abstract Supplement, available analysis suggests that well-matched patients with
at the 14th World Conference on Lung Cancer. NSCLC who underwent VATS lobectomy did not
have inferior long-term survival outcomes when
compared to those who underwent open lobectomy.
Surgery - Outcomes Wednesday, 6 July 2011 14:30-16:00 Keywords: propensity score analysis, video-
assisted thoracic surgery, lobectomy, Non-small cell
O24.07 VIDEO-ASSISTED THORACIC lung cancer
SURGERY LOBECTOMY FOR NON-
SMALL CELL LUNG CANCER – A A revised/updated abstract may be included in
PROPENSITY SCORE ANALYSIS the Late Breaking Abstract Supplement, available
BASED ON A MULTI-INSTITUTIONAL at the 14th World Conference on Lung Cancer.
REGISTRY
Jianxing He
Department Of Cardiothoracic Surgery, The First
AfÀliated Hospital Of Guangzhou Medical College/
China
Background: We conducted a multi-institutional

propensity-matched study comparing video-assisted
thoracic surgery (VATS) with conventional open
Session O25: NSCLC - Early Stage overall and quality adjusted survival outcomes
stratiÀed by age, sex, smoking history, COPD,
Wednesday, 6 July 2011 and T-stage. Sensitivity analyses on the quality
of life utility (QoL) of SBRT, treatment-related
death, and proportion of patients with recurrent
NSCLC - Early Stage Wednesday, 6 July 2011 14:30-16:00 disease receiving radical treatments were performed
to determine thresholds for treatment modality
O25.01 SBRT FOR MEDICALLY preference.
OPERABLE AND INOPERABLE EARLY Results: For surgical patients, overall survival (OS),
NSCLC: MARKOV INSIGHT FOR cancer speciÀc survival, and other causes of death
OPTIMAL PATIENT SELECTION outcomes as predicted by our model correlated closely
Alexander V. Louie1, George Rodrigues1, Malek with Adjuvant! Online, with OS differences ranging
Hannouf2, David Palma1, Gregory S. Zaric2, Suresh from 0.0% to 3.8% at 5 years. OS differences at 5
Senan3 years between surgery and SBRT ranged from 2.2%
1
Radiation Oncology, London Regional Cancer to 3.0% and 0.07 to 0.09 in quality adjusted life years,
Program/Canada, 2Clinical Epidemiology And both in favor of surgery. SBRT was preferred over
Biostatistics, University Of Western Ontario/Canada, surgery if the QoL of SBRT was 0.90. Outcomes
3
Radiation Oncology, VU University Medical Center/ were sensitive to the QoL SBRT, the proportion of
Netherlands local and regional recurrences treated with radical
versus palliative treatments, and the surgical and
Background: Randomized clinical trials evaluating SBRT treatment-related mortalities. For high risk
the role of SBRT in stage I NSCLC are now ongoing patients, our model predicted for a beneÀt in 5-year
but will require several years before mature results OS of 4.0% to 38.2% and 8.8 to 17.4 quality-adjusted
are available. We therefore developed Markov life months in favor of SBRT over BSC for the 4
models, which are tools for statistical modeling, classes. The relative beneÀt of SBRT appeared to be
to simulate both short- and long-term outcomes in the least for T2, GOLD III-IV patients. Outcomes
different sub-groups of patients presenting with this were not sensitive to the disutility associated with
disease. SBRT or disease progression.
Methods: We constructed a Markov model to Conclusion: Markov modeling suggests that
simulate the clinical history of (i) medically operable withholding SBRT from patients based upon their
stage I NSCLC patients treated with either SBRT age and/or COPD severity appears to be unjustiÀed.
or lobectomy, and (ii) patients aged 75 years with In addition, SBRT may offer comparable overall
COPD (i.e. high risk) who undergo SBRT or best survival and quality adjusted life expectancy in
supportive care (BSC), both for a 5-year timeframe. operable cases, as compared to surgical resection.
Clinical parameters for recurrence rates and Markov Keywords: Stereotactic radiotherapy, markov
state utilities for appropriate AJCC stages of NSCLC model, lobectomy, best supportive care
were extracted and adapted to monthly time intervals
using population based data from the California
Cancer Registry, a prospective database of high-risk NSCLC - Early Stage Wednesday, 6 July 2011 14:30-16:00
SBRT patients treated at the VUMC Amsterdam,
and the available literature. For medically operable O25.02 CURATIVE TREATMENT
patients, age- and sex-speciÀc rates of death from OF STAGE I NON-SMALL CELL
all other causes were extracted from the Centre for LUNG CANCER IN PATIENTS WITH
Disease Control and Prevention standard life tables SEVERE COPD: STEREOTACTIC
and varied according to smoking habit. To validate RADIOTHERAPY OUTCOMES AND
the model, surgical outcomes were compared to SYSTEMATIC REVIEW
Adjuvant! Online. Elderly COPD patients were David Palma1, Frank J. Lagerwaard2, George
stratiÀed into 4 classes according to T stage (1 vs. Rodrigues1, Cornelis J. Haasbeek3, Suresh Senan3
1
2) and COPD GOLD score (I-II vs. III-IV). The Radiation Oncology, London Regional Cancer
4 patient classes were: I (T1, GOLD I-II), II (T2, Program/Canada, 2Radiation Oncology,
GOLD I-II), III (T1, GOLD III-IV), and IV (T2, VU University Medical Center/Netherlands,
3
GOLD III-IV). We report various treatment strategy Radiotherapy, VU Medical Centre/Netherlands
1
Background: Patients with severe chronic Radiation Oncology, VU University Medical Center/
obstructive pulmonary disease (COPD) have a Netherlands, 2Epidemiology And Biostatistics, VU
high risk of lung cancer, and a high risk of post- University Medical Center/Netherlands, 3Pulmonary
surgical complications. We studied outcomes after Diseases, VU University Medical Center/
stereotactic ablative radiotherapy (SABR) in patients Netherlands
with severe COPD (as deÀned by Global Initiative
for Chronic Obstructive Lung Disease [GOLD] Background: Stereotactic ablative radiotherapy
criteria), and performed a systematic review of the (SABR) is now a standard treatment option for
literature on outcomes after SABR or surgery in patients with stage I NSCLC who are at high-
these patients. risk for surgical mortality and morbidity, or those
Methods: A single-institution cohort of 173 patients refusing surgery. A high proportion of patients are
with COPD GOLD III-IV and stage I NSCLC treated treated with SABR because of poor pulmonary
with SABR was evaluated. A systematic review function (PF) precluding a lobectomy. As long-term
identiÀed studies reporting outcomes after SABR or data on post-SABR PF are scarce, we investigated
surgery for stage I NSCLC in patients with GOLD serial pulmonary function tests (PFT) in patients
III-IV or a predicted post-operative FEV1 of 40%. undergoing SABR at a single center.
Results: In the single-institution cohort, median Methods: Baseline and serial PFT data after SABR,
follow-up was 21 months and median overall survival including forced expiratory volume in 1 second
(OS) was 32 months. Actuarial 3-year local control (FEV1) and vital capacity (VC) were available in
was 89%, and 1- and 3-year OS were 79% and 47%, 201 stage I NSCLC patients. In a subset, baseline
respectively (Figure 1A-B). COPD severity correlated (n=134) and serial (n=86) measurements of diffusion
with OS (p=0.01, Figure 1C). The systematic review capacity for carbon monoxide (DLCO) were also
identiÀed four other studies (two surgical, two SABR, available. One hundred and seventy-one patients
n=196 patients). SABR studies were published more (85%) had a diagnosis of COPD, classiÀed as
recently and included older patients than surgical GOLD I/II (104 patients) and GOLD III/IV (67
studies. Mean thirty-day mortality was 0% post-SABR patients). Mixed linear models were used to estimate
and 10% after surgery. Local or loco-regional control post-SABR changes in PFT parameters. Several
was high (89%) after both treatments. Post-SABR, patient and treatment factors were investigated for
actuarial OS was 79-94% at 1 year and 43-70% at prognostic relevance on PF changes.
3 years. Post-surgical actuarial OS was 45-86% at 1 Results: Median baseline FEV1, VC and DLCO
year and 31-66% at 3 years. were 1500 ml (59% predicted), 2940 ml (92%
Conclusion: SABR and surgery differ in risk of 30- predicted) and 54% of predicted, respectively.
day mortality in patients with severe COPD. Despite SigniÀcant decreases in all three PFT parameters
the negative selection of SBRT patients, survival were seen following SABR (all p<.0001). The mean
at 1- and 3-years is comparable between the two observed annual declines were 97 ml or 3.2% of the
treatments. predicted value for FEV1, 111 ml (2.5% predicted)
Keywords: Non-small cell lung cancer, chronic for VC and 3.5% of predicted for DLCO. The extent
obstructive pulmonary disease, Surgery, Stereotactic of PF-decline correlated with baseline PF. The mean
radiotherapy decline in FEV1 in patients without COPD was
5.3% versus 3.8% in COPD GOLD I/II and 1.5%
in COPD GOLD III/IV (p=.003). Similarly, DLCO-
NSCLC - Early Stage Wednesday, 6 July 2011 14:30-16:00 decline was 5.2% of predicted in the highest tertile
(baseline DLCO>70%) versus 3.1% in the middle
O25.03 QUANTIFYING PULMONARY tertile (DLCO 50-70%) and 1.5% in the lowest
FUNCTION CHANGES AFTER tertile (DLCO<50%) (p=.032). The DLCO-decline
STEREOTACTIC ABLATIVE was signiÀcantly greater with increasing PTV size
RADIOTHERAPY (SABR) FOR STAGE I (p=.0490) and age 75 years (p=.0346). Age, PTV
NON-SMALL-CELL LUNG CANCER size, smoking history, tumor stage and location failed
Erik C. Phernambucq1, Frank J. Lagerwaard1, Peter to show a signiÀcant correlation with extent of PF-
M. Van De Ven2, Herman Groepenhoff3, Pieter E. change in FEV1 or VC.
Postmus3, Ben Slotman1, Egbert F. Smit3, Suresh Conclusion: SigniÀcant decreases in commonly
Senan1 used PFT parameters were observed following
SABR. The largest decreases were observed in of 811 patients enrolled from 31 institutions, 545
patients who had normal baseline PFTs, implying adenocarcinoma patients who underwent lobectomy
that the changes are SABR-related rather than due to and lymph node dissection were included in this
the natural course of underlying pulmonary disease. analysis. Based on contrast-enhanced thin-section
Limited PF decline in patients with severe/very computed tomography (TSCT) scans, we determined
severe COPD may explain the tolerability of SABR consolidation/tumor (C/T) ratio as the proportion of
in these patients. the maximum consolidation diameter to the maximum
Keywords: Stage I NSCLC, Stereotactic ablative tumor diameter. Radiological non-invasive lung
radiotherapy, Pulmonary function changes adenocarcinoma was deÀned as a tumor with a C/T
ratio 0.5. We also examined exploratory deÀnition
with a C/T ratio 0.25 in the cT1a population.
NSCLC - Early Stage Wednesday, 6 July 2011 14:30-16:00 Pathological non-invasive cancer was deÀned as a
cancer without nodal involvement, vascular invasion,
O25.05 FIVE YEAR-SURVIVAL and lymphatic permeation. The primary endpoint was
DATA OF RADIOLOGICAL NON- the speciÀcity for the radiological diagnoses of non-
INVASIVE PERIPHERAL LUNG invasive lung adenocarcinoma based on C/T ratios.
ADENOCARCINOMA; PROSPECTIVE We set the expected speciÀcity to be greater than 97%.
COHORT STUDY FOR STAGE IA LUNG Overall survival (OS) was calculated by the Kaplan-
ADENOCARCINOMA (JCOG0201) Meier method.
Tomoyuki Hishida1, Kenji Suzuki2, Teruaki Koike3, Results: There were 233 men and 312 women.
Masahiko Kusumoto4, Hisao Asamura4, Kanji Median age was 62 years (range, 35 to 75). Median
Nagai1, Tada Hirohito5, Motohiro Yamashita6, follow-up period was 6.1 years (range, 0 to 7.5).
Tetsuya Mitsudomi7, Norihiko Ikeda8, Taro Shibata9, Radiological non-invasive lung adenocarcinomas
Hisashi Saji8, Masahiro Tsuboi10, Japan Lung Cancer were observed in 121 (22.2%) patients among the
Surgical Study Group (JCOG-LCSSG)4 entire population and 35 (12.1%) in cT1a population
1
Thoracic Surgery, National Cancer Center Hospital (n = 289), respectively. Among radiological non-
East/Japan, 2General Thoracic Surgery, Juntendo invasive lung adenocarcinomas, pathological non-
University School Of Medicine/Japan, 3Chest invasive cancers were diagnosed in 115 (95.0%)
Surgery, Niigata Cancer Center Hospital/Japan, patients in the entire population and 34 (97.1%) in
4
National Cancer Center Hospital/Japan, 5Osaka cT1a patients, respectively. The speciÀcities for the
City General Hospital/Japan, 6Shikoku Cancer radiological correct diagnosis of pathological non-
Center Hospital/Japan, 7Aichi Cancer Center invasive lung adenocarcinomas were 96.4% (95%
Hospital/Japan, 8Tokyo Medical University/Japan, CI: 92.3-98.7%) for all population and 98.7% (95%
9
Jcog Data Center, National Cancer Center/Japan, CI: 93.2-100.0%) for patients with cT1a tumor.
10
Kanagawa Cancer Center Hospital/Japan Our radiological deÀnition of non-invasive lung
adenocarcinoma on TSCT did not statistically meet
Background: Patients with peripheral small our pre-determined criterion for speciÀcity. However,
lung adenocarcinomas are increasing in number. the exploratory deÀnition of C/T ratio 0.25 for
Pathological non-invasive lung adenocarcinomas cT1a tumor demonstrated acceptable speciÀcity. The
might be cured by limited lung resection with an 5-year OS rates of the entire population and cT1a
adequate surgical margin. However, pathological population were 90.5% and 93.0%, respectively. For
non-invasiveness needs to be correctly predicted in radiological non-invasive cancers, the 5-year OS
preoperative radiological examinations to indicate rates were 96.7% and 97.0% in the cT1 (n = 121)
limited surgery. The aim of this study is to validate and cT1a (n = 35) patients, respectively. One patient
our radiological deÀnition of non-invasive lung with radiological non-invasive lung adenocarcinoma
adenocarcinoma by pathological Àndings and to in the entire cT1 cohort died of cancer recurrence,
evaluate long-term prognosis. but none of the cT1a patients died of cancer.
Methods: Patients with a tumor suspected or Conclusion: Our pre-deÀned criterion failed
diagnosed as clinical T1N0M0 peripheral lung to predict pathological non-invasive lung
adenocarcinoma were prospectively recruited by adenocarcinoma, but exploratory deÀnition of a C/T
a multi-institutional study (JCOG0201) between ratio 0.25 in T1a tumor demonstrated promising
December 2002 and May 2004. Among a total speciÀcity and good survival. This exploratory
deÀnition can be used to select candidates for nodule size was 17.4 mm (6-30), including, 66
wide wedge resection or segmentectomy without (57,3%) patients with nodules up to 20 mm (T1a)
lymph node dissection. The result of our ongoing and 49 (42.7%) greater than 20 mm (T1b). 18 patiens
prospective limited resection trial based on this of the T1a group presented subcentimeter nodules.
deÀnition (JCOG0804/WJOG4507L) is awaited. Men: 54.7%. Mean age 61 years (44-85). Histology:
Keywords: small lung adenocarcinoma, non- adenocarcinoma (82.6%), squamous (6.1%),
invasive lung adenocarcinoma, Limited Resection bronchioloalveolar (5.2%), large cell undifferentiated
(3.5%), adenosquamous (1.7%) and large cell
neuroendocrine (0.9%). Lobectomy was performed
NSCLC - Early Stage Wednesday, 6 July 2011 14:30-16:00 in 101 patients (87.8%) and sublobar resection in 14
(12.2%). 55.2% were smokers, 21% former smokers
O25.06 UNSUSPECTED N2 IN PATIENTS and 23.8% never smoked. 97.9% were asymptomatic.
WITH CLINICAL STAGE IA NON- Unsuspeted N2 compromise was present in 9 (7.8%)
SMALL CELL LUNG CANCER: IMPACT patients. When divided into subgroups, 3 (4.5%)
OF CURRENT STAGING AND TUMOR were T1a and 6 (12.2%) were T1b (p=0,14). All the
LOCATION. unsuspected N2 was observed un tumors located
Gustavo A. Lyons1, Leonardo Pankl1, Silvia un upper or middle lobes (9/80,11,2%), and none in
Quadrelli2, Carlos Silva3, Domingo J. Chimondeguy1 lower lobes (0/35,0%) (p= 0,03). No nodules less
1
Thoracic Surgery, Buenos Aires British Hospital/ than 10 mm showed N2 disease. The side, age, sex,
Argentina, 2Respiratory Medicine, Buenos Aires tumor type and histology does not correlates with
British Hospital/Argentina, 3Oncology, Buenos Aires unsuspected N2 (P=NS). The Àve years survival was
British Hospital/Argentina 91% in T1a, and 84% in T1b patients (p=0,12). 8
patients (12,1%) have a recurrence in T1a group and
Background: Accurate staging in non small cell lung 11 (22,4%) in T1b (p=0,01). The Àve years survival
cancer (NSCLC) is essential to deÀne the appropriate was 83% in N2 patients.
treatment, primary being the affection of mediastinal Conclusion: In patients with clinical stage IA with
lymph node groups (N2). For this, many imaging and nodules up to 2 cm (T1a) the incidence of unsuspected
invasive mediastinal staging tests are available. The N2 disease is very low (4,5%). The surgical resection,
data are confusing because patients with particular without invasive staging, achieves a satisfactory
characteristics (ie, node size or location) are selected 5 years survival (91%) in this group of patients.
for different staging procedures. The purpose of this Subcentimeter and lower lobes nodules nodules
study was to determine the incidence of unexpected N2 showed no unsuspected N2 nodal metastastasis.
compromise in patients with clinical stage I NSCLC. Keywords: Lung cancer, Early Stage NSCLC,
Methods: This study was designed as a retrospective Lymph nodes, Metastasis
cohort. An analysis of consecutive patients operated
on with curative intent in a single thoracic surgery
department, presenting as a pulmonary nodule up NSCLC - Early Stage Wednesday, 6 July 2011 14:30-16:00
to 3 cm in diameter, with no hilar or mediastinal
lymphadenopathy on computed tomography or O25.07 TUMOR RESPONSE AND
clinical examination in supraclavicular region, with TOXICITY IN NEO-ADJUVANT
Ànal histological diagnosis of NSCLC between 2000 ERLOTINIB IN EARLY STAGE NSCLC
and 2010 was carried out. When present, site-speciÀc PATIENTS
symptoms were evaluated with the most appropiate Eva E. Schaake1, Houke M. Klomp2, J A. Burgers3
1
study (eg, bone scans, magnetic resonance imagery Thoracic Oncology, NKI-AVL/Netherlands,
2
or CT of the brain). Incidence of unsuspected N2 Surgical Oncology, NKI-AVL/Netherlands,
3
disease was analyzed according the tumor size (2 Thoracic Oncology, The Netherlands Cancer
cm, >2 to 3 cm), side, lobe location (upper and Institute/Netherlands
midde, versus lower lobes), sex, age, tumor type
and smoking history. Survival rates were calculated Background: Despite radical surgery in patients with
by the Kaplan-Meier method, while survival curves early-stage non-small cell lung cancer (NSCLC), disease
were compared using a log-rank test. recurs in 40% of the patients. The development of
Results: There were 115 patients. The average “targeted therapy” has created new options to improve
outcome in selected patients. This report presents the Table patient characteristics
results regarding toxicity and response to neoadjuvant
erlotinib in NSCLC. Total Enriched Unselected
Methods: This study was designed as an open-label Characteristics population population population
N=60 % N=29 % N=31 %
phase II trial, performed in four hospitals in the
Netherlands, according to a Simon’s minimax 2-stage
Sex M/F 26/34 43-57 3/26 11/99 22/09 72/28
procedure. Initially, operable patients with early-
Mean Age at range
stage NSCLC (minimum of n=15) entered from an diagnose 64 37-38 59,4 36-73 64 50-76
“enriched” population (two or more of the following Histology
features: never-smoker, female, non-squamous Large cell 4 7 1 3 3 11
histology and/or Asian ethnicity), thereafter inclusion Squamouscell 12 20 0 0 12 39
was open for all operable patients to a total of 60 Adenoca 38 63 26 90 12 39
patients. Patients received preoperative erlotinib 150 Other 6 10 2 7 4 13
mg once daily for 3 weeks. Response to treatment was Mutation status
evaluated with [18F]-FDG-PET, CT and pathological EGFR mutation 7 12 5 17 2 7
examination of the resection specimen. Primary K-ras mutation 12 20 6 21 6 19
endpoints were toxicity and pathologic response. -78% -78%
Median change to to -56%
Results: Between December 2006 and November SUV max -10% 76% -20% 43% 0,70% to 76%
2010, 60 patients were included. In total 29 patients
met the enrichment criteria and 31 patients without Median change -39 to -39 to -35 to
mm T -0,3 68 -1,3 17 -0,7 68
enriched features were entered. Seven patients stopped
erlotinib prematurely (12%). No unexpected toxicity or
Median % 0 to 0 to 0 to
postoperative complications were seen. Skin toxicity, necrosis 29% 97% 40% 97% 18% 60%
any grade, was present in 37 patients (62%), diarrhea in
21 patients (35%). PET evaluation revealed a metabolic Conclusion: We conclude that only 3-weeks of daily
response (>25% SUV decrease) in 14 patients (26%), erlotinib has sufÀcient activity to deserve further
CT evaluation by RECIST showed response in 3 testing in future studies in an enriched population
(5%), whereas pathologic response was seen in 14 (response 34%). Metabolic evaluation of response
patients (23%), with 3 (5%) near-complete pathologic by [18F]-FDG-PET may reÁect clinical activity of
responses. The enriched population showed metabolic erlotinib more accurately than CT.
response in 10 patients versus 6 in the unselected Keywords: toxicity, erlotinib, Neo adjuvant
population. Both EGFR and k-RAS mutation status treatment, Treatment response
were found in both populations, with 5 EGFR
mutations and 6 k-RAS mutations in the enriched
population and respectively 2 and 6 mutations in the Session O26: Molecular Pathology I,
unselected population. In eight cases not enough tumor EGFR
material was available to assess the tumor mutation
status. Characteristics and response data of both groups
are shown in the Table.
Molecular Pathology I, EGFR Wednesday, 6 July 2011 14:30-16:00
O26.01 GENOMIC HETEROGENEITY

BETWEEN PRIMARY NON-SMALL CELL
LUNG CANCER AND ITS METASTASES
Wen-Zhao Zhong1, Zhi-Yong Chen2, Xu-Chao
Zhang1, Jian Su1, Xue-Ning Yang1, Zhi-Hong Chen1,
Jin-Ji Yang1, Qing Zhou1, Hua-Jun Chen1, Tony
Mok3, Yi-Long Wu1
1
Guangdong Lung Cancer Institute, Guangdong
General Hospital And Guangdong Academy Of
Medical Sciences/China, 2Guangdong Lung Cancer
Institute, Guangdong Academy Of Medical Sciences Molecular Pathology I, EGFR Wednesday, 6 July 2011 14:30-16:00
& Guangdong General Hospital/China, 3Department
Of Clinical Oncology, The Chinese University Of O26.02 KRAS AND EGFR MUTATIONAL
Hong Kong/Hong Kong RATE, DISCORDANCE AND OUTCOME
ANALYSIS IN METASTATIC
Background: Patients with epidermal growth factor LUNG ADENOCARCINOMAS
receptor (EGFR) activated mutation are known to IN COMPARISON TO PRIMARY
have mixed response to tyrosine kinase inhibitor LUNG ADENOCARCINOMA. A
(TKI). Intertumoral heterogeneity in EGFR and/ RETROSPECTIVE STUDY OF 344 CASES.
or KRAS mutation heterogeneity is a potential Delicia Munfus-Mccray1, Shuko Harada2, Rex C.
explanation and this study aims to investigate the Yung3, Christina Adams1, Frederic Askin4, Edward
discordance of these mutations in patients with non- Gabrielson5, Qing Kay Li6
1
small cell lung cancer(NSCLC). Pathology, Johns Hopkins Medical Institutes/United
Methods: We performed direct sequencing for EGFR States Of America, 2Molecular Genetic Pathology,
and KRAS mutation in 219 pairs of tumor samples Johns Hopkins Medical Institutes/United States Of
(from a database of 2873 samples). The matching America, 3Medicine- Pulmonary And Critical Care
samples were divided into four groups: Group T are Medicine, Johns Hopkins Medical Institutes/United
primary tumors detected at different time points (n = States Of America, 4Pathology, Johns Hopkins
72), Group N are primary lung tumor with matched Medical Institutes At Bayview/United States Of
metastatic lymph nodes (n = 58), Group M1a are America, 5Molecular Pathology, Johns Hopkins
multiple pulmonary nodule (n = 53), and Group Medical Institutes/United States Of America,
6
M1b are primary lung tumor with matched distant Cytopathology, Johns Hopkins Medical Institutes/
metastases (n = 36). Multivariate analysis and kappa United States Of America
values were used to explore the role of heterogeneity.
Results: EGFR, KRAS, and EGFR/KRAS Background: In primary lung adenocarcinoma,
heterogeneity discordance of the studied population EGFR and KRAS mutations have been reported in
(185 paired samples without exposure to TKI) is approximately 10-20% and 20-30%, respectively.
14% (kappa = 0.67), 8.8% (kappa = 0.59), and 21.2% Although EGFR mutation is associated with a 70-
(kappa = 0.51), respectively. Group M1a has the 80% response rate to tyrosine-kinase inhibitors
highest EGFR/KRAS mutation discordance of 37.6% (TKIs) therapy and a longer progression free
(18/48; kappa = 0.38, p < 0.001), followed by Group survival rate, an association between the KRAS
N at17.3% (9/52; kappa = 0.64),Group T at 17.2% mutation and lack of response to TKIs has also been
(10/58; kappa = 0.63), and Group M1b at 7.4% (2/27; observed. However, the utility of determining KRAS
kappa = 0.84). The EGFR/KRAS heterogeneity mutational status in both primary and metastatic
was 19.6% in the remaining 107 cases without tumors remains unclear. In this study, we have
systematic therapy. In the total 219 paired samples(34 investigated EGFR and KRAS mutational status in
pairs samples with TKI therapy, 78 pairs samples both primary and metastatic lung adenocarcinoma,
with chemotherapy, 107 pairs samples without any with an emphasis on metastatic tumors.
systematic therapy), the potential mutagenic effects Methods: Using department of pathology
of TKI therapy (p = 0.001) were not reÁected in archives at the Johns Hopkins Hospital, 2,657
chemotherapy (p = 0.43) in multivariate analysis. lung adenocarcinomas were found from January
Conclusion: Heterogeneity in EGFR/KRAS mutation 2007 to December 2010. EGFR and KRAS studies
status is signiÀcant and particularly in patients with were performed in 375 cases. Among them, 221
multiple pulmonary nodule. Our results provide a primary and 123 metastatic adenocarcinomas were
potential explanation for the mixed tumor response to analyzed, which included thirteen pairs of primary
EGFR TKI. and matched metastases. DNA was isolated from
Keywords: Lung neoplasms, Epidermal growth factor the samples, quantiÀed and ampliÀed by polymerase
receptor, Kras, heterogeneity chain reaction (PCR) using primers to exons 18-21
of the EGFR gene and exon 2 of the KRAS gene
A revised/updated abstract may be included in (in codons 12 and 13). PCR products were analyzed
the Late Breaking Abstract Supplement, available by Genzyme for EGFR mutations and by Sanger
at the 14th World Conference on Lung Cancer. sequencing for KRAS mutations.
Results: Patient ages ranged from 29 to 90 years old Background: EGFR mutation status is the best
with a median of 62 years old. In metastatic cases, predictor of response to tyrosine kinase inhibitors
59.3% were Caucasian, the male:female ratio was in adenocarcinoma of lung. Approximately 70%
1:0.92 and 67.5% (83/123) were current or former of lung cancers are diagnosed in advanced stages
smokers. EGFR and KRAS mutations in both where small biopsies and cytological specimens
primary and metastatic tumors were summarized in are the only source of material for both diagnosis
Table 1. In metastasis, KRAS mutations occurred and mutation testing. Recently antibodies that can
exclusively in smokers and revealed higher detect mutant EGFR protein have been introduced.
mutational rates in all sites than that of primary We evaluated the detection of EGFR mutation
tumors, except in the pleura. 36 of the 41 (87.8%) by immunohistochemistry (IHC) in small biopsy
KRAS mutational cases presented as stage III or IV specimens of lung adenocarcinoma and correlated
cancers and were associated with a shorter survival. with EGFR mutation status.
Furthermore, of the 13 paired cases, EGFR and Methods: 38 cases of adenocarcinoma were
KRAS mutations were concordant in 84.6%; one analyzed (8 core biopsies and 30 cytology cell
pair displayed acquisition of KRAS mutation, while blocks). Antibodies against the L858R mutation and
one pair showed loss of EGFR mutation in the the exon 19 deletion (15bp deletion) were used under
corresponding metastasis. optimized condition (C ell Signaling Technology).
EGFR and KRAS Analysis in Lung Adenocarcinoma Stains were scored as negative , 1+ (weak and
EGFR mutation KRAS Mutation focal positivity), 2+ (moderate intensity and focal
Number
Categories
of cases
Number Number (ratio, positivity), 3+ (strong and diffuse positivity). All
(ratio, percentage) percentage) biopsies and cell blocks were analyzed by standard
Primary
221 44 (44/221, 19.9%) 52 (52/221, 23.5%) molecular methods to detect EGFR mutations. The
Carcinoma
results of these two techniques were correlated.
Metastatic
123 19 (19/123, 15.4%) 41 (41/123, 33.3%) Results: Deletions in exon 19 were detected in 36
Carcinoma
Lymph node 62 6 (6/62, 9.7%) 25 (25/62, 40.3%) %, (8 cores and 6 cell blocks) and L858R mutation
Brain 17 5 (5/17, 29.4%) 5 (5/17, 29.4%) in 16% (6 cell blocks) of all cases by standard
Pleural 19 5 (5/19, 26.3%) 1 (1/19, 5.3%) molecular methods. Using a cutoff of 2+ or 3+ as
Bone 5 0 3 (3/5, 60%) positive by IHC, the positive predictive value (PPV)
Other 20 3 (3/20, 15%) 7 (7/20, 35%) for L858R mutation and exon 19 deletion was 100%
each (no false positive cases were detected at this
Conclusion: Our data suggested that EGFR and cut-off point). The negative predictive values (NPP)
KRAS status might not be stable in metastases, thus, were 88% and 78 % respectively which reÁect the
they should be tested in metastasis regardless of rate of false negative results (4 cases for L858R and
known mutations of the primary tumor.Additional 6 cases for exon 19 deletion). When staining scores
studies are needed to further investigate mechanisms of 1+ are considered positive, the PPV for L858R
of higher KRAS mutations and discordances in mutation is of 100%, and 88% for exon 19 deletion.
metastatic tumors. The drop in PPV is a result of 2 false positive cases
Keywords: Adenocarcinoma, Metastatic, EGFR, detected at this cut-off point using L858R speciÀc
Kras antibody. The negative predictive value is of 100%
for both antibodies since no false negative cases are
indentiÀed.
Molecular Pathology I, EGFR Wednesday, 6 July 2011 14:30-16:00 Conclusion: Immunostain for speciÀc mutant EGFR
show a good correlation with mutation analysis
O26.03 USE OF MUTATION SPECIFIC and can be used as a screening method to identify
ANTIBODIES TO DETECT EGFR patients for tyrosine kinase inhibition therapy. Cases
STATUS IN SMALL BIOPSY AND with weak positivity (1+) should be considered
CYTOLOGY SPECIMENS OF LUNG equivocal due to risk of false positive results. Only
ADENOCARCINOMA. cases with positivity of 2-3+ should be considered as
Andre L. Moreira, Adnan Hasanovic true positive which increases the PPV of the test. All
Pathology, Memorial Sloan-Kettering Cancer equivocal (1+) and negative results by IHC should
Center/United States Of America prompt standard molecular methods for detection of
EGFR mutation. The IHC methodology is potentially
Table 1 Total Resection Biopsy FNA Fluid P value

useful as a screnning test for the detection of mutated Cases
EGFR specially in areas where molecular analysis N 601 230 290 55 26 -
is not available and for use in small biopsies when N % N % N % N % N % -
material is too scant for molecular analysis. Mutation (+) 219 36.4 83 36.1 104 35.9 23 41.8 9 34.6 0.85**
Keywords: EGFR mutation, small biopsy, EGFR m(+) 106 17.6 36 16.0 54 18.6 12 21.8 4 15.4 0.67**
Ex19del 55 9.2 20 8.9 27 9.3 7 12.7 1 3.8 0.62**
immunohistology L858R 27 4.4 8 3.6 12 4.1 4 7.3 3 11.5 0.16***
Other* 33 5.5 10 4.4 20 6.9 3 5.5 0 0 0.44***
A revised/updated abstract may be included in KRAS m(+) 114 19.0 47 20.4 51 17.6 11 20.0 5 19.2 0.87**
Codon 12 104 17.3 43 18.7 47 16.2 9 16.4 5 19.2 0.88**
the Late Breaking Abstract Supplement, available Codon 13 10 1.7 4 1.7 4 1.4 2 3.6 0 0 0.58***
at the 14th World Conference on Lung Cancer. InsufÀcient 17 2.8 0 0 14 4.8 2 3.6 1 3.8 0.001***
* Values of mutation sub-type do not add up to total mutation count as
some specimens have dual mutations (most notably T790M in conjunction
with other mutations) ** Chi-square test for differences across groups (not
Molecular Pathology I, EGFR Wednesday, 6 July 2011 14:30-16:00 including Total Cases group) *** Fisher exact test for differences across
groups (not including Total Cases group) Abbreviations: m: mutation; (+):
O26.05 MUTATIONS ARE DETECTED positive result; Ex19del: Exon 19 deletion
AT COMPARABLE FREQUENCIES IN A Conclusion: These data indicate that all specimen

VARIETY OF SPECIMEN TYPES IN NON- types evaluated are potentially adequate substrates
SMALL CELL LUNG CARCINOMA for mutation testing in NSCLC, and that mutation
Kevin L. Tyler1, Kathleen Torkko1, David R. testing can be successfully performed on small
Camidge2, Robert C. Doebele2, Wilbur Franklin1, specimens such as biopsies, FNAs or Áuids. These
Dara L. Aisner1 Àndings further suggest that small specimens are
1
Pathology, University Of Colorado Denver/United potentially adequate substrates for molecular testing
States Of America, 2Medical Oncology, University Of in the setting of post-treatment re-biopsy for the
Colorado/United States Of America purpose of ‘molecular restaging’, although treatment
related changes may impact the number and viability
Background: Molecular characterization of non- of tumor cells . These data also conÀrm that non-
small cell lung carcinoma (NSCLC) is increasingly resection cases have a higher rate of insufÀcient
critical for selection of optimal therapy in advanced material for testing compared to resection cases.
stage disease. In most patients with advanced- Keywords: Mutation, biomarker, EGFR, Kras
stage disease, diagnosis is based upon small biopsy
or cytopathology specimens, which can present
challenges for molecular testing. To determine the Molecular Pathology I, EGFR Wednesday, 6 July 2011 14:30-16:00
feasibility of testing on various specimen types, we
evaluated the outcome of mutation testing for EGFR O26.06 MOLECULAR CORRELATION
and KRAS with regard to specimen type. WITH HISTOLOGIC PATTERNS OF
Methods: We retrospectively evaluated all NSCLC MUCIN IN LUNG ADENOCARCINOMA
cases tested for EGFR and KRAS mutation status, as (ADC)
determined by direct sequencing, from October, 2008 Kyuichi Kadota1, Kei Suzuki2, S P. D’Angelo2,
to January, 2011 by review of the in-house laboratory Natasha Rekhtman2, Andre L. Moreira2, Camelia S.
database. Specimens were classiÀed according to Sima2, Gregory J. Riely2, Mark G. Kris2, Valerie W.
specimen type as surgical resection (R), biopsy (Bx), Rusch2, Prasad S. Adusumilli2, William D. Travis2
1
Àne needle aspiration (FNA) and Áuids (F). Overall Department Of Pathology And Surgery, Memorial
mutation detection rate for any mutation in both Sloan-Kettering Cancer Center/United States Of
EGFR and KRAS was determined, as was detection America, 2Memorial Sloan-Kettering Cancer Center/
rate for individual mutations. United States Of America
Results: 601 cases of NSCLC were evaluated for
EGFR and KRAS mutation in the study period. Background: The new IASLC/ATS/ERS
Similar overall mutation detection rate, EGFR classiÀcation of lung ADC identiÀes invasive
mutation detection rate and KRAS mutation mucinous adenocarcinoma (IMA) and colloid
detection rate was found in all specimen types (Table adenocarcinoma (COL) as variant subtypes. While
1). InsufÀcient specimen rates were higher in non- signet-ring cell (SRC) and extracellular mucinous
resection cases compared to resection cases. (ECM) features are additional patterns, they are not
regarded as histologic subtypes as they can occur well recognized. It can occur with multiple ADC
in multiple subtypes. The aim of this study was to histologic subtypes (mostly acinar) and it shows a
investigate the association between the spectrum of strong association with KRAS mutation. Patients
mucinous patterns in ADC with EGFR and KRAS with >10% ECM had a favorable 3 yr RFS (82%).
mutation status. KRAS mutation was also associated with IMA, but
Methods: H&E slides of 784 resected ADC (603 was present in only 25% of COL.
stage I, 94 stage II, 87 stage IIIA) with EGFR and Keywords: histologic pattern, lung,
KRAS mutation data from 2002 to 2009 were Adenocarcinoma, Kras
reviewed with an emphasis on mucinous patterns.
Comprehensive histologic subtyping was used to
estimate the percentage of each histological subtype, Molecular Pathology I, EGFR Wednesday, 6 July 2011 14:30-16:00
and tumors were classiÀed according to the new
IASLC/ATS/ERS classiÀcation. Signet-ring cell O26.07 FEASIBILITY OF MUTATIONAL
(SRC) features and ECM were estimated in 10% ANALYSIS OF EGFR AND K-RAS IN
increments. CYTOLOGICAL SAMPLES OF NSCLC
Results: There were 1 mucinous minimally invasive PATIENTS: CORRELATION WITH
adenocarcinoma (MIA), 29 IMA, 4 COL, 38 cases CLINICAL OUTCOMES.
with 10% SRC features, and 83 cases with 10% Maria D. Lozano1, Tania Labiano1, Jose I.
ECM (Table). The patient with mucinous MIA had Echeveste1, Alfonso Gurpide2, Luis M. Seijo3, Javier
KRAS mutation. Among the IMA patients, 66% had J. Zulueta3, Anabel Del Barrio2, Salvador Martin-
KRAS mutation. Of the 4 COL patients, one had Algarra2, Ruben Pio4, Jose Luis Perez-Gracia2
1
KRAS mutation with the other 3 being wild type. Pathology, University Of Navarra/Spain, 2Oncology,
IMA/COL subtype correlated with KRAS mutation University Of Navarra/Spain, 3Respiratory Medicine,
compared to EGFR mutation and wild type (p<0.001 University Of Navarra/Spain, 4Center For Applied
and p<0.001, respectively). Among the patients with Medical Research. Division Of Oncology, University
SRC features, 26% had KRAS mutation, 8% EGFR Of Navarra/Spain
mutation, and 66% wild type. Among the patients
with ECM, 42% had KRAS mutation, 7% EGFR Background: Determination of molecular predictive
mutation, and 51% wild type. Presence of ECM factors should be considered and performed
correlated with KRAS mutation compared to EGFR if deemed necessary in every NSCLC patient.
and wild type (p<0.001, each). The mucinous MIA Epidermal growth-factor receptor (EGFR) and K-ras
patient has no evidence of disease at the time of this mutations guide treatment selection in non-small cell
study while three-year recurrence free survival (RFS) lung cancer (NSCLC) patients. Although mutation
was 46% in IMA, 50% in COL, 75% in ADC with status is routinely assessed in biopsies, cytological
SRC, and 82% in ADC with ECM. specimens are frequently the only samples available.
These samples are commonly regarded as inadequate
for comprehensive molecular analysis. Then, patients
diagnosed by cytology are frequently considered
ineligible for molecular analysis and individualized
treatment selection, leaving the options of either
obtaining a new tumor sample or not performing
molecular analysis. We determined EGFR and K-ras
mutations in a series of 254 cytological samples.
Methods: DNA was extracted from 254 consecutive
samples, including: 204 Papanicolau smears
(80.3%), 21 cell blocks (8.3%), 9 fresh samples
(3.5%), 13 ThinPrep (5.1%), and 6 body cavity
Áuids (2.4%). Papanicolau smears were analyzed
when they had >50% of malignant cells. PCR and
direct sequencing of exons 18-21 of the EGFR gene
Conclusion: ECM is a histologic feature occurring and of exon 2 of the K-ras gene were performed.
in approximately 10% of lung ADC that is not EGFR mutations were simultaneously determined in
biopsies and cytological samples from 50 patients. Background: The EGFR acquired mutation
Activity of EGFR tyrosine-kinase inhibitors (TKI) resistance T790M causes resistance to the reversible
was assessed. ATP-competitive EGFR kinase inhibitors geÀtinib
Results: Cytological diagnosis was adenocarcinoma or erlotinib, and to the irreversible EGFR inhibitors
in 187 samples (73.6%), Sqcc in 48 (18.9%), and BIBW2992 and HKI-272 in non-small cell lung
NSCLC-NOS in 19 (7.4%). EGFR mutations cancer. PF00299804 (PF) is an irreversible EGFR
were identiÀed in 32 samples (12.6%) and K-ras inhibitor effective in NSCLC models harboring
mutations in 28 (11%). EGFR and K-ras mutations EGFR T790M and WZ4002 (WZ) is a mutant-
were mutually exclusive. In EGFR mutated cases, selective EGFR inhibitor with high potency against
DNA was obtained from stained smears in 204 cases the EGFR T790M. The mechanisms of resistance to
(80.3%), fresh samples in 17 (6.7%), ThinPrep in 13 PF and WZ in EGFR mutated models are not well
(5.1%), and cell block in 21 (8.3%). Response rate to deÀned.
EGFR TKI in patients harboring mutations was 75%. Methods: Resistant clones were obtained by
Mutation status was identical in patients who had prolonged exposure of PC9 cells (EGFR del E746_
both biopsies and cytological samples analyzed. A750) to increasing doses (up to 1 M) of PF (PFR
Conclusion: Cytological samples, including clones) and high doses (1 M) of WZ (WZR clones).
stained smears, are adequate for determination IC50 was > 1 M (>100 fold higher than that of
of EGFR and K-ras mutation status in NSCLC parental PC9 cells) for the PFR clones and > 100 nM
patients. The quality of the sample, rather than the (>10 fold higher than that of parental PC9 cells) for
method to obtain it, is a critical factor to obtain the WZR clones.
adequate results. Joint mutation assessment in both Results: We found that both PFR and WZR clones
cytological samples and biopsies, was concordant, maintained Akt but neither EGFR nor ERK 1/2
suggesting mutation analysis from cytological activity upon PF or WZ treatment. No T790M
samples is comparable to that derived from biopsy or C797S mutation was detected. However,
samples. This technique might allow to perform the resistant cells contained activated IGF1R
individualized treatment selection in NSCLC patients signaling. Concomitant treatment with the IGF1R
diagnosed by cytological samples, precluding the kinase inhibitor BMS 536924 led to phospho-
need for additional biopsies. Akt downregulation and inhibition of growth
Keyword: NSCLC, Cytology, Papanicolau stained proliferation in PFR and WZR clones upon EGFR
smears, EGFR, K-ras, TKI inhibition. IGFBP3 was down-regulated in the
resistant clones, both at the mRNA and protein
levels, and treatment with recombinant IGFBP3
Session O27: Biomarkers and Resistance re-sensitized these cells to EGFR inhibition.
Knockdown of IGFBP3 through RNA interference
Wednesday, 6 July 2011 in parental PC9 cells conferred partial resistance to
PF treatment. Sustained exposure of the resistant
clones to PF or WZ (1 M) led to the emergence
Biomarkers and Resistance Wednesday, 6 July 2011 14:30-16:00 of clones with a different phenotype characterized
by maintained Akt and ERK 1/2 but not EGFR
O27.01 RESISTANCE TO EGFR T790M activity upon PF or WZ treatment, and loss of
KINASE INHIBITORS THROUGH A DUSP6 expression. These cells (named “PFR+”
MULTISTEP PROCESS INVOLVING THE and “WZR+”) were resistant to EGFR and IGF1R
IGF1R PATHWAY inhibitors combination but sensitivity was partly
Alexis B. Cortot1, Claire E. Repellin1, Takeshi restored with the addition of the MEK inhibitor
Shimamura1, Marzia Capelletti1, Kreshnik CI-1040 or overexpression of DUSP6. PFR+ cells
Zejnullahu1, James Christensen2, Kwok-Kin Wong1, had a proliferative advantage over PFR cells in the
Natanael Gray1, Pasi A. Janne1 presence of PF.
1
Medical Oncology, Dana Farber Cancer Institute/ Conclusion: Resistance to EGFR inhibitors that
United States Of America, 2Department Of Research are effective against EGFR T790M in PC9 cells
Pharmacology, PÀzer Global Research And can occur through a multistep process that involves
Development/United States Of America sequential activation of IGF1R and MAP kinase
signaling. Our Àndings reveal both mechanistic
insights and the challenges to developing therapeutic the antibody. The puriÀed antiserum was
strategies against EGFR inhibitor resistant cancers. used to examine brain extracts from wildtype
Keywords: irreversible inhibitors, EGFR, T790M, and PIMT deÀcient mice, and it was used for
Resistance immunohistochemistry of human and murine SCLC
tumors.
Results: HuD is highly prone to isoaspartyl
Biomarkers and Resistance Wednesday, 6 July 2011 14:30-16:00 conversion in vitro. Examination of brain extracts
from wildtype and PIMT deÀcient mice by Western
O27.02 SMALL-CELL LUNG CANCER blot using our anti-isoaspartyl-HuD antiserum shows
AUTOANTIGEN HU IS PRONE TO THE a strong band in the PIMT deÀcient mice, but very
ANTIGENIC ISOASPARTYL POST- little signal in wildtype brain extracts. The antiserum
TRANSLATIONAL MODIFICATION also reacts with murine and human SCLC tissue.
Ite A. Laird-Offringa1, Meleeneh Kazarian1, Mario We show that PIMT levels in the lung are much
Pulido1, Jeffrey A. Tsou1, Trang Luc2, Dana Aswad2 lower than in the brain. Thus, we hypothesize that
1
Norris Cancer Center, University Of Southern PIMT may not be sufÀciently available to repair
California/United States Of America, 2Molecular isoaspartylated HuD in the SCLC tumors, potentially
Biology And Biochemistry, University Of California, leading to an immune reaction against HuD in the
Irvine/United States Of America tumor. Spreading of the immune response to Hu
protein present in the nervous system could then lead
Background: Small-cell lung cancer (SCLC) is the to autoimmunity.
most aggressive lung cancer subtype. It spreads very Conclusion: HuD is highly prone to isoaspartyl
quickly and is usually diagnosed when the cancer has conversion in vitro. Isoaspartylated HuD is also
disseminated. A number of rare autoimmune diseases seen in vivo, in the brains of genetically engineered
are associated with SCLC and are characterized mice deÀcient for PIMT, the enzyme that normally
by high titers of auto-antibodies against normally repairs this highly immunogenic post-translational
neuronally expressed proteins. A substantial fraction modiÀcation. Immunohistochemical analyses of
of SCLC patients without autoimmune symptoms SCLC tumors indicate that isoaspartylation of
also carries these antibodies, but at low titer. One Hu proteins occurs in human and murine SCLC
antigen family against which autoantibodies are tumors. Our data suggests a possible mechanism
seen in SCLC are the Hu family of a neuronal RNA- for the development of immuno-responsiveness in
binding proteins. These proteins are misexpressed SCLC. Elucidation of the mechanism of immuno-
in all SCLC tumors. The mechanism causing responsiveness in SCLC could lead to new tools for
immuno-responsiveness of SCLC patients against early detection, diagnosis and treatment.
these proteins is currently unknown. Based on Keywords: SCLC, Small cell lung cancer,
the N-terminal amino acid sequence of HuD, the paraneoplastic disease, HuD
neuronal Hu protein most commonly expressed in
SCLC, we hypothesized that a post-translational
modiÀcation, known as isoaspartylation, might Biomarkers and Resistance Wednesday, 6 July 2011 14:30-16:00
trigger the autoimmune response. Isoaspartyl
conversion is a spontaneous process that can occur O27.04 ROUTINE
at asparagines and aspartate residues as proteins age. IMMUNOHISTOCHEMICAL STAINING
When not properly repaired by protein-L-isoaspartyl FOR ALK IS SPECIFIC FOR THE
(D-aspartate) O-methyltransferase (PIMT), DETECTION OF ALK-REARRANGED
isoaspartyl residues have been shown to be highly LUNG ADENOCARCINOMAS
immunogenic. Joanna H. Tong1, Ching Y. So1, Wei Kang1, Chit
Methods: Using an assay in which isoaspartylated Chow1, Peggy P. Law1, Shuk L. Chau1, Raymond W.
substrates are radioactively labeled by the PIMT Lung1, Tony Mok2, Ka F. To1
1
enzyme, we examined whether HuD is prone to Anatomical And Cellular Pathology, The Chinese
isoaspartylation when incubated in vitro under University Of Hong Kong/Hong Kong, 2Department
physiological conditions. We raised a rabbit Of Clinical Oncology, The Chinese University Of
polyclonal antiserum against an isoaspartylated Hong Kong/Hong Kong
HuD peptide, and afÀnity puriÀed and absorbed
Background: The echinoderm microtubule-

associated protein-like 4-anaplastic lymphoma
kinase (EML4-ALK) fusion gene has been
identiÀed as a potent driver mutation in non-small
cell lung cancers (NSCLC). It deÀnes a unique
subgroup of lung adenocarcinoma that may be
responsive to speciÀc targeted therapy. Detection of
ALK-rearrangement in lung cancers by molecular
methods, like FISH or RT-PCR is not routinely
available in most laboratories. We report a reliable
immunohistochemical staining for the routine
detection of ALK fusion in lung cancers.
Methods: A total of 326 resectable lung Conclusion: All the ALK IHC positive
adenocarcinoma samples were retrieved from adenocarcinomas were conÀrmed to have ALK-
department of Anatomical and Cellular Pathology, rearrangement. Routine immunohistochemistry
Prince of Wales Hospital, Hong Kong. Three can speciÀcally detect ALK-rearrangement in lung
representative tumor parafÀn block samples adenocarcinomas. It may provide a reliable tool
were taken from each case for tissue microarray for the identiÀcation of candidates that may be
construction. Immunohistochemistry was performed responsive to ALK inhibitors.
on tissue array sections using anti-ALK antibody Keywords: ALK, immunohistochemistry, lung
(Abcam 5E4) and Envision FLEX+ visualization adenocarcinoma
system. Fluorescence in situ hybridization (FISH)
for ALK-rearrangement was performed using
Abbott break-apart probe to conÀrm the presence of Biomarkers and Resistance Wednesday, 6 July 2011 14:30-16:00
ALK gene rearrangement. When suitable materials
were available, fusion gene transcripts were also O27.05 MESOTHELIN IS A COMMONLY
studied by RT-PCR. EXPRESSED TUMOR MARKER IN
Results: Nineteen out of 326 (5.8%) lung LUNG ADENOCARCINOMA (LAC) THAT
adenocarcinomas in this cohort were positive IMPARTS AN AGGRESSIVE PHENOTYPE
for ALK immunohistochemical (IHC) stain. The – A CANDIDATE MOLECULAR TARGET
tumor cells demonstrated granular staining in the Stefan S. Kachala1, Kei Suzuki1, Eva Vertes1, Luis
cytoplasm of various intensities. No expression Rodriguez1, Kyuichi Kadota1, Camelia S. Sima2,
was observed in normal bronchial epithelium, Valerie W. Rusch1, William D. Travis3, Michel
alveolar pneumocytes and stromal cells. All the Sadelain4, Prasad S. Adusumilli1
1
ALK IHC positive cases were conÀrmed by Department Of Surgery, Thoracic Service, Memorial
FISH using ALK break-apart probe. EML4-ALK Sloan-Kettering Cancer Center/United States Of
variants 1, 2 and 3b were the most common fusion America, 2Epidemiology And Biostatistics, Memorial
products detected by RT-PCR. Histologically, the Sloan-Kettering Cancer Center/United States Of
ALK positive adenocarcinomas displayed mixed America, 3Pathology, Memorial Sloan-Kettering
growth patterns including solid with mucin, Cancer Center/United States Of America, 4Center
papillary, acinar and bronchioalveolar patterns. For Cell Engineering, Memorial Sloan-Kettering
Figure 1 shows the representative photos of ALK Cancer Center/United States Of America
immunohistochemistry, FISH and the sequence
electropherogram from an lung adenocarcinoma Background: Mesothelin is a cell surface tumor-
harboring EML4-ALK variant 2. associated antigen. It is commonly expressed in
mesothelioma, pancreatic, and ovarian cancers,
imparting an aggressive tumor phenotype and
chemotherapy resistance. We seek to evaluate the
expression of mesothelin in LAC and investigate
the clinical and preclinical correlations for its
consideration as a molecular target.
Methods: Mesothelin expression was assessed by
immunohistochemical staining in a stage I LAC Conclusion: Mesothelin is a commonly expressed

(n=474, 1995-2005) tissue microarray, and correlated antigen in LAC associated with poor outcomes and
with survival. InÁuence of mesothelin expression KRAS mutant/EGFR wild-type tumors. Preclinical
in LAC was examined through: clinical correlatives data reveals a phenotype characterized by in vitro
(n=98, LAC stage I-III; NIH Director’s Challenge therapy resistance. Mesothelin’s association with
dataset – mRNA microarray proÀles and EGFR/ clinically aggressive tumors provides rationale for its
KRAS mutation status) and preclinical correlatives targeting in LAC.
utilizing mesothelin-expressing (H1299M) and Keywords: lung adenocarcinoma, mesothelin, Kras,
control (H1299) LAC cells. Preclinical investigation biomarker
conducted in vitro by migration and invasion
[Boyden chamber assay], chemo- and radio-
resistance [cell proliferation and colony formation Biomarkers and Resistance Wednesday, 6 July 2011 14:30-16:00
on soft agar] after exposure to cisplatin (IC50 31uM)
or radiation (0-16Gy); in vivo assessment employed O27.06 MIF AND IL-17 PROMOTE
Kaplan-Meier analysis of median survival in SCID/ CHEMOKINE DEPENDENT ADAPTIVE
bg mice, bearing orthotopically implanted H1299 TUMOR ANGIOGENESIS IN THE
and H1299M LAC. CONTEXT OF VEGF INHIBITION.
Results: Mesothelin is expressed in 52% of LAC Douglas Arenberg, Shannon Carskadon, Liujian
and highly expressed (intense staining in >50% Zhao
of the tumor core) in 19% of LAC tumors (Figure Internal Medicine, University Of Michigan/United
1A). High mesothelin expression in stage I LAC States Of America
(n=88) demonstrated decreased overall survival as
compared to low mesothelin (n=386) expressing Background: Angiogenesis in lung cancer is
LAC (Figure 1B; median survival 71 vs 92 months, driven by multiple mechanisms. We have shown
p=0.02). High expression of mesothelin in LAC that many lung cancer tumors (both experimental
was associated with a history of smoking (p=0.005), and human tumors) express angiogenic CXC
number of pack years (p=0.005), EGFR wild- chemokines in greater levels than traditional
type (p=0.02), and KRAS mutant (p=0.02), and angiogenic factors (VEGF), suggesting diversity
upregulation of genes promoting tumor invasiveness and perhaps adaptability in the mechanism by which
(FDR=0.0062). In vitro, H1299M cells demonstrated tumor angiogenesis can occur. We hypothesized
increased migration and invasion (p<0.0001 that inhibition of tumor angiogenesis would trigger
and p=0.0005 respectively), increased viability activation of adaptive responses to maintain tumor
(Figure 1C; p=0.002) and colony formation on angiogenesis, and we sought to characterize the
soft agar (p=0.027) following cisplatin treatment adaptive mechanism.
or radiation (Figure 1D, p<0.0001). In vivo, mice Methods: We established heterotopic tumors in mice
with orthotopic H1299M lung tumors had decreased with LLC cells and used two different methods to
median survival as compared to H1299 lung tumors inhibit angiogenic pathways in tumors. We targeted
(Figure 1E; n=30, 44 vs 56 days, p=0.0012). VEGF mediated angiogenesis with a mononclonal
antibody against murine VEGFR2 (DC101. 250
ƫg three times weekly). To target CXC chemokine
mediated angiogenesis, we used CXCR2 knockout
and control (C57Bl6) mice.
Results: In both models, initial tumor growth (up
to 14 days) was inhibited in the experimental group
compared with controls. By day 28, tumor growth
in both anti-angiogenic groups caught up to control
groups. Tumors were removed and analyzed at
both early and late time points. Early time points
demonstrated reduced tumor vascularity in the
smaller tumors of treated mice. At later time points
vascularity was equivalent in both groups, but the
anti-VEGFR group demonstrated higher levels
3
of MIF, CXCL1, CXCL2, and CXCL5. We also Flagship Biosciences/United States Of America,
4
discovered that IL-17A was expressed in tumors after Osi Pharmaceuticals/United States Of America,
5
anti-VEGFR treatment, but not in other groups. In Novella Clinical/United States Of America,
6
contrast, levels of VEGF in CXCR2 knockout mice Ospedale Di Perugia/Italy, 7Medical Oncology,
were signiÀcantly elevated compared to wild type The Maria Sklodowska-curie Institute Of Oncology/
control mice, in which CXC chemokine levels were Poland, 8Univesity Of Chicago/United States Of
increased. Next, anti-VEGFR and control antibodies America, 9Taichung Veterans General Hospital/
were used to treat CXCR2 knockout mice and Taiwan, 10Royal Marsden Hospital/United Kingdom,
11
controls. The duration of tumor-growth inhibition Saint Vincent Hospital, Catholic University Of
in CXCR2 mice by anti-VEGFR2 was signiÀcantly Korea/Korea, 12Gil Hospital, Gachon University,/
longer than in control mice, suggesting that the Korea
compensatory response to anti-angiogenic therapy
was dependent upon angiogenic CXC chemokine Background: Laboratory analyses of selected
signaling. biomarkers are complete for the all of the 974
Conclusion: Tumors display adaptability in th patients that were enrolled in RADIANT, a phase
econtext of anti-angiogenic strategies. Our data III trial comparing erlotinib 150 mg daily vs.
demonstrate that the compensatory response of placebo (2:1) in stage IB-IIIA NSCLC patients with
tumors to VEGF inhibition requires angiogenic CXC surgically resected EGFR-positive tumors (IHC and/
chemokine signaling via CXCR2. We hypothesize or FISH).
that VEGF targeted therapy results in tumor Methods: Biomarker analyses completed include:
hypoxia that increases expression of inÁammatory protein expression by IHC of EGFR (EGFR
cytokines MIF, and/or IL-17A, both of which PharmDx Kit, with + 1% positive tumor cells,
are known to potently up-regulate expression of Dako) and e-cadherin/vimentin (E-cad/vim prototype
angiogenic CXC chemokine. Our Àndings would comp Dx kit, Dako); FISH for EGFR gene copy
sugest that angiogenic targeting, much like other number (Vysis, Abbott), and mutations in EGFR
cancer treatment strategies, would be improved by (Exon 19 Del + Exon 21 L858R) and Kras (Wave
simultaneous targeting of multiple pro-angiogenic HS-DHPLC, Transgenomic Inc.)
pathways. Results: Preliminary data analyses of results from
Keywords: angiogenesis, VEGF, microenvironment, the tumors demonstrated that: 96 % (937/973) were
chemokines EGFR IHC+ and 73 % (699/955) EGFR FISH+, 17
% (161/938) had an activating EGFR mutation, 16
% (139/873) had a Kras mut, 80 % (725/905) were
Session O28: Biomarkers III E-cad+ and 48 % (436/911) were vim+ based on
a preset cut-point derived from previous studies.
Wednesday, 6 July 2011 EGFR mut occurred in 27 % (105/388; 59 Del-46
L858R) of females, 10 % (56/542; 30 Ex 19 Del-
26 Ex 21 L858R) of males; it occurred in 46 %
Biomarkers III Wednesday, 6 July 2011 14:30-16:00 (76/164; 37 Ex 19 Del- 39 Ex 21 L858R) of Asians,
4 % (1/25; Ex 19 Del) of Blacks, 11 % (84/739
O28.01 SELECT BIOMARKER ANALYSES ; 51 Ex 19 Del-33 Ex 21 L858R) of Caucasians;
OF COMPLETELY RESECTED NSCLC and it occurred in 53 % (101/191) never smokers,
TUMORS FROM ENROLLED PATIENTS 4 % (4/106) current smoker, 9% 56/631 former
IN AN ADJUVANT ERLOTINIB smokers > 100 cig/lifetime. Kras mut occurred in:
(TARCEVA®) CLINICAL TRIAL 6% (10/175) of never smokers, 14 % (15/105) of
(RADIANT) current smokers, 20% (115/592) of former smokers >
Frank Richardson1, Katherine Richardson2, David 100 cig/lifetime.. Twenty eight percent (155/560) of
Young3, Regina Sennello4, Julie Horan5, Angela adenocarcinomas had an EGFR activating mutation
Davies4, Lucio Crino6, Maciej Krzakowski7, Philip and 23 % (121/528) had a Kras mut whereas 4%
Hoffman8, Gee Chen Chang9, Mary O’Orian10, Hoon- (8/286) of squamous cell carcinomas had an EGFR
Kyo Kim11, Eun Kyung Cho12 mut and 2 % (6/264) had a Kras mut. There were
1
Samm, Osi Pharmaceuticals/United States Of 7/936 Exon 18 G719A mutations, 15/928 dup/
America, 2Transgenomic/United States Of America, insertions in Exon 20 and 4/924 L861Q mutations
in Exon 21. There was one T790M mutation, platinum-regimens .

no simultaneous Exon 19 Del/Exon 21 L858R Methods: CDA polymorphisms were analyzed on
mutations, and only one possible simultaneous blood and parafÀn-embedded samples by PCR,
Exon 21 L858R/Kras mutation observed in this whereas CDA activity was evaluated by HPLC.
enrolled population. Currently 93 % (901/974) and Univariate and multivariate analyses compared
69 % (670/974; 210 did not consent) patients have biological and clinical parameters with response,
provided serum and blood samples respectively. clinical beneÀt, toxicity, time-to-progression (TTP)
Additional data on these biomarkers, including and overall survival (OS).
mutation types/frequencies, scoring frequencies, and Results: Patients with CDA A79A/A79C genotypes
Ànal biomarker demographics, will be presented. had a statistically signiÀcant longer TTP (6.0 vs
Conclusion: Laboratory analyses of selected 3.0 months; P=0.001) and OS (11.0 vs 5.0 months;
biomarkers in the RADIANT population are P=0.001) than patients with CDA C79C genotype.
complete. The results already comprise one of the Patients harbouring CDA C435C/C435T genotypes
largest datasets in NSCLC with multiple biomarker also had a longer OS (P=0.025), resulting in a
data for each patient; and more analyses in serum, combined genotype (CDA C79C+T435T) effect
blood, as well as tissue are yet to be conducted. on OS, but no correlations were observed between
These data will provide a large scale characterization SNPs and objective responses, clinical beneÀt, or
of a multitude of biomarkers in the early-stage toxicity. Conversely patients with low CDA activity
NSCLC population. had a signiÀcantly higher response rate (37.7%
Keywords: Biomarkers, RADIANT, NSCLC vs 13.8%; P= 0.006), clinical beneÀt (91.8% vs.
Adjuvant, EGFR 51.7%; P<0.001), as well as longer TTP (8.0 vs
3.0 months; P<0.001) and OS (19.0 vs 6.0 months;
P<0.001). Furthermore, enzymatic activity emerged
Biomarkers III Wednesday, 6 July 2011 14:30-16:00 as independent predictor for death/progression risk at
multivariate analysis.
O28.02 CORRELATION OF CYTIDINE Conclusion: CDA enzymatic activity appears to
DEAMINASE POLYMORPHISMS AND be the strongest candidate biomarker of activity
ACTIVITY WITH CLINICAL OUTCOME and efÀcacy of platinum-gemcitabine based
IN GEMCITABINE/PLATINUM-TREATED chemotherapy and should be validated in a
ADVANCED NON-SMALL-CELL LUNG prospective study.
CANCER PATIENTS
Carmelo Tibaldi1, Elisa Giovannetti2, Marcello
Tiseo3, Leticia G. Leon4, Armida D’incecco1, Nienke Biomarkers III Wednesday, 6 July 2011 14:30-16:00
Loosekoot4, Marco Bartolotti3, Richard Honeywell2,
Federico Cappuzzo1, Andrea Ardizzoni3, Godefridus O28.04 THE VALUE OF CLINICAL TRIAL
J. Peters4 RESEARCH FOR ERCC1 TESTING IN
1
Department Of Oncology, Division Of Oncology, STAGE I NON-SMALL CELL LUNG
Azienda Usl-6/Italy, 2Medical Oncology, VU CANCER (NSCLC)
University Medical Center/Netherlands, 3Medical Joshua A. Roth1, Josh J. Carlson1, Lotte Steuten2,
Oncology Unit, University Hospital Of Parma/Italy, Scott D. Ramsey3, David L. Veenstra1
4 1
Department Of Medical Oncology, VU University Pharmacy, University Of Washington/United States
Medical Center/Netherlands Of America, 2Health Technology And Services
Research, University Of Twente/Netherlands,
3
Background: Cytidine deaminase (CDA) is the Population Health Sciences, Fred Hutchinson
main enzyme in gemcitabine catabolism and the Cancer Research Center/United States Of America
common single nucleotide polymorphisms (SNPs) Background: Value of research analysis can be used
79 A>C and 435 C>T might alter its activity as to assess the value of proposed clinical trials and
well as clinical outcome after gemcitabine-based prioritize research funding decisions. We applied this
treatment. The aim of this study was to evaluate method to assess the value of additional clinical trials
whether CDA SNPs and/or CDA enzymatic activity to investigate ERCC1 expression testing to guide
inÁuenced clinical outcome in a cohort of advanced adjuvant chemotherapy decisions in fully resected
NSCLC patients (N=126) treated with gemcitabine- Stage I NSCLC in the United States.
Methods: We developed a decision-analytic model

and used value of information methodology to
assess the value of research (VOR) comparing two
treatment strategies: 1) ERCC1 testing to guide
adjuvant chemotherapy decisions, with ERCC1-
positive patients receiving no chemotherapy
and ERCC1-negative patients receiving
cisplatin+vinorelbine chemotherapy; 2) standard
care, with all patients receiving no chemotherapy.
Model parameters and uncertainty ranges for test
characteristics and treatment effects were based Keywords: ERCC1, Value of Research, Non-small
on the International Adjuvant Lung Cancer Trial, cell lung cancer
which demonstrated signiÀcant overall survival
gains in ERCC1-negative patients treated with A revised/updated abstract may be included in
cisplatin+vinorelbine (HR: 0.65, 95% CI: 0.5 to the Late Breaking Abstract Supplement, available
0.86), but non-signiÀcant overall survival differences at the 14th World Conference on Lung Cancer.
in ERCC1-positive patients (HR: 1.14, 95% CI:
0.84 to 1.55). Cost and health-related quality of life
parameters were derived from published literature Biomarkers III Wednesday, 6 July 2011 14:30-16:00
and government sources. The potential affected
population was examined over a 10-year time O28.05 WNT/BETA-CATENIN
horizon (Table 1). To estimate the economic beneÀts PHARMACOGENETICS IN PLATINUM-
of treatment outcomes, we used a willingness to TREATED PATIENTS WITH ADVANCED
pay of $150,000 per quality-adjusted life year, in NON-SMALL CELL LUNG CANCER
accordance with implied thresholds in the United (NSCLC)
States. David J. Stewart1, David W. Chang2, Yuanqing Ye2,
Results: There was a high degree of uncertainty Margaret R. Spitz2, Charles Lu1, Xifeng Wu2
1
about ERCC1-guided care vs. standard care, with Thoracic And Head And Neck Medical Oncology,
the ERCC1 strategy producing greater net-beneÀt in M.D. Anderson Cancer Center/United States Of
63% of simulations. The consequence of selecting America, 2Epidemiology, M.D. Anderson Cancer
the wrong strategy was $14,000 in lost value, a Center/United States Of America
combination of lost health beneÀts and unnecessary
costs. The 10-year affected population was 309,470. Background: In NSCLC, Wnt/beta-catenin
For this affected population, the VOR for an ideal signaling is important in tumor development and
trial large enough to reduce all uncertainty in the progression. Expression of Wnt/beta-catenin
modeled parameters was $1.5 billion, of which $858 pathway components is common and is associated
million was attributable to the value of reducing with poor prognosis clinically in NSCLC, and is
uncertainty about the overall survival hazard ratio associated with cell growth rate and resistance in
for ERCC1-negative patients (Table 1). Preliminary cell lines. Since tumors inherit genes from the host,
estimates suggest a VOR of $3 to $672 million for host genotype may inÁuence patient outcome. We
a randomized trial with samples of 100 to 1,000 per assessed associations between overall survival and
arm, respectively (Table 1). Wnt/beta-catenin pathway pharmacogenetics in
Conclusion: Clinical trial research of ERCC1 testing NSCLC patients receiving cisplatin- or carboplatin-
in NSCLC likely represents a good investment of based regimens for advanced NSCLC.
research funds. Forthcoming results will compare Methods: In 598 patients with inoperable stage
the VOR of various trial designs and sample sizes to III-IV NSCLC, we extracted DNA from peripheral
the estimated cost of such trials to determine which blood mononuclear cells, then used Illumina’s
trials are expected to produce the greatest net beneÀt. InÀnium iSelect HD Custom Genotyping BeadChips
These Àndings can assist research organizations and (Illumina, San Diego, CA) and BeadStudio software
funding agencies in prioritizing funding in cancer to assess 441 host SNPs in 50 Wnt/beta-catenin
genomics. pathway genes. Hazard Ratios (HRs) were estimated
using Cox’s proportional hazards model, using the
most common genotype as the reference group and A revised/updated abstract may be included in
with adjustment for age, stage, gender, smoking, the Late Breaking Abstract Supplement, available
performance status, ethnicity and therapy modality. at the 14th World Conference on Lung Cancer.
P values <0.05 were considered signiÀcant. We
then calculated q values (a false discovery rate
adjusted P-value) to correct for effects of multiple Biomarkers III Wednesday, 6 July 2011 14:30-16:00
comparisons. The combined effects of unfavorable
genotypes and survival tree analysis of higher-order O28.06 CORRELATION BETWEEN
gene-gene interactions were then assessed using TISSUE PLATINUM CONCENTRATION
SNPs with q<0.10, AND TUMOR RESPONSE IN NON-SMALL
Results: Per BeadStudio software assessments, all CELL LUNG CANCER
441 SNPs had call rates of > 95% and were included Eric Sung-Yung Kim1, Guangan He2, Chi-Wan
in the analysis. Survival correlated (p<0.05) with 57 Chow3, Junya Fujimoto3, Neda Kalhor4, Stephen G.
SNPs from 21 Wnt pathway genes, including SNPs Swisher5, Ignacio Wistuba6, David J. Stewart7, Zahid
in AXIN2 (9 SNPs), LRP5 (7 SNPs), Wnt-5A (4 H. Siddik2
1
SNPs), AXIN1, LRP6, WIF1, Wnt-2, Wnt-4, Wnt- Division Of Cancer Medicine, M.D. Anderson
3 and Wnt-5B (3 SNPs each), CXXC4, Wnt-3A, Cancer Center/United States Of America,
2
Wnt-7A, Wnt-9A and TLE2 (2 SNPs each), and Experimental Therapeutics, M.D. Anderson
DVL3, FRZB, FZD4, Wnt-6, Wnt-9B and Wnt-11 Cancer Center/United States Of America,
3
(1 SNP each). Survival did not correlate with any Thoracic / Head & Neck Medical Oncology, Ut
SNPs assessed for the following genes: APC, APC2, M.D. Anderson Cancer Center/United States Of
CTN1, CTNNB1 (beta-catenin), DIXDC1, DKK1, America, 4Pathology, M.D. Anderson Cancer Center/
DKK4, DVL2, FSHB, FZD1, FZD2, FZD3, FZD7, United States Of America, 5Thoracic Surgery, M.D.
FZD10, LEF1, PPP2CA, PPP2CB, PYGO1, SFRP1, Anderson Cancer Center/United States Of America,
6
SFRP2, SFRP5, TCF7,TLE3, TLE4, TLE6, Wnt-2B, Pathology And Thoracic/Head & Neck Medical
Wnt-8A, Wnt-8B, Wnt-10A, Wnt-10B, and Wnt- Oncology, Ut M.D. Anderson Cancer Center/United
16. Five SNPs remained signiÀcant in multivariate States Of America, 7Thoracic And Head And Neck
analysis after correcting for multiple comparisons: Medical Oncology, M.D. Anderson Cancer Center/
AXIN2 SNP rs11868547 (HR for variant vs. United States Of America
reference SNP=0.77 [95% CI, 0.66-0.89], p=0.0006),
AXIN2 SNP rs4541111 (HR=0.77 [0.68-0.91], Background: Platinum-based chemotherapy
p=0.0015), Wnt-5B SNP rs12819505 (HR=1.58 is the mainstay of treatment for advanced non-
[1.19-2.09], p=0.0015), CXXC4 SNP rs4413407 small cell lung cancer (NSCLC). Despite initial
(HR=1.28 [1.10-1.50], p=0.0017), and WIF1 SNP sensitivity, most tumors develop resistance. Reduced
rs10878232 (HR=1.36 [1.12-1.66], p=0.0022). For intracellular drug accumulation is one of the most
these 5 SNPs, median survival was 19.7, 15.6 and consistently identiÀed features of platinum-resistant
10.7 months for patients with 1, 2 or 3-5 unfavorable cell lines, but clinical data are limited. We assessed
genotypes, respectively (p=3.8 x 10-9). Higher order correlations between tissue platinum concentrations
gene-gene interactions were suggested by survival and response in NSCLC.
tree analysis using 4 of these SNPs which classiÀed Methods: We measured total platinum
patients into 2 low- vs high-death-risk groups, with concentrations in 17 archived fresh frozen NSCLC
median survival 17.3 and 11.3 months, respectively specimens from patients who received neoadjuvant
(p=4.7 x 10-8). platinum-based chemotherapy. Approximately 30
Conclusion: In keeping with the important role mg of tumor was homogenized in benzethonium
of the Wnt/beta-catenin pathway in NSCLC hydroxide. After acidiÀcation, samples were
biology, survival with platinum-based regimens analyzed by Áameless atomic absorption
correlated with host Wnt/beta-catenin pathway spectrophotometry (FAAS) to assess absorbance
SNPs in inoperable stage III-IV NSCLC. It remains reading associated with platinum content. Two
uncertain whether these SNPs alter tumor growth vs specimens from patients who underwent surgery
chemotherapy sensitivity. only were analyzed as negative controls. Absorbance
Keywords: Wnt, NSCLC value per mg of tissue was correlated with
percent change in tumor diameter on post- vs pre-
chemotherapy CT scans. Session O29: Nursing II

Results: Platinum absorbance values ranged from
0.00077 to 0.00470 per mg of tissue while two Wednesday, 6 July 2011
negative controls demonstrated absorbance readings
similar to 0.1N HCL (Table 1). Platinum absorbance
correlated negatively with percent change in tumor Nursing II Wednesday, 6 July 2011 14:30-16:00
size (R2=0.45, P=0.003) (Figure 1).
O29.01 A LETTER FROM A DYING
WOMAN – A MESSAGE FROM THE
OTHER SIDE OF THE “WALL OF
SILENCE”
Vito D’Alessandro, Mario Freda, Ruggiero Boragine,
Piergiorgio Cela, Angela P. Piscitelli, Anna Giannolo,
Gianluigi Vendemiale
Respiratory Oncology Section - Internal Medicine
Department, ScientiÀc Institute “Casa Sollievo Della
Sofferenza” Hospital/Italy
Background: To communicate the diagnosis of

tumor is not easy, especially if the diagnosis is lung
cancer. In Italy, perhaps particularly in southern Italy,
the patient’s family very often ask the physician to
not communicate the true diagnosis to the tumor
patient, especially if elderly, for fear of a consequent
strong psychological distress, including anxiety and
depression. Communication between the patients and
their relatives therefore becomes difÀcult, both in
respect of the illness and of general communication,
determining the so-called “conspiracy of silence”.
Methods: We used a letter that appeared in 1998
in an Italian magazine, Famiglia Cristiana, as a tool
to try to improve communication between the sick
and their family. In this letter a female tumor patient
afÀrms that the debate whether or not tell the patient
the truth is a false problem, since the tumor patients
often already know the truth, even if they pretend
nothing has happened, and that are the patients
themselves, for the most part, who have to protect
their relatives, lost and fragile, from the news of
the illness. The letter was given to the family when
they themselves were not at ease when faced with
the same problem. We developed a 12-item ad hoc
Conclusion: This is the Àrst tissue-based study to questionnaire to assess family-perceived barriers
demonstrate a correlation between total platinum to diagnosis communication with the patient. The
concentrations and response in NSCLC. Reduced family was also asked to Àll this questionnaire
intracellular platinum accumulation may constitute to enable us to understand their difÀculties in
a signiÀcant mechanism of platinum resistance even communication and to see whether the letter had in
in clinical specimens. Further studies investigating any way improved such difÀculties. The physicians
factors that modulate intracellular platinum gave their availability to discuss any such problems
concentration are warranted. with the relatives in presence of patient, if possible.
Keywords: platinum, Cisplatin, Resistance, NSCLC Results: Between 2005 and 2010 we gave 104
letters and questionnaires to families of hospitalized
patients in our department. We analyzed 97 according to criteria deÀned in literature and with
questionnaires. The mean (SD) age of the patients help of the software SPSS 15.0.
was 66.4 (5.8) years; more than 80% were male, Results: We veriÀed that most patients (68.4%)
and 81% suffered from advanced stage lung cancer. showed a considerable high level of distress at
Before receiving the letter, in only 9% of the cases the beginning of the treatment. There was a fall of
the family had openly talked about the diagnosis of patients with high level of distress at the middle
tumor to their own relative. 76% of relatives declared (21%) and at the last day of treatment (18.2%).
the reading of this letter very useful. 69% of family The frequencies of items checked in the PL were
members believed that the general communication examined using multiple response analyses. The
with their relative improved and in 57% of the cases frequencies of practical problems progressively
they succeeded in speaking more openly of the decreased (beginning to last day of treatment),
illness. in descending order were insurance/Ànancial
Conclusion: Devoting time and giving the family (36.7% - 23.8%), housing (27.3% - 6.1%), work
a simple letter can be an effective strategy for (18.2% - 7.3%) and transportation (18.2% - 3.2%).
improving the communication between the lung In the family category, items dealing with children
cancer patients and their relatives. (54.5% - 23%) and with partner (27.3% - 6.3%)
Keywords: Communication, Information, Lung were endorsed. In the emotional category, the most
cancer, palliative care frequently checked items were worry (54.5% -
23.8%), sadness (45.5% - 13.7%), nervousness
(45.5% - 13.7%), loss of interest in usual activies
Nursing II Wednesday, 6 July 2011 14:30-16:00 (42.4% - 11.5%), depression (36.4% - 11.5%), and
fears (18.2% - 4.9%). Any patients checked the
O29.02 PSYCHOLOGICAL DISTRESS spiritual/religious concern item. With regard to
AMONG LUNG CANCER PATIENTS: A physical problems, the Àve most frequently endorsed
PILOT STUDY items were sleep (54.5% - 43.4%), pain (36.4% -
Cristiane D. Bergerot1, Marco M. Buso2 12.6%), appearance (36.4% - 25.6%), eating (36.4%
1
Psycho-Oncology, Cettro - Centro De Câncer De - 23.4%), and fatigue (36.4% - 22.4%).
Brasília/Brazil, 2Oncology, Cettro - Centro De Conclusion: The high incidence of distress in the
Câncer De Brasília/Brazil beginning of therapy demonstrates the importance
of screening and effective management of the
Background: Lung is among the most common emotional disturbs related to the diagnosis and
cancer site and is the most common cause of cancer- cancer treatment. Establishing a routine assessment
related death in the world. In a study examining of distress and the multidisciplinary discussion opens
psychological distress and its relation to the site of up the opportunity to work before the symptoms
cancer, primary lung cancer was strongly associated appear and to choose the best intervention tailored
with psychological distress in oncology patients. In to each case. Treating emotional distress must
addition, several previous studies have demonstrated be viewed as integral part of quality patient care,
that the highest prevalence of psychological distress improving adherence to treatment, quality of life and
was observed among patient with lung cancer. coping with diagnosis and treatment. The distress
Methods: The present pilot study evaluated management could be an indicator of the quality
the incidence of distress during three stages of service offered.
chemotherapy (beginning, middle and last day), Keywords: distress, quality of care, psycho-
among 19 patients of booth genders (52.6% male oncology
and 47.4% female), with age between 48 and 81
years (mean = 64), with advanced lung cancer, from
a private cancer center in Brazil. This research was
authorized by the ethics committee. The procedures
of gathering data included the acceptance of the
patients, application of the Distress Thermometer
(DT) and the Problem List (PL), followed by a
multidisciplinary discussion to deÀne the best
intervention for each case. The data were analyzed
Nursing II Wednesday, 6 July 2011 14:30-16:00 Results: Nine lung cancer patients and seven
partners participated in the program. About 5%
O29.03 LIVING IN THE MOMENT: of the patients and 3% of the partners missed a
MINDFULNESS BASED STRESS training-session and 1 couple dropped out. Sixty-
REDUCTION FOR LUNG CANCER seven percent received chemotherapy during MBSR.
PATIENTS AND THEIR PARTNERS MBSR resulted in a 22% decrease of anxiety and
Miep A. Van Der Drift1, Desiree G.M. Van Den depression according to The Hospital Depression
Hurk2, Johan Molema2, Judith B. Prins2, Anne E.M. and Anxiety Scale. Patients reported a greater
Speckens2 appreciation of life, a more open attitude towards
1
Pulmonology, Radboud University Nijmegen negative emotions, a better communication between
Medical Centre/Netherlands, 2Radboud University partners, and more self-reliance. Partners also
Nijmegen Medical Centre/Netherlands reported less perceived stress and better coping.
Conclusion: MBSR in (locally) advanced lung
Background: The generally poor prognosis of cancer patients and their partners is feasible despite
lung cancer patients is often accompanied by an often short life acceptancy and oncological
emotional distress resulting in reduced quality of treatment. MBSR resulted in a decrease of anxiety
life and increased use of medical care. Emotional and depression and improvement in adjustment of
distress in the oncology setting is most frequently the disease and symptoms.
characterized by anxiety, depression, fatigue and Keywords: Lung cancer, mindfulness, psychosocial
sleep disorders, and can be deÀned as an adjustment treatment
disorder. Compared to patients with other cancer
diagnoses, patients with lung cancer report higher
clinically signiÀcant levels of distress (33% and 43- Nursing II Wednesday, 6 July 2011 14:30-16:00
62%, respectively). Although many studies describe
the impaired quality of life and amount of distress O29.05 FAMILY CAREGIVER QOL
in lung cancer patients, not much is known about AND SELF CARE CONCERNS IN LUNG
psychosocial treatment. Mindfulness is deÀned CANCER
as moment to moment present awareness with an Mihaela C. Cristea1, Betty Ferrell2, Marcia Grant2,
attitude of non-judgement, acceptance and openness. Marianna Koczywas1, Arti Hurria1, Matthew
Recent cancer studies suggest that mindfulness Loscalzo3, Gloria Juarez2, Shirley Otis-Green2, Gwen
based stress reduction (MBSR) may improve cancer Uman4, Tami Borneman2
1
patients’ psychosocial adjustment to their disease, Medical Oncology And Therapeutic Research,
reduce stress and anxiety, and enhance their coping City Of Hope/United States Of America, 2Nursing
and well-being. The number of lung cancer patients Resreach & Education, Dept. Of Population
in these studies was low and even less is known Sciences, City Of Hope/United States Of America,
3
about participation of their partners. It is not clear Population Sciences, City Of Hope/United States Of
if MBSR is feasible in lung cancer patients who America, 4Vital Research/United States Of America
often have a short life expectancy. The current study
is a preliminary exploration of the feasibility and Background: Family caregivers play a key role
effectiveness of MBSR in lung cancer patients and in cancer care and are of signiÀcant support in
their partners. advanced diseases such as lung cancer. This National
Methods: An 8-week MBSR program of weekly Cancer Institute funded Program Project (P01)
two and a half-hour sessions with one full retreat addresses palliative care, quality of life (QOL), and
day and daily home practice was offered to (locally) self care for family caregivers in lung cancer. The
advanced lung cancer patients and their partners. purpose of this study is to test usual care versus
MBSR consisted of formal and informal mindfulness a family caregiver interdisciplinary intervention
practices, including practices of the body scan, encompassing a QOL education intervention.
meditation and mindful movement. Questionnaires Methods: Project 3 of this Program focuses on
about symptoms of stress, anxiety, depression, family caregivers in lung cancer, a group with
mindfulness and coping were taken at baseline, post- signiÀcant QOL concerns. The study uses a two
treatment and at 3 months follow-up in patients and group, prospective tandem enrollment comparing
partners. usual care to a structured palliative care intervention.
Family caregivers are followed for 6 months in Background: Quality of life (QOL) and palliative
late stage disease and 12 months in early stage care in the treatment of cancer have been areas
lung cancer. Outcome measures include the Family of increased focus in recent literature. Lung
Caregiver QOL tool, Caregiver Burden tool, cancer has been well established as a disease
Self Care Assessment, Psychological Distress with consistently high rates of morbidity and
and Caregiver Preparation measures. A Geriatric mortality. The speciÀc aims of the present analysis
Core supports this Project to advise on caregiver were to document changes in quality of life
concerns for the geriatric patient such as burden and (QOL) and spirituality in lung cancer patients
caregiving skill acquisition as well as to evaluate the (pts) using validated instruments before and after
needs of the caregiver. radiotherapy (RT) and also to describe differences
Results: Family caregivers (N=96) were mean age from pts undergoing RT for different diagnoses.
of 57 years, 60% female, 70% spouses/partners, and Methods: A retrospective, IRB-approved chart
40% minority subjects. Sixty percent had chronic review was performed of 406 pts, 50 with lung
illnesses of their own. Key caregiver QOL concerns cancer (LC) and 356 with non-lung cancer (non-
(0= worst to 10 = best outcomes) included distress of LC) diagnoses, receiving RT between 1/1/2006
the initial diagnosis (x=1.3), family distress (x=2.89) and 12/31/2008 at an NCI-Designated Cancer
fear of metastasis (x =3.03) or recurrence (x =3.16) Center. Subjects completed the Functional
for the patient, living with uncertainty (x =3.68) and Assessment of Cancer Therapy General (FACT-G)
distress from the patient’s treatment. Key areas of and Spirituality (Sp-12) PRO questionnaire
caregiver burden and stress included time demands, tools. Pre- and immediately post-RT course
overall stress, needing help navigating health scores were compared using student t-tests with
services, and accessing community resources and Bonferroni correction for multiple comparisons
health information. (8 comparisons, alpha =.00625). Distributions of
Conclusion: Findings demonstrate gaps in responses as reported by LC and non-LC pts were
supporting family caregivers in lung cancer. The next compared utilizing chi-square analysis.
phase of this Program Project tests a comprehensive Results: Prior to treatment, LC pts reported
education intervention for family caregivers and a signiÀcantly poorer scores in physical well-
self care plan for each caregiver. Elements include being (PWB) (p<0.001), emotional well-being
preparing caregivers in managing symptoms in lung (EWB) (p<0.001), functional well-being (FWB)
cancer, supporting patients physical, psychological (p<0.001), meaning-peace (p<0.001) and Sp12
and social concerns and addressing spiritual and end (p<0.001) measures, compared to non-LC pts.
of life care. Following RT, the LC cohort continued to have
Keywords: Lung cancer, Quality of Life poorer scores in EWB (p<0.001) and FWB
(p=0.001). FACT-G scores in LC pts improved
nonsigniÀcantly (p=0.631) over the course
Nursing II Wednesday, 6 July 2011 14:30-16:00 of RT and a signiÀcant difference in FACT-G
scores (p=0.002) was noted between the two pt
O29.06 QUALITY OF LIFE AND cohorts following RT. Differences between the
SPIRITUALITY BEFORE AND AFTER two cohorts in PWB (p=0.338), meaning-peace
RADIOTHERAPY IN PATIENTS WITH (p=0.018), and Sp12 (p=0.168) scores became
LUNG CANCER: PRELIMINARY nonsigniÀcant following RT. Pts receiving RT
RESULTS FROM THE KNIGHT CANCER for non-LC diagnoses demonstrated clinically
INSTITUTE and statistically signiÀcant worsening of PWB
Bethany T. Samuelson1, Erik K. Fromme2, Charles R. (p<0.001), statistically signiÀcant improvement
Thomas3, Faisal Siddiqui2 in EWB (p>0.001) and worsening in overall well-
1
School Of Medicine, Oregon Health & Science being (p<0.001) over the course of treatment while
University/United States Of America, 2Radiation LC pts reported no signiÀcant changes in any
Medicine, Oregon Health & Science University category.
Knight Cancer Institute/United States Of America,
3
Dept. Of Radiation Medicine, Ohsu/United States
Of America
Chi-Square Analysis Comparing LC to non-LC Patient Quality of Background: The website of the Dutch Lung
Life at Pre- and Post-Treatment Timepoints Cancer Information Center (DLIC) was established
MID* Pre-Treatment Scores Post-Treatment Scores
in 2003. Beside providing information, it is also
LC Non-LC P-Value LC Non-LC P-Value
possible to pose questions on the interactive page
Physical
Well-Being 2-3 18.19 22.67 0.000 17.32 19.67 0.338 “Ask the Physician”. The website is currently visited
Social by 20.000 visitors per month, mostly lung cancer
Well-Being 2-3 21.86 22.80 0.102 21.68 22.69 0.242 (LC) patients and caregivers. Objectives: To explore
Emotional the reasons why LC patients and caregivers search
Well-Being 2-3 15.88 18.76 0.000 17.26 19.57 0.000
the internet for information and ask the online lung
Functional
Well-Being 2-3 12.81 18.81 0.000 13.38 18.21 0.001
specialists of the DLIC additional questions about
FACT-G 3-7 68.83 83.02 0.053 69.91 80.11 0.002 lung cancer beside face-to-face consultations with
Meaning- their own treating specialists.
Peace Methods: Qualitative study with semi-structured
subscale N/A 22.32 25.27 0.000 23.28 25.44 0.018 telephone interviews about medical information
Faith
seeking behavior (e.g. information needs, reasons
subscale N/A 10.67 10.86 0.079 10.97 11.32 0.276
Sp-12 N/A 32.99 36.13 0.000 34.25 36.76 0.168
asking questions to online specialists) Population: 5
LC patients and 20 caregivers who posed a question
*MID: previously calculated minimally important on the interactive page of the DLIC website.
difference Results: Patients and caregivers use the internet
and the DLIC website for a better understanding of
Conclusion: At the time of presentation for the information given by their own specialist. They
radiotherapy LC pts reported worse physical, want to be prepared for the treatment trajectory
emotional, functional and spiritual well-being than pts and course of disease. Respondents are positive
undergoing therapy for other diagnoses. Some of these about this mode of information supply because not
differences equalized over the course of treatment, only it is supportive for coping, but also it fosters
with LC pts reporting no signiÀcant changes in any of hope. The use of the interactive webpage serves as
these measures over the course of RT. second opinion as well (e.g. conÀrmation about the
Keywords: Quality of Life, Lung cancer, Radiation administered treatment). The absence of face-to-face
Therapy, Spirituality contact makes respondents feel more free to ask for
any kind of information. By being able to pose a
question instantly, it gives relief of anxiety and the
Nursing II Wednesday, 6 July 2011 14:30-16:00 (relatively quick) reply from the online specialist
gives an answer to urgent questions within a short
O29.07 WHY DO PATIENTS AND space of time, without having to wait until the next
CAREGIVERS SEARCH THE consultation with their treating specialist.
INTERNET FOR INFORMATION AND Conclusion: The DLIC website with its interactive
ASK QUESTIONS TO ONLINE LUNG page is a valuable complementary mode of
SPECIALISTS? A QUALITATIVE STUDY information supply for LC patients and caregivers.
Romane M. Schook1, Cilia Linssen2, Marjan J. Because the online specialist is not able to answer
Westerman3, Franz M.N.H. Schramel4, Jan Festen2, patient-speciÀc questions, the use of e-mail contact
Ernst Lammers5, Pieter E. Postmus6 between treating specialists and patients /caregivers
1
Department Of Pulmonary Diseases/longziekten, might be considered as a useful tool.
VU University Medical Center/Netherlands, Keywords: online lung specialists, patients,
2
Lung Cancer Information Centre: Longkanker caregivers, internet
Informatiecentrum/Netherlands, 3Department
Of Health Sciences, Methodology And Applied
Biostatistics, Vrije Universiteit Amsterdam/
Netherlands, 4Department Of Pulmonology, Sint
Antonius Hospital/Netherlands, 5Department
Of Pulmonary Diseases, Gelre Ziekenhuizen/
Netherlands, 6Department Of Pulmonary Diseases,
VU University Medical Center/Netherlands
Session O30: Malignant Pleural P/D 12.9%). Comparing cTNM to pTNM, 80.8%
Mesothelioma of stage I, 65.5% of stage II and 22.8% of stage III
patients were upstaged. Median survivals by cTNM
and pTNM were similar: stage I, 21 months, stage II,
19 months, stage III 16 months, stage IV, 12 months.
Median survival by histology was epithelioid
Malignant Pleural Mesothelioma Wednesday, 6 July 2011 14:30-16:00 19 months, biphasic 13 months, sarcomatoid 8
months. Median survivals by stage and surgical
O30.01 INITIAL ANALYSIS OF IASLC procedure were better for EPP vs. P/D in stage I
MESOTHELIOMA DATABASE (40 vs.23 months) but not in higher stage tumors.
Valerie Rusch1, Dori Giroux2, Catherine Kennedy3, By multivariable analyses, signiÀcant differences
David Rice4, Enrico RufÀni5, Harvey I. Pass6, David in overall survival were seen for: stages III and IV
Waller7, John Edwards7, Ayten K. Cangir8, Hisao vs. I (p<.0001) but not II vs. I, epithelioid histology
Asamura9 vs. other (p<.0001); female vs. male (p=.0001),
1
Surgery, Memorial Sloan-Kettering Cancer CTR/ age (p=.007); palliative vs. curative intent surgery
United States Of America, 2Cancer Research And (p<.0001); T4 vs T3 and T3 vs T2 (p=.003 and
Biostatistics/United States Of America, 3University p=.03) but not T2 vs. T1 (p=.09); N0 vs. N1 and N2
Of Sydney/Australia, 4M.D. Anderson Cancer (p=.007 and <.0001) but not N1 vs. N2 (p=.275).
Center/United States Of America, 5Chirurgia Conclusion: This is currently the largest
Toracica, Ospedale San Giovanni Battista/Italy, international multicenter database examining
6
Cardiothoracic Surgery, Nyu School Of Medicine/ outcomes in surgically managed MPM patients.
United States Of America, 7GlenÀeld Hospital/United Survival differences by tumor stage, histology and
Kingdom, 8Department Of Thoracic Surgery, Ankara surgical treatment previously reported from smaller
University Faculty Of Medicine/Turkey, 9National databases are conÀrmed. Initial analyses suggest
Cancer Center Hospital/Japan the need to revise T and N staging. These should be
addressed through prospective data collection which
Background: The validity of the current UICC has just been initiated by the ISC.
staging system for malignant pleural mesothelioma Keywords: mesothelioma, international database,
(MPM) is controversial. To assess whether changes Staging
should be made to this system, the Mesothelioma
Domain of the IASLC Staging Committee (ISC) A revised/updated abstract may be included in
developed an international database of MPM the Late Breaking Abstract Supplement, available
patients. These initial analyses focus on retrospective at the 14th World Conference on Lung Cancer.
data from patients managed surgically.
Methods: Participation was solicited from all centers
known internationally to have MPM registries. Malignant Pleural Mesothelioma Wednesday, 6 July 2011 14:30-16:00
Common data elements were established and data
were analyzed by the ISC Statistical Center at O30.02 DISEASE CONTROL RATE
Cancer Research and Biostatistics (CRAB,Seattle, AT 9 AND 18 WEEKS AS PRIMARY
Wa, USA). Survival was analyzed by Kaplan Meier, ENDPOINTS FOR PHASE II
the signiÀcance of prognostic factors assessed CLINICAL TRIALS IN PATIENTS
by logrank and Cox regression model. p<.05 was WITH MALIGNANT PLEURAL
considered signiÀcant. MESOTHELIOMA: AN INDIVIDUAL
Results: Data were submitted on 3101 patients PATIENT DATA COMBINED ANALYSIS
from 15 centers on 4 continents. cTNM staging OF 10 EUROPEAN ORGANISATION
was available on 1398 patients, pTNM on1976 FOR RESEARCH AND TREATMENT
and best TNM(bTNM) on 2316 patients. Median OF CANCER (EORTC) LUNG CANCER
patient age was 63 years, 79% male patients. GROUP STUDIES.
bTNM stages were: stage I, 11%; stage II, 21%; Laurent Greillier1, Baktiar Hasan2, Paul Baas3,
stage III, 48%; stage IV, 20%. Tumor histology was John Welch2, Jan P. Van Meerbeeck4, Rabab M.
62.3% epithelioid. Surgery with curative intent was Gaafar5, Richard Sylvester2, Sabine Margerit2, Denis
performed in 1494 (64.5%) patients (EPP 51.4%, Lacombe2, Mary O’Brien6
1
Service D’Oncologie Multidisciplinaire Et smaller. Therefore, DCR at 9 weeks should be
Innovations Thérapeutiques, Assistance Publique- taken into consideration as primary endpoint when
Hôpitaux De Marseille, Université De La designing future phase II clinical trials in MPM.
Méditerranée/France, 2Headquarters, European Keywords: Disease Control Rate, mesothelioma,
Organisation For Research And Treatment Of Clinical trial, Primary endpoint
Cancer/Belgium, 3Thoracic Oncology, NKI AVL/
Netherlands, 4Respiratory Medicine, Ghent
University Hospital/Belgium, 5Medical Oncology, Malignant Pleural Mesothelioma Wednesday, 6 July 2011 14:30-16:00
National Cancer Institute/Egypt, 6Royal Marsden
Hospital/United Kingdom O30.03 DETECTION OF
MESOTHELIOMA IN ASBESTOS
Background: The development of new drugs is EXPOSED INDIVIDUALS WITH
urgently needed in malignant pleural mesothelioma SOMAMER PROTEOMIC TECHNOLOGY
(MPM) to improve the efÀcacy of Àrst-line treatment Rachel Ostroff1, Michael R. Mehan1, Alex Stewart1,
and identify effective second-line therapies. In phase Stephen Williams1, Stephen Levin2, Brad Black3,
II trials, the response rate (RR) is generally used as Michael Harbut4, Harvey I. Pass5
1
the primary endpoint to assess the biological activity Medical, Somalogic, Inc./United States Of America,
2
of drugs. However, response criteria have always Mt. Sinai Medical Center/United States Of America,
3
been difÀcult to apply to MPM, due to its unique Libby Mt Center For Asbestos Related Diseases/
pattern of growth. We hypothesized that the disease United States Of America, 4Karmanos Cancer
control rate (DCR) could be a relevant primary Center/United States Of America, 5Cardiothoracic
endpoint for phase II trials in MPM patients. Surgery, Nyu School Of Medicine/United States Of
Methods: Individual patient data from 10 EORTC America
Lung Cancer Group studies (9 phase II and 1 phase
III trials) of Àrst-line chemotherapy in MPM were Background: Malignant pleural mesothelioma is
pooled. WHO criteria were used to assess response an aggressive, asbestos-related pulmonary cancer
to therapy in all trials except the 2 most recent trials, which is increasing in incidence. This disease causes
which used RECIST. Landmark analyses (LA) were an estimated 15,000 to 20,000 deaths per year
performed to assess the association of the DCR at worldwide. Between 1940 and 1979, approximately
a Àxed time point with overall survival (OS). Two 27.5 million people were occupationally exposed
different time points, namely 9 weeks and 18 weeks to asbestos in the United States. The incidence
after registration or randomization, were considered. of pleural mesothelioma in the US is 3,000 new
Patients who died or were lost to follow up before cases/year and will not peak for another 20 years.
the speciÀed landmark time were excluded from Mesothelioma has a latency period of 20-40 years
LA. Disease control status at the speciÀed time from asbestos exposure, but once diagnosed this
points was determined provided that the progression aggressive disease is often fatal within 14 months.
date and best overall response were recorded in the Because diagnosis is difÀcult, most patients present
database. at a clinically advanced stage where possibility of
Results: 523 eligible patients were entered in the 10 cure is minimal. Therefore, we have conducted a
studies. Based on 435 patients (370 deaths) in the LA broad search for new serum biomarkers with our
at 9 weeks, disease control (versus progression) was aptamer-based proteomic platform and deÀned
associated with longer survival times, with a hazard a classiÀer for the detection of mesothelioma in
ratio (HR) of 0.37 (95%CI, 0.30-0.47). For the 377 asbestos exposed individuals.
patients (315 deaths) in the LA at 18 weeks, disease
control was also conÀrmed as a predictor of OS with Secreted proteins and those released during
a corresponding Àgure for HR = 0.50 (95%CI, 0.38- apoptosis from tumor cells and surrounding tissues
0.65). undoubtedly contain important biologic information
Conclusion: Both DCR at 9 weeks and DCR at that would theoretically enable early diagnosis and
18 weeks were predictors of OS in MPM patients. prognostic and therapeutic decisions in oncology.
DCR at 9 weeks shows some further advantage as it However, there is great difÀculty in Ànding and
can be observed as early as the time of Àrst disease quantifying such signals for large numbers of low
assessment. In addition, the HR was numerically abundance proteins. We therefore created a highly
multiplexed proteomic assay that currently measures Malignant Pleural Mesothelioma Wednesday, 6 July 2011 14:30-16:00
>1000 proteins simultaneously from 10ul blood,
with throughput of 300 samples/day. The average O30.05 A MULTICENTER, RANDOMIZED
dynamic range of each protein in the assay is >3 PHASE III MAINTENANCE STUDY
logs and the median lower limit of quantiÀcation is OF THALIDOMIDE (ARM A) VS.
below 1 pM. The median coefÀcient of variation for OBSERVATION (ARM B) IN PATIENTS
each protein is <5%. This assay performance arises WITH MALIGNANT PLEURAL
from the selection of high afÀnity SOMAmers (Slow MESOTHELIOMA (MPM) AFTER
Offrate ModiÀed Aptamers) that bind selectively to INDUCTION CHEMOTHERAPY.
their target proteins with slow off-rates. Wieneke A. Buikhuisen1, Andrew Vincent2, Rob J.
Methods: The objective of this study was to Van Klaveren3, Franz Schramel4, Nick Pavlakis5,
discover proteins which are involved in malignant Anna Nowak6, Frenk Custers7, Hugo Schouwink8,
mesothelioma and to develop algorithms and Harry J.M. Groen9, W f m Strankinga10, J A.
classiÀers for detection of the disease. To this Burgers1, Paul Baas1
1
end, blood samples from three study centers were Thoracic Oncology, The Netherlands Cancer
analyzed with the SOMAmer proteomics platform Institute/Netherlands, 2NKI-AVL/Netherlands,
3
in a prospectively designed case:control study. We Erasmus Medical Center/Netherlands, 4Sint
compared 170 serum samples from 90 patients Antonius Ziekenhuis/Netherlands, 5Australasian
diagnosed with malignant mesothelioma to 80 Lung Cancer Trials Group (altg)/Australia, 6NHMRC
asbestos exposed controls. These samples were Clinical Trials Centre (CTC)/Australia, 7Atrium
divided into 75% for training and 25% set aside Medisch Centrum/Netherlands, 8Medisch Spectrum
as a blinded test set for classiÀer development and Twente/Netherlands, 9Umc Groningen/Netherlands,
10
veriÀcation. Bovenij Hospital/Netherlands
Results: The initial results are promising. Nineteen
signiÀcant biomarkers were discovered by applying Background: Since standard chemotherapy does not
a backwards selection strategy. ClassiÀers were built lead to long-term survival in MPM, new treatment
with subsets of these biomarkers resulting in an AUC approaches are required. MPM is known for a high
of 0.95 or better with an overall accuracy of 93%. vessel count and high levels of vascular growth
Applying a 13-plex Random Forest classiÀer to the factors. Both are known to be poor prognostic
blinded test set resulted in a speciÀcity of 100% and factors. Suppression of the neo-vasculature by adding
sensitivity of 80% for distinction of asbestos exposed thalidomide in the maintenance setting may lead to
controls from mesothelioma, including detection of improved time to progression (TTP). We here report the
15/19 Stage I/II cases. Ànal results of TTP, overall survival (OS) and toxicity.
Conclusion: ReÀnement and conÀrmation of Methods: Patients who had been treated with
classiÀer performance will be established through pemetrexed (500 mg/m2) and cisplatin (75mg/m2) or
ongoing validation studies. Implementation of carboplatin (AUC 5) q3wks for > 4 courses and did
such a test for screening high risk asbestos exposed not show signs of progression were eligible. After
individuals could lead to earlier detection of obtaining informed consent patients were randomized
mesothelioma, when effective treatment options are to receive either thalidomide 200 mg/day orally (A)
available. or no treatment (B). CT of the thorax and physical
Keywords: proteomics, mesothelioma, Early examination was performed every 2 months or earlier
Detection, Aptamer when indicated in both groups. TTP and OS were
calculated from start of randomization. A number of
190 events were required to show an improvement of
50% in TTP.
Results: From 05/2004 until 12/2009 222 patients
from 8 Dutch and 4 Australian centers were included
in this study (111 in each arm). One patient withdrew
informed consent. Median age: 64 yrs (range 41-82);
86% epithelial type; 215 WHO 0-1 and 6 WHO 2.
Based on the physician reported outcome there were
207 tumor progressions observed, with median TTP in
arm A of 16 weeks compared to 15 weeks in the control Methods: The Mesothelioma and Radical Surgery
arm; p=0.83; HR 0.96 (0.7-1.3). Median OS was 11 (MARS) feasibility study was a multi-centre
and 13 months respectively; p=0.09; HR 1.3 (0.94-1.8). randomised controlled trial. In a pre-randomisation
There was no difference in grade 3+ toxicity in both registration phase all patients underwent induction
groups observed. platinum based chemotherapy followed by clinical
Conclusion: This is the largest maintenance study in review and further consent for randomisation to EPP
patients with MPM. Minimal toxicity was associated followed by postoperative hemithorax irradiation or to
with the use of thalidomide, however there is no No EPP. The primary aim was to assess the feasibility
evidence of beneÀt in TTP nor in survival. of a larger randomised trial. Secondary study
endpoints included QL and peri-operative mortality.
Results: Between October 2005 and November
Malignant Pleural Mesothelioma Wednesday, 6 July 2011 14:30-16:00 2008 112 patients were registered through 12
UK hospitals and 50 (44.6%) were subsequently
O30.07 FEASIBILITY PHASE OF THE randomised (24 EPP, 26 No EPP). The main reasons
MESOTHELIOMA AND RADICAL for not proceeding to randomisation were disease
SURGERY (MARS) RANDOMISED progression/inoperability (38 patients) and patient
CONTROLLED TRIAL COMPARING choice (19 patients). EPP was completed satisfactorily
EXTRA-PLEURAL PNEUMONECTOMY in 16/24 (66.7%) patients randomised to EPP, in 5
(EPP) WITH NO EPP IN PATIENTS WITH patients EPP was not started and in 3 patients EPP
MALIGNANT PLEURAL MESOTHELIOMA. was abandoned. Three EPP patients died in the
Michael P. Snee1, Tom Treasure2, Judith Bliss3, Loic perioperative period and one patient in the No EPP
Lang-Lazdunski4, David Waller5, Carol Tan6, James group died after received EPP off-trial. There were no
Entwisle7, Mary O’Brien8, Gillian Thomas9, Lucy statistically signiÀcant differences in median QL and
Kilburn10, Suresh Senan11, James Spicer4, Kenneth J. survival, although both were lower in the EPP group.
O’Byrne12, David Landau4, Gillian Coombes3, John Conclusion: Many patients accepted randomisation
Edwards13, Liz Darlison5, Julian Peto14 between these radically different treatment options,
1
Oncology, St James Institute Of Oncology/United and inability to encourage more clinicians to refer
Kingdom, 2Clinical Operational Research Unit, patients was the main obstacle to recruitment. In view
University College London, London, UK/United of the high morbidity associated with EPP in this trial
Kingdom, 3ICR Clinical Trials & Statistics Unit (ICR- and in other non-randomised studies, a larger trial
CTSU), The Institute Of Cancer Research, Sutton, of EPP is unlikely to attract enough support to be
UK/United Kingdom, 4Guy’s And St Thomas’ NHS feasible.
Foundation Trust, London, UK/United Kingdom, Keyword: mesothelioma surgery radiotherapy
5
GlenÀeld Hospital, Leicester, UK/United Kingdom, chemotherapy
6
St George’s Hospital, London UK/United Kingdom,
7
Wellington Hospital, Wellington, New Zealand/New
Zealand, 8Royal Marsden NHS Foundation Trust, Session O31: Medical Oncology III
London & Sutton UK/United Kingdom, 9Leicester
Royal InÀrmary, Leicester UK/United Kingdom, Wednesday, 6 July 2011
10
Clinical Trials & Statistics Unit (ICR-CTSU),
The Institute Of Cancer Research, Sutton, UK/
United Kingdom, 11VU University Medical Center, Medical Oncology III Wednesday, 6 July 2011 14:30-16:00
Amsterdam, Netherlands/Netherlands, 12St James’s
Hospital And Trinity College Dublin, Ireland/Ireland, O31.01 SIMILAR EFFICACY OF EGFR
13
Northern General Hospital, ShefÀeld, UK/United TYROSINE KINASE INHIBITORS
Kingdom, 14London School Of Hygiene And Tropical REGARDLESS OF TREATMENT
Medicine, London, UK/United Kingdom SEQUENCE FOR THE PATIENTS
WITH EGFR MUTATION-POSITIVE
Background: The effectiveness of extra-pleural PULMONARY ADENOCARCINOMA
pneumonectomy (EPP) for malignant pleural Dong Hoe Koo1, Kyu-Pyo Kim1, Chang-Min Choi1,
mesothelioma on survival and quality of life (QL) has Dae-Ho Lee1, Jae Cheol Lee1, Jung-Shin Lee1, Se Jin
never been evaluated in a randomised trial. Jang2, Sang-We Kim1
1
Oncology, Asan Medical Center/Korea, 2Pathology, Medical Oncology III Wednesday, 6 July 2011 14:30-16:00
Asan Medical Center/Korea
O31.02 INTERCALATED ERLOTINIB
Background: Although epidermal growth factor WITH GEMCITABINE/PLATINUM IN
receptor (EGFR) tyrosine-kinase inhibitors (TKIs) THE FIRST-LINE TREATMENT OF
are known to be highly effective approach in non- ADVANCED NON-SMALL-CELL LUNG
small-cell lung cancer (NSCLC) patients with EGFR CANCER (NSCLC): THE PHASE III,
mutation, little is known about the efÀcacy according PLACEBO-CONTROLLED FASTACT-II
to sequence of EGFR-TKIs. STUDY
Methods: Between March 2006 and May 2010, a Jin Soo Lee1, Yi-Long Wu2, Guia Ladrera3, Vichien
total of 1250 patients with recurrent or metastatic Srimuninnimit4, Virote Sriuranpong5, Sumitra
NSCLC were evaluated EGFR mutational sequence Thongprasert6, Chong-Jen Yu7, Li Zhang8, Benjamin
at a single institution. And we analyzed response Margono9, Tony Mok10
1
rate, progression free survival (PFS) and overall Oncology, National Cancer Center Korea/
survival (OS) of EGFR mutation-positive patients Korea, 2Guangdong General Hospital And
who had been treated with EGFR-TKIs from the date Guangdong Academy Of Medical Sciences,
of initiating EGFR-TKIs, retrospectively. Guangdong Lung Cancer Institute/China, 3Lung
Results: Two-hundred thirty-seven patients Center Of The Philippines/Philippines, 4Siriraj
were revealed to receive EGFR-TKIs and have Hospital, Mahidol University/Thailand, 5Faculty
EGFR mutation-positive NSCLC. Among them, Of Medicine, Chulalongkorn University And The
222 patients who had EGFR mutation-positive King Chulalongkorn Memorial Hospital/Thailand,
6
adenocarcinoma were evaluated. EGFR-TKIs were Department Of Internal Medicine, Chiangmai
given to 97, 109 and 16 patients as Àrst, second University/Thailand, 7National Taiwan University
and third-line therapy with a median follow-up Hospital/Taiwan, 8Medical Oncology, Sun Yat-
duration of 27.5 months (range, 8.3-69.2). The 3 Sen University Cancer Center/China, 9Airlangga
groups showed similar response rates to EGFR-TKIs Medical Faculty/Indonesia, 10Department Of Clinical
(71.1%, 72.5%, 75.0%; p = 0.802). No signiÀcant Oncology, The Chinese University Of Hong Kong/
difference was seen according to Àrst, second and China
third-line EGFR-TKIs in terms of median PFS
(10.6, 13.0, 10.4 months; p = 0.670) and median OS Background: The phase II FASTACT study
(20.5, 26.2, 17.1 months; p = 0.142). On univariate demonstrated that sequential administration of
analysis, good performance, recurrent disease (vs. erlotinib following Àrst-line platinum-based
metastatic disease), bronchioloalveolar carcinoma chemotherapy signiÀcantly prolonged progression-
(vs. other forms of adenocarcinoma), mutation free survival (PFS) versus chemotherapy alone (Mok
in exon 19 or 21 (vs. others, which consisted of et al., J Clin Oncol 2009). FASTACT-II is a phase III,
mutation in exon 18, 20 or 2 exons), geÀtinib (vs. randomised, placebo-controlled, double-blind study
erlotinib) were associated with better PFS and designed to further assess the efÀcacy of this treatment
OS. On multivariate analysis, good performance, approach in a larger patient population. The principle
recurrent disease and mutation in exon 19 or 21 were of pharmacodynamic separation involves avoiding
independently associated with better PFS and OS. potential negative interactions between agents by
Conclusion: When EGFR-TKIs were given to alternating treatments in an optimal sequence. This
patients with EGFR mutation-positive pulmonary concept has important implications for the use of
adenocarcinoma, it may show similar efÀcacy erlotinib in combination with chemotherapeutic agents
regardless of sequence. Good performance status, (including pemetrexed, as investigated by Li et al.,
recurrent disease and mutation in exon 19 or 21 Curr Drug Targets 2010), particularly in EGFR wild-
showed better PFS and OS for EGFR-TKIs in our type NSCLC populations.
analysis. Methods: Eligible patients with untreated stage
Keywords: Treatment sequence, Adenocarcinoma, IIIB/IV NSCLC were randomised (1:1) to receive
EGFR mutation, Tyrosine kinase inhibitor gemcitabine (1,250mg/m2 on days 1 and 8 of a 4-week
cycle) plus platinum (either carboplatin 5×AUC or
cisplatin 75mg/m2 on day 1 of a 4-week cycle) with
either sequential erlotinib (150mg/day) or placebo
1
(both administered on days 15–28 of each cycle). Oncology (Hope), St James’s Hospital/Ireland,
2
Patients were stratiÀed by disease stage, histology, Medical University Of Vienna/Austria, 3Merck
smoking status and chemotherapy regimen. The KGaA/Germany, 4Hospital Universitario Virgen Del
primary endpoint is PFS; secondary endpoints include Rocio/Spain
overall survival (OS), response rate, safety, quality of
life and subgroup/biomarker analyses. Abstract under Embargo.
Results: From 29 April 2009 to 9 September 2010,
a total of 451 patients were recruited across 28 sites
in seven countries: China (n=151), Thailand (n=88), Medical Oncology III Wednesday, 6 July 2011 14:30-16:00
the Philippines (n=67), Taiwan (n=46), Hong Kong
(n=40), South Korea (n=30) and Indonesia (n=29). O31.05 PHASE 2 DATA FOR CRIZOTINIB
Baseline patient demographics for the overall study (PF-02341066) IN ALK-POSITIVE
population are: median age 57 years (range 18–81 ADVANCED NON-SMALL CELL LUNG
years); male/female: 60%/40%; ECOG performance CANCER (NSCLC): PROFILE 1005
status 0/1: 26%/74%; stage IIIB/IV: 10%/90%; Gregory j Riely1, Dong-Wan Kim2, Lucio Crinò3,
current/former/never smoker: 29%/23%/49%; Pasi A. Janne4, Fiona H. Blackhall5, David R.
adenocarcinoma/squamous-cell/other: 76%/16%/8%. Camidge6, Vera Hirsh7, Tony S.K. Mok8, Ben
All patients are of Asian ethnicity; 92% are receiving Solomon9, Jean-Charles Soria10, Keunchil Park11,
gemcitabine/carboplatin and 8% are receiving Shirish M. Gadgeel12, Renato G. Martins13, Ji-Youn
gemcitabine/cisplatin. Of the 451 enrolled patients, Han14, Tommaso De Pas15, Andrew Bottomley16,
397 (88.0%) gave consent for tumour sample Anna Polli17, Jennifer A. Petersen18, Vanessa R.
collection and 301 samples were provided for Tassell19, Alice T. Shaw20
1
analysis, giving a tissue acquisition rate of 66.7%. Medicine, Memorial Sloan-Kettering Cancer
An interim safety review by the Data and Safety Center/United States Of America, 2Internal
Monitoring Board occurred after 100 patients were Medicine, Seoul National University Hospital/Korea,
3
enrolled into the study. No concerning safety signal Medical Division, Azienda Ospedaliera Di Perugia/
was observed. Italy, 4Lowe Center For Thoracic Oncology, Dana
Conclusion: The FASTACT-II study will provide Farber Cancer Institute/United States Of America,
5
important clinical insights into the use of intercalated Medical Oncology, Christie NHS Foundation Trust/
erlotinib and platinum-based chemotherapy in Àrst- United Kingdom, 6Medical Oncology, University
line NSCLC. The high tissue acquisition rate for this Of Colorado Denver/United States Of America,
7
study will allow for analysis of efÀcacy relative to Department Of Oncology, Mcgill University Health
biomarker and histological status. Centre/Canada, 8Prince Of Wales Hospital, The
Keywords: Non-Small-Cell Lung Cancer, Àrst-line, Chinese University Of Hong Kong/Hong Kong,
9
FASTACT II, erlotinib Division Of Cancer Medicine, Peter MacCallum
Cancer Centre/Australia, 10Institut Gustave-Roussy/
France, 11Div Of Hem/Onc, Dept Of Medicine,
Medical Oncology III Wednesday, 6 July 2011 14:30-16:00 Sungkyunkwan University School Of Medicine/
Korea, 12Oncology, Karmanos Cancer Institute/ayne
O31.03 ASSOCIATION OF EPIDERMAL State University/United States Of America, 13Medical
GROWTH FACTOR RECEPTOR Oncology, University Of Washington/United States
(EGFR) EXPRESSION WITH CLINICAL Of America, 14Center For Lung Cancer, National
OUTCOME IN FLEX STUDY PATIENTS Cancer Centre/Korea, 15Thoracic Oncology Unit,
WITH ADVANCED NON-SMALL European Institute Of Oncology/Italy, 16Quality Of
CELL LUNG CANCER (NSCLC) Life Department, EORTC,/Belgium, 17Statistics,
RECEIVING CHEMOTHERAPY PLUS PÀzer Oncology/Italy, 18Health Economics And
CETUXIMAB AS FIRST-LINE THERAPY: Global Outcomes Research, PÀzer Oncology/
SAFETY ANALYSIS OF EXPRESSION United States Of America, 19Clinical Research And
SUBGROUPS Development, PÀzer Oncology/United States Of
Kenneth J. O’Byrne1, Robert Pirker2, Yvonne America, 20Cancer Center, Massaschusetts General
Schnaars3, Karl-Maria Schumacher3, Thomas Hospital/United States Of America
Goddemeier3, Luis Paz Ares4
Background: Crizotinib is a selective, ATP- Medical Oncology III Wednesday, 6 July 2011 14:30-16:00
competitive, small molecule anaplastic lymphoma
kinase (ALK) inhibitor. The ALK fusion gene is a O31.06 CRIZOTINIB IMPROVES
key oncogenic driver in a subset of patients with OVERALL SURVIVAL OF ALK-POSITIVE
NSCLC, and crizotinib demonstrated clinical activity PATIENTS WITH ADVANCED NSCLC
with a high response rate in an expanded cohort COMPARED WITH HISTORICAL
study in such patients. Here we present data from an CONTROLS
ongoing Phase 2 study of crizotinib in patients with Alice T. Shaw1, Beow Yeap1, Ben Solomon2, Gregory
ALK-positive NSCLC. J. Riely3, A J. Iafrate1, Geoffrey Shapiro4, Daniel B.
Methods: This study included patients with ALK- Costa5, Mohit Butaney4, Sai-Hong I. Ou6, Robert
rearranged NSCLC (conÀrmed by centralized Maki3, Yung-Jue Bang7, Marileila Varella-Garcia8,
FISH test) from 57 sites in 12 countries, who had Ravi Salgia9, Keith Wilner10, Kimary Kulig10, Paulina
progressed after 1 chemotherapy regimens for Selaru10, Yiyun Tang11, Eunice Kwak1, Jeffrey Clark1,
recurrent/advanced/metastatic disease (including David R. Camidge8
1
treated brain metastases). Patients received oral Cancer Center, Massaschusetts General Hospital/
crizotinib 250 mg BID continuously in 3-week United States Of America, 2Peter MacCallum Cancer
cycles. Disease response was evaluated by RECIST Centre/Australia, 3Medicine, Memorial Sloan-kettering
(version 1.1) every 6 weeks and safety/tolerability Cancer Center/United States Of America, 4Dana-farber
was evaluated every 3 weeks. Cancer Institute/United States Of America, 5Thoracic
Results: Currently, 136 patients are evaluable for Oncology, Beth Israel Deaconess Medical Center/
safety and 76 are evaluable for tumor response. United States Of America, 6Department Of Internal
Median age was 52 years, 94% of patients had Medicine, Chao Family, Comprehensive Cancer Center/
adenocarcinoma, 68% had never smoked, and 53% United States Of America, 7Department Of Internal
were female. The majority of patients had received Medicine, Seoul National University Hospital/Korea,
8
2 prior systemic therapy regimens (93%; range Medical Oncology, University Of Colorado/United
1–11). At the time of this analysis, patients had States Of America, 9Medical Oncology, University Of
received a median of 9 weeks of crizotinib treatment Chicago/United States Of America, 10Department Of
(range 0.1–36 weeks’ treatment) and 88% remained Research Pharmacology, PÀzer Global Research And
on therapy. A waterfall plot of tumor measurements Development/United States Of America, 11Oncology,
in evaluable patients showed target lesion shrinkage PÀzer Inc./United States Of America
in approximately 90% of patients (41 pts had 30%
shrinkage). Seven patients experienced objective Background: Anaplastic lymphoma kinase (ALK)
progression by RECIST. The most frequent represents a new molecular target in lung cancer. The
treatment-related adverse events (AEs) were nausea ALK tyrosine kinase inhibitor crizotinib is highly active
(46%), vision disorder (45%), vomiting (39%), in patients with advanced, ALK+ NSCLC. To determine
and diarrhea (29%), and AEs were mostly Grade whether crizotinib impacts the overall survival (OS)
1/2 in severity. Treatment-related Grade 3/4 AEs of ALK+ patients, we compared the OS of crizotinib-
were reported in 15% of patients (mostly increased treated patients with that of matched historical controls.
ALT [4%], dyspnea [3%], and neutropenia [2%]). Methods: We determined overall survival of 82 ALK+
Six patients discontinued study treatment due to patients who enrolled in the international clinical
treatment-related events (pneumonitis [two patients], trial of crizotinib (Kwak et al., NEJM, 2010). For
nausea, dyspnea, increased ALT and death of comparators, we identiÀed 37 ALK+ patients from
unknown cause). Updated efÀcacy and safety data clinical sites who were not treated with crizotinib
will be presented. (ALK+ controls), as well as 253 ALK-negative/EGFR-
Conclusion: Preliminary data from this Phase 2 negative patients from one site (ALK- controls). All
global clinical study suggest crizotinib was safe and ALK+ and ALK- controls had advanced NSCLC.
well tolerated with preliminary evidence of clinically Results: Among the 82 ALK+ patients treated with
meaningful antitumor activity in patients with pre- crizotinib, the median OS from the date of Àrst dose
treated ALK-rearranged NSCLC. has not been reached (NR); 1-yr OS was 77% and
Keywords: Crizotinib, PF-02341066, Non-small cell 2-yr OS was 64%. OS did not differ based on sex
lung cancer (p=0.35), ethnicity (Asian vs non-Asian, p=0.46),
smoking history (never vs any smoking, p=0.82) or
1
age ( or >60 yrs, p=0.93). Among the 37 ALK+ Medical Oncology, Christie Hospital Nhs Trust/
controls, median OS from the date of metastatic United Kingdom, 2Health Economics And Global
diagnosis was 20 mos; 1- and 2-yr OS was 73% and Outcomes Research, PÀzer Oncology,/United
33%, respectively. As ALK+ controls were identiÀed States Of America, 3Oncology Business Unit, PÀzer
at sites outside of Korea, we compared controls with Oncolgoy,/United States Of America, 4Department
the non-Korean cohort of crizotinib-treated patients Of Oncology, Mcgill University Health Centre/
(n=56). Both groups were similar in age (median 51 Canada, 5Cancer Center, Massachusetts General
vs 51, p=0.97), sex (57% vs 46% F, p=0.40), smoking Hospital,/United States Of America, 6Internal
history (68% vs 79% never smokers, p=0.33), presence Medicine, Seoul National University Hospital,/
of brain metastases at any time (49% vs 48%, p=1.00), Korea, 7Peter MacCallum Cancer Centre And
number of prior therapies (mean 2.05 vs 2.09, p=0.17), Cancer Trials Australia,/Australia, 8Lowe Center For
and types of prior chemotherapy. From the time of 2nd Thoracic Oncology, Dana-farber Cancer Institute,
line therapy, the survival of 32 patients treated with 2nd Harvard Medical School,/United States Of America,
9
/3rd line crizotinib was signiÀcantly longer than that Statistics, Specialty BU, PÀzer Oncology,/United
of 24 ALK+ controls treated with any 2nd line therapy States Of America, 10Statistics, PÀzer Oncology,/
(p=0.004): median OS was NR vs 11 mos, 1-yr OS Italy, 11Statistics, Specialty Care Business Unit,
was 71% vs 46%, and 2-yr OS was 61% vs 9% for PÀzer Oncology,/United States Of America, 12Quality
the subset of crizotinib-treated patients vs the subset Of Life Department, Eortc,/Belgium
of ALK+ controls, respectively. Among 123 ALK-
controls who received any 2nd line therapy, median OS Background: Current broad chemotherapy options
from the time of 2nd line therapy was 11 mos, and the for NSCLC provide limited survival and quality of
1- and 2-yr OS was 49% and 33%, respectively. life (QoL) beneÀts. The ALK fusion gene is a key
oncogenic driver recently identiÀed in a subset of
patients with NSCLC. In an early clinical study, a
high response rate (61%) was observed to crizotinib,
a potent and selective, adenosine triphosphate
(ATP)-competitive, small-molecule ALK inhibitor,
in patients with ALK-positive advanced NSCLC.
PROs were incorporated into the subsequent single
arm Phase 2 study in second- and third-line ALK-
positive NSCLC patients since understanding the
Conclusion: In patients with advanced ALK+ improvements patients may experience on crizotinib
NSCLC, treatment with crizotinib is associated with therapy is a key goal in this patient population.
a longer OS than that seen with historical, crizotinib- Clinically signiÀcant changes from baseline disease/
naive controls. treatment-related symptoms and QoL scores were
Keywords: ALK, Crizotinib, Tyrosine kinase inhibitor evaluated in this preliminary analysis of PROs.
Methods: Patients with ALK-positive advanced
NSCLC (conÀrmed by centralized FISH test)
Medical Oncology III Wednesday, 6 July 2011 14:30-16:00 from 57 sites in 12 countries, whose disease had
progressed after 1 chemotherapy regimens for
O31.07 PROFILE 1005: PRELIMINARY recurrent/locally advanced/metastatic disease
PATIENT-REPORTED OUTCOMES (including treated brain metastases) were treated in
(PROS) FROM AN ONGOING PHASE 2 this study. Patients received oral crizotinib 250 mg
STUDY OF CRIZOTINIB (PF-02341066) BID continuously in 3-week cycles. Study endpoints
IN ANAPLASTIC LYMPHOMA KINASE included best tumour response, safety/tolerability,
(ALK)-POSITIVE ADVANCED NON- overall and progression-free survival, and the
SMALL CELL LUNG CANCER (NSCLC) assessment of PROs by the EORTC QLQ-C30/LC13.
Fiona H. Blackhall1, Jennifer A. Petersen2, Keith Mean score and clinically signiÀcant change from
Wilner3, Vera Hirsh4, Alice T. Shaw5, Dong-Wan baseline scores (deÀned as a 10 point change from
Kim6, Ben Solomon7, Pasi A. Janne8, Arlene L. baseline; Osoba et al. J Clin Oncol 1998;16:139-44)
Reisman9, Anna Polli10, Rajiv Mundayat11, Andrew were assessed at each cycle.
Bottomley12 Results: On 29 October 2010, 109 patients were
evaluable for the PRO change from baseline analysis Department, Nanjing University/China, 3Department
and 76 patients for tumour response. Patients Of Respiratory Medicine, Southern Medical
received a median of 9 weeks of crizotinib and University/China, 4Department Of Respiratory
88% were still on treatment at the time of analysis. Medicine, Nanjing Chest Hospital/China,
5
Questionnaire compliance rate was exceptionally Department Of Oncology, The First Hospital
high (>90%) for all cycles and most patients had Of Nanjing/China, 6Department Of Respiratory
completed four PRO assessments at the time of Medicine, Nanjing University, Jinling Hosipital/
analysis. Patients reported clinically signiÀcant China
reductions of 10 points in key symptoms of
NSCLC, including pain (29.5 baseline mean score), Background: Can single-agent maintenance therapy
dyspnea (35.9 baseline mean score on the QLQ C30 be considered an ideal strategy for non-small cell
scale), and cough (40.0 baseline mean score) as early lung cancer (NSCLC) treatment to achieve prolonged
as Cycle 2. Clinically signiÀcant reductions in pain survival and tolerated toxicity? Researchers differ on
(pain, pain in arm or shoulder, pain in other parts, this question. A systematic review and meta-analysis
and pain in chest), dyspnea (QLQ-C30 scale), cough, was performed to elucidate this issue.
fatigue, insomnia, and alopecia symptom scales were Methods: The PubMed and Embase online
maintained with therapy. Post-baseline increases in databases and American Society of Clinical
constipation, diarrhea, and nausea/vomiting were Oncology (ASCO) annual proceedings (2001-2010)
also reported; however, only increase in constipation were searched for randomized controlled trials
was clinically signiÀcant over the course of therapy. (RCTs) comparing single-agent maintenance therapy
Improvement in mean QoL was also reported but versus placebo, best support care or observation.
changes were not clinically signiÀcant, indicating The overall response rate (ORR) in patients with or
that QoL was maintained with treatment. Additional without maintenance therapy was extracted from
and updated PRO information will be presented. each study as an estimation of the curative effect
Conclusion: This phase 2 study provides of the therapy. The required data for estimation of
preliminary evidence that patients with ALK-positive individual hazard ratios (HRs) for survival were
advanced NSCLC treated with crizotinib appeared to extracted from the publications and a combined HR
experience clinically signiÀcant improvements in key was calculated. The incidences of Grade 3/4 toxicity
symptoms of NSCLC while QoL was maintained. in the two treatment regimens were also extracted
PROs will continue to be monitored in this study and to estimate the safety of single-agent maintenance
work is ongoing within randomized phase III trials to therapy.
further assess the impact of treatment and hopefully Results: Ten RCTs to date, involving a total of 3513
conÀrm these initial Àndings. patients and with trial sizes ranging from 130 to 889,
Keywords: Crizotinib, PF-02341066, Non-small cell were identiÀed. We found a statistically signiÀcant
lung cancer, Symptons higher probability of tumor response for patients
with maintenance therapy versus controlled patients
(odds ratio (OR): 2.80, 95% CI: 2.15-3.64, P <
Session O32: Medical Oncology VI 0.001). Patients receiving single-agent maintenance
therapy had signiÀcantly longer progression-free
Wednesday, 6 July 2011 survival (HR: 0.67, 95% CI: 0.62-0.71, P < 0.001)
and overall survival (HR: 0.84, 95% CI: 0.78-0.90,
P < 0.001). However, maintenance therapy was
Medical Oncology VI Wednesday, 6 July 2011 14:30-16:00 associated with more severe toxicities.
Conclusion: In patients with advanced NSCLC, the
O32.01 SINGLE-AGENT MAINTENANCE use of single-agent maintenance therapy is associated
THERAPY IN NON-SMALL CELL LUNG with higher response rate and signiÀcantly prolongs
CANCER: A SYSTEMATIC REVIEW AND PFS and OS despite of the risk of additional toxicity.
META-ANALYSIS Keywords: Non-small cell lung cancer, maintenance
Dongmei Yuan1, Shuzhen Wei2, Yanling Lv3, Xiaohui therapy, meta-analysis, systematic review
Miao2, Like Yu4, Jinfei Chen5, Yi Shi6, Yong Song1
1
Department Of Respiratory Medicine, Nanjing
University, Jinling Hospital/China, 2Medical
Medical Oncology VI Wednesday, 6 July 2011 14:30-16:00 gender 68%, median age 62 (range 36-84), PS 0/1
45/49%, squamous cell histology 19%, stage IV 79%,
O32.02 PEMETREXED VERSUS interval from last 1st-line chemotherapy course and
PEMETREXED PLUS CARBOPLATIN randomization 3 months in 71% of patients (42%
IN PRETREATED PATIENTS WITH 6 months), prior response to 1st-line chemotherapy
ADVANCED NON-SMALL CELL LUNG 50%. Despite identical eligibility criteria in the two
CANCER: A POOLED ANALYSIS OF TWO studies, there was heterogeneity for some clinical
RANDOMIZED TRIALS characteristics (more squamous tumors, more advanced
Marcello Tiseo1, Andrea Ardizzoni1, Luca Boni2, A. PS, longer treatment-free interval in the Dutch study).
Vincent3, S Buti4, Andrea Camerini5, R. Labianca6, In the overall population, survival was not improved
Giovenzio Genestreti7, Francesca Zanelli8, L. by the addition of carboplatin to pemetrexed; the HR
Ciuffreda9, F. Di Costanzo10, F. De Marinis11, Lucio for death was 0.88 (95%CI: 0.71-1.07; p = 0.202; p
Crino12, A. Santo13, A. Pazzola14, F. Barbieri15, N. for heterogeneity = 0.693). Objective response rate
Zilembo16, I. Colantonio17, C. Tibaldi18, Egbert F. was increased in the carboplatin-containing arm with
Smit19 an OR of 1.78 (95%CI: 1.01-3.12; p = 0.046; p for
1
Medical Oncology Unit, University Hospital Of heterogeneity = 0.060). A non-statistically signiÀcant
Parma/Italy, 24centro Per Il Coordinamento Delle increase in PFS favouring combined chemotherapy
Sperimentazioni Cliniche, Istituto Toscano Tumori/ was observed with a HR of 0.85 (95%CI: 0.71-1.02; p
Italy, 3National Cancer Institute/Netherlands, = 0.082; p for heterogeneity = 0.019). In the subgroup
4
Ospedale Di Cremona/Italy, 5Ospedale Di Lido Di analyses, there was a statistically signiÀcant interaction
Camaiore/Italy, 6Ospedali Riuniti Di Bergamo/Italy, between histological subtype and treatment: in fact,
7
Oncology, Irst Meldola/Italy, 8Ospdale Di Reggio the addition of carboplatin to pemetrexed in patients
Emilia/Italy, 9Ospedale Molinette/Italy, 10Ospedale with squamous tumours led to a statistically signiÀcant
Careggi/Italy, 11San Camillo Forlanini/Italy, improvement of PFS from 2 to 3.2 months (adjusted
12
Ospedale Di Perugia/Italy, 13Ospedale Di Verona/ HR: 0.42; 95%CI 0.27-0.65; p of interaction test =
Italy, 14Ospedale Di Sassari/Italy, 15Policlinico Di 0.001) and of OS from 5.4 to 9 months (adjusted HR:
Modena/Italy, 16Istituto Nazionale Tumori/Italy, 0.57; 95%CI 0.36-0.90; p of interaction test = 0.05).
17
Ospedale Di Cuneo/Italy, 18Ospedale Di Livorno/ Conclusion: Single agent pemetrexed remains
Italy, 19Pulmonology Department, Vrije Universiteit the standard of care 2nd-line chemotherapy in
Medical Centre/Netherlands patients with relapsed non-squamous lung tumors.
Although pemetrexed has presently no indication
Background: To evaluate the beneÀt of adding in the treatment of squamous subtype NSCLC, the
carboplatin to single-agent pemetrexed chemotherapy results of this pooled analysis can support further
in 2nd-line treatment of advanced NSCLC, by pooling investigation of the carboplatin-pemetrexed regimen
the results of two identical phase II randomized trials in the 2nd-line treatment of this histological subtype.
(GOIRC 02.2006 and NVALT-7 trials) carried out in Keywords: NSCLC, second-line chemotherapy,
Italy and The Netherlands, respectively. Pemetrexed, Carboplatin
Methods: Main eligibility criteria in both trials were:
diagnosis of advanced NSCLC, disease progression
after 1st-platinum-based chemotherapy, normal organ Medical Oncology VI Wednesday, 6 July 2011 14:30-16:00
function and ECOG performance status 0-2. Patients
were randomized to receive pemetrexed 500 mg/m2 O32.03 COMPARISON OF PEMETREXED
alone or combined with carboplatin (AUC5). Cycles PLUS CISPLATIN WITH OTHER FIRST-
were repeated every 3 weeks for a maximum of 4 LINE DOUBLETS IN ADVANCED NON-
courses. Both studies were designed to detect a 33% SMALL CELL LUNG CANCER (NSCLC):
decrease in the hazard of disease progression in the A COMBINED ANALYSIS OF THREE
combination arm. The pooled analysis was pre-planned PHASE 3 TRIALS
and designed to assess the impact of adding carboplatin Joseph Treat1, Giorgio Scagliotti2, Guangbin Peng1,
to pemetrexed in terms of overall survival (OS) in the Gerhardt Pohl1, Coleman Obasaju1
1
overall population and in certain subgroups. Medical, Eli Lilly & Company/United States Of
Results: A total of 479 patients were randomized in America, 2Department Of Clinical And Biological
the two trials. Main patients characteristics were: male Sciences, University Of Turin, S. Luigi Hospital/Italy
Medical Oncology VI Wednesday, 6 July 2011 14:30-16:00

Background: In a Àrst-line study of advanced
NSCLC, pemetrexed plus cisplatin (PC) was more O32.05 IMPACT OF NEW
effective among patients (pts) with nonsquamous CHEMOTHERAPEUTIC AND TARGETED
histology compared with gemcitabine-cisplatin (GC, AGENTS ON SURVIVAL IN STAGE IV
OS=11.8 v 10.4 m, P=.005) while survival with NON-SMALL CELL LUNG CANCER
PC was shorter than with GC in pts with squamous Joanne L. Yu1, Christine Simmons2, Charles Victor3,
cell carcinoma. The comparability of PC to other Dolly Han2, Sophie Hogeveen2, Natasha Leighl4,
commonly used regimens within histology subgroups Sunil Verma1
1
needs to be explored. Division Of Medical Oncology, University Of
Methods: This retrospective analysis combined the Toronto/Canada, 2St. Michael’s Hospital/Canada,
3
pt-level data from 3467 pts enrolled in one of three Dalla Lana School Of Public Health, University
similar phase 3 trials (N=607, 1725, and 1135) with Of Toronto/Canada, 4Princess Margaret Hospital/
mature survival data comparing the efÀcacy of Àrst- Canada
line doublets (6 cycles) in advanced NSCLC. Cox
covariate-adjusted treatment hazard ratios (HRs) Background: SigniÀcant advances in the systemic
with 95% CI were obtained for OS. Overall and management of metastatic non-small cell lung
histology subgroup analyses were reported without cancer (NSCLC) have occurred over the past
adjustment for multiplicity. decade, with options now including multiple lines of
Results: In the overall analysis, adjusted HRs chemotherapy, EGFR inhibitors, and anti-angiogenic
favored PC (HR <1.0) to each of the other 5 agents. Improvements in overall survival have been
regimens. Among pts with nonsquamous histology, demonstrated in randomized controlled trials comparing
PC produced favorable HRs to each of the other these newer agents to best supportive care (BSC) or
regimens, achieving statistical signiÀcance when standard therapy. This study examined uptake of these
compared with vinorelbine-cisplatin and GC. Among therapies in general practice and their impact on survival.
pts with squamous histology, 4 of the 5 comparison Methods: This retrospective cohort study compared
regimens were favored to PC (HR >1.0), with demographic, treatment and survival data among
only the comparison to GC achieving statistical 987 patients diagnosed with stage IV NSCLC at two
signiÀcance. HR (95% CI) for contrast with institutions in 1998, 2003, and 2008. Cohorts were
pemetrexed-cisplatin selected based on intervals when doublet chemotherapy,
second line chemotherapy, and targeted agents were
Non-squamous Squamous incorporated into the standard treatment regimen.
Comparitors Overall
subgroup subgroup Results: The proportion of patients receiving
Gemcitabine- systemic therapy increased over time (20% in 1998,
0.88 (0.65, 1.18) 0.80 (0.57, 1.14) 0.96 (0.53, 1.73)
carboplatin
42% in 2008). Treated patients diagnosed in 2008
Gemcitabine-
0.94 (0.84, 1.05) 0.85 (0.75, 0.97) 1.23 (1.01, 1.51) were more likely to receive 2 lines of systemic
cisplatin
Gemcitabine- therapy (60% vs. 7% in 1998). Overall survival
0.91 (0.68, 1.22) 0.79 (0.56, 1.02) 1.26 (0.70, 2.27)
paclitaxel improved signiÀcantly across cohorts (P <0.001),
Paclitaxel- with 2 year survival rates of 0.3% in 1998, 4% in
0.91 (0.71, 1.17) 0.78 (0.58, 1.05) 1.34 (0.84, 2.11)
carboplatin
2003, and 15% in 2008. After controlling for other
Vinorelbine-
cisplatin
0.80 (0.62, 1.03) 0.67 (0.50, 0.91) 1.25 (0.78, 2.02) variables, risk of death was diminished by 55% in
patients receiving 1 line of systemic therapy and
Conclusion: In the absence of randomized trial 72% in those receiving 2 lines, compared with BSC
data comparing PC to commonly used doublets alone. Elderly patients (age 70 years) were also
in advanced NSCLC other than GC, this analysis more likely to receive systemic therapy over time,
provides estimates for such comparisons. with improved overall survival (P <0.001).
Keywords: NSCLC, Pemetrexed Conclusion: Over the past decade, there has been
increased use of systemic therapy in stage IV NSCLC
patients, including the elderly. This has been associated
with signiÀcantly improved overall survival.
Keywords: stage IV, NSCLC, systemic therapy,
survival
Medical Oncology VI Wednesday, 6 July 2011 14:30-16:00 well balanced between arms. nab-PC produced higher
ORR compared with PC (33 vs 25%, P = 0.005). A
O32.06 NAB-PACLITAXEL AND signiÀcant improvement of ORR was observed for
CARBOPLATIN COMPARED WITH nab-PC (n = 229) vs PC (n = 221) in squamous cell
CREMOPHOR-BASED PACLITAXEL carcinoma patients (41 vs 24%, P<.001), while nab-PC
AND CARBOPLATIN IS EFFECTIVE was as effective as PC in nonsquamous cell carcinoma
AND SAFE AS FIRST-LINE THERAPY IN patients. Age (75 vs <75 years old), smoking status,
ADVANCED NON-SMALL CELL LUNG and geographic location did not effect primary efÀcacy
CANCER: FINAL RESULTS OF A PHASE outcome. Differences were observed in the average
3 STUDY number of cycles administered per regions: 11 cycles
Mark A. Socinski1, Igor Bondarenko2, Nina in Australia/New Zealand, 7 in Eastern Europe, 4
Karaseva3, Anatoly Makhson4, Ihor Vynnychenko5, in Japan, and 5 in North America. nab-PC was well
Isamu Okamoto6, Jeremy Hon7, Vera Hirsh8, Paul tolerated, with signiÀcantly improved safety proÀle
Bhar9, Gregory Berk9, Jose Iglesias10 vs PC despite 30% higher mean total paclitaxel dose
1
University Of North Carolina, University Of North delivered (1528 vs 1170 mg/m2). Of the statistically
Carolina/United States Of America, 2City Clinical signiÀcant grade 3 adverse events, neutropenia,
Hospital/Ukraine, 3City Oncology Center/Russian neuropathy, myalgia, and arthralgia were lower in
Federation, 4Moscow Oncology Hospital #62/ the nab-PC arm, and thrombocytopenia and anemia
Russian Federation, 5Sumy Regional Oncology were lower in the PC arm. No bleeding was associated
Centre/Ukraine, 6Kinki Univercity Faculty Of with thrombocytopenia. No hypersensitivity reaction
Medicine/Japan, 7Clearview Cancer Inst/United occurred in the nab-PC arm without prophylactic
States Of America, 8Department Of Oncology, Mcgill premedication, while 3 occurred in the PC arm with
University Health Centre/Canada, 9Celgene/United premedication (grade 1, 2, and 3, respectively). PFS
States Of America, 10Celgene/Canada analysis with 47% events revealed no signiÀcant
differences between the 2 arms.
Background: Platinum-based doublet therapy in Conclusion: The primary endpoint was met, with
non-small cell lung cancer (NSCLC) has reached signiÀcantly improved ORR (31% improvement),
a therapeutic plateau, regardless of combinations. and nab-PC was highly active in the squamous
The nanoparticle albumin-bound formulation cell carcinoma subset. Interim PFS did not show a
of paclitaxel, nab-paclitaxel, reaches the tumor difference between the arms; Ànal survival results
microenvironment efÀciently via caveolae-mediated with 70% patients with an event will be presented.
transcytosis, is approved for the treatment of nab-PC is efÀcacious and safe as Àrst-line therapy
metastatic breast cancer, and has shown promising for advanced NSCLC.
antitumor activity in various advanced solid tumors, Keywords: nab-paclitaxel, Abraxane, taxane,
including NSCLC. This phase 3 trial compared Advanced NSCLC
the efÀcacy and safety of nab-paclitaxel plus
carboplatin (nab-PC) vs a standard platinum-taxane
combination treatment, paclitaxel plus carboplatin Medical Oncology VI Wednesday, 6 July 2011 14:30-16:00
(PC), in patients with advanced NSCLC. Previously
we reported that overall response rate (ORR), the O32.07 PEMETREXED AND
primary endpoint, was signiÀcantly higher in the CARBOPLATIN VERSUS DOCETAXEL
nab-PC arm compared with the PC arm. Here we AND CARBOPLATIN AS FIRST-LINE
report the Ànal analysis of the survival results. TREATMENT FOR PATIENTS WITH
Methods: First-line stage IIIB or IV NSCLC patients ADVANCED, NON-SQUAMOUS, NON-
(ECOG 0/1) were randomized to receive carboplatin SMALL CELL LUNG CANCER (NSCLC)
AUC6 q3w and either nab-paclitaxel 100 mg/m2 qw Vinod Ganju1, Jose Pereira2, Joo-Hang Kim3,
without premedication (n = 521) or paclitaxel 200 Manuel Magallanes4, Dae-Ho Lee5, Jie Wang6, Luis
mg/m2 q3w with premedication (n = 531). Primary Martinez7, Helen Barraclough8, Maximiliano Van
endpoint was ORR by independent radiologic review. Kooten9, Mauro Orlando10
1
The main secondary endpoints included progression- Peninsula Oncology Centre, Frankston Private
free survival (PFS), overall survival, and safety. Hospital/Australia, 2Oncopneumology Department,
Results: Baseline and histologic characteristics were Instituto Arnaldo Vieira De Carvalho/Brazil,
3
Oncology, Yonsei Cancer Center/Korea, 4Medical longer with PC than DC (median 3.2 months vs.
Oncology Dept, Military Hospital Of Mexico/ 0.7 months, log-rank p<0.001; HR = 0.45 [95% CI:
Mexico, 5Asan Medical Center, University Of 0.35 to 0.58]). This signiÀcant difference remained
Ulsan College Of Medicine/Korea, 6Department Of when SWT was adjusted for prognostic baseline
Thoracic Oncology, Beijing Cancer Hospital And characteristics (adjusted HR = 0.45 [95% CI:
Institute/China, 7Oncology Dept, National Institute 0.34 to 0.61], p<0.001). There were no signiÀcant
Of Respiratory Diseases/Mexico, 8Statistics, Icis, differences between PC and DC in progression-free
Eli Lilly Australia Pty Ltd/Australia, 9Medical, Eli survival, duration of response, or overall survival
Lilly Australia Pty Ltd/Australia, 10Medical, Eli Lilly (OS). Median OS was 14.9 months for PC and
Interamerica Inc./Argentina 14.7 months for DC (adjusted HR = 0.93 [95% CI:
0.72 to 1.42], p=0.698). The tumor response rate
Background: In a previous randomized, phase was 34.0% for PC and 22.9% for DC (p=0.074).
3 study, second-line treatment with pemetrexed More patients in the DC arm than the PC arm had
resulted in clinically equivalent efÀcacy outcomes 1 Grade 3 or 4 AE (81.9% vs. 63.2%) or 1 study
compared to docetaxel in patients with advanced drug-related TEAE (90.5% vs. 80.2%). Grade 3 or 4
NSCLC, but had a more favorable toxicity proÀle. treatment-emergent neutropenia, febrile neutropenia,
Platinum-based cytotoxic doublets are recommended leukopenia, or dyspnoea occurred in more patients
as Àrst-line treatment for patients with advanced in the DC arm than the PC arm, whereas grade 3
NSCLC and good performance status (PS). In a or 4 anemia or thrombocytopenia occurred more
recent phase 3 study, pemetrexed and cisplatin frequently in the PC arm.
resulted in superior outcomes and less toxicity Conclusion: The favorable beneÀt-to-risk proÀle of
compared to gemcitabine and cisplatin in non- PC observed in this study suggests that PC may be
squamous NSCLC. Relatively few studies have an appropriate Àrst-line treatment option for patients
assessed treatment outcomes with pemetrexed/ with advanced, non-squamous NSCLC, given the
carboplatin (PC), although docetaxel/carboplatin palliative nature of therapy in this setting.
(DC) is a well-accepted Àrst-line option. The primary Keywords: Pemetrexed, Docetaxel, Non-squamous
objective of this multicenter, randomized, phase 3 nsmall cell lung cancer, Carboplatin
trial was to compare survival without grade 3 or 4
toxicity (SWT) following Àrst-line treatment with PC
versus DC in patients with advanced non-squamous Session O33: Preclinical Models I
NSCLC.
Methods: Chemotherapy-naïve patients with stage Wednesday, 6 July 2011
IIIB/IV, non-squamous NSCLC, aged 18 years,
with an Eastern Cooperative Oncology Group PS 0
to 2 were randomized to receive carboplatin (AUC 5) Preclinical Models I Wednesday, 6 July 2011 14:30-16:00
with pemetrexed (500 mg/m2) and standard vitamin
supplementation or docetaxel (75 mg/m2) every 21 O33.01 ENHANCING EGFR-DIRECTED
days for a maximum of 6 cycles. Patients in both THERAPIES THROUGH A NOVEL
arms received dexamethasone supplementation. RESEARCH PLATFORM INTEGRATING
SWT was deÀned as the time from the date of DATA FROM GENETICALLY
randomization to the Àrst date of any Grade 3 or 4 ENGINEERED MICE, PATIENT DERIVED
treatment-emergent adverse event (TEAE) or death XENOGRAFTS AND CLINICAL TRIALS
due to any cause. (IGXT)
Results: Between October 2007 and April 2009, 226 David R. Gandara1, Terry A. Van Dyke2, Zoe Weaver
patients with non-squamous histology were enrolled Ohler2, Tianhong Li1, Primo N. Lara1, Phillip Mack1,
at 23 investigative sites in 6 countries, of whom 211 Royce F. Calhoun1, Regina Gandour-Edwards3,
(93.4%) were evaluable. The median age was 59.5 Kathleen Danenberg4, Ralph Devere White1, Neal
years, 41.7% were East Asian, 46.0% were females, Goodwin5
1
and 35.5% were never-smokers. There were more Oncology, Uc Davis Cancer Center/United States
females and never-smokers in the DC arm than in Of America, 2Center For Advanced Preclinical
the PC arm. The median number of cycles delivered Research (capr), National Cancer Institute/United
was 5 for DC and 6 for PC.SWT was signiÀcantly States Of America, 3Department Of Pathology And
Laboratory Medicine, UC Davis/United States pts, histopatholgic features, molecular proÀles and
Of America, 4Response Genetics/United States Of initial treatment results in PDXs and patients will be
America, 5The Jackson Laboratory/United States Of presented.
America Conclusion: This EGFR-direct pilot project supports
the feasibility of systematically integrating data
Background: Previously described preclinical derived from iGXT models in order to optimize drug
models have proven suboptimal for directing clinical development and treatment strategies to address drug
application of new anti-cancer therapies. Here we resistance mechanisms. Findings from this platform
describe an integrated research platform (iGXT) are likely to advance understanding of differences in
engaging core resources at The Jackson Laboratory inter- and intra-patient tumor biology and hasten the
(JAX-WEST), the NCI Center for Advanced transition to personalized cancer therapy.
Preclinical Research (CAPR) and a clinical trials Keyword: research platform
consortium based at the UC Davis Cancer Center.
Pilot studies using this strategy are focusing on non-
small cell lung cancer (NSCLC) due to molecular Preclinical Models I Wednesday, 6 July 2011 14:30-16:00
targets of interest, such as epidermal growth factor
receptor (EGFR), heterogeneity in NSCLC tumor O33.02 MURINE TRANSGENIC LUNG
biology and the complexity of cancer signaling CANCER MODELS GUIDE A WINDOW
pathways. OF OPPORTUNITY VORINOSTAT TRIAL
Methods: In this pilot project, EGFR-directed drugs IN LUNG CANCER PATIENTS
of interest (example: erlotinib +/-AKT inhibitor Tian Ma1, Fabrizio Galimberti1, Cherie P. Erkmen2,
MK2206 or pan-HER inhibitor BIBW2992) Vincent Memoli2, William Nugent2, James R. Rigas2,
are being studied at NCI CAPR in genetically David Johnstone2, Hua Li1, James Direnzo1, Yongli
engineered mice (GEMs) bearing tumors with Guo1, Sarah Freemantle1, Konstantin H. Dragnev3,
deÀned EGFR-related characteristics, together Ethan Dmitrovsky1
1
with in vitro models at UC Davis, while NSCLC Pharmacology And Toxicology, Dartmouth Medical
patients (pts) and JAX Nod Scid Gamma (NSG) School/United States Of America, 2Dartmouth-
mice with patient-derived xenografts (PDXs) from hitchcock Medical Center/United States Of America,
3
those pts are concurrently treated in a co-clinical Medicine, Dartmouth Medical School/United States
trial paradigm, taking advantage of the NSG mouse Of America
for propagating PDXs. Results in NSG models and
pt trials are assessed by genome-wide technologies, Background: Lung cancer is the most common
integrated with data from CAPR, and extrapolated cause of cancer mortality. New treatments for
back to individual pt outcomes to gain insight into lung cancer are needed. We previously engineered
mechanisms of drug resistance and how to overcome murine transgenic cyclin E models that recapitulated
them. frequent features of lung cancers in patients. These
Results: Over 200 cancer pt tumors have included chromosome instability, hedgehog pathway
been xenotransplanted into NSG mice (~60 and cyclin D1 activation as well as single or multiple
from NSCLC). NSCLC PDXs show excellent pre-malignant and malignant (adenocarcinoma) lung
histopathologic and molecular correlation to parent lesions. Metastases were observed. Cell lines (ED-
patient tumors, including mutation status for KRAS, 1 and ED-2) were derived from these murine lung
EGFR and gene expression levels. Pilot studies cancers. After tail vein injections of ED-1 or ED-2
at CAPR in GEMs with EGFR mutant (Tet-op- cells into syngeneic FVB mice, lung cancers began
EGFR L858R +/- T790M) tumors demonstrate to form within 2 weeks. These models are useful
efÀcacy of MK2206 +/- erlotinib and BIBW2992. tools to identify promising anti-neoplastic agents.
Complementary in vitro studies at UCD with the This study used these murine lung cancer models to
c-MET inhibitor PHA-665752 or MK2206 conÀrm guide a window of opportunity trial of the histone
the ability of MK2206 to overcome c-MET-related deacetylase inhibitor vorinostat in lung cancer
resistance to erlotinib. Simultaneously, an ongoing patients.
erlotinib-MK2206 clinical trial with associated PDXs Methods: For in vitro studies, murine lung cancer
is designed to evaluate mechanisms of resistance to cell lines ED-1 and ED-2 and human lung cancer cell
erlotinib and overcome them. Demographics of host lines HOP62, H522 and H23 were each treated with
vorinostat (1-5ƫM) for 2 or 4 days to investigate Preclinical Models I Wednesday, 6 July 2011 14:30-16:00
growth inhibitory and apoptotic effects. Expression
of the cell cycle proteins cyclin D1, cyclin E and p27 O33.03 PEP02 (LIPOSOME IRINOTECAN)
were examined after vorinostat treatments. For in EFFECTIVELY INHIBITS HUMAN
vivo studies, cyclin E transgenic mice were treated LUNG SQUAMOUS CELL CARCINOMA
with vorinostat to investigate effects on cyclin D1, AND SMALL CELL LUNG CANCERS IN
cyclin E and ki-67 expression in lung cancers. FVB SUBCUTANEOUS AND ORTHOTOPIC
mice harboring transplanted syngeneic murine lung XENOGRAFT TUMOR MODELS
cancer cells were treated with vorinostat to evaluate Daniel C. Chan1, Zhiyong Zhang1, Paul A. Bunn1,
effects on lung cancer formation. For the window Grace Yeh2
1
of opportunity clinical trial, patients with resectable Medical Oncology, University Of Colorado Denver/
non-small cell lung cancer (NSCLC) were treated United States Of America, 2Pharmaengine, INC/
with vorinostat (400mg) orally once daily for 7 Taiwan
days before surgical resection. Paired pre-treatment
and post-treatment tumor biopsies were scored for Background: PEP02 is a nanoparticle liposome
immunohistochemical changes in cyclin D1, cyclin E formulation of irinotecan (CPT-11), a topoisomerase
and Ki-67. I inhibitor, used for the treatment of various tumor
Results: Among a panel of drugs that caused growth types including lung cancers. In preclinical and clinical
inhibition of lung cancer cells and repression of studies, PEP02 has been shown to greatly modify the
cyclin D1 protein, vorinostat was found as most pharmacokinetics and biodistribution of CPT-11 and
potent. Vorinostat treatment caused dose-dependent its active metabolite, SN-38, thereby improving its
and time-dependent growth inhibition and apoptosis therapeutic efÀcacy. In this report, we evaluated the in
induction in murine and human lung cancer cells. vivo efÀcacy of PEP02 in three xenograft models of
Effects were reversed by washouts of vorinostat. human lung tumors.
Vorinostat treatments repressed cyclin D1 and cyclin Methods: Xenograft models of subcutaneous H157
E proteins, but increased p27 expression in ED-1 squamous cell carcinoma (SCC), known to be resistant
cells. Notably, vorinostat treatments of cyclin E to various EGFR inhibitors, and H841 small cell
transgenic mice substantially repressed cyclin D1 lung cancer (SCLC), known to be resistant to several
expression in pre-malignant and malignant lung conventional therapeutic agents, were established in
tissues. Vorinostat treatment signiÀcantly reduced mice and rats. Animals (10-12 per group) were treated
lung tumor formation (P = 0.047) in the murine by weekly iv injections after the tumor reached 200
transplantation lung cancer model. To translate these cubic mm in size with placebo liposome, CPT-11 at 50
studies into the clinic, 10 patients were recruited for (mouse ) or 25 (rat) mg/kg/wk, docetaxel at 8 (mouse)
the vorinostat window of opportunity clinical trial. or 12 (rat) mg/kg/wk, or PEP02 at 15, 30 and 50 mg/
Among 7 of the paired tumor specimens examined, kg/wk for three or four weeks. Tumor volumes were
3 had decreased Ki-67 and cyclin E levels, 2 had measured with digital calipers. For the orthotopic
decreased cyclin D1 expression, and 4 showed model, Kaplan-Meier survival curves were generated.
necrosis in post-treatment biopsies. Results: (1) PEP02 effectively suppressed H157
Conclusion: Substantial anti-neoplastic effects of subcutaneous SCC tumor growth in a dose dependent
vorinostat occurred in cultured lung cancer cells and manner, much more efÀcient than CPT-11 or docetaxel.
in vivo in murine transgenic and transplantable lung PEP02 at 15, 30 and 50 mg/kg/wk inhibited tumor
cancer models. Findings were validated in the clinic growth by 86.7%, 92.9% and 97.6%, respectively
through a vorinostat window of opportunity trial. when compared with that of placebo liposome, and
These studies underscore the value of clinically- the suppressions persisted for 12 to 15 days after the
relevant murine lung cancer models for guiding last treatment. In contrast, CPT-11 and docetaxel
clinical trials in lung cancer patients. only inhibited tumor growth by 29.8% and 71.4%,
Keywords: window of opportunity trial, NSCLC, respectively. Retreatment of the regrowth was achieved
Vorinostat, murine lung cancer model with PEP02 at 50 mg/kg/wk which extended the tumor
suppression until 130 days. (2) For the SCLC H841
xenograft, PEP02 at 15, 30 and 50 mg/kg/wk also
impressively inhibited tumor growth by 81.7%, 96.3%
and 98.3% respectively, much better than CPT-11 by
51.6%, when compared with that of placebo liposome. Background: Lung cancers harboring anaplastic
Inhibition of tumor growth persisted more than 20 days lymphoma kinase (ALK) rearrangements represent a
after the last treatment with PEP02 at 15 and 30 mg/ unique subpopulation of patients. Crizotinib, an ALK
kg/wk before tumor grew again. In contrast, complete tyrosine kinase inhibitor (TKI) is clinically effective
tumor regression was achieved at 50 mg/kg/wk. (3) in this genomically deÀned patient subset. However,
When implanted orthotopically in the left lung of the clinical success of treatment with ALK-TKIs is
athymic nude rats, H157 SCC tumor grew aggressively often limited by the development of acquired drug
and metastasized contra-laterally to right lungs, and resistance. In this study, we examined resistance
eventually rats died from tumor burden with a median mechanisms to ALK-TKIs. The understanding
survival of 24 days in the placebo liposome group. At of resistance mechanism(s) is critical to the
the maximum tolerated dose, CPT-11 at 25 mg/kg/wk development of effective subsequent treatments.
or docetaxel at 12 mg/kg/wk did not extend rat survival Methods: We examined tumor biopsies from
at all. However, PEP02 at 15, 30 and 50 mg/kg/wk patients treated with crizotinib that had developed
prolonged median survivals by 4, 12 and 26 days, acquired resistance to crizotinib. We also generated
respectively. In all three models, no obvious side effects an ALK-TKI resistant H3122 cell (H3122TR3) by
or weight loss were noted in the PEP02 treated groups. exposing the increasing dose of TAE684. Finally
Conclusion: PEP02 effectively inhibited tumor we generated a cell line (DFCI076) from a pleural
growth, regrowth, and prolonged survival in effusion of a NSCLC patient that developed acquired
subcutaneous and orthotopic lung tumor xenograft resistance to crizotinib. We examined whether
models. PEP02 has great clinical potential for the genomic changes (mutations or copy number
treatment of human lung SCC and SCLC in which changes) were present in the ALK TKI resistant
there are high unmet medical needs. tumors and cells. In addition, we evaluated for the
Keywords: Liposomal irinotecan, subcutaneous and presence of co-activated signaling pathways.
orthotopic models, Squamous carcinoma and SCLC Results: We identiÀed a secondary mutation in
ALK, F1174L (also detected in neuroblastoma), in a
A revised/updated abstract may be included in patient with an inÁammatory myoÀbroblastic tumor
the Late Breaking Abstract Supplement, available (IMT) harboring a RANBP2-ALK translocation
at the 14th World Conference on Lung Cancer. who progressed while on crizotinib therapy. When
present in cis with an ALK translocation, the F1174L
mutation causes an increase in ALK phosphorylation,
Preclinical Models I Wednesday, 6 July 2011 14:30-16:00 cell growth and downstream signaling. This mutation
likely promotes the active conformation of ALK
O33.05 ANAPLASTIC LYMPHOMA which disfavors crizotinib binding as it binds the
KINASE (ALK) DEPENDENT AND inactive conformation of ALK. Treatment with a
CO-DEPENDENT MECHANISMS structurally distinct ALK inhibitor, TAE684, or with
OF RESISTANCE TO ALK KINASE 3-fold above the current efÀcacious concentrations of
INHIBITORS IN EML4-ALK NON-SMALL crizotinib was sufÀcient to inhibit the growth of Ba/
CELL LUNG CANCER F3 cells harboring the F1174L mutation. In contrast
Takaaki Sasaki1, Jussi Koivunen2, Atsuko Ogino3, the DFCI076 cells (EML4-ALK), were resistant to
Katsuhiro Okuda3, Masahiko Yanagita3, Marzia both crizotinib and TAE684. These cells contained
Cappelletti3, Keith Wilner4, James Christensen4, a novel L1152R ALK secondary mutation. Ba/F3
Michael Eck3, Natanael Gray3, Pasi A. Janne5 cells with EML4-ALK L1152R were also resistant
1
Respiratory Center, Asahikawa Medical University to crizotinib and the L1152R mutation diminished
Hospital/Japan, 2Department Of Oncology And crizotinib mediated inhibition of downstream
Hematology, Oulu University Hospital/Finland, phosphorylation. In addition, we determined that the
3
Medical Oncology, Dana-farber Cancer Institute/ DFCI076 cells had evidence of signiÀcant Epidermal
United States Of America, 4Department Of Research Growth Factor Receptor (EGFR) phosphorylation.
Pharmacology, PÀzer Global Research And Infection of an ALK shRNA inhibited the growth
Development/United States Of America, 5Lowe of DFCI076 cells to 40% of control; however the
Center For Thoracic Oncology, Dana Farber combination of ALK knockdown and PF00299804,
Cancer Institute/United States Of America an irreversible pan-ERBB inhibitor, led to further
growth inhibition (19% of control). The H3122TR3
cells were resistant in vitro to both TAE684 and the current study, we evaluated the therapeutic and
crizotinib but did not contain a secondary ALK radiosensitizing effects of cediranib and paclitaxel,
mutation. However, the H3122TR3 cells contained alone and in combination, in an orthotopic model
activation of EGFR signaling mediated by autocrine of human lung adenocarcinoma that mimics clinical
EGF production. The combination of crizotinib and patterns of malignant progression.
PF00299804 effectively inhibited the growth of Methods: PC14PE6 human lung adenocarcinoma
H3122TR3 cells. cells (1 x 106) were injected into the left lungs of
Conclusion: Multiple mechanisms of resistance, nude mice. After 2 weeks, mice were randomized (8/
including secondary mutations in ALK and co- group) to treatment with vehicle control, cediranib
activation of parallel signaling pathways, can (3 mg/kg/day po), paclitaxel (200 g/week ip),
develop in response to ALK TKIs and can develop radiation to the lung and mediastinum (20 Gy in 5
simultaneously. Our Àndings suggest the need to fractions over 2 weeks), or radiation with cediranib
develop alternative strategies to inhibit ALK and/or and/or paclitaxel. When control mice became
to develop effective combination therapies that target moribund, all mice were sacriÀced and assessed for
both ALK and EGFR. A phase I clinical trial of lung tumor burden and regional metastasis. Tumor
crizotinib and PF00299804 is currently underway. tissues were subjected to immunohistochemical
Keywords: Non-small cell lung cancer, gene analyses.
translocation, kinase inhibitor, anaplastic large cell
kinase Results:
Inhibition of tumor growth and metastasis by cediranib, radiation,

Preclinical Models I Wednesday, 6 July 2011 14:30-16:00 and paclitaxel treatment in an orthotopic human lung adenocarcinoma
(PC14PE6) model in mice
Left lung
O33.06 VEGF SIGNALING INHIBITION Treatment
Tumor
Left lung
weight
Tumor
Plueral
effusion
Mediastinal
lynph node
BY CEDIRANIB ENHANCES THE incidence
(mg)
volume
(mm3)
(l) metastasis
ANTITUMOR AND ANTI-METASTATIC 710 (490- 753 (254-
EFFECTS OF RADIATION THERAPY Vehicle 8/8
1210) 1089)
360 (0-850) 7/8
MORE SUBSTANTIALLY THAN Paclitaxel

8/8
545 (150- 506 (37-
150 (0-400) 6/8
PACLITAXEL IN A MURINE 200ug/week 860) 817)
Radiation 220** (50- 154* (34-
ORTHOTOPIC MODEL OF LUNG 20Gy/5fraction
8/8
360) 270)
0 (0-200) 4/8
CANCER Cediranib 3mg/ 215* (70- 137* (13-
8/8 0 (0-150) 4/8
Osamu Takahashi1, Ritsuko Komaki1, Juliane M. kg/day 540) 316)
Jürgensmeier2, Anderson J. Ryan3, Paul D. Smith2, Radiation + 185** (60- 87** (21-
8/8 0 (0-100) 2/8
Paclitaxel 260) 268)
Ignacio I. Wistuba4, Benjamin N. Bekele5, Ramesh Cediranib + 125** (60- 41** (0-
C. Tailor1, Jörg J. Jacoby6, Maria V. Korshunova1, 7/8 0 (0-150) 1/8+
Paclitaxel 260) 150)
Anna Biernacka1, Keiko Hosho1, Baruch Erez6, Roy Radiation +
3/8
50** (40- 0** (0-
0* (0) 0/8+
S. Herbst6, Michael S. O’Reilly1 Cediranib 260) 28)
1 Radiation +
Radiation Oncology, The University Of Texas M.D. Cediranib + 3/8
40** (40-
0** (0-1) 0* (0) 0/8+
60)
Anderson Cancer Center/United States Of America, Paclitacel
2
Astrazeneca/United Kingdom, 3Astrazeneca (current Data are presented as median and range or as incidence. +p<0.05 vs vehicle
(Lymph nodes), *p<0.01, p<0.001 vs vehicle (others)
Address, Department Of Oncology, University Of
Oxford)/United Kingdom, 4Pathology, The University
Of Texas MD Anderson Cancer Center/United All treatments were well tolerated. Cediranib,
States Of America, 5Biostatistics, The University Of radiation, or paclitaxel monotherapy inhibited
Texas M.D. Anderson Cancer Center/United States primary lung tumor growth by 83.1, 80.4, and 33.7%
Of America, 6Thoracic/head And Neck Medical compared to control, respectively, and only partially
Oncology, The University Of Texas MD Anderson inhibited mediastinal metastasis. Radiation and
Cancer Center/United States Of America cediranib, cediranib and paclitaxel, and radiation
with paclitaxel reduced primary tumor volume
Background: Cediranib (AZD2171, RECENTIN™) by 99.3, 92.7, and 87.0% compared with control,
is an orally available and highly potent inhibitor of respectively. In the cediranib plus radiation group,
VEGFR1–3 currently in phase III clinical trials. In metastasis and pleural effusion were completely
inhibited, whilst paclitaxel only marginally improved Background: Synthetic lethality represents a
the effects of radiation. Trimodality therapy resulted novel therapeutic strategy in the treatment of
in the near complete suppression of tumor growth cancer, as exempliÀed by the recent advent of poly
and metastasis with microscopic tumors detected (ADP-ribose) polymerase (PARP) inhibition in
in only 3 of 8 treated mice. Immunohistochemical BRCA1/2 mutated tumours. Inhibition of PARP, a
analyses of lung tumors revealed that radiation or single strand (ssDNA) break repair protein, leads
cediranib reduced microvessel density and tumor to an accumulation of DNA double strand breaks,
proliferation and increased tumor and endothelial speciÀcally in S-phase cells. Normally these breaks
apoptosis. VEGFR2 expression was not impacted are repaired via homologous recombination (HR),
by any treatments but its activation was blocked a process requiring functional BRCA1/2 However,
by cediranib. The most profound antiangiogenic the dual loss of both PARP-mediated ssDNA
and apoptotic effects were observed after treatment repair upon PARP inhibition and defective HR, in
with cediranib and radiation or trimodality therapy BRCA-deÀcient cells, results in the accumulation of
but the inhibition of tumor cell proliferation was DNA damage and ultimately cell death. Currently,
not substantially enhanced with combined modality it is unknown whether synthetic lethality due to
therapy. inhibition of PARP-mediated DNA repair in HR-
Conclusion: Trimodality therapy with cediranib, defective tumours requires mitochondrial apoptosis.
paclitaxel, and radiation resulted in the near The underlying mechanisms involved in cell killing,
complete suppression of lung tumor growth and involving the accumulation of catastrophic DNA
metastasis with markedly enhanced antiangiogenic damage, would be predicted to induce cell death
and apoptotic effects. The radiosensitizing effects independently of the canonical mitochondrial death
of cediranib upon lung tumors and their vasculature pathway. However, this hypothesis has not yet been
was superior to those of paclitaxel with markedly fully investigated.
enhanced apoptosis. The combination of cediranib Methods: The effect of BRCA1-depletion and
with radiotherapy or chemoradiotherapy is a in-vitro response to PARP inhibitor treatment
potentially promising therapy for cancer and our was performed using clonogenic assays in a
data provides a strong basis for the design of clinical panel of NSCLC cell line models. In addition,
trials in lung cancer patients. BAX/BAK-deÀcient and cisplatin resistant
Keywords: orthotopic lung cancer model, Non-small NSCLC cell line models were employed. BRCA1
cell lung cancer, cediranib (AZD2171), Radiation immunohistochemistry was performed on 302
Therapy primary NSCLC tumours from two independent
cohorts to determine the frequency of BRCA1-
immunodeÀciency
Preclinical Models I Wednesday, 6 July 2011 14:30-16:00 Results: We demonstrate that BRCA1-depletion
enhances sensitivity to PARP inhibitor therapy
O33.07 PARP INHIBITION INDUCES in a panel of NSCLC cell lines and that this
BAX/BAK INDEPENDENT SYNTHETIC effect is independent of mitochondrial apoptosis.
LETHALITY OF BRCA1-DEFICIENT Furthermore, we demonstrate that BRCA1
NON-SMALL CELL LUNG CANCER inhibition cannot override platinum resistance
Ian Paul1, Kienan I. Savage1, Jaine Blainey1, but can induce sensitisation to PARP inhibition in
Elisabeth Lamers1, Kathy Gately2, Keith M. Kerr3, the platinum resistant setting. We also report the
Michael Sheaff4, Derek J. Richard5, Peter Hamilton1, existence of a subgroup of NSCLC with BRCA1-
Jackie James1, Kenneth J. O’Byrne2, Paul Harkin1, immunodeÀciency representing 11% and 19%
Jennifer E. Quinn1, Dean A. Fennell1 respectively, in two independent NSCLC patient
1
Centre For Cancer Research And Cell Biology, cohorts.
Queen’s University Belfast/United Kingdom, Conclusion: Targeting BRCA1-depleted NSCLC
2
Department Of Clinical Medicine, St. James’s with PARP inhibitors induces synthetic lethality,
Hospital/Ireland, 3Department Of Pathology, results in bypass of mitochondrial apoptosis
Aberdeen Royal InÀrmary/United Kingdom, block and can override platinum resistance.
4
Department Of Pathology, Barts And The London BRCA1-immunodeÀcient NSCLC represents
Nhs Trust/United Kingdom, 5Queensland University a molecular subgroup that could be effectively
Of Technology/Australia targeted by PARP inhibitors in the clinic. BRCA1
immunohistochemistry (IHC) presents a robust, and two experts in assessment.

relatively simple and cost effective approach for
identifying a subgroup of BRCA1-immunodeÀcient
NSCLC, who may derive beneÀt from treatment with
PARP inhibitors. This biomarker assay now merits
testing in the clinical trial setting.
Keywords: apoptosis, BRCA1, Non small cell lung
cancer, PARP inhibitor
Three trainees who had performed less than 50

Session O34: Nodal Staging by EUS procedures and three consultants who had
Ultrasound Endoscopy and Alternative performed more than 100 procedures were included
Image Guided Diagnosis in the study. Each physician performed 5 EUS
procedures on patients scheduled for mediastinal
staging. All procedures were observed by an expert
Wednesday, 6 July 2011 who Àlled out the assessment form. Furthermore all
procedures were recorded and assessed blindly and
Nodal Staging by Ultrasound Endoscopy and Alternative Image independently by two EUS experts.
Guided Diagnosis Wednesday, 6 July 2011 14:30-16:00 Results: The assessment tool could sufÀciently
discriminate between trainees and consultants,
O34.01 RELIABLE AND VALID p=0.001. The intra-rater reliability was high,
ASSESSMENT OF EUS AND EUS-FNA Cronbach’s Alpha 0.80, and the inter-rater
COMPETENCE IN PULMONOLOGY reliability was very high, Cronbach’s Alpha 0.87.
Lars Konge1, Jouke Annema2, Peter Vilmann3, Paul
Clementsen4, Charlotte Ringsted1
1
Centre For Clinical Education, Rigshospitalet,
University Of Copenhagen/Denmark, 2Department
Of Pulmonology, Leiden Medical Centre/
Netherlands, 3Department Of Surgery, Endoscopic
Unit, Copenhagen University Hospital Gentofte/
Denmark, 4Pulmonology, Gentofte University
Hospital/Denmark
Background: Accurate staging is essential for

choosing treatment for non-small-cell lung cancer. Conclusion: The novel assessment tool for
Sampling of tissue from the mediastinum has been measuring competence in performance of EUS and
revolutionized by ultrasound guidance, and it seems EUS-FNA for lung cancer staging is reliable and
that the combination of EUS-FNA and EBUS-TBNA valid. It can be used for direct observation or blinded
will replace more invasive methods for diagnosis using video-recordings. The assessment tool can
and staging of lung cancers in the near future. This provide valuable feed-back to trainees and help to
will create a huge need for doctors who master the decide when basic competency is established.
new techniques. EUS training and implementation Keywords: Assessment, EUS, Training, Staging of
requirements are under discussion. A reliable NSCLC
and valid assessment tool is necessary to provide
structured feed-back to trainees, measure the effect
of training methods, and help certify physicians.
The aim of this study was to explore the reliability
and validity of a new assessment tool designed to
measure competence in EUS-FNA for mediastinal
staging.
Methods: The tool was created by a group of four
physicians: Two experts in endoscopic ultrasound
Nodal Staging by Ultrasound Endoscopy and Alternative Image stations, our study shows that very little, if anything,
Guided Diagnosis Wednesday, 6 July 2011 14:30-16:00 is gained by an additional mediastinoscopy and can
be avoided
O34.02 IS MEDIASTINOSCOPY Keywords: Lung cancer, EBUS-TBNA,
NECESSARY IN PATIENTS WITH Mediastinoscopy
NEGATIVE EBUS-TBNA- A CHALLENGE
TO THE ESTS GUIDELINES FOR
STAGING OF LUNG CANCER? Nodal Staging by Ultrasound Endoscopy and Alternative Image
Mark Krasnik1, Birgit G. Skov2, Anders Guided Diagnosis Wednesday, 6 July 2011 14:30-16:00
Mellemgaard2, Peter Vilmann3, Felix J. Herth4
1
Thoracic And Cardiovasc.surg, Rigshospitalet O34.03 COST-EFFECTIVENESS AND
Copenhagen University/Denmark, 2Pathology, QUALITY OF LIFE RESULTS FROM THE
Bispebjerg University Hospital/Denmark, ASTER STUDY: ENDOBRONCHIAL AND
3
Department Of Surgery, Endoscopic Unit, ENDOSCOPIC ULTRASOUND VERSUS
Copenhagen University Hospital Gentofte/Denmark, SURGICAL STAGING IN POTENTIALLY
4
Dept. Of Pneumology And Respiratory Critical Care RESECTABLE LUNG CANCER
Medicine, Thoraxklinik, University Of Heidelberg/ Robert C. Rintoul1, Jouke T. Annema2, Kurt G.
Germany Tournoy3, Christophe Dooms4, Ella Wheaton5,
Victoria Hughes1, Alistair Grant1, Chris Jackson5,
Background: Mediastinoscopy is the golden Lavinia Magee1, Gethin L. GrifÀth6, Martin Buxton6,
standard for mediastinal staging of lung cancer.The Linda D. Sharples5
1
aim of the present study was to examine whether Department Of Thoracic Oncology, Papworth
mediastinoscopy may be avoided if a standardized Hospital/United Kingdom, 2Respiratory Medicine,
EBUS-TBNA procedure using the same criterias as Leiden University Medical Centre/Netherlands,
3
required during mediastinoscopy with representative Respiratory Medicine - Thoracic Oncology, Ghent
biopsies without malignant cells from lymph nodes University Hospital/Belgium, 4Respiratory Oncology
in station 4R, 7 and 4L, is performed. Unit, University Hospitals Leuven/Belgium, 5Mrc
Methods: Patients with known or suspected lung Biostatistics Unit, Institute Of Public Health/United
cancer underwent a standardized EBUS-TBNA Kingdom, 6Health Economics Research Group,
procedure. . All patients with EBUS-TBNA from Brunel University/United Kingdom
station 4 R, 4L and 7 without cancer cells og a
speciÀc diagnose were further referred for a VATS/ Abstract under Embargo - will be presented in a
thoracotomy press conference during WCLC 2011.
Results: A total of 76 out of 95 consecutive patients,
48 males, 28 females were enrolled. Mean age 65
years (range 40-85). The mean sizes of the lymph Nodal Staging by Ultrasound Endoscopy and Alternative Image
nodes in all 3 stations were 9mm (range 2 - 35mm). Guided Diagnosis Wednesday, 6 July 2011 14:30-16:00
The Ànal primary diagnosis was cancer in 67 patients
and benign diagnoses in 8 patients . In 4 patients O34.05 IN VIVO MICROSCOPIC
mediastinal metastases were found by surgery (5%). IMAGING OF THE BRONCHIAL
One patient had a metastasis in station 4 R and 2 MUCOSA USING AN ENDO-CYTOSCOPY
patients in station 5 and one patient in station 6. The SYSTEM
NPV was 0.95 and with a speciÀcity of 1 Kiyoshi Shibuya1, Nao Okada1, Hiromasa Kohno1,
In total the false negative rate of EBUS-TBNA in Naomichi Iwai1, Masahiro Noro2, Bunshiro Akikusa2,
mediastinal staging of lung cancer was 4 out of 76 Hidehisa Hoshino3, Ichiro Yoshino3
1
(5%). Chest Surgery, Matsudo City Hospital/Japan,
2
Conclusion: The results of the present study seem Pathology, Matsudo City Hospital/Japan, 3General
to challenge mediastinoscopy as the gold standard. Thoracic Surgery, Chiba University/Japan
When EBUS-TBNA is performed under the same
standardised conditions as described by the ESTS Background: We investigated the capabilities of
guidelines for mediastinoscopy with demonstration an Endo-Cytoscopy system (ECS) that enables
of lymphatic tissue from relevant lymph node microscopic imaging of the tracheobronchial tree
during bronchoscopy, including normal bronchial Nodal Staging by Ultrasound Endoscopy and Alternative Image
epithelium, dysplastic mucosa and hilar lung cancer. Guided Diagnosis Wednesday, 6 July 2011 14:30-16:00
Methods: The newly developed integrated-type
ECS for the bronchoscope has a built-in two O34.06 REAL-TIME IMAGE GUIDANCE
imaging system with a conventional mode and a OF BRONCHOSCOPIC PROCEDURES
high-power endocytoscopic mode. ECS has a high USING X-RAY FLUOROSCOPY AND
magniÀcation of 570 X. Forty-two patients with 11 EBUS FOR PERIPHERAL PULMONARY
hilar lung cancer, 7 abnormal sputum cytology,21 LESIONS
follow up squamous dysplasia, and 3 after Ye Xu1, Mingying Zeng2, Di Xu3, Sheng Xu4, Rex C.
photodynamic therapy were entered into the study Yung2
1
and underwent white light, narrow band imaging and Clinical Informatics, Interventional, And
autoÁuorescence imaging bronchoscopy. Both the Translational Solutions, Philips Research North
abnormal area of interest and surrounding normal America/United States Of America, 2Pulmonary
bronchial mucosa were stained with 0.5% methylene And Critical Care Medicine, Johns Hopkins
blue and examined with ECS. Histological University School Of Medicine/United States Of
examinations with haematoxylin and eosin stain America, 3Department Of Biomedical Engineering,
were performed using the biopsied specimens. The Johns Hopkins University School Of Engineering/
ECS imaging was analyzed and correlated with the United States Of America, 4Clinical Informatics,
corresponding histological examination. Interventional And Translational Solutions, Philips
Results: ECS imaging could distinguish between Research North America/United States Of America
different types of bronchial epithelium including
normal bronchial mucosa, squamous dysplasia, and Background: In bronchoscopic procedures, it is
hilar lung cancer. Of 16 pathological diagnosed difÀcult to navigate the bronchoscope to peripheral
dysplastic lesions, superÀcial cells with rounded lesions due to the limited local view of the
nuclei and abundant cytoplasm were visible in bronchoscope. In addition, the airways to peripheral
13 lesions. Of 13 pathological diagnosed hilar targets are often too small for the bronchoscope to
lung cancers, polygonal or ovoid malignant tumor reach. X-ray Áuoroscopy can provide intra-operative
cells were observed in 11 lesions. Squamous image feedback of the biopsy instruments even for
dysplasia and hilar lung cancer were predictive with the regions beyond the reach of the bronchoscope,
sensitivity of 81.3% (13/16) and 84.6% (11/13) facilitating global navigation to peripheral targets.
and speciÀcity of 100 %( 13/13), respectively. Radial Endobronchial Ultrasound (EBUS) can
characterize the tissue beyond the airway walls
and is often used as a local conÀrmation before
biopsy samples are obtained. This paper reports the
effectiveness of using real-time image guidance
of X-ray Áuoroscopy and EBUS in bronchoscopy
procedures to peripheral targets.
Methods: 323 brochoscopic procedures were
performed by one bronchoscopist (RY) at the Johns
Hopkins Hospital from Jan 2009 to Dec 2010.
97 of the 323 procedures involved at least one
Conclusion: This novel technology has an excellent peripheral pulmonary lesion (PPL) and these were
potential to provide in vivo diagnosis during selected for further analysis under the approval of
bronchoscopic examinations. the Johns Hopkins University Institutional Review
Board. Radial EBUS and/or X-ray were selected
for real-time image guidance based on the need of
the procedures, and rapid on-site cytopathologic
examination (ROSE) was used in all procedures.
The tissue samples underwent pathologic
examination and the results were compared with the
Ànal diagnosis according to additional follow up
examination.
Results: In the 97 cases with peripheral targets, a total approaches to biopsy of peripheral pulmonary
of 158 PPLs were sampled. Lesion size distribution lesions (PPL). SpeciÀc clinicoradiologic features
was <10 mm (n=32), 10–20 mm (n=51), 21–30 mm may guide choice of initial investigation, though
(n=36), and >30 mm (n=39). X-ray and EBUS usage in many patients therefore the optimal method of
was as follows: 62 procedures involved both X-ray investigation is not clear.
and EBUS; 7 procedures involved X-ray only; 18 Methods: We performed a prospective randomized
procedures involved only EBUS; and 10 cases involved pragmatic trial to determine the comparative
neither. Final diagnosis of the 97 procedures resulted effectiveness of endobronchial ultrasound-guided
in 56 cases of cancer, 35 of speciÀc benign pathology, transbronchial lung biopsy (EBUS-TBLB) and
and 6 of non-diagnostic pathology. Overall diagnostic CT-guided percutaneous needle biopsy (CT-PNB)
yield was 94%, and the diagnostic yield was 84%, 91%, for the investigation of PPL in patients in whom
95% and 100% for PPL<10mm, 10-20mm, 21-30mm, clinicoradiologic features could not determine the
and >30mm respectively. All cancer and speciÀc optimal investigation. Consecutive patients referred
benign cases were correctly diagnosed, with the only for evaluation of PPL were randomized to undergo
bronchoscopic non-diagnostic Àndings being the same either procedure. Primary outcomes examined were
6 cases that were non-diagnostic on follow up as well. diagnostic accuracy and complication rates.
Of the 6 cases nondiagnosed by bronchoscopy, 5 used Results: 358 patients were referred to our service
X-ray and EBUS, and 1 used EBUS-only. for initial evaluation of PPL during the study period.
Conclusion: In this cohort of 97 patients with 71 were eligible for inclusion and 51 (72%) of these
peripheral lesions, the bronchoscopist chose to use were randomized. No signiÀcant difference between
real-time imaging from X-ray or EBUS in 90% of EBUS-TBLB and CT-PNB in diagnostic accuracy
cases, resulting in a diagnostic yield of 94%. Other was seen (87.5% (95%CI 71–96) v. 93.3% (95%CI
authors have reported diagnostic yields of 35%, 61.4%, 68–99) respectively, p=1.0). Overall complication
and 94.7% for PPLs <=10, 10-20, and >20 mm, rates were higher in those undergoing CT-PNB
respectively, using X-ray guidance alone; and 29.7% (27% v 3%, p=0.03). Diagnostic yield in patients
and 75.6% for PPLs <=20 and >20 mm, respectively, undergoing EBUS-TBLB was higher in patients with
using EBUS guidance alone. Although this is a pilot lung cancer (p=0.025).
study conducted at a single institution, the high Conclusion: Diagnostic accuracy of EBUS-TBLB
diagnostic yield, especially in comparison to historical in evaluation of PPL is non-inferior to CT-PNB.
data, suggests a navigational beneÀt of using both Complication rates following EBUS-TBLB are
real-time imaging modalities when targeting peripheral signiÀcantly lower than following CT-PNB. SpeciÀc
lesions that are not directly visible in the bronchoscope. complex clinicoradiologic factors will inÁuence
Keywords: Bronchoscopic procedure, X-ray the cost-beneÀt analysis between EBUS-TBLB and
Áuoroscopic guidance, EBUS, peripheral pulmonary CT-PNB for individual patients. Further studies are
lesions required to examine the effect of these factors on
clinical decision-making.
Keywords: Non-inferiority, Pneumothorax,
Nodal Staging by Ultrasound Endoscopy and Alternative Image Diagnostic accuracy
Guided Diagnosis Wednesday, 6 July 2011 14:30-16:00
O34.07 COMPARATIVE EFFECTIVENESS

OF RADIAL PROBE ENDOBRONCHIAL
ULTRASOUND VERSUS CT-GUIDED
NEEDLE BIOPSY FOR EVALUATION OF
PERIPHERAL PULMONARY LESIONS: A
RANDOMIZED PRAGMATIC TRIAL
Daniel P. Steinfort1, Stefan Heinze2, Janette Vincent2,
Phillip Antippa2, Louis Irving1
1
Respiratory Medicine, Royal Melbourne Hospital/
Australia, 2Royal Melbourne Hospital/Australia
Background: No studies have previously compared
Session O35: Radiation Oncology II tumor was too extensive for radical RT. Overall
survival (OS) and alteration of RT treatment planning
Thursday, 7 July 2011 volume were secondary outcomes. The radiation
target volumes were deÀned in the treatment protocol
and included the primary tumor, ipsilateral hilar and
Radiation Oncology II Thursday, 7 July 2011 12:30-14:00 mediastinal nodes according to the location of the
primary. Any biopsy proven mediastinal node, nodes
O35.01 AN ONTARIO CLINICAL 1 cm and any Áuorodeoxyglucose (FDG) avid
ONCOLOGY GROUP (OCOG) nodes were included in the target volume.
RANDOMIZED TRIAL (PET START) Results: Overall 310 patients were randomized, 152
OF FDG PET/CT IN PATIENTS WITH to the PET/CT and 158 to standard CT planning. 118
STAGE 3 NON-SMALL CELL LUNG (78%) of the 152 patients randomized to the PET/CT
CANCER (NSCLC): IMPACT OF PET ON arm received radical RT compared with 146 (92%)
RADIATION TREATMENT VOLUMES of the 158 CT patients. The median follow-up was
Yee C. Ung1, Chu-Shu Gu2, Kathryn Cline3, 17 months. With regards to the primary outcome, 26
Alexander Sun4, Robert Macrae5, Jim Wright6, patients were unsuitable for CMT: 22 in the PET/CT
Edward Yu7, Lisa Ehrlich8, Karen Gulenchyn3, Harry arm and 4 in the CT arm. Thus, 22 of 152 (14.5%)
Shulman8, Ian Dayes6, Bindi Dhesy-Thind9, Gail in the PET/CT arm achieved the primary outcome
Darling10, Natasha Leighl11, William K. Evans12, Jim compared with 4 of 158 (2.5%) patients in the CT
Julian3, Mark Levine9 arm, P= 0.00014. The 2-year OS of the PET/CT
1
Radiation Oncology, Sunnybrook Odette Cancer group was 47% compared with 39% for the CT arm
Centre/Canada, 2Ontario Clinical Oncology Group, (hazard ratio [HR] = 0.8; 95% conÀdence interval
Mcmaster University/Canada, 3Mcmaster University/ [CI]: 0.6 - 1.0). The overall recurrence rate was
Canada, 4Department Of Radiation Oncology, 59/118 (50%) in the PET/CT arm compared with
Princess Margaret Hospital/Canada, 5Radiation 92/146 (63%) in the CT arm. InÀeld recurrences
Oncology, The Ottawa Hospital Cancer Center/ were similar in the PET/CT (16/59 or 27.1%) and
Canada, 6Radiation Oncology - Oncology, Juravinski CT (22/92 or 23.9%) arm. Outside of radiation Àeld
Cancer Center - Mcmaster University/Canada, recurrences were also similar in the PET/CT (37/59
7
Radiation Oncology, London Regional Cancer or 62.7%) and CT (61/92 or 66.3%) arm. The RT
Program/Canada, 8Sunnybrook Health Sciences parameters evaluated included the planning target
Centre/Canada, 9Medical Oncology, Juravinski volume (PTV), maximum spinal cord dose, volume
Cancer Centre/Canada, 10Dept. Of Surgery, Toronto of heart receiving 40 Gy and the total volume of
General Hospital/Canada, 11Medical Oncology, lung minus the PTV receiving 20 Gy. There were
University Health Network/Princess Margaret no signiÀcant differences in any of these parameters
Hospital/Canada, 12Administration, Juravinski in the PET/CT or CT arm.
Cancer Centre/Canada Conclusion: The PET START trial is the Àrst
randomized trial comparing PET/CT planning with
Background: Patients with stage 3 non-small standard CT planning in patients with NSCLC.
cell lung cancer (NSCLC) are potentially curable As expected, the use of PET/CT resulted in fewer
using combined modality therapy (CMT) with patients receiving radical RT. The OS trend favoring
chemotherapy and radical radiation therapy (RT). PET/CT may be primarily due to more accurate
PET/CT imaging is commonly used to stage patients staging. There were no differences in the two arms in
with NSCLC. In addition, PET/CT for planning the radiation treatment parameters but this trial did
of RT may improve the deÀnition of RT treatment not compare targeting only FDG avid areas on PET/
volumes compared with conventional CT planning CT versus CT abnormalities only.
and thus improve outcomes. Keywords: PET CT, Radiation Planning, Lung
Methods: Patients with stage 3 NSCLC, who were cancer
considered candidates for CMT, were randomized
to either PET/CT or CT alone for RT treatment
planning. The primary outcome was the proportion
of patients who did not receive CMT because their
tumor was upstaged to stage 4 or their intrathoracic
Radiation Oncology II Thursday, 7 July 2011 12:30-14:00 for survival, as did tumor size < 3 cm. Survival
according to tumor size is shown in the table:
O35.02 THE EFFECT OF TUMOR SIZE
ON PROGNOSIS IN PATIENTS TREATED Multivariate
Univariate
WITH RADICAL RADIOTHERAPY (adjusting for other factors)
OR CHEMORADIOTHERAPY FOR 5 yr P-value
Median (%) (vs Hazard P-value
NON-SMALL CELL LUNG CANCER IN
(yrs) previous ratio (vs previous level)
THE IASLC LUNG CANCER STAGING Size (cm) level)
PROJECT DATABASE. <= 3 1.8 16.9
David Ball1, Alan Mitchell2, Dori Giroux2, Ramon > 3 & <= 5 1.3 12.9 0.008 1.249 0.0223
Rami-Porta3 > 5 & <= 7 1.4 16.3 0.625 0.973 0.9333
1
Radiation Oncology, Peter MacCallum Cancer >7 1.1 10.2 0.105 1.178 0.1681
Centre/Australia, 2Cancer Research And
Biostatistics/United States Of America, 3Matua Conclusion: In patients treated with radiotherapy
Terrassa University Hospital/Spain with or without chemotherapy, tumor size < 3 cm
was associated with better survival than larger
Background: Analysis of the IASLC database tumors. Evidence for an effect of size on prognosis
revealed that for patients with completely resected above this was weak. Five year survival >10% was
node negative NSCLC, increasing tumor size was observed in all four size categories.
associated with worsening survival (Rami-Porta Keywords: Non-small cell lung cancer, Staging,
et al, J Thor Oncol 2007; 2:593). This analysis Radiotherapy
was performed to determine the effect of size
on prognosis in patients in the same database
but who were treated with radiotherapy or Radiation Oncology II Thursday, 7 July 2011 12:30-14:00
chemoradiotherapy.
Methods: Patients were eligible if they had O35.03 BOOSTING A SUB-VOLUME
pathologically conÀrmed NSCLC; no evidence WITHIN THE PRIMARY TUMOR ON
of distant metastases; intended treatment radical THE BASIS OF FDG UPTAKE: RESULTS
radiotherapy (minimum 50 Gy) or combined OF TREATMENT PLANNING IN AN
chemotherapy and radiotherapy; no surgery; and ONGOING RANDOMIZED PHASE II
tumour diameter was available. Survival was TRIAL (PET BOOST TRIAL)
estimated using the Kaplan-Meier method and Anke Van Der Salm1, Wouter Van Elmpt1, Eugène
comparisons using the logrank test. Univariate and Damen2, Annemarie Lakeman2, Judith Van Der
multivariate Cox regression was used to model the Stoep1, Daisy Emans1, Michel Öllers1, Jan Jakob
effect of primary tumor size and other prognostic Sonke2, José Belderbos2, Dirk De Ruysscher1
1
factors on survival. Department Of Radiation Oncology (MAASTRO),
Results: 868 patients were available for analysis. Grow, Maastricht University Medical Centre/
Patient characteristics: male sex 65.3%; median age Netherlands, 2Department Of Radiation Oncology,
64 years (range 32-88); ECOG performance status The Netherlands Cancer Institute - Antoni Van
0 - 55%, 1 – 33%, >2 – 5%; chemotherapy 74%, no Leeuwenhoek Hospital/Netherlands
chemotherapy 18%; weight loss < 5 % -70%, >5%
- 25%; clinical N stage N0 – 18%, N1 – 5%, N2 – Background: Improving local control increases
63%, N3 – 14%. Primary tumor size (based on TNM survival in stage II/III NSCLC patients. We and
7th edition): <3 cm – 27%, >3 and < 5 cm – 34%, > others have shown that the site of relapse is mostly
5 and < 7cm – 20%, > 7 cm – 19%. On univariate located in the high FDG-uptake region within the
analysis, the following factors were prognostic for primary tumor prior to treatment. We recently
survival: age (continuous) (P=0.0035), performance embarked on a randomized phase II trial where
status > 1 (P=0.0021), weight loss <5% (P<0.0001), patients are randomized between receiving a dose-
chemotherapy (P=0.0189) and primary tumor size escalation of the entire primary tumour (Arm A) or
(continuous) (P=0.0002). Sex and clinical nodal to the high FDG-uptake region (50% maximum SUV
stage were not signiÀcant. On multivariate analysis, volume) inside the primary tumour (Arm B). Both
age and weight loss remained signiÀcant factors arms are escalated up to predeÀned normal tissue
constraints using IMRT. Here we present detailed risk was the large vessels in the mediastinum.
results of the treatment planning strategy of the Àrst Keywords: FDG-PET imaging, treatment planning,
15 patients. sub volume boosting, dose-escalation
Methods: The PET Boost Trial (NCT01024829)
registered 15 patients on February 1, 2011. During
treatment planning, Arm A and Arm B are planned. Radiation Oncology II Thursday, 7 July 2011 12:30-14:00
Radiotherapy dose to the primary tumour and the
involved hilar and mediastinal lymph nodes is 66 Gy O35.04 DETAILED ANALYSIS OF TUMOR
in 24 daily fractions of 2.75 Gy with an integrated REGRESSION DURING RADICAL
boost to the whole primary tumour (arm A) or the RADIOTHERAPY IN LUNG CANCER
region within the primary tumor with an uptake PATIENTS
>50% of the maximum SUV inside the primary Eva E. Schaake1, José Belderbos2, Simon Rit2, Simon
tumour (arm B). In case of overlap between target Van Kranen2, Suzanne Van Beek2, H J. Teerstra3, Jan
and organs-at-risk (OAR), 15% of the primary Jakob Sonke2
1
tumour PTV may be underdosed to the dose- Thoracic Oncology, NKI-AVL/Netherlands,
2
constraint value of the appropriate organ-at-risk. The Radiotherapy, NKI-AVL /Netherlands, 3Radiology,
lung toxicity parameter Mean Lung Dose (MLD) is NKI-AVL /Netherlands
forced equal in both arms by downscaling the arm
with the highest MLD to the other arm, thus ensuring Background: In patients with inoperable, locally
the same chance to develop lung toxicity in both advanced lung cancer high dose radiotherapy is
arms (iso-toxic trial design). The biological corrected the treatment of choice. Despite new techniques
dose-constraint to lung is: MLD20 Gy. Other dose- local control could be improved in these patients.
constraints: esophagus (V35<80%), spinal cord Tumor regression during the 5-6 weeks course of
(max. 52 Gy), brachial plexus (max. 66 Gy), heart irradiation is frequently observed. This raises the
(mean dose<46 Gy) and the mediastinal structures clinical question whether the treatment plan should
(max. 94 Gy) All constraints are in biologically be adapted to the regressing tumor during the course
equivalent dose (EQD2). Patients are randomized of irradiation. Using cone-beam CT (CBCT) images,
between arm A and B if the dose-escalation of the tumor regression patterns were studied to assess
primary tumour in arm A is at least 72 Gy. if treatment volumes could be adapted during the
Results: Twelve out of 15 patients could be planned treatment course
randomized (i.e. receive a dose of at least 72 Gy in Methods: Tumor volume change was analyzed in
24 fractions). The average ratio between the volume 114 consecutive lung cancer patients during the
of the entire primary tumour (GTV) and the 50% course of high dose radiotherapy (mainly 17x3
maximum SUV volume was: 35±14%. Average or 24x2,75 gray). Patient characteristics, volume
prescribed dose-values were 77.8 Gy (3.24 Gy/ change and pathological characteristics were
fraction) [range: 72.2 – 102.7 Gy; 3.01 – 4.28 Gy/ compared. The process of tumor regression during
fraction] and 88.1 Gy (3.67 Gy/fraction) [range: the 5-6 weeks course of radiotherapy was analyzed
76.8 – 129.6 Gy; 3.20 – 5.40 Gy/fraction] for arm A on the basis of visual tumor regression on CBCT.
and B, resp. Average mean dose inside the primary The CBCT scans were made three times during
tumour was comparable: 76.7 vs. 76.5 Gy for arm A the Àrst week en weekly thereafter. In patients
vs. B, resp. The MLD was comparable (as forced by with >30% tumor regression, two types of tumor
iso-toxic design): A vs. B: 15.7 Gy vs. 15.5 Gy. Most regression were distinguished: 1) Elastic, in which
frequent observed dose-limiting constraints were surrounding tissue moves along with the shrinking
the mediastinal structures (11/12) and the brachial tumor. 2) Non-elastic tumor regression in which
plexus (3/12). the surrounding tissue remains at the same location
Conclusion: Selective dose-escalation using IMRT while the tumor shrinks.
planning with an integrated boost could be achieved Results: Of the 114 patients that were analyzed,
while keeping the dose-constraints to the organs 65 were male. Eighty-nine patients with a NSCLC
at risk at safe levels. This integrated boost to the tumor, 13 with a SCLC tumor and 12 patients
primary tumour or the high FDG-uptake region without a histologically conÀrmed diagnose
was feasible up to 77.8 and 88.1 Gy (24 fractions), were included, 75% of the patients were treated
respectively. The most frequently limiting organ-at- with either induction chemotherapy followed by
radiotherapy (34%) or concurrent chemoradiotherapy Oncology, University Of North Carolina/United

(41%). Tumor regression during treatment was found States Of America, 3Division Of Hematology/
in 52 patients (46%), while 4 patients had tumor oncology, University Of North Carolina/United
progression. The average volume decrease was 33% States Of America
observed in these patients. Tumor regression analysis
in 27 patients showed four patients (15%) with Background: For patients with advanced stage
elastic tumor regression, nine (33%) with non-elastic IIIB/IV NSCLC and good performance status,
tumor regression, and 14 (52%) with a combination palliative thoracic radiotherapy is typically reserved
of both types of regression. The different tumor for patients with symptomatic disease or for those
regression types are illustrated in the Figure. with obstructing central disease leading to collapsed
lung. The aim of this study is to identify clinical and
radiographic factors found early in a patient’s course
that predict for the subsequent need for palliative
radiotherapy or collapsed lobes.
Methods: We conducted a pooled analysis of 11
prospective phase II and III clinical trials involving
Àrst line, platinum-based chemotherapy. Baseline
clinical and radiographic characteristics identiÀed
before trial enrollment were analyzed as possible
factors for subsequent pulmonary events (deÀned as
either a course of palliative thoracic radiotherapy or
a new subsequent collapased lobe).
Results: 318 consecutive patients who enrolled at
a single institution were studied; 2 were excluded
with no follow-up information available. 48
patients received a palliative course of thoracic
Conclusion: Detailed analysis of tumor regression radiation and 50 exhibited evidence a new lobar
was performed using repeat CBCT scans acquired collapse on follow-up chest imaging. On univariate
over the course of irradiation. Tumor regression analysis by log-rank test, pulmonary symptoms
occurs during the 5-6 weeks of curative radiotherapy at presentation (p=0.032), pre-chemotherapy
in about half of the patients occurred relatively diagnosis of pneumonia (p<0.001), increasing
late. Partial response was seen right at the end size of hilar disease (p<0.001), and evidence of
of treatment in 24% of the patients. With elastic obstruction of major bronchi or vessels on pre-
regression it is potentially safe to adapt the treatment chemotherapy CT (p=0.001) were associated with
plan as healthy tissue moves into the high dose subsequent pulmonary events. On multivariate
region. True elastic regression, however, was rarely analysis by Cox proportional hazards regression,
observed. hilar disease >3cm in size (HR 1.6, p=0.007) and
Keywords: Tumor regression, adaptive treatment, pre-chemotherapy pneumonia (HR 2.1, p<0.001)
cone beam CT scan were associated with pulmonary events. Those with
both risk factors or hilar disease >5cm exhibitied
>50% risk of pulmonary events. These high risk
Radiation Oncology II Thursday, 7 July 2011 12:30-14:00 groups for pulmonary events were also associated
with diminshed overall survival (p<0.001).
O35.06 PREDICTING THE NEED
FOR PALLIATIVE THORACIC
RADIOTHERAPY FOR ADVANCED NON-
SMALL CELL CARCINOMA
Daniel S. Higginson1, Ronald C. Chen1, Jan Halle2,
David E. Morris1, Mark A. Socinski3, Lawrence B.
Marks1
1
Radiation Oncology, University Of North Carolina/
United States Of America, 2Department Of Radiation
Conclusion: Patients with bulky hilar diseaes and (MAR-LC) was preformed.
a history of pneumonia at presentation exhibit Methods: This updated individual patient data
a high risk for subsequent lung collapse and meta-analysis was restricted to patients with non
palliative thoracic radiation after Àrst line platinum metastatic lung cancer and included randomized
chemotherapy. We propose that these patients may trials comparing modiÀed radiotherapy (accelerated,
be studied to determine if early thoracic radiation, hyperfractionated or both) to conventional
administered before severe pulmonary symptoms radiotherapy (one 1.8- to 2-Gy fraction per day, 5
arise, could be beneÀcial to preserve quality of life days a week and a minimum total dose of 40 Gy for
and performance status. small cell lung cancer -SCLC- and 60 Gy for non-
Keywords: RADIATION, palliative thoracic small cell lung cancer –NSCLC). Data were centrally
radiation, stage IV non-small cell lung cancer collected and checked. Trials were combined using
the stratiÀed (by trial) log rank test to calculate
pooled hazard ratio (HR). Overall survival (OS),
Radiation Oncology II Thursday, 7 July 2011 12:30-14:00 deÀned as the time from randomization to death from
any cause, was the main endpoint.
O35.07 EVALUATION OF MODIFIED Results: Among the twelve trials identiÀed,
FRACTIONATION RADIOTHERAPY two were excluded due to lost data. Two trials
EFFECT IN NON METASTATIC LUNG with concurrent chemotherapy were split into
CANCER: AN UPDATED INDIVIDUAL two separate trials each (with and without
PATIENTS DATA META-ANALYSIS ON chemotherapy), allowed by the factorial design (for
10 RANDOMIZED TRIALS AND 2685 concomitant chemotherapy) and the stratiÀcation
PATIENTS design (adjuvant chemotherapy) used. Finally,
Cécile Le Péchoux1, Audrey Mauguen2, Michael twelve trials were analyzed including 2685 patients.
Baumann3, Steven E. Schild4, Mahesh Parmar5, In NSCLC (10 trials, 2000 patients, 1849 deaths
Andrew T. Turrisi6, William Sause7, David with a median follow-up of 6.9 years), modiÀed
Ball8, Chandra P. Belani9, Katarzyna Behrendt10, fractionation improved OS as compared to
Jean-Pierre Pignon On Behalf On The Mar-lc conventional radiotherapy (hazards ratio HR=0.88,
Collaborative Group2 95% conÀdence interval [0.80-0.97], p=0.009),
1
Radiotherapy Unit, Institut Gustave Roussy/France, resulting in an absolute beneÀt of 3% at 5 years
2
Service De Biostatistique, Institut Gustave Roussy/ (from 8% to 11%). No heterogeneity between trials
France, 3University Hospital And Medical Faculty was found and no subgroup of patients beneÀted
Carl Gustav Carus Dresden/Germany, 4Radiation more or less from modiÀed RT. Similar beneÀt was
Oncology, Mayo Clinic/United States Of America, found on lung cancer deaths (HR=0.89 [0.81-0.98],
5
Clinical Trial Unit London, Medical Research p=0.02) and on non-lung cancer deaths even if
Council/United Kingdom, 6Radiation Oncology not signiÀcant (HR=0.87 [0.66-1.15], p=0.33). No
Center, Sinai Grace Hospital/United States Of signiÀcant effect of modiÀed fractionation was found
America, 7Intermountain Medical Center/United on the progression-free survival (PFS, HR=0.94
States Of America, 8Radiation Oncology, Peter [0.86-1.03], p=0.19). In SCLC (2 trials, 685 patients,
MacCallum Cancer Centre/Australia, 9Medicine, 622 deaths with a median follow-up of 12.1 years),
Penn State Hershey Cancer Institute/United States equivalent results were found but non signiÀcant
Of America, 10Maria Skãadowska-curie Memorial (OS: HR=0.87 [0.74-1.02], p=0.08; PFS: HR=0.88
Cancer Center And Institute Of Oncology, Gliwice [0.75-1.03], p=0.11). In both histological types, the
Branch/Poland use of modiÀed radiotherapy was associated with
an increased risk of acute esophageal toxicity (304
Background: There have been numerous debates events, OR=2.4 [1.9-3.1] in NSCLC and 123 events,
regarding altered fractionation in radiotherapy OR=2.4 [1.6-3.6] in SCLC; p<0.001) and in SCLC,
for lung cancer. Randomized trials assessing an increased acute cardiac toxicity (17 events,
hyperfractionated or accelerated radiotherapy OR=3.0 [1.1-7.7], p=0.03). No association was found
yielded conÁicting results for both progression-free with acute hematological or pulmonary toxicity.
survival and overall survival. To distinguish between Conclusion: Accelerated or hyperfractionated
inefÀciency of treatment and moderate effect, the radiotherapy is beneÀcial to patients with non-
Meta-Analysis of Radiotherapy in Lung Cancer metastatic lung cancer, in NSCLC as well as in
SCLC. This beneÀt was mainly associated to an carcinomas, and three atypical adenomatous
increased, but expected, risk of acute esophageal hyperplasias. A total of 373 patients (93%) were
toxicity. Supported by PHRC, LNCC, SanoÀ- pN0, 15 (4%) pN1, 8 (2%) pN2, and 3 (1%) pN3.
Aventis. No nodal involvement was observed in any of
Keywords: meta-analysis, modiÀed fractionation the 136 patients with G100 or G75, in 4 out of
radiotherapy, randomized trials 103 patients (4%) with G25, and in 22 out of 160
patients (14%) with G0. No vessel invasion was
observed in any of the 49 patients with G100, in
Session O36: Surgery - Treatment 2 out of 87 patients (2%) with G75, in 11 out of
Proposals 103 patients (11%) with G25, and in 85 out of 160
patients (53%) with G0. Pulmonary metastasis to
the same lobe is detected in 4 patients (3%) with
G0. No visceral pleural involvement (PL0) was
observed in G100 and G75, however, that was
Surgery - Treatment Proposals Thursday, 7 July 2011 12:30-14:00 observed (PL1<) in 7 (5%) with G25 and in 34
(21%) with G0. SUV was over 1.62 in 26 patients
O36.01 GGO RATIO ON HRCT AND SUV with lymph node metastasis, vessel invasion,
BY PET INDICATE LIMITED SURGERY or pulmonary metastasis. It was suggested that
FOR CT1AN0M0 NON-SMALL-CELL limited operation should be indicated by individual
LUNG CANCER tumor character due to percentage of GGO area
Hiroshi Niwa, Masayuki Tanahashi, Haruhiro and SUV by PET. G100 is good indication for
Yukiue, Eriko Suzuki, Hiroshi Haneda, Naoko Yoshii partial resection or segmental resection depending
Thoracic Surgery, Seirei Mikatahara General on tumor location. Although there is no node
Hospital/Japan metastasis in G75, possibility of vessel invasion
recommends segmentectomy with pathological
Background: Many patients with cT1aN0M0 certiÀcation of no nodal metastasis. Limited
non-small-cell lung cancer (NSCLC) are expected resection for G0 and G25 should be avoided;
good prognosis after surgery. Especially presence however, a few tumors with SUV 1.5 or less
of GGO on HRCT and low FDG uptake of the will be an indication for segmentectomy. Sixty-
tumor measured by standardized uptake value seven (G100:34, G75:30, G25 and G0:3) patients
(SUV) by positron emission tomography (PET) underwent limited pulmonary resection due to this
are good prognostic factors. Standard lobectomy indication. No recurrence is observed and 5-year
with lymphadenectomy is not always required survival is 100%.
for those patients predicted good prognosis. If we Conclusion: Since GGO ratio on HRCT and
select those patients before surgery, both pulmonary SUV by PET well reÁect malignant potential of
functional preservation and good prognosis are cT1aN0M0 NSCLC, limited surgery based on
obtained by limited resection. HRCT and PET promise functional preservation
Methods: We retrospectively analyzed 399 patients and good prognosis.
with cT1aN0M0 NSCLC. All patients were staged Keywords: GGO, SUV, limited surgery, T1aN0M0
as cT1aN0M0 by HRCT and/or PET and underwent
pulmonary resection. Our data were collected
based on preoperative GGO ratio (percentage of
GGO area in the lesion) on the basis of HRCT
and FDG uptake of the tumor measured by SUV
and pathological nodal status, vessel invasion,
pulmonary metastasis in the same lobe, and visceral
pleural involvement. Patients were separated in 4
groups by the GGO ratio (G); G=100% (pure GGO,
G100), 50%<G<100% (G75), 0%<G<=50% (G25),
G=0% (solid, G0).
Results: There were 353 adenocarcinomas, 39
squamous cell carcinomas, four adenosquamou
Surgery - Treatment Proposals Thursday, 7 July 2011 12:30-14:00 operative complications and the operative mortality
was 0.97%. CK19 mRNA positive expression in
O36.02 LONG-TERM SURVIVAL peripheral blood was found in 141 patients. The
OF PERSONALIZED SURGICAL positive rate of CK19 mRNA positive expression
TREATMENT FOR LOCALLY was 27.3% in peripheral blood samples in the
ADVANCED NON-SMALL CELL LUNG 516 cases. The positive rates of micrometastasis
CANCER BASED ON MOLECULAR in peripheral blood was signiÀcantly related to
STAGING histological classiÀcation, P-TNM staging and N
Qinghua Zhou1, Jun Chen2, Daxing Zhu2 staging of the cancer (P<0.05), but not to age, sex,
1
Tianjin Lung Cancer Institute, Tianjin Medical smoking status of the patients, and size of primary
University General Hospital/China, 2Tianjin Medical tumor, and locations of the tumor (P>0.05). The
University General Hospital/China median survival time was 43.74 months. The 1, 3,
5 and 10 year survival rates of the 516 cases was
Background: Approximately 35%-40% of 89.1%, 39.3%, 19.8% and 10.4%, respectively. The
patients with newly diagnosed non-small cell 1,3,5 and 10 year survival rates in patents without
Lung cancer have locally advanced disease. The and with micrometastasis was 94.8%,56.6%,38.9%
average survival time of these patients only have and 14.5%, and 84.6%, 9.7%, 0.5% and 0%
6-8 months with chemotherapy.The aim of this respectively. The postoperative survival rate was
study is to explore and summarize the probability remarkably correlated with micrometastasis,
of detection of micrometastasis in peripheral histological classiÀ- cation and size of primary
blood for molecular staging, and for selection of cancer and LN metastasis (P<0.05). Multivariable
indication of surgical treatment, and beneÀciary Cox model analysis showed that “personalized
of neoadjuvant chemotherapy and postoperative molecular P-TNM staging”, micrometastasis in
adjuvant therapy in locally advanced non-small cell peripheral blood, pathological types of the tumor
lung cancer(LANSCLC); to summarize the long- and mediastinal lymph node metastasis of the cancer
time survival result of personalized surgicaltreatment were the most signiÀcant factors for predicting
of 516 patients with LANSCLC based on molecular prognosis in the patients with LANSCLC.
staging methods. Conclusion: Detecting of CK19 mRNA expression
Methods: CK19 mRNA expression of peripheral in peripheral blood will be helpful for selection of
blood samples was detected in 516 LANSCLC surgical treatment indication, the beneÀciary of
patients by RT-PCR before operation for molecular neoadjuvant chemotherapy and postopertive adjuvant
diagnosis of micrometastasis, personalized therapy in LANSCLC patients. Personalized surgical
molecular staging, and for selection of indication of treatment can signiÀcantly improve prognosis and
personalized surgical treatment and the beneÀciary increase curative rate and long-term survival rate of
of neoadjuvant chemotherapy and postoperative LANSCLC based on personalized molecular staging.
adjuvant therapy in patients with LANSCLC Keywords: LANSCLC, molecular staging,
invaded heart, great vessels or both. The long-term personalized surgical treatment, micrometastasis
survival result of personalized surgical treatment was
retrospectively analyzed in the 516 patients based on A revised/updated abstract may be included in
molecular staging methods. the Late Breaking Abstract Supplement, available
Results: There were 322 squamous cell carcinoma at the 14th World Conference on Lung Cancer.
and 194 adenocarcinoma. 112 patients had IIIA
disease and 404 had IIIB disease according to
P-TNM staging. 97 patients had M-IIIA disease,
278 had M-IIIB disease and 141 had M-IV disease
according to molecular staging. Of the 516 patients,
bronchoplastic procedures and pulmonary artery
reconstruction was carried out in 256 cases; double
sleeve lobectomy combined with resection and
reconstruction of partial left atrium, superior vena
cava, carina, aorta and postcava was performed
in 260 cases in this series. Five patients died of
Surgery - Treatment Proposals Thursday, 7 July 2011 12:30-14:00
Lobectomy Limited Resection p-value

O36.03 LIMITED RESECTION OF
155 32
EARLY STAGED LUNG CANCER: A Mean Age (SD) 67 (11) 70 (11) 0.257
RETROSPECTIVE REVIEW OF OUR Male Female 77 (50%) 77 (50%) 13(41%) 19 (59%) 0.437
DATABASE COMPARING LOBAR FEV 0.8 (0.2) 0.7 (0.2) 0.078
RESECTION AND SEGMENTAL AND Smoking Hx 40 (1,122 ) 46 (7,100 ) 0.495
WEDGE RESECTION. PILOT. Median packs
John D. Miller, Yaron Shargall, Christian Finley, M (min, max)
Alabdulmohsin, C Ostrander LOS (days) 7 (3,71 ) 6 (4,55 ) 0.12
Thoracic Surgwery, Mcmaster University/Canada Median (min,
max)
Follow-up 50 (0,93) 43 (1,73 ) 0.109
Background: The Canadian Lung Cancer Study (months) Median
Group (LCSG) published their Àndings comparing (min, max)
lobectomy and segmental resection of early stage Stage IA 70 (45%) 19 (59%) 0.175
lung cancer in 1997. Despite the fact that little or no Stage IB 85 (55%) 13 (41%)
clear survival advantage was demonstrated by the Central 72 (54%) 14 (44%) 0.329
larger resection (lobectomy) the thoracic community Peripheral 61 (46%) 18 (56%)
has not embraced limited resection. Lobectomy <2cm 122 (79%) 20 (62.5%) 0.068
remains the basic standard operation for patients with >2cm 33 (21%) 12 (37.5%)
resectable lung cancer. NCIC-BR5 in association Mean (SD) 3.2 (1.7) 2.4 (1.3) 0.010
with international intergroup study has begun a new Adenocarcinoma 66 (43%) 14 (45%)
randomized controlled trial to evaluate segmental Squamous cell 17 (11%) 1 (3%)
and lobar resections for lung tumours 2cms or less Non-small cell 45 (29%) 11 (36%)
carcinoma
in diameter. This report is a retrospective review of
Carcinoid 7 (5%) 3(10%)
our experience with limited resection over the past
BAC 13 (9%) 0
several years.
Large Cell 3 (2%) 0
Methods: a:Objective: This pilot assessment of
Small Cell 3 (2%) 2 (7%)
long term outcomes will help develop our role and
Local Recurrence 3 (1.9%) 2 (6.3%)
understanding as we prepare to evaluate limited
Distant 41 (27%) 9 (28%)
resection in a multinational RCT (NCIC-BR5). Recurrence
Disease recurrence and disease free and overall With LNs 33 (26%) 7 (37%) 0.651
survival are our primary outcomes. sampled
Methods: b:Source and Statistics:Using the Without LNs 3 (45%) 4 (31%) 0.406
Division of Thoracic Surgery Data base and ofÀce sampled
and hospital charts, consecutive patients who have Recurrence age 22 (31%) 8 (45%) 0.677
>71 yrs
undergone either a lobectomy or lesser resection
Age < 71 yrs 21 (25%) 3 (20%) 0.256
for early staged lung cancer is shown in Table 1.
Recurrence 39 (32%) 6 (30%) 0.861
Survival appears equivalent between groups but tumour >2 cm
lesser resections are associated with more local 2 cm and under 4 (12%) 5 (42%) 0.043
recurrences. A Kaplan-Meier survival analysis Survival 3 years 84.5% (78-90) 73% (57-89) 58% 0.146
was performed comparing the time survived since Survival 5 years 72% (62-81) (35-81)
surgery between the two treatment groups. Disease free 79% (72-86) 70% 68% (51-85) 56% 0.271
Results: The overall survival appeared better in the survival 3years (62-78) (47-70%)
years 5 years
lobectomy group, sample size limits statistically
signiÀcant. Figure Survival rate Figure Disease-free survival rate
Conclusion: These results show a trend toward

increased survival in the lobectomy treated group.
Although safer, as more early deaths occured in the
lobectomy group, segmental resection did not confer
any long term survival beneÀt over lobectomy even
in the smaller tumours (<2cms). Lessor resections p<0.001; DSS not reached vs.136 months, Log
must be saved only for those severely disabled rank p<0.001). Multivariate analysis controlling for
patients who cannot tolerate a bigger operation. The covariates also showed patients with lobectomy had
results of this study encourage us to more fully study better survival {hazard ratio (CI): OS = 0.8(0.72-
the possible advantage of a sub-lobar resection and 0.88); DSS = 0.79 (0.68-0.91)}. Multivariate Cox
the long term outcomes. regression performed on propensity-matched
Keywords: segmental resection, Lung cancer, groups conÀrmed superior survival of patients with
survival lobectomy vs. sub-lobar resection {hazard ratio (CI):
OS = 0.75(0.65-0.85); DSS = 0.71 (0.59-0.85)}.
Surgery - Treatment Proposals Thursday, 7 July 2011 12:30-14:00
O36.05 LOBECTOMY IS SUPERIOR

TO SUBLOBAR RESECTION OF NON-
SMALL CELL LUNG CANCERS LESS
THAN 2 CM. Conclusion: Lobectomy confers a survival beneÀt
Rohit Sharma1, Michael Demmy2, Adrienne for patients with small (< 2 cm) non-small cell lung
Groman3, Mark Hennon4, Elisabeth U. Dexter4, cancers when compared to sublobar resection not
Chukwumere Nwogu4, Todd L. Demmy4, Austin explained by selection bias alone. These observations
Miller3, Sai Yendamuri4 should be veriÀed in a prospective trial.
1
Surgical Oncology, Roswell Park Cancer Institute/ Keywords: Lung cancer, SEER, sub-lobar resection
United States Of America, 2Thoracic Surgery,
Roswell Park Cancer Institute/United States
Of America, 3Division Of Biostatistics, Roswell Surgery - Treatment Proposals Thursday, 7 July 2011 12:30-14:00
Park Cancer Institute/United States Of America,
4
Department Of Thoracic Surgery, Roswell Park O36.06 COMBINED INTERVENTION TO
Cancer Institute/United States Of America IMPROVE PATHOLOGIC STAGING OF
NON-SMALL CELL LUNG CANCER
Background: Extent of resection for stage IA Mathew Ninan
(< 2 cm) non-small cell lung cancers (NSCLCs) is Thoracic Surgery, Sarah Cannon Cancer Center/
controversial. This question was addressed using United States Of America
the Surveillance Epidemiology End Results (SEER)
database. Background: Quality of pathologic staging during
Methods: Patients with a history of one resected lung cancer resection remains poor, as evidenced
stage I NSCLC < 2 cm after 1987 were selected. by multiple studies and quality improvement efforts
Overall survival (OS) and disease speciÀc survival have rarely been documented in the literature. We
(DSS) associated with lobectomy and sublobar aimed to improve pathologic staging of non-small
resection were compared using multivariate cell lung cancer at one tertiary level community
proportional hazards methods controlling for age, hospital and to study the effects on specialist and
gender, race, grade and number of lymph nodes non-specialist thoracic surgeons.
examined (LNE). P values <0.01 were deemed Methods: Surgeons and pathologists were trained
statistically signiÀcant. Analyses were repeated using to conform to National Cancer Center Network
propensity-matched samples. (NCCN) criteria and to College of American
Results: Of 7006 patients that Àt the selection Pathologists (CAP) reporting criteria for curative
criteria, 1701 (24.3%) had sublobar resection. lung cancer resection, respectively. All operating
Univariate analysis showed that patients with a room nursing personnel on multiple teams were
lobectomy had better OS and DSS when compared trained on AJCC lymph nodal map and provided
to sublobar resection (OS 120 m vs. 69 m, Log rank with a specimen list and a pre-labeled, sterile
specimen collection tray. The test group consisted of Surgery - Treatment Proposals Thursday, 7 July 2011 12:30-14:00
all curative NSCLC resections from 1 January 2010
to 30 June 2010 and the same resections performed O36.07 COMPARISON OF SHORT-
from 1 January 2008 to 30 June 2008 formed the TERM OUTCOMES BETWEEN ROBOT-
control group. Quality training was commenced in ASSISTED AND VATS LOBECTOMY FOR
July 2008 and operations were performed by the EARLY STAGE LUNG CANCER
same surgeons in both periods. Data was further Hyun-Sung Lee, Hee-Jin Jang, Seong Yong Park, Jae
analyzed by whether resection was performed by a Ill Zo
specialist thoracic surgeon (GTS) or a cardiothoracic Center For Lung Cancer, National Cancer Center,
surgeon (CTS). Republic Of Korea/Korea
Results: There were 72 resections in the 6 month
period of 2008 (27 GTS and 45 CTS) and 68 Background: Robotic surgery has proven to be one
resections in the six month period of 2010 (30 of the most effective cutting-edge technologies for
GTS and 38 CTS). No signiÀcant differences successful minimally invasive surgery. The approach
existed between groups with respect to age, sex, addresses many drawbacks of thoracoscopic surgery,
histology, resection by surgeon specialty, stage or yet few reports have studied robotic surgery in lung
extent of resection. Operations were performed by cancer. This study aimed to compare the feasibility
1 GTS and 5 CTS. Overall, resections conforming and safety of robotic approach for the treatment of
to NCCN criteria increased from 31 (43%) to early stage lung cancer with VATS lobectomy and
51(75%) (p=0.001), mean number of nodal stations mediastinal lymph node dissection.
evaluated increased from 3.29 to 4.54 (p<0.0001) Methods: From February 2009 to February 2011,
and pathology reports conforming to CAP guidelines one hundred patients underwent robot-assisted
increased from 41(57%) to 63(93%, p<0.0001), lobectomy for clinical stage I or II non-small cell
in 2008 and 2010 respectively. On subgroup lung cancer. The dissection and anatomical isolation
analysis, in 2008, NCCN criteria were fulÀlled in of the hilar structures were performed using two
22(81%) of GTS resections versus 9(20%) of CTS arms or three arms of the Da Vinci S system®.
resections (p<0.0001). This improved to 28(93%) The consecutive 100 patients were compared with
of GTS resections (p=0.1734) and 23(61%) of 100 patients who underwent VATS lobectomy and
CTS resections in 2010. Statistically signiÀcant MLND during the same period. Clinicopathologic
improvement was seen between 2008 and 2010 in characteristics and surgical outcomes were analyzed.
the CTS group for NCCN criteria (20% vs. 61%, Results: Adenocarcinoma was more prominent in
p=0.0002) and for number of lymph nodal stations VATS group than robotic lobectomy group (p=0.04).
(2.31 vs. 3.39, p= 0.001). Tumor size was larger in robot group with 3.2cm in
Conclusion: 1. An intervention inclusive of mean size of tumor. The mean number of harvested
surgeons, pathologists and nurses with use of a pre- lymph nodes was similar in two groups. Robot-
labeled specimen tray improves pathologic staging assisted lobectomy needed longer operation time
of non-small cell lung cancer. 2. There are signiÀcant than VATS group. However, the console time during
differences in resections fulÀlling NCCN criteria operation was similar with operation time in VATS
and number of nodal stations evaluated between lobectomy. The median length of postoperative stay
specialist and non-specialist thoracic surgeons. 3. was signiÀcantly shorter after robotic surgery than
Pathologic staging of non-small cell lung cancer VATS. Also, robotic surgery showed signiÀcantly
can be signiÀcantly improved by targeted quality lower rate of postoperative complications.
interventions especially when resections are
performed by non-specialist surgeons.
Keywords: Lung Cancer Staging, lobectomy, lung
cancer surgery
utility, several trials are already prospectively

randomizing NSCLC patients by ERCC1 status.
ERCC1 tumour assessment is also commercially
available. We aimed to characterize the prognostic
and predictive effect of ERCC1 by systematic review
and meta-analysis.
Methods: Eligible studies assessed survival and/
or chemotherapy response in NSCLC by ERCC1
status. Effect measures of interest were the hazard
ratio (HR) for survival or relative risk (RR) for
chemotherapy response. Random-effects meta-
analyses were used to account for between-study
heterogeneity, with unadjusted/adjusted effect
estimates considered separately. Direct evidence
Conclusion: Robot-assisted lobectomy with lymph on ERCC1 predictive utility for platinum-based
node dissection for early stage lung cancer is safe chemotherapy, was assessed from the interaction
as well as feasible, and it results in a satisfying between platinum-based versus non-platinum-based
postoperative outcomes compared with those after chemotherapy and ERCC1 status within studies.
VATS lobectomy. Robot-assisted surgery may Indirect predictive inÁuence was assessed by
provide a good alternative to thoracoscopic surgery collating evidence on ERCC1 prognostic effect in
for lung cancer, provided that the cost effectiveness platinum-treated and non-platinum-treated groups
and long-term prognosis are conÀrmed. available separately from studies, and relationship
Keywords: Robotic surgery, minimally invasive between ERCC1 and response to platinum-based
surgery, video-assisted thoracic surgery, Lung cancer chemotherapy. In addition, we used clinicaltrials.
gov to review the portfolio for lung cancer trials that
explicitly involve ERCC1 in the design.
Session O37: Biomarkers IV Results: 20 eligible studies provided survival results
in 2,434 patients. Marked variability in thresholds
Thursday, 7 July 2011 deÀning ‘low’ and ‘high’ ERCC1 was observed.
This partly contributed to substantial heterogeneity
observed in all meta-analyses (I2 always >30%).
Biomarkers IV Thursday, 7 July 2011 12:30-14:00 Only 1 study reported a direct predictive utility
for ERCC1, and this was statistically signiÀcant
O37.01 EXCISION REPAIR CROSS- (p=0.009). For indirect assessment of ERCC1 utility,
COMPLEMENTATION GROUP 1 (ERCC1) meta-analysis of unadjusted estimates showed high
STATUS AND NON-SMALL CELL LUNG ERCC1 was associated with signiÀcantly worse
CANCER (NSCLC) OUTCOMES: A META- overall survival in platinum-treated NSCLC (average
ANALYSIS OF PUBLISHED STUDIES unadjusted HR=1.61, 95%CI:1.23-2.1, p=0.014),
AND RECOMMENDATIONS but not in NSCLC untreated with chemotherapy
Sanjay Popat1, Richard D. Riley2, Lucinda J. (average unadjusted HR=0.82, 95%CI:0.51-1.31).
Billingham3, Richard A. Hubner4 Meta-analysis of adjusted estimates was limited by
1
Department Of Medicine, Royal Marsden Hospital/ variable choice of adjustment factors and potential
United Kingdom, 2Department Of Public Health, publication bias (Egger’s p<0.0001). Relationship
Epidemiology And Biostatistics, University Of between ERCC1 expression and platinum-based
Birmingham/United Kingdom, 3Cancer Research chemotherapy response was reported in 10
Uk Clinical Trials Unit And Mrc Midland Hub datasets, comprising 656 patients. High ERCC1
For Trials Methodology Research, University Of was signiÀcantly associated with reduced response
Birmingham/United Kingdom, 4Department Of (average RR=0.80; 95%CI:0.64-0.99) with moderate
Medical Oncology, Christie NHS Foundation Trust/ heterogeneity (I2=25.3%) and no evidence of small
United Kingdom study effects (Egger’s test: p=0.36). 15 NSCLC trials
being run in Europe, United States and Asia that
Background: Despite discrepant results on clinical involve ERCC1 within the design were identiÀed
from clinicaltrials.gov. The majority involve patients and metastasis. In contrast to other cancers, the
with stage IIIB/IV disease. Four are phase III trials, STK11 gene is frequently inactivated by somatic
the remainder are single arm or randomised phase II mutations in NSCLC.
or observational. Trial designs at both phases involve Methods: Fourteen high resolution melting (HRM)
ERCC1 either in marker-directed therapy or as a assays were developed to cover the entire coding
stratiÀcation factor and some studies are designed to sequences of STK11. STK11 mutations were
provide purely a correlative analysis with outcome. screened by HRM in a panel of 195 fresh frozen
No trial is powered to test for biomarker-treatment NSCLC samples. All HRM positive samples were
interaction. Ongoing studies are inconsistent in the then characterised by Sanger sequencing.
methods that they use to measure ERCC1. Results: A total of 30 STK11 mutations, comprising
Conclusion: Current evidence suggests high ERCC1 27 non-synonymous mutations and 3 synonymous
may be prognostic of poorer survival and response changes were detected, giving a mutation frequency
in platinum-treated NSCLC patients, but not in of 15%. The non-synonymous mutations consisted
non-platinum treated, although deÀnitive evidence of 9 nonsense, 5 frameshift, 6 missense, and 7
of a predictive inÁuence is lacking. Interpretation splice site variants. STK11 muations were detected
of results from ongoing studies will continue to be in all coding exons except for exon 7 and were not
problematic due to their variable designs. A properly recurrent except with exceptions of a nonsense
validated predictive tool involving ERCC1 needs mutation (K191X) and a splice site variant (c.291-
to be developed and evaluated in a clinical trial to 1G>T), which were each found in two tumours.
enable platinum-based treatment to be stratiÀed Single base substitutions (25/30, 83%) were more
according to ERCC1 in future clinical practice. Until common than small insertions/deletions (5/30, 17%)
then ERCC1 assessment should not be used for and the size of insertions/deletions were less than
routine treatment decision-making. 20 base pairs. The majority of mutations (28/30,
Keywords: ERCC1, meta-analysis, systematic 93%) were present in the kinase domain and the two
review, Chemotherapy remaining changes were located in the C-terminal
regulatory domain.
Conclusion: These results conÀrm that a signiÀcant
Biomarkers IV Thursday, 7 July 2011 12:30-14:00 proportion of NSCLC patients have STK11
mutations and demonstrate the utility of HRM
O37.02 DETECTION OF LKB1/STK11 analysis for the cost efÀcient screening of somatic
MUTATIONS IN NSCLC PATIENTS STK11 mutations in clinical NSCLC samples.
USING HIGH RESOLUTION MELTING Keywords: mutation detection, high resolution
ANALYSIS. melting, LKB1, STK11
Hongdo Do1, Guenaelle Levallet2, Emmanuel
Bergot3, Martine Antoine4, Franck Morin5, Bernard
Milleron6, Gérard Zalcman3, Alexander Dobrovic1 Biomarkers IV Thursday, 7 July 2011 12:30-14:00
1
Pathology, Peter MacCallum Cancer Centre/
Australia, 2Pathology, Caen University Hospital/ O37.03 DNA REPAIR PROTEINS MSH2,
France, 3Chest Medicine Department, Caen XRCC5, ERCC1, O6MGMT, AND BRCA1
University Hospital/France, 4Pathology, Tenon IN EARLY LUNG CANCER PATIENTS
University Hospital/France, 5Intergroupe TREATED BY PERIOPERATIVE
Francophone De Cancérologie Thoracique (IFCT)/ CHEMOTHERAPY IN THE IFCT-0002
France, 6Pulmonary Medicine Department, Tenon PHASE III TRIAL
University Hospital/France Gérard Zalcman1, Emmanuel Bergot1, Guenaelle
Levallet2, Martine Antoine3, Pierre Fouret4, Elisabeth
Background: Germline mutations in the tumour Brambilla5, Françoise Galateau-Sallé6, Laurence
suppressor gene STK11 (also known as LKB1) cause Baudrin7, Christian Creveuil8, Michele Beau-Faller9,
Peutz–Jeghers syndrome which is characterised by Florence Defraipont10, Mounia Mounawar11, Virginie
mucocutaneous pigmentation, intestinal hamartomas Westeel12, Jacques Cadranel13, Elisabeth Quoix14,
and increased risk of developing cancers. In lung Didier Debieuvre15, Julien Mazières16, Jean-Louis
cancer, STK11 plays a crucial role in pulmonary Pujol17, Denis Moro-Sibilot18, Franck Morin19,
tumorigenesis, controlling initiation, differentiation, Bernard Milleron13
1
Chest Medicine Department, Caen University specimens were also collected for DNA methylation
Hospital/France, 2Pathology Department, Caen (O6MGMT) and mutations (TP53) studies,
University Hospital/France, 3Department Of respectively using methylation-speciÀc PCR and
Pathology. Hopital Tenon/France, 4Pathology DHPLC followed by genomic sequencing of TP53
Department, La Pitié University Hospital/France, exons 4-9. Prognosis values for Progression-free
5
Institut Albert Bonniot, Inserm U823/France, Survival (PFS) and Overall Survival (OS), were
6
Pathology, Caen University Hospital/France, assessed using Cox models. Kaplan-Meier survival
7
Intergroupe Francophone De Cancérologie curves were calculated and Cox models used to
Thoracique/France, 8Biostatistics And Clinical adjust for patients characteristics associated with the
Research Unit, Caen University Hospital/France, corresponding outcome (PFS or OS) with p-value
9
Chu De Strasbourg, Molecular Laboratory, under 0.2 in univariate analysis.
Ea 4438/France, 10Cancer Biochemistry & Results: Median follow-up was 55 months. TP53
Biotherapy Unit, Grenoble University Hospital/ mutations were found in 27.6% of the 208 specimens
France, 11Biomarker Group, I.A.R.C/France, analyzed. O6MGMT promoter methylation was
12
Chest Medicine Department, Besançon found in 14.9% of the specimens. ERCC1, MSH2,
University Hospital/France, 13Pulmonary Medicine XRCC5 and BRCA1 immunostainings were
Department, Tenon University Hospital/France, successful in respectively 420, 356, 397 and 221
14
Pulmonary Medicine Department, Strasbourg specimens. Neither TP53 mutations, O6MGMT
University Hospital/France, 15Pulmonary Medicine methylation, XRCC5 nor ERCC1 expression
Department, Haute Saône Community Hospital/ showed any inÁuence on survival. Conversely, high
France, 16Pulmonary Medicine Department, expression of MSH2 protein (over median value),
Toulouse University Hospital/France, 17Pulmonary and BRCA1 expression signiÀcantly impacted
Medicine Department, Montpellier University survival in univariate as multivariate analyses. In
Hospital/France, 18Chest Medicine Department, multivariate Cox Overall Survival model, including
Grenoble University Hospital/France, 19Intergroupe stage and number of administered chemotherapy
Francophone De Cancérologie Thoracique (IFCT)/ cycles (2 or less vs. 3-4, according to response after
France 2 cycles), MSH2 expression higher than the median
H-score value, signiÀcantly predicted a worse OS:
Background: DNA-repair proteins ERCC1, HR=1.47, 95%CI[1.057-2.036], p=0.02. Conversely,
MSH2 and BRCA1 have been previously reported as previously reported in other studies, BRCA1 low
to play a central role in cisplatin resistance, and H-Score, under median value predicted worse PFS
immunohistochemical expression of those proteins as worse OS, HR for OS=1.940 95%CI[1.27-2.97],
were shown to alter survival of early NSCLC p=0.0022. A prognostic score was then constructed
patients, either in retrospective series, or in IALT and validated by a bootstrap re-sampling strategy,
phase 3 trial of adjuvant therapy (for ERCC1 that accurately deÀnes three groups of early-lung
and MSH2). We therefore aimed to study a panel cancer patients from low to high risk of recurrence
of DNA repair proteins involved in Nucleotide and death despite perioperative cisplatin-based
Excision Repair (NER), Base Excision Repair chemotherapy.
(BER), Mismatch Repair (MR), Non Homologous Conclusion: A systematic survey of DNA repair
EndJoining (NHEJ) repair, in stage I-II lung cancer proteins in a phase 3 controlled trial, led us to
patients included in the IFCT-0002 randomized identify MSH2 and BRCA1 immunostainings as
phase 3 trial of peri-operative chemotherapy independent prognostic biomarkers in patients
Methods: The IFCT-0002 phase III trial compared with early lung cancer that received preoperative
two chemotherapy timings, all pre- vs. peri- platinum-based doublets. Conversely neither ERCC1
operative, and two regimens, CDDP-Gem vs. nor XRCC5/Ku80 had any inÁuence on survival
CBDCA-Pac (V. Westeel, ASCO 2009). ParafÀn- contrasting with previous reports. A DNA-repair
embedded surgical post-chemotherapy specimens gene expression-based prognostic score will be
were prospectively collected and processed for presented which accurately discriminates in early-
IHC studies with speciÀc primary antibodies stage lung cancer patients, three groups of high,
previously described. Semi-quantitative classical intermediate, and low risk of death, according to
H-scores were applied to evaluate immunostainings their respective tumour expression of MSH2 and
by expert thoracic pathologists. 208 snap-frozen BRCA1.
Keywords: early lung cancer, DNA repair proteins, (49.4%) belonged to HDGF high expression group,
prognostic biomarker the 5-year survival rate was sharply decreased to
38.2%, the difference was statistically signiÀcant
(P=0.009). Linear correlation analysis discovered
Biomarkers IV Thursday, 7 July 2011 12:30-14:00 that the HDGF expression showed a signiÀcantly
negative correlation with the survival of the 158
O37.05 HDGF AS A NOVEL PROGNOSTIC cases of resected non-small cell lung cancers (R=-
AND PREDICTIVE BIOMARKER 0.183, P=0.022). Patients who received postoperative
PREDICTING A WORSE PROGNOSIS chemo-radiation therapy (47 cases) had a higher
FOR PATIENTS WITH SURGICALLY 5-year survival rate of 67.2% when compared
RESECTED NON-SMALL CELL LUNG with those who received surgery only but without
CANCER adjuvant chemo-radiation (111 cases) whose 5-year
Jun Zhang1, Juan Qi2, Anguang He3 survival was 44.7% (P=0.010). When stratiÀed, in
1
Department Of Molecular Targeted Therapeutics the 78 HDGF highly expressed cases, the 5-year
Of The First Hospital Of China Medical University, survival rate for those who received postoperative
China Medical University Lung Cancer Center The chemo-radiation therapy (19 cases) was 57.0%,
First Hospital Of China Medical University/China, higher than those who did not receive adjuvant
2
Department Of Molecular Targeted Therapeutics chemo-radiation whose 5-year survival was 32.1%
Of The First Hospital Of China Medical University/ (59 cases) (P=0.029); however, in the HDGF lowly
China, 3China Medical University Lung Cancer expressed cases, postoperative chemo-radiation did
Center/China not improve the 5-year survival rate with a statistic
signiÀcance (P=0.232). Cox proportion hazard
Background: Our recent studies revealed that model analysis revealed that pathological stages,
hepatoma-derived growth factor (HDGF) was postoperative chemo-radiation therapy and HDGF
highly expressed in non-small cell lung cancer cells, expression were the independent factors inÁuencing
and using siRNA silencing HDGF could inhibit the prognosis of this group of 158 cases of resected
signiÀcantly the growth and invasion of non-small non-small cell lung cancer.
cell lung cancer cells, including adenocarcinoma Conclusion: HDGF is highly expressed in human
cells A549, and squamous carcinoma cells H226. non-small cell lung cancer tissues, and highly
Here we detect the expression of HDGF in 158 cases expressed HDGF predicts worse prognosis in
of surgically resected non-small cell lung cancer, to resected non-small cell lung cancers, suggesting
further evaluate the signiÀcance of HDGF expression that HDGF is a useful novel molecular biomarker
in predicting the prognosis of resected non-small cell for predicting the prognosis of resected non-small
lung cancer. cell lung cancer. Importantly, HDGF could be a
Methods: Immunohistochemical SP method was novel useful predictive biomarker helping decide
used to detect the expression of HDGF in 158 cases if postoperative chemo-radiation therapy should
of resected non-small cell lung cancer tissues and be selected or not for surgically resected non-small
12 normal control lung tissues. Survival analysis cell lung cancer patients; adjuvant chemo-radiation
and multivariate analysis were further conducted therapy might beneÀt NSCLC patients with highly
to evaluate the signiÀcance of HDGF expression in expressed HDGF much more, instead of NSCLC
predicting the postoperative prognosis. patients with lowly expressed HDGF.
Results: The expression of HDGF in 158 cases of Keywords: Lung neoplasms, Survival analysis,
non-small cell lung cancer tissues was higher with Prognostic and Predictive Biomarker, HDGF
a average HDGF expression level of 170.08±77.97,
when compared with the average HDGF expression
level of 113.33±42.07 in the 12 cases of normal
control lung tissues, the difference was statistically
signiÀcant (P=0.000). When the 158 cases of non-
small cell lung cancer was divided into two groups
by the average level of HDGF expression, 80
cases (50.6%) belonged to HDGF low expression
group, the 5-year survival rate was 63.1%; 78 cases
Biomarkers IV Thursday, 7 July 2011 12:30-14:00 43% of the exon 9 mutations occurred in ampliÀed
tumours while none of the exon 20 mutations
O37.06 PI3KCA ALTERATIONS IN LUNG occurred concomitantly with the gene ampliÀcation.
SQUAMOUS CELL CARCINOMAS: ROLE Conclusion: These results indicate a complementary
FOR MUTATIONS AND AMPLIFICATION relationship between PIK3CA ampliÀcation and
Barbara Angulo1, Esther Conde1, Ana Suarez- PIK3CA mutations in lung SCCs.
Gauthier1, Ricardo Garcia-Lujan2, Montserrat Keywords: PIK3CA, Mutation, gene ampliÀcation,
Sanchez-Cespedes3, Angel Lopez-Encuentra2, Luis squamous lung carcinoma
Paz Ares4, Fernando Lopez-Rios1
1
Laboratorio De Dianas Terapéuticas, Hospital
Universitario Madrid Sanchinarro/Spain, 2Hospital Biomarkers IV Thursday, 7 July 2011 12:30-14:00
Universitario 12 De Octubre/Spain, 3Institut
D’Investigacions Biomediques Bellvitge (IDIBELL)/ O37.07 STAGE I NON-SMALL CELL
Spain, 4Hospital Universitario Virgen Del Rocio/Spain LUNG CANCER EXPRESSING SOX2
SHOW MORE RECURRENCE IN
Background: PIK3CA is a well-established oncogene ELDERLY MALE PATIENTS WITH NON-
that is commonly activated by point mutations. In lung ADENOCARCINOMA HISTOLOGY
cancer, PIK3CA mutations are found infrequently. Spasenija Savic1, Coya Tapia1, Inti Zlobec2,
However gene ampliÀcation at 3q26, close to where Mariacarla Andreozzi1, Sandra Schneider1, Mathias
the PIK3CA gene resides, is among the most common Gugger2, Lukas Bubendorf1, Didier Lardinois3
1
gene ampliÀcation events. In a previous microarray Institute For Pathology, Institute For Pathology,
study (Angulo et al., J Pathol 2008), we identiÀed an University Hospital Basel/Switzerland, 2Institute For
increased PIK3CA expression due to gene ampliÀcation Pathology, University Berne/Switzerland, 3Surgery,
in lung squamous cell carcinomas (SCC). This Division Of Thoracic Surgery University Hospital
observation conÀrms the potential oncogenic nature Basel/Switzerland
of this alteration and suggests a candidate marker of
sensitivity to therapy with PI3K inhibitors. Our aim Background: Around 30% of patients with
was to further conÀrm our previous Àndings in another, early-stage non-small cell lung cancer (NSCLC)
larger, independent series. relapse after surgery. Therefore, new prognostic
Methods: PIK3CA gene mutations were analyzed and predictive molecular markers are needed to
using a previously described protocol in 178 NSCLC, identify patients who could beneÀt from adjuvant
including 123 SCC, 51 adenocarcinomas (AC), and treatment. SOX2 (sex determining region Y-box
four large cell carcinomas (LCC). Based on our 2) at the gene locus 3q26.33 is regarded as an
previous experience, the analysis of the PIK3CA oncogene involved in carcinogenesis of squamous
gene ampliÀcation by FISH was limited to SCCs. cell lung carcinoma. Nevertheless, comprehensive
We used a commercial probe (Kreatech, Amsterdam, data on SOX2 gene status and expression as well
Netherlands). The cut-off value to deÀne the PIK3CA as its prognostic relevance in early-stage NSCLC
gene ampliÀcation was established in ratio > 2 are not yet available. The aim of the present study
(relationship between the number of gene signals and was to investigate the prevalence and the prognostic
the number of centromeric signals). signiÀcance of SOX2 gene status and expression in a
Results: We identiÀed 12 PIK3CA mutations large series of stage I NSCLC patients.
(6.89%), most of them in well-known hot-spot Methods: A tissue micro array with 568 parafÀn-
codons (four E545K, three E542K, four H1047R, embedded stage I NSCLC with comprehensive
and one less frequent M1043I). Only one AC carried histopathological and clinical data, including
PIK3CA mutations, compared with 11 SCCs. We follow-up on overall and tumor-speciÀc survival
identiÀed PIK3CA gene ampliÀcation in 44 SCCs was analyzed. SOX2 gene status was determined
(38%). Interestingly, 61% of the ampliÀed tumours by Áuorescent in situ hybridization (FISH) using
carried >7 PIK3CA copies per cell, conÀrming our direct-labeled BAC clones (SOX2: RP11-938O9;
previous microarray results. We also identiÀed the reference probe (RP): RP11-286G5). SOX2 gene
presence of polysomy in 14 tumours (12%). When status was recorded as follows: AmpliÀcation (ratio
comparing the presence of PIK3CA mutations with SOX2/RP 2.2), polysomy (more than 4 signals in
the gene ampliÀcation, it is important to note that the CEP or the gene probe) and normal (ratio: 0.8-
1
1.8). Semi-quantitative expression of SOX2 protein Pulmonary Diseases, Vrije Universiteit Medical
was determined by immunohistochemistry (IHC). Centre/Netherlands, 2Pathology, Vumc/Netherlands,
3
Any nuclear reaction of tumor cells was regarded as Department Of Pulmonary Diseases, Vu University
a positive result. FISH and IHC data were correlated Medical Center/Netherlands, 4Pathology,
with clinicopathological features and overall survival. Vu University Medical Center/Netherlands,
5
Results: An increased SOX2 gene number Epidemiology And Biotatistics, Vumc/Netherlands
(ampliÀcation or polysomy) was observed in 4%
of NSCLC (17/429). 94% of NSCLC (16/17) with Background: Lung cancer is one of the most
an increased SOX2 gene number were observed common types of cancer world-wide, both in men
in squamous- and large cell carcinomas (non- and women. Since a few years, EGFR-TKI’s are
adenocarcionomas). Using logistic regression analysis available for treatment of a subset of lung cancer
an increased SOX2 gene number was signiÀcantly patients, i.e., those with a tumor-speciÀc, activating
(p<0.001) associated with SOX2 protein expression. EGFR mutation. Mutation analysis requires extra
SOX2 protein expression was detected in 48% of time and costs in the diagnostic evaluation of lung
NSCLC and was signiÀcantly associated with a non- cancer patients. Ideally, a pre-screening test to select
adenocarcinoma histology (p<0.001): it was expressed specimens eligible for molecular testing would be
in 78% of squamous cell carcinomas (178/227), available to avoid unnecessary molecular testing.
in 35% of large cell carcinomas (12/34) and only Immunohistochemical analysis may serve as such
in 15% of adeno-carcinomas (29/191). SigniÀcant a rapid and less expensive method. Yatabe et al¹
associations with SOX2 protein expression were suggested that the presence of EGFR-mutations is
observed with high grade tumors (p<0.001), elderly speciÀc for Terminal Respiratory Unit (TRU)-type
(>50years; p=0.001) and male (p>0.001) patients. adenocarcinoma, which express TTF-1 as determined
Elderly male patients with non-adenocarcionoma by immunohistochemistry. The aim of the current
histology and a smoking history expressing SOX2 had study is to further investigate the possibility of TTF-
a tendency toward more recurrence (p=0.06). 1 immunohistochemistry as a pre-screening test to
Conclusion: An increased SOX2 gene number is select patients for EGFR mutation analysis.
rare in stage I NSCLC and it is mostly detected in Methods: A database was constructed of 824
squamous and large cell carcinomas. SOX2 protein non-small cell lung cancer patients referred for
expression stratiÀes a subgroup of NSCLC from EGFR mutation testing from 2006 until December
elderly patients with a smoking history and non- 2010. Initially mutation analysis was performed
adenocarcinoma histology. SOX2 two could become a with PCR- sequencing and since 2008 with high
potential therapeutic target molecule in a subgroup of resolution melting conÀrmed by sequencing.
patients with early stage NSCLC. Immunohistochemistry for TTF-1 was performed
Keywords: SOX2, non-small cell lung cancer, with clone 8G7G3/1 (Dako). A negative and an
SOX2, immunohistochemistry, FISH external positive control was used with every
immunohistochemical staining procedure.
Results: A series of 824 lung cancers were evaluated
Session O38: Molecular Pathology IV for EGFR mutation status. EGFR-mutations were
detected in 175 cases (21%). Of 743 /824 cases
Thursday, 7 July 2011 (90.2%) TTF-1 expression was available: 238
cases were TTF-1-negative (32%), 23 case were
1+-positive (3.1%), 29 cases 2+ (3.9%) and 453
Molecular Pathology IV Thursday, 7 July 2011 12:30-14:00 cases 3+ (61%). In the cases with EGFR mutation
23 cases were TTF-1-negative (15.2%), 1 case was
O38.01 CAN TTF1 STAINING BE USED 1+-positive (0.7%), 2 cases 2+ (1.3%) and 125 cases
AS SELECTION FOR EGFR-MUTATION 3+ (82.8%). Strong TTF1 immunohistochemical
ANALYSIS IN PATIENTS WITH LUNG staining was signiÀcantly associated with the
CANCER? presence of EGFR mutations (p = 2.4x10-8). If
Julien Vincenten1, Egbert F. Smit1, Wim Vos2, in the histological sections of EGFR mutated
Katrien Grunberg2, Pieter E. Postmus3, Danielle cases with negative TFF1 in the tumor cells, an
Heideman4, Peter J. Snijders4, Gerrit A. Meijer4, Dirk internal control was present, this showed strong
J. Kuik5, Erik Thunnissen2 positivity for TTF1, supporting the quality of TTF1
immunohistochemical procedure. a joint model based on sensitivity, speciÀcity and an

Conclusion: The presence of EGFR mutation is assumed prevalence using Beta(1,1) priors on both
strongly related to TTF-1 positive lung cancer, sensitivity and speciÀcity. WinBugs was used for
supporting the TRU hypothesis. Nonetheless, in Àtting the model for NPV and the mean and 95%
15% of the lung cancer patients with an EGFR conÀdence interval (CI) for NPV per prevalence
mutation the tumor cells are negative for TTF1, were plotted.
indicating that this marker cannot be used to exclude Results: Out of the 693 ACs, TTF-1 status was
cases from EGFR mutation analysis. ¹ Yatabe et al, known in 301, and EGFR mutations were present
AmJSurgPathol 2005;29:633-639 in 224 specimens (74%). Only 2 of the 224
Keywords: lung carcinoma, TTF1, EGFR mutation, EGFR mutation positive specimens were TTF-1
TRU negative. See table below for association between
EGFR mutation status, and TTF-1, sensitivity and
speciÀcity calculations. For true EGFR mutation
Molecular Pathology IV Thursday, 7 July 2011 12:30-14:00 rates of 13% and 15%, the estimated NPVs (95%
CIs) are 99.5% (98.6%-99.9%) and 99.4% (98.4%-
O38.02 NEGATIVE THYROID 99.9%), respectively. The estimated NPV with
TRANSCRIPTION FACTOR (TTF-1) the 95% CI for a range of prevalences of EGFR
STATUS PREDICTS FOR NEGATIVE mutations are shown in Àgure1.
EPIDERMAL GROWTH FACTOR
RECEPTOR (EGFR) MUTATIONS
STATUS WITH A HIGH NEGATIVE
PREDICTIVE VALUE (NPV) IN PATIENTS
WITH ADENOCARCINOMAS (ACS) OF
THE LUNG.
Neeta Somaiah1, Elizabeth Garrett-Mayer2, Xu
Huang3, Amy Wahlquist2, Kathleen Danenberg3,
George Simon1
1
Hematology/oncology, Medical University Of South Conclusion: ACs of the lung that are TTF-1
Carolina/United States Of America, 2Biostatistics negative have a 99% probability of being negative
And Epidemiology, Medical University Of South for EGFR mutations and therefore could be initiated
Carolina/United States Of America, 3Response on chemotherapy while their EGFR mutation result
Genetics/United States Of America is awaited, allowing for earlier initiation of treatment
in 30% of patients.
Background: TTF-1 is expressed in about 72% of
ACs. EGFR mutations are present in 13-15% of A revised/updated abstract may be included in
unselected patients with AC. High TTF1 expression the Late Breaking Abstract Supplement, available
and EGFR mutations are associated with female at the 14th World Conference on Lung Cancer.
sex, never-smoking status and longer survival.
TTF-1 immunohistochemistry is available in most
pathology laboratories. However, most clinics Molecular Pathology IV Thursday, 7 July 2011 12:30-14:00
depend on commercial laboratories for EGFR
mutation testing, which takes 2 - 4 weeks for results. O38.03 IMMUNOHISTOCHEMICAL
We hypothesized that ACs negative for TTF-1 will STAINING FOR THYROID
also be negative for EGFR mutations. TRANSCRIPTION FACTOR-1 (TTF-1) IN
Methods: Microdissected formalin-Àxed parafÀn- ADENOCARCINOMAS OF THE LUNG:
embedded tumors from 693 patients with NSCLC THE SPT24 CLONE IS MORE SENSITIVE
were analyzed for EGFR mutations by allele- THAN 8G7G3/1, REGARDLESS OF
speciÀc PCR. TTF-1 status was determined by the TISSUE PRETREATMENT AND
pathology report and was documented as positive, DETECTION SYSTEM
negative or not reported. Patients’ whose TTF-1 Alexander J.J. Smits1, Aryan Vink2, D Castigliego3,
status was not reported were excluded. NPV for a Wim Vos3, P Van Der Valk3, I. Stuij4, Katrien
range of prevalences (1%-50%) was estimated using Grunberg3
1
Pathology, St. Antonius Hospital/Netherlands, predictive value for selection for mutation analysis,
2
Pathology, University Medical Center Utrecht/ while speciÀcity of TTF-1 for lung primary
Netherlands, 3Pathology, Free University carcinoma in metastases might decrease.
Medical Center, Amsterdam/Netherlands, Keywords: thyroid transcription factor-1, TTF-1,
4
Stichting Kwaliteitsbewaking Medische immunohistochemistry, lung adenocarcinoma
Laboratoriumdiagnostiek/Netherlands
Background: Thyroid Transcription Factor-1 (TTF- Molecular Pathology IV Thursday, 7 July 2011 12:30-14:00
1) is a highly speciÀc immunohistochemical marker
for primary adenocarcinomas of the lung, and for O38.05 PERIPHERAL VERSUS CENTRAL
those that may harbour EGFR or KRAS mutations RESECTED PRIMARY SQUAMOUS
in particular. We assessed TTF-1 sensitivity as part CELL CARCINOMAS OF THE LUNG - A
of a national immunohistochemistry lab feedback REVIEW OF 526 CASES.
program (Stichting Kwaliteitsbewaking Medische Holly Pattenden1, Manjiri Deshmukh2, Michael
Laboratoriumdiagnostiek). Dusmet1, Peter Goldstraw1, Eric Lim1, Simon
Methods: Standard tissue array slides were prepared Jordan1, George Ladas1, Sanjay Popat3, Alexandra
(Elizabeth Hospital, Tilburg, The Netherlands) and Rice4, Jan Von Der Thusen2, Andrew G. Nicholson4
1
distributed to participating labs. The array contained Thoracic Surgery, Royal Brompton Hospital/United
normal lung and 2 adenocarcinomas with moderate Kingdom, 2Department Of Histopathology, Royal
and strong TTF-1 expression, respectively. Each Brompton Hospital/United Kingdom, 3Department
lab performed TTF-1 staining according to its own Of Oncology, The Royal Marsden Hospital/United
routine protocol, and Àlled in a questionnaire on Kingdom, 4Histopathology, Royal Brompton
technical aspects. All slides were read and scored for Hospital/United Kingdom
technical quality (0-3 scale, 0: no staining, 3: intense
staining of correct structures) and for diagnostic Background: Although the frequency of squamous
adequacy (0-3 scale, 0: inadequate, 3: highly cell carcinoma (SQCC) of the lung is said to be
adequate); a total score of at least 4 was considered decreasing in relation to adenocarcinoma, little is
sufÀcient. Scoring was done by 2 couples, in each known about how this relates to tumour location
a pathologist and a technician, blinded to lab and to within the lung. The aim of the study was to assess
technical details of the staining protocol. As TTF-1 resected squamous cell carcinomas, speciÀcally in
positivity was observed to vary considerably in the relation to central versus peripheral location.
moderately staining adenocarcinoma, less than 50% Methods: From resected non-small cell
positivity was arbitrarily considered diagnostically carcinoma (NSCLC) specimens received from
inadequate (score 0-1). January 1993-December 2010, 526 SQCCs were
Results: 50 labs participated, of which 48 also retrospectively analysed in relation to tumour
submitted the questionnaire. 20/50 had insufÀcient location. Central tumours were deÀned as those
total scores (0-3). 16/18 of these used 8G7G3/1 centered on main stem or lobar bronchi, or showing
clone, 2/18 used SPT24 (Chi square p = 0.0001). predominant growth within segmental airways.
2/23 SPT24 stained slides scored insufÀcient. 3 Results: There was a reversal in the ratio of central
used other clones, all scoring sufÀcient. Score was to peripheral location from 1.7:1 in 1993-2001 to
not signiÀcantly affected by pretreatment, type of 0.8:1 from 2002-2010. The percentage of resected
immunostainer and detection system. InsufÀcient SQCCs, in relation to NSCLCs overall, remained
scores were mainly due to low sensitivity in the steady (32-36%) throughout this period. There was
moderately staining adenocarcinoma. Normal lung a lower male: female ratio in peripheral versus
and the strongly staining adenocarcinoma were central tumours (2.8:1 versus 4.4:1). Synchronous
generally diagnostically adequately stained. pre-neoplastic disease and nodal involvement
Conclusion: In conclusion, SPT24 is a were commoner in central tumours. Nearly all
more sensitive clone than G7G3/1 for patients in both groups were current or ex-smokers
immunohistochemical detection of TTF-1 in (n=140/143).
lung adenocarcinomas, particularly for those Conclusion: Resected peripheral SQCCs became
with moderate and/or variable expression. Use of more commonly seen than central SQCCs from
SPT24 is likely to increase sensitivity and positive around the year 2001. This may be the result of a
change in the type and intake of cigarette smoke resistance to therapy (EGFR). In particular, the role
and/or divergent carcinogenetic pathways. The of PI3Kơ in NSCLC has not been studied.
percentage of SQCCs per resected NSCLCs Methods: Eight tissue microarrays (TMAs) comprising
remained constant during the study period. 211 surgically resected formalin-Àxed parafÀn-
Keywords: Central Tumours, Peripheral Tumours, embedded NSCLC specimens (99 squamous cell
squamous cell carcinoma carcinomas; 112 adenocarcinomas) were examined by
IHC using validated antibodies directed against PI3Kơ
and PTEN. Cores were scored (0+, 1+, 2+, 3+) in a
Molecular Pathology IV Thursday, 7 July 2011 12:30-14:00 blinded fashion by a clinical pathologist (without prior
knowledge of the purpose of the study) and the level of
O38.06 IDENTIFICATION OF PI3Kơ expression correlated with PTEN expression for
A LOW PHOSPHATASE AND squamous and adenocarcinoma specimens. In addition,
TENSIN HOMOLOG (PTEN) HIGH an independent investigation was conducted at the
PHOSPHATIDYLINOSITOL-3 KINASE MDACC using the same validated antibody methods
(PI3K) ȕ EXPRESSING SUBSET OF across 32 TMAs comprising 290 squamous and 530
SQUAMOUS NON-SMALL-CELL LUNG adenocarcinoma samples
CANCER (NSCLC) Results: Tumour expression of PI3Kơ was largely
Marie Cumberbatch1, Xi ming Tang2, Garry Beran1, cytoplasmic, while PTEN was localized to both
S Luke1, P Singh1, A Kvist1, Sabina Cosulich1, Paul cytoplasmic and nuclear compartments. Results
D. Smith1, Carmen Behrens2, Edward Kim2, Madhuri from the AZ dataset reveal signiÀcantly (p<0.001)
Warren3, Chris Womack1, Neil Gray1, Ignacio elevated expression of cytoplasmic PI3Kơ expression
Wistuba2, David P. Blowers1 in squamous cell carcinomas (88.9% positive;
1
Oncology Innovative Medicines, Astrazeneca/United 57.6% 2+ and 3+) compared with adenocarcinomas
Kingdom, 2M.D. Anderson Cancer Center/United (51.8% positive; 14.3% 2+ and 3+). Conversely,
States Of America, 3Pathology Diagnostics Ltd/ adenocarcinoma samples displayed signiÀcantly higher
United Kingdom levels of cytoplasmic (p<0.001) and nuclear (p<0.001)
PTEN (88.3% and 74.8% positive, respectively)
Background: The PI3K/AKT/mTOR signalling compared with squamous samples (60.6% and 45.5%
network is a critical regulator of many cellular positive, respectively). Interestingly, over-expression
processes including proliferation, survival and of cytoplasmic PI3Kơ in squamous samples correlated
transformation. The lipid kinase PI3Kơ is a signiÀcantly (66.3% of squamous samples; p<0.001)
member of the class I PI3K family of enzymes with negative or low cytoplasmic and nuclear PTEN
which comprise p110Ơ, p110ơ, p110ƣ (class IA) expression, with only 11.5% of adenocarcinoma
and p110Ƣ (class IB); proteins that are activated to samples showing this pattern of expression and 50%
varying extents by receptor tyrosine kinases and exhibiting a converse relationship. Adjacent normal
G-protein coupled receptors. PI3KƠ and PI3Kơ are lung tissues (n=20) were either weak positive (1+;
positioned on chromosome 3q (3q25-27), a region 53.8%) or negative for cytoplasmic PI3Kơ and all
often ampliÀed in NSCLC. The activity of the PI3K adjacent normal lung samples were positive (1+ or
enzymes is counteracted by the tumor suppressor 2+) for cytoplasmic and nuclear PTEN. Preliminary
PTEN, a nonredundant phosphatase. Clinically, analyses of data derived from the MDACC indicate a
PTEN mutations and deÀciencies are prevalent in similar proÀle of expression conÀrming identiÀcation
many types of human cancers and severe PTEN of a subset of squamous NSCLC samples with over-
deÀciency is also associated with advanced tumor expression of PI3Kơ and low or negative PTEN.
stage and therapeutic resistance. In lung cancer, loss Conclusion: These data identify a pattern of over-
of PTEN protein occurs via a number of mechanisms expression of PI3Kơ in squamous NSCLC that,
including promoter methylation and LOH, however, accompanied by loss/reduced PTEN, could represent
neither epigenetic silencing nor deletion appear to a subset for therapeutic intervention.
predict for protein loss by immunohistochemistry Keywords: NSCLC, Squamous, PI3Kb, PTEN
(IHC). The molecular characterization of the PI3K/
AKT/mTOR signalling network in lung cancer is A revised/updated abstract may be included in
not as well deÀned as in other tumour types, yet the Late Breaking Abstract Supplement, available
de-regulation of this pathway has been linked to at the 14th World Conference on Lung Cancer.
Molecular Pathology IV Thursday, 7 July 2011 12:30-14:00 signal pathways, rather than the quantity of genomic
aberrations.
O38.07 DNA COPY NUMBER Conclusion: We established a prognostic genomic
ALTERATIONS PREDICT SURVIVAL proÀle including 41 DNA regions in lung SCC. The
OF PATIENTS WITH LUNG SQUAMOUS characteristic chromosome aberrations identiÀed
CELL CARCINOMA in this study indicated a further study of the critical
Yan Cao1, Dongmei Lin1, Yu Liu2, Yanjing Gao2, genetic landmarks or key genes involved in lung
Kaitai Zhang2, Ting Xiao2, Shujun Cheng2 SCC progression.
1
Pathology, Cancer Institute (oHspital), Peking Keywords: Lung cancer, Metastasis, Prognosis,
Union Medical College & Chinese Academy Of DNA copy number
Medical Sciences/China, 2State Key Laboratory Of
Molecular Oncology, Department Of Etiology And
Carcinogenesis, Cancer Institute (Hospital), Peking Session O39: Biomarkers V - EGFR
Union Medical College & Chinese Academy Of
Medical Sciences/China Thursday, 7 July 2011
Background: Tumor metastasis is strongly
associated with overall survival of patients with lung Biomarkers V - EGFR Thursday, 7 July 2011 12:30-14:00
cancer. Although lymph node status at surgery is one
of the important prognosis factors, some patients O39.01 OUTCOME OF ADVANCED
without lymph node metastasis had very poor NSCLC PATIENTS WITH EGFR EXON
survival, inferring that lymph node status alone can 19 AND 21 MUTATIONS TREATED
not be an accurate indicator for patients’ outcome WITH ERLOTINIB (E) ALONE OR IN
in lung cancer. In this study, we aimed to establish COMBINATION WITH CARBOPLATIN/
a prognostic genomic proÀle in lung squamous cell PACLITAXEL (CP) IN CALGB 30406.
carcinoma (SCC). Pasi A. Janne1, Xiaofei Wang2, Mark A. Socinski3,
Methods: One hundred lung SCC patients were Jeffrey Crawford4, Lin Gu2, Marzia Capelletti1,
included in this study. Fifty of the patients survived Martin J. Edelman5, Miguel A. Villalona-Calero6,
for more than Àve years after surgery were Robert A. Kratzke7, Everett Vokes8, Vincent A.
categorized as a group at low death risk, whereas Miller9
1
50 patients died in two years were at high death Lowe Center For Thoracic Oncology, Dana Farber
risk. DNA copy number alterations in all the cancer Cancer Institute/United States Of America, 2Duke
patients were investigated using high resolution University/United States Of America, 3University Of
array-CGH analysis. North Carolina/United States Of America, 4Medical
Results: After Àltering potential false positive Oncology, Duke University Medical Center/United
and negative DNA regions, we found a series of States Of America, 5Cancer Center, University
genomic variants that were associated with patients’ Of Maryland/United States Of America, 6Medical
survival. A collection of 41 aberrant DNA regions Oncology, The Ohio State University/United States
was established for prognosis evaluation. Among Of America, 7Department Of Medicine, University
these regions, loss of 3p21.31 and 4q35.1 and Of Minnesota/United States Of America, 8University
gains of 5p13.2, 14q32.33 and 19p13.11 were more Of Chicago/United States Of America, 9Medicine,
closely related with patients’ survival. Thirteen genes Memorial Sloan-Kettering Cancer Center/United
were identiÀed to locate in these regions, including States Of America
DAG1, BSN, SLC25A4, SLC1A3, PLD4, GPR132,
PBX4 EDG4, N1CN1, SNX25, LRP2BP, C14orf79 Background: EGFR kinase inhibitors are
and CDCA4. In addition, our results showed that effective therapies in NSCLC patients harboring
the complexity of genome variations was not somatic EGFR mutations. CALGB 30406
directly related with progression of lung SCC. For prospectivelyevaluated E and ECP in never or
example, copy number alterations in the high death light former smokers with chemotherapy naïve
risk group were not more complex than those in the advanced lung adenocarcinoma and determined the
low-risk group. Biological behaviors of lung SCC impact of EGFR mutations on outcome. Patients
might depend on the alterations of key genes or cell with EGFR mutations had similar outcomes in both
arms. Updated data from the study and based on the Conclusion: E and ECP are effective Àrst line
speciÀc EGFR mutation is reported. therapies in EGFR mutant NSCLC. Patients with
Methods: Chemotherapy naïve, never or light exon 19 deletions have a trend towards improved
former (< 10 pack years, > 1year since cessation) outcome (RR and PFS) treated with either E or ECP
smokers, with advanced lung adenocarcinoma (do compared to L858R patients.
you need to save these characters) were randomized Keywords: EGFR mutation, erlotinib, Randomized
to E alone (150 mg/day) or ECP (E 150 mg/day Phase II clinical trial
given continuously; C (AUC = 6) & P (200 mg/m2)
both q21 days) for 6 cycles followed by E. Primary
endpoint was progression free survival (PFS) in Biomarkers V - EGFR Thursday, 7 July 2011 12:30-14:00
both arms. Collection of pre-treatment tumor for
assessment of EGFR mutations was mandatory. O39.02 INITIAL DETECTION OF THE
Results: Between 8/05 and 4/09 188 pts were DOUBLE EPIDERMAL GROWTH
accrued; 181 pts randomized (E = 81; ECP = 100) FACTOR RECEPTOR (EGFR) MUTATION
and treated. Baseline clinical characteristics (E/ECP) (L858R OR DELETION IN EXON 19 [DEL
were well balanced: Female: 60%/58%; Caucasian: 19] PLUS T790M) IN NON-SMALL-CELL
75%/84%; never smokers: 79%/78%; ECOG PS0: LUNG CANCER (NSCLC) PATIENTS (P)
62%/48%; adenoca: 87%/84%. Median number of WITH BRAIN METASTASES (METS)
cycles: E:6; ECP:8.Toxicity: Grade 3/4 hematologic AND THE INFLUENCE OF FIRST-LINE
toxicity: E: 2/0 (2%) ; ECP: 29/20 (49%). Grade CHEMOTHERAPY ON OUTCOME TO
3/4 non-hematologic toxicity: E: 18/2 (24%); ECP: ERLOTINIB
39/13 (52%). EGFR genotyping possible in 164 Jia Wei1, Christian Rolfo2, Teresa Moran3, Jose
pts (91%). EGFR mutant/wild type: 66 (40%)/98 Javier Sanchez4, Miguel Angel Molina5, Jordi
(60%). Exon 19 del: 39; L858R: 27. Outcomes are Bertran-Alamillo6, Ana Jimenez-Capitan6, Susana
shown in the Table. Median follow up is 36 mos. Benlloch6, Miquel Taron3, Bartomeu Massuti7,
67% of pts have died. Primary endpoints were met Carlos Camps8, Rut Porta9, Dolores Isla10, Guillermo
in both arms. EGFR mut pts had a signiÀcantly Lopez-Vivanco11, Isabel Bover12, Rosario Garcia-
better RR (p < 0.0001 both arms), PFS (p < 0.0001 Campelo13, Fernanda Salazar6, Enric Carcereny3,
both arms) and OS (p = 0.0198 E; p = 0.011 ECP) Felipe Cardenal14, Ignacio Magri6, Rafael Rosell3
1
than EGFR WT pts. OS for EGFR mut pts is longer Oncology, Comprehensive Cancer Center Of
with ECP vs. E (38 vs. 31 mos) but not signiÀcant Drum Tower Hospital/China, 2Clínica Rotger/
(p=0.9227). The RR (79% vs. 59%; p = 0.0743) and Spain, 3Oncology, Catalan Institute Of Oncology,
PFS (17.7 vs. 12.1 mos; p = 0.1777) are better for Hospital Germans Trias I Pujol/Spain, 4Statistics,
exon 19 vs. L858R pts. (both arms combined). PFS Autonomous University Of Madrid/Spain, 5Oncology,
is longer for exon 19 deletion pts. receiving ECP vs. Pangaea Biotech, Dexeus University Institute/Spain,
6
E (27.5 vs. 15.7 mos) but not signiÀcant (p=0.2153) Pangaea Biotech, Dexeus University Institute/Spain,
7
E (n=81) RR PFS months OS months (95%CI) Hospital General De Alicante/Spain, 8Hospital
(95%CI) General De Valencia/Spain, 9Catalan Institute Of
All patients 35% 5.0 (2.9-7.0) 24.6 (18.4-33.8) Oncology, Hospital Josep Trueta/Spain, 10Hospital
EGFR mut (n=33) 70% 14.1 (7.0-19.6) 31.3 (23.8-NA) Lozano Blesa/Spain, 11Hospital De Cruces De
Barakaldo/Spain, 12Hospital Son Llatzer/Spain,
Exon 19 (n= 23) 83% 15.7 (6.9-20.4) 31.3 (22.7-NA) 13
Hospital Teresa Herrera/Spain, 14Catalan Institute
Exon 21 (n=10 ) 40% 12.6 (1.6-23.8) 29.8 (3.7-NA) Of Oncology, Hospital Duran I Reynals/Spain
EGFR WT (n=44) 9% 2.6 (1.4-3.9) 18.1 (9.5 – 27.8)
ECP (n =100 ) Background: Progression-free survival (PFS) in
All patients 46% 6.6 (5.4-8.2) 19.8 (14.4-27.8) EGFR-mutant NSCLC p treated with erlotinib is
EGFR mut (n=33) 73% 17.2 (8.2-27.8) 38.1 (19.6 -NA)
unpredictable at the individual level. The initial
presence of double mutations (EGFR L858R or
Exon 19 (n= 16) 75% 27.5 (7.4-NA) 37.5 (18.7- NA)
del 19 plus T790M) is associated with shorter PFS.
Exon 21 ( n = 17) 71% 11.2 (6.8-23.4) 40.0 (10.4- NA) We hypothesized that the site of mets and/or prior
EGFR WT (n=54) 30% 4.8 (2.8 – 5.6) 14.4 (8.7 – 20.2) chemotherapy could also inÁuence outcome in these
p with double EGFR mutations.
Methods: The T790M mutation was assessed in Denver/United States Of America

129 advanced NSCLC p by TaqMan assay in the
presence of a peptide-nucleic acid designed to inhibit Background: Established biomarkers to predict the
the ampliÀcation of the wild-type allele. beneÀt from EGFR TKI therapy in Non-small cell
Results: De novo T790M mutations were identiÀed lung cancer (NSCLC) are mutations of Epidermal
in 35% (45 of 129) of EGFR-mutant p before Growth Factor Receptor (EGFR), however, only
receiving erlotinib. PFS was 12 months (m) for 70-80% will respond. Ultimately, all patients
p with double mutations and 18 for p with only (pts) develop drug resistance and the insulin-like
L858R or del 19 (P=0.02). The T790M mutation was growth factor-1 (IGF-1) pathway may have a role in
detected more frequently in p with bone mets (35.6% EGFR TKI resistance. We assessed IGF-1R protein
vs 16.7%; P=0.03). No effect on PFS or MS was expression and its association to progressive disease
observed in p with the T790M mutation according (PD) and outcome in EGFR TKI treated NSCLC pts
to bone, lung, liver or pleura mets. However, when p using immunohistochemistry (IHC) and automated
with T790M were divided according to the presence quantitative Áuorescence analysis technology
of brain mets, PFS was 1 m for 4 p with brain mets (AQUA).
vs 13 m for 41 p without brain mets (P=0.002), Methods: IGF-1R protein expression was analyzed
and MS was 6 m for p with brain mets vs 36 m for in 98 geÀtinib-treated Japanese NSCLC pts with
those without (P=0.009). Overall, in the multivariate IHC (Ventana Medical Systems, Inc, Tucson, AZ)
analysis, the presence of the double mutation did and in 70/98 of them with AQUA (HistoRx Inc,
not affect the risk of shorter MS (HR, 1.3; P=0.49), New Haven, CT). IHC scoring was performed by
but p who had received prior chemotherapy had evaluating membrane and cytoplasm with the Hybrid
signiÀcantly longer MS (HR, 0.48; P=0.02). (H) scoring method (0 to 400).
Conclusion: The initial double EGFR mutation Results: IGF-1R expression was signiÀcantly higher
(EGFR L858R or del 19 plus T790M) is a marker in pts with PD vs disease control (DC = CR + PR +
for poor prognosis in p with brain mets. In SD) using any method of assessment for IHC. Using
addition, initial chemotherapy can play a role in the ROC curve analyses, the best discrimination of PD
management of NSCLC p with the double EGFR vs DC was obtained with IHC scoring of membrane
mutation. + cytoplasm and a cutoff of 165, with an accuracy
Keywords: erlotinib, T790M, EGFR mutation, Non- of 72%, sensitivity and speciÀcity of 68% and 73%
Small-Cell Lung Cancer with an area under the curve of 0.75 (p = 0.0006).
Overall survival (OS) from geÀtinib was worse in pts
with high IGF-1R using the 165 cutoff (median 13.2
Biomarkers V - EGFR Thursday, 7 July 2011 12:30-14:00 vs 22.6 months (ms), p = 0.0199). Progression free
survival (PFS) was shorter in high IGF-1R pts in the
O39.03 IGF-1R IS A PREDICTIVE whole cohort (median 3.5 vs 12.0 ms, p = 0.0020), as
BIOMARKER FOR EGFR TKI well as in the adenocarcinomas (n = 78) where high
(GEFITINIB) RESISTANCE IN NON- IGF-1R showed worse OS and PFS relative to low
SMALL CELL LUNG CANCER USING IGF-1R (median 15.6 vs 26.3 ms, p = 0.0642 and 4.4
IHC AND AQUA TECHNOLOGY vs 12.1 ms, p = 0.0169). Even in the subgroups of
Yasufumi Kato1, Murry W. Wynes1, Céline patients with EGFR mutated tumors (n = 55), high
Mascaux1, Bernadette G. Reyna Asuncion1, Cindy IGF-1R showed worse PFS (9.5 vs 17.9, p = 0.0435).
Tran1, Koichi Yoshida2, Jun Matsubayashi3, Tatsuo Evaluation of over expression (H score >300) versus
Ohira2, Kinya Furukawa4, Toshitaka Nagao3, no/very low-expression (H score 100) showed that
Norihiko Ikeda2, Fred R. Hirsch5 the overexpression had a shorter OS (3.7 vs 29.1 ms,
1
Division Of Medical Oncology, University Of p = 0.0220) and PFS (2.5 vs 29.1 ms, p <0.0001).
Colorado Denver/United States Of America, In overexpression pts the response rate was 0%
2
Division Of Thoracic Surgery, Tokyo Medical (0/8; 3 PD, 4 SD and NE). IGF-1R expression as
University/Japan, 3Division Of Anatomic Pathology, assessed by AQUA was also signiÀcantly higher in
Tokyo Medical University/Japan, 4Division Of pts with PD vs DC. Using ROC curve analyses, the
Thoracic Surgery, Tokyo Medical University, best discrimination of PD vs DC was obtained with
Ibaraki Medical Center/Japan, 5Division Of Medical an AQUA cutoff of 7.656, High IGF-1R expression
Oncology And Pathology, University Of Colorado evaluated by AQUA was also predictive of PD (p =
0.033) and shorter PFS (3 vs 9.2 ms, p = 0.0406) in a Methods: 80 adenocarcinomas of the lung were
70 pts subset. included in the study, 40 samples with proven
Conclusion: High IGF-1R protein expression, mutation status evaluated by different methods
evaluated both by IHC and AQUA, predicted and 40 predominantly acinar or papillary
primary resistance to geÀtinib therapy in NSCLC adenocarcinomas with undetermined EGFR mutation
and was associated with worse OS and shorter PFS. status. EGFR-mutation analysis in the Àrst group
This observation was also true in the subgroups of was previously done by either classical sequence
adenocarcinoma and more interestingly in patients analysis, pyrosequencing, LightCycler® assay,
wiht EGFR mutated tumors. Thus, IGF-1R protein BioFilmChip® microarray hybridisation, IHC
expression appears to be a clinically relevant with mutant speciÀc antibodies, or the use of a
biomarker to identify NSCLC pts with intrinsic commercial kit (DxS). DNA was isolated from all
EGFR TKI resistance, even in pts having EGFR 80 samples and EGFR mutations in exon 18 to 21
mutations. were tested with the GenomeFlex 454 sequencing
Keywords: AQUA, immunohistochemistry, IGF-1R, system (Roche). This method has proven to be
Predictive marker extremely sensitive, having the power to detect
single cell mutations enabling a clonal analysis on
cellular level. Different patients were encrypted by
Biomarkers V - EGFR Thursday, 7 July 2011 12:30-14:00 a genetic ‘barcode’ (4 to 6bp nucleotidadapter) by
PCR to facilitate a simultaneous sequencing of many
O39.05 VERY EARLY DETECTION patient samples. Cut-off was set according to Wang
OF SMALL CLONES HARBORING (Genome Res. 2007).
EGFR MUTATIONS IN NSCLC BY 2ND Results: 1829 mutations were found in 79 patient
GENERATION SEQUENCING samples (silent mutations were not included). 77
Claudia Vollbrecht1, Fabian Mairinger2, Slave different previously evaluated mutations could be
Trajanoski3, Iris Halbwedl4, Teresa Maierhofer3, G. conÀrmed. Additional 158 different new mutations
Michelitsch3, Martin Filipits5, Katharina Schmid5, J. were detected in the tumor cells. When compared
Kollmeier6, Thomas Mairinger6, Helmut H. Popper4 to the other tested methods our results show a better
1
Biotechnology, 1lausitz University Of Applied speciÀcity and better sensitivity. Cases analyzed by
Sciences/Germany, 2Lausitz University Of Applied Light Cycler® assay and pyrosequencing showed
Sciences/Germany, 3Centre For Medical Research, 100% correspondence to 454 sequencing, whereas
Medical University/Austria, 4Institute Of Pathology, the results of IHC with mutant speciÀc antibodies
Medical University Graz/Austria, 5Cancer Research showed 1 false positive and 2 false negative results
Center, Medical University/Austria, 6Pathology, (n=28). The comparison of Sanger sequencing
Helios Klinikum/Germany analysis showed a high discrepancy between the
different Institutes. All other applied methods
Background: Activating mutations of the EGFR showed deviations as well, nevertheless with
gene are present in non-small-cell-lung-cancer acceptable boundaries. Several mutations present in
(NSCLC) and respond to EGFR tyrosine kinase small tumor cell clones were not detected by any of
inhibitor (TKI) therapy. Despite the therapeutic the other methods. Furthermore, T790M resistance
success of EGFR-TKIs, about 50% of these mutation combined with an activating mutation
patients will ultimately show disease progression could be found in two untreated patient samples.
during the course of treatment, possibly due to Conclusion: The discrepancy between different
resistant tumor cell clones either primarily present conventional methods used for routine diagnostics
as small clones within the carcinoma, or due to result in several samples incorrectly diagnosed. This
secondary mutations during TKI treatment. These implicates the importance of using either a second
clones may gain a selection advantage, resulting method for conÀrmation, or using a more sensitive
in tumor growth unaffected by TKI-treatment. We method to minimize the risk of a false diagnosis.
tested adenocarcinomas of the lung for known and The results underline the need for standardization
unknown EGFR mutations comparing different of mutation analysis. However, the application of
methods for mutation analysis, and also tried to such a sensitive method requires an even closer
correlate the new adenocarcinoma classiÀcation with collaboration between pathologists and oncologists,
EGFR mutation status. since the impact of small tumor cell clones (1% and
less) harboring an activating mutation with respect to promoter. Whole blood cells were then stained using
treatment is not entirely clear. The T790M mutations a LIVE/DEAD® Fixable Red Dead Cell Stain Kit.
found in untreated patients support the hypothesis Immunohistochemistry was performed on slides
that NSCLC can harbor TKI resistant clones already using a tyramide signal ampliÀcation kits with
before treatment besides the more common advent of Alexa 350-labeled tyramide as the substrate for
a secondary somatic resistance mutation. This is of horseradish peroxidase (HRP). Anti-CEA and anti-
importance, because TKI treatment will result in an HRP-goat anti-mouse were applied as primary and
earlier resistance in these patients because of clone secondary antibodies, respectively. Two slides for
selection. each patient were also processed for Áuorescence
Keywords: EGFR mutation analysis, deep microscopy. Software Image-Pro Plus Ver. 6.0
sequencing, primary resistance clone, NSCLC (Media Cybernetics) was used to count the number
of GFP expressing cells and measure GFP intensity.
GFP positive cells were assumed to have at least a
Biomarkers V - EGFR Thursday, 7 July 2011 12:30-14:00 200,000 mean equivalent Áuorochrome labeling,
which is the cut-off level of GFP intensity previously
O39.06 CIRCULATING TUMOR CELLS obtained using lung, breast, and gastric cell lines,
IN PERIPHERAL VENOUS BLOOD OF and more. Dead cells were assumed to be 20 ƫm
PRIMARY NON-SMALL CELL LUNG diameter or more. The GFP-positive cells were
CANCER PATIENTS: DETECTION USING regarded as viable CTCs, and the clinicopathologic
ADENOVIRUS GFP-LABELING factors were compared with the results of CTC
Yukitoshi Satoh1, Dai Ishii1, Hirotsugu Yamazaki1, analysis.
Fumihiro Ogawa1, Yoshio Matsui1, Kazu Shiomi1, Results: Seventy-three (92%) patients had positive
Hideki Amano1, Naomi Kurouzu1, Hidenori Hara1, GFP results (33 women, 40 men), in contrast to none
Kenji Nezu1, Akira Iyoda1, Tomoya Fukui2, Satoshi of the 72 healthy controls. The mean GFP-positive
Igawa2, Masato Katagiri2, Noriyuki Masuda2, Akinori cell count per 7.5 ml PVB was 9.2 (range, 0 - 86).
Kawai3, Jun Sato3, Yukio Tsujino3 As for clinical stages, GFP-positive cells were
1
Department Of Thoracic Surgery, Kitasato detected in 92% for Stage IA, 100% each for Stages
University School Of Medicine/Japan, 2Department IB, IIB, IIIA, and IIIB, and 78% for IV (p=0.29).
Of Respiratory Medicine, Kitasato University School There was no signiÀcant correlation with the stages
Of Medicine/Japan, 3Central Research Laboratories, or between GFP-positive cell count or any other
Sysmex Corporation/Japan patient characteristic including age (p=0.68), gender,
smoking habit (p=0.36), tumor size (p=0.13), and
Background: Circulating tumor cells (CTCs) in histologic type (p=0.20). Among the total 49 patients
peripheral venous blood (PVB) are considered as underwent surgical resection, and 46 (94%) had
potential surrogates for distant metastases, a critical positive GFP results. With reference to postoperative
factor inÁuencing decision making and therapy stages, CTCs were detected in 90% for Stage IA,
of primary non-small cell lung cancer (NSCLC) 100% each for Stages IB, IIA, IIB, and IIIA, and
patients. We here evaluated viable CTCs in NSCLC 50% for IIIB (p=0.85).
patients using a new assay with telomerase-speciÀc Conclusion: CTCs were frequently detected in
replication-selective adenovirus expressing green clinical and postoperative Stage IA diseases. These
Áuorescent protein (GFP). results indicate that detection of viable CTCs with
Methods: From May 2009 to April 2010, a total of our GFP-expression virus-based method provides
79 consecutive NSCLC patients (43 men, 36 women) supersensitive information for NSCLC patients. The
who underwent treatment were included. CTCs in long-term outcome should be analyzed to assess the
PVB were quantitatively examined before treatment. prognostic impact.
For this 7.5 ml aliquots of PVB were collected Keywords: Circulating tumor cell, Non-small cell
using CPD-anticoagulant agent and incubated at lung cancer, green Áuorescent protein, telomerase
37ºC with OBP-401® (Oncolys BioPharma, Japan)
viruses for 24 hours. Adenovirus OBP-401® features A revised/updated abstract may be included in
a human telomerase reverse transcriptase gene the Late Breaking Abstract Supplement, available
promoter inserted upstream of the E1 genes, along at the 14th World Conference on Lung Cancer.
with a GFP gene driven by a Cytomegalovirus
Biomarkers V - EGFR Thursday, 7 July 2011 12:30-14:00 based chemotherapy. The predictive role of TS or
TTF1 expression is required to be validated in a
O39.07 SIGNIFICANCE OF prospective randomized study.
THYMIDYLATE SYNTHASE AND Keywords: Pemetrexed, Thyroid transcription factor
THYROID TRANSCRIPTION FACTOR 1, Thymidylate synthase, predictive factor
1 EXPRESSION IN PATIENTS WITH
NONSQUAMOUS NON-SMALL
CELL LUNG CANCER TREATED Session O40: Genetic Aberrations
WITH PEMETREXED-BASED
CHEMOTHERAPY Thursday, 7 July 2011
Jong-Mu Sun, Myung Ja Kim, So Young Cheon, Se
Young Lee, Jin Seok Ahn, Myung-Ju Ahn, Keunchil
Park Genetic Aberrations Thursday, 7 July 2011 12:30-14:00
Internal Medicine, Samsung Medical Center/Korea
O40.01 COMPLETE GENOME
Background: We try to evaluate whether SEQUENCING OF A HUMAN B3
thymidylate synthase (TS) or thyroid transcription THYMOMA
factor 1 (TTF1) protein expression can predict Iacopo Petrini, Yisong Wang, Marbin Pineda, Sean
clinical outcomes for pemetrexed-based Davis, Giuseppe Giaccone
chemotherapy in patients with nonsquamous non- National Cancer Institute, National Institute Of
small cell lung cancer (NSCLC). Health/United States Of America
Methods: A total of 285 consecutive patients with
nonsquamous NSCLC treated with pemetrexed- Background: Molecular biology of thymomas is
based chemotherapy were reviewed for the poorly understood. We sequenced the whole genome
expression of TS and TTF1 by Immunohistochemical of one B3 thymoma and the matched normal DNA
stain. from blood sample of the same patient.
Results: TS and TTF1 expression were successfully Methods: Frozen primary tumor and blood were
analyzed in 193 and 284 cases, respectively. collected from a Caucasian 53 female with B3/
Tumors with TS-negativity or TTF1-positivity was stage IVA thymoma after surgery. DNA and RNA
more frequent in group of female, younger age, were extracted using All Prep kit (Qiagen). Array
adenocarcinoma, or never-smoker. Higher response Comparative genomic hybridization (CGH) was
rates for pemetrexed-based chemotherapy were performed on 180K array (Agilent) and Agilent
associated with TS-negativity (33.7% vs. 14.1%, platform. Transcriptome sequencing was performed
P = 0.002) and TTF1-positivity (28.1% vs. 9.8%, using 72bp paired-end sequencing and 2 Áow cell
P < 0.001), respectively. In univariate analysis, lanes of genome analyzer II (Illumina). Whole
progression-free survival (PFS) for pemetrexed- genome sequencing (WGS) was performed on tumor
based chemotherapy was signiÀcantly longer in and normal DNA using Complete Genomic Inc
groups of adenocarcinoma (2.9 vs. 1.4 months, P = platform.
0.001), TS-negativity (4.1 vs 2.0 months, P = 0.001), Results: In the WGS analysis, a total of 222.02
and TTF1-positivity (3.9 vs. 1.3 months, P < 0.001). gigabases (Gb) of sequence were mapped (95.3% of
In multivariate analysis, TS-negativity (HR = 0.69; genome called) for the tumor sample and 234.53 Gb
95% CI, 0.50 – 0.96) and TTF1-positivity (HR = (96.4% of genome called) for the matched normal
0.51; 95% CI, 0.36 – 0.73) were independently control. Sequence reads were aligned to a human
associated with longer PFS, respectively. Patients reference genome (NCBI Build 37) and a local de
with TTF1-positive tumors had also signiÀcantly novo assembly was used to call and score variants.
longer overall survival time than patients with TTF1- Both array CGH and copy number (CN) aberrations
negative tumors (25.4 vs. 14.2 months, HR = 0.55; estimated from WGS showed CN imbalance patterns
95% CI, 0.39 – 0.77). comparable with those previously described for
Conclusion: Low TS or high TTF1 protein B3 thymomas with CN gain of chromosomes 1q,
expression was signiÀcantly associated with 5, 7 and X and CN loss of 3p, 6, 11q42.2-qter and
better clinical outcomes in nonsquamous NSCLC q13. We observed 3,096,049 single nucleotide
patients who were treated with pemetrexed- variations (SNVs) in the tumor and 3,314,611 in
the normal DNA. The transition/transversion ratio tumor. The Áuorescence-in situ hybridization (FISH)
was 2.14 and 1.83 for germ line and somatic SNVs, probe for CSNK2A1P (chromosome 11p15.3) was
respectively. Somatic SNVs were deÀned as those purchased from BACPAC Resources (Oakland,
variations present in tumor but not normal matched CA). The chromosome 11 centromere was labeled
DNA. We observed 5946 diploid somatic indels by Vysis CEP 11 SpectrumGreen™ probe (Abbott
and 6530 SNVs, of which 43 and 83 were within Molecular, Abbott Park, IL). The allele-speciÀc
exonic regions, respectively. 29 indels and 25 SNVs ampliÀcation was measured using the ABI PRISM
were not previously described as SNPs, nor in 7700 sequence detection system. For determination
segmental duplication, or synonymous mutations. of the kinase activity of the expressed CSNK2A1
By comparison with the transcriptome sequencing and CSNK2A1P proteins, Casein Kinase 2 Assay
data of the same tumor sample, we conÀrmed the Kit (Millipore, Bedford, MA) was used according
expression of 6 mutated genes, while for 45 mutated to manufacture’s protocol. The data are shown as
genes there were not enough reads to conÀrm the mean values ± standard deviation (SD). Student’s
calls. t-test was used to compare results between control
Conclusion: WGS and accompanying transcriptome and experimental groups in the colony formation
sequencing offer an unprecedented view of the assay. Chi-square test was used to compare the
genome of a thymoma cancer patient sample. We frequency of the CSNK2A1P polymorphisms
are actively engaged in determining the potential between lung cancer tissues and normal controls.
functional signiÀcance of the genomic variants in Pearson correlation coefÀcient was used to access
the context of transcriptome sequencing and copy the correlation between mRNA expression and
number variation to gather clues as to the underlying copy numbers of the CSNK2A1P gene in cancer
biology driving this relatively rare tumor type. cell lines. Statistical analysis was carried out using
Keywords: Thymoma, Next generation sequening, SPSS (version 10.0, Chicago, IL). A P value of less
Whole genome sequencing, CGH than 0.05 was considered statistically signiÀcant. All
statistical tests were two-sided.
Results: We found evidence of ampliÀcation and
Genetic Aberrations Thursday, 7 July 2011 12:30-14:00 over-expression of the CSNK2A1P gene in non-
small cell lung cancer and leukemia cell lines and
O40.02 CK2 INTRONLESS GENE 25% of the lung cancer tissues studied. The mRNA
AMPLIFICATION IN NON-SMALL CELL expression levels correlated with the copy numbers
LUNG CANCER of the CSNK2A1P gene. We also identiÀed a
Ming-Szu Hung1, Yu-Ching Lin1, Zhidong Xu2, novel polymorphic variant (398T/C, I133T) of the
David M. Jablons2, Liang You2 CSNK2A1P gene and showed that the 398T allele
1
Chang Gung Memorial Hospital/Taiwan, 2Surgery, is selectively ampliÀed over the 398C allele in 101
University Of California/United States Of America non-small cell lung cancer tissue samples compared
to those in 48 normal controls (p = 0.013<0.05).
Background: Protein kinase CK2 is frequently up- We show for the Àrst time CSNK2A1P protein
regulated in human cancers, although the mechanism expression in transfected human embryonic kidney
of CK2 activation in cancer remains unknown. In 293T and mouse embryonic Àbroblast NIH-3T3
this study, we investigated the role of the CK2Ơ cell lines. Both alleles are transforming in these
intronless gene (CSNK2A1P, a presumed CK2Ơ cell lines, and the 398T allele appears to be more
pseudogene) in the pathogenesis of human lung transforming than the 398C allele. Moreover, the
cancer. 398T allele degrades PML tumor suppressor protein
Methods: The human cancer (Jakurt, H1299, more efÀciently than the 398C allele and shows a
A549, A427, H441, H1703, H322, H460, HCT116, relatively stronger binding to PML. Knockdown of
H1975, H322, H358, H838, H28, H2052, Hela and the CSNK2A1P gene expression with speciÀc siRNA
H1650) and normal lung (WI-38 and CCL-211) cell increased the PML protein level in lung cancer cells.
lines were obtained from American Type Culture Conclusion: We report, for the Àrst time, that the
Collections (Manassas, VA). Fresh tumor tissues and CSNK2A1P gene is a functional proto-oncogene
adjacent normal tissues were obtained from patients in human cancers and its functional polymorphism
with non-small cell lung cancer (NSCLC) who appears to degrade PML differentially in cancer
were undergoing surgical resection of the primary cells. These results are consistent with an important
role for the 398T allele of the CSNK2A1P in human within.

lung cancer susceptibility. Methods: Gene dosage in lung cancer specimens
Keywords: ampliÀcation, NSCLC, oncogene, CK2 was assessed by whole-genome array CGH. DNA
methylation was assessed using the Illumina
HumanMethylation27 platform, with additional
Genetic Aberrations Thursday, 7 July 2011 12:30-14:00 data obtained by MS-PCR for cancer specimens
and matched normal lung tissues where available
O40.03 EYA4 IS A FREQUENTLY and appropriate. Gene expression was assessed
INACTIVATED TUMOUR SUPPRESSOR using various microarray platforms, qTR-PCR,
GENE WITHIN THE 6Q LUNG CANCER and western blot techniques. Genotyping studies
SUSCEPTIBILITY LOCUS were performed using Affymetrix SNP arrays.
Ian Wilson1, Emily A. Vucic1, Katey S.S. EnÀeld1, EYA4 knock-down and knock-in experiments were
Raj Chari2, Yu-An Zhang3, Niki Radulovich4, Daniel performed by stable viral transfection of appropriate
Starczynowski5, Judit Banath6, May Zhang6, Andrea constructs.
Pusic6, Megan Fuller7, Kim Lonergan6, Timon Results: Using integrated genomic and epigenomic
Buys6, John Yee8, Ite A. Laird-offringa9, Pengyuan analysis of sporadic lung cancers, we have identiÀed
Liu10, Ming S. Tsao11, Marshall Anderson12, Ming frequent two-hit inactivation of the gene EYA4
You13, Kevin Bennewith1, Aly Karsan7, Calum E. which is located within the locus at 6q23.2. It is
Macaulay14, Stephen Lam7, Adi F. Gazdar15, Wan inactivated by either deletion or hypermethylation in
Lam1, Suhaida Selmat16 over 75% of tumours examined and is inactivated by
1
Integrative Oncology, British Columbia Cancer both at the same time (two-hit) in 20% of those same
Research Centre/Canada, 2Genetics, Harvard lung tumours. In addition to frequent inactivation
Medical School/United States Of America, by these two mechanisms, DNA sequencing in a
3
Pathology, Ut Southwestern/United States Of panel of lung cancer cell lines and tumour tissues
America, 4University Health Network/Canada, identiÀed a missense mutation which is predicted
5
Cincinnatti Children’s Hospital/United States Of to be pathogenic. Interestingly, this mutation occurs
America, 6Integrated Oncology, British Columbia in lung cancer cells demonstrating deletion but
Cancer Research Centre/Canada, 7Medical not hypermethylation. Other somatic and germline
Biophysics, British Columbia Cancer Research unclassiÀed DNA sequence variants were also
Centre/Canada, 8Thoracic Surgery, British Columbia discovered in the UTR and intronic regions of the
Cancer Agency/Canada, 9Biochemistry & Molecular gene, which may impact gene regulation or splicing.
Biology, University Of Southern California/ We have conÀrmed the role of DNA methylation in
United States Of America, 10Surgery, Washington silencing the gene by pharmacologic restoration of
University/United States Of America, 11Princess EYA4 expression in hypermethyalted cells and by
Margaret Hospital/Canada, 12Cancer And Cell demonstrating a robust correlation between DNA
Biology, University Of Cincinnati Medical Center/ methylation levels and mRNA expression levels
United States Of America, 13Medical College Of in lung cancer cells. We have identiÀed deletion of
Wisconsin Cancer Center/United States Of America, EYA4 at the earliest stages of disease (in carcinoma
14
Integrative Oncology, Bc Cancer Research in situ) as well as hypermethylation of the gene
Centre/Canada, 15Ut Southwestern Medical Center/ in histologically normal epithelia of people with
United States Of America, 16Norris Cancer Center, cancer. Our functional studies in vitro have shown
University Of Southern California/United States Of that cells depleted of EYA4 exhibit delayed DNA
America repair and avoidance of apoptosis - consistent with
its proposed role as a tumour suppressor gene and
Background: While the environmental factors a susceptibility gene. Taken together, these data
predisposing to lung cancer are well known, indicate that disruption of EYA4 is likely a causal
the genetics underlying lung cancer risk have event in tumorigenesis. Additionally, examination of
only recently begun to be unravelled. The recent a familial lung cancer cohort has identiÀed 5 SNPs
discovery of the familial lung cancer susceptibility in EYA4 which are associated with lung cancer risk.
locus at chromosome 6q23-25 has been a pivotal The clinical relevance of EYA4 is further highlighted
discovery in this regard and has spurred further work by the association of low EYA4 expression with poor
to identify the important gene, or genes, located prognosis in a number of survival datasets. Finally,
preliminary results in both in vitro soft agar colony them, 1265 were over-expressed in tumour tissues
formation assays as well as in vivo subcutaneous and 1725 were under-expressed suggesting that
tumour growth assays suggest that EYA4 suppresses different LC types have more similarity in depression
lung tumour growth. of some processes than in activation. The numbers
Conclusion: Our results indicate that EYA4 is of speciÀc genes were 687, 1049, and 5104 for
a frequently inactivated tumour suppressor gene ADC, SCC, and carcinoid tumour, respectively. GO
located in the previously described lung cancer analyses showed that the biological processes and
susceptibility locus, inactivation of which is molecular functions common to different types of
associated with both poor prognosis and lung cancer LC included an increase of proliferative potential, an
risk. increase of the cell independence, and a decrease in
Keywords: susceptibility, hypermethylation, tumour mediators of normal morphology and tissue integrity,
suppressor gene while biological processes for different cancer
types reÁect the pathophysiologic features, cell-of-
origin, and localization of the tumours. Although
Genetic Aberrations Thursday, 7 July 2011 12:30-14:00 there was an overlap of biofunctions between the
different cancer types, we found the direction and
O40.05 GLOBAL GENE EXPRESSION speciÀcity of some biofunctions was different in
PROFILING TO IDENTIFY COMMON different cancer types, reÁecting pathophysiologic
NETWORKS UNDERLYING LUNG features of the tumours. WGCNA analysis for genes
CANCER AND SPECIFIC MARKERS differentially expressed between tumours and normal
OF DIFFERENT LUNG CANCER tissues identiÀed Àve modules of tightly correlated
HISTOLOGICAL TYPES genes. GO analysis of the module members revealed
Maxim B. Freidin1, Andrew G. Nicholson2, Eric an increase of cell independence, a decrease of
Lim3, Miriam F. Moffatt1, William O. Cookson1 normal lung morphology and function, an increase of
1
National Heat And Lung Institute, Imperial College proliferation, and an increase in keratinisation. One
London/United Kingdom, 2Academic Department Of of the modules showed a signiÀcant correlation with
Histopathology, Royal Brompton Hospital/United NSCLC subtypes (R = 0.7616; P= 5.5e-08) and was
Kingdom, 3Academic Department Of Thoracic mainly represented by the genes encoding keratins,
Surgery, Royal Brompton Hospital/United Kingdom serpins, and desmosome component proteins. Six
genes from this module were tested for their ability
Background: Gene expression proÀles have the to discriminate between SCC and ADC. Three of
potential to discover molecular mechanisms of them were well-known markers (KRT17, DSG3,
underlying lung cancer. They may also identify new TP63), and three of them were chosen based on their
and better biomarkers of disease progression and module membership score (novel gene (NG)1, NG2,
treatment efÀciency. and NG3). The best discrimination model included
Methods: Gene expression proÀling was performed DSG3 and NG1, and was strongly veriÀed in an
in tumour and matched normal tissues of 104 lung independent publicly available dataset. It was also
cancer (LC) patients using Affymetrix HumanGene possible to identify genes speciÀc for other tumour
1.1ST microarrays. We identiÀed genes that were types, which we are currently verifying.
differentially expressed between tumour and Conclusion: Lung cancer subtypes share common
normal tissues as well as between different lung molecular processes, but also evidence the
cancer subtypes. Common LC genes were deÀned expression of speciÀc genes relevant to cell-of-
as the genes which are differentially expressed origin and localization of tumours. GO and WGCNA
between normal and tumour tissues in carcinoid analyses revealed clusters of genes characterising
tumour, squamous cell carcinoma (SCC), and different aspects of disease manifestation. Based on
adenocarcinoma (ADC). SpeciÀc LC genes were the WGCNA results, new effective biomarkers for
deÀned as genes differentially expressed between SCC/ADC were discovered.
one cancer type versus the others. Weighted gene Keywords: Lung cancer, gene expression proÀles,
correlation network analysis (WGCNA) was genetic networks, Biomarkers
applied to reveal modules of tightly correlated genes
characterising different tumour types.
Results: We found 2990 common LC genes; among
Genetic Aberrations Thursday, 7 July 2011 12:30-14:00 by histology. We identiÀed 171 CpG loci highly
methylated in tumours which exhibited substantially
O40.06 DISTINCT METHYLATION higher methylation levels compared to commonly
PROFILES IN LUNG CANCER AND ITS methylated markers such as CDKN2A, MGMT and
MAJOR SUBTYPES DAPK1. The most frequently methylated genes
Casey M. Wright1, Santiyagu M.F. Savarimuthu2, belonged to 3 major groups, the HOX family,
Krishna B. Sriram2, Mitchell Stark3, Nick K. Polycomb repressor complex associated genes or
Hayward3, Ian A. Yang4, Rayleen Bowman4, Kwun both. Five high priority candidate genes (HOXB4,
M. Fong4 HOXA9, PTGDR, PRDM14 and HOXD9) were
1
School Of Medicine, University Of Queensland/ selected for further analyses on the basis of high
Australia, 2University Of Queensland/Australia, methylation differences between normal and
3
Oncogenomics Laboratory, Queensland Institute tumour lung. Methylation levels of two candidates
Of Medical Research/Australia, 4Department Of PTGDR and PRDM14 were then validated using
Thoracic Medicine, The Prince Charles Hospital/ an independent method, Sequenom’s Epityper.
Australia Moderate correlations were observed between copy
number and methylation for PRDM14 (Spearmann
Background: Epigenetic gene inactivation of Rho = 0.238, P=0.008). Next we demonstrate
tumour suppressor genes underlies several human samples frequently methylated across multiple genes
cancers. The potential to develop targeted therapies demonstrate a survival advantage (Log-rank=0.031).
is being driven by the recent development of high- Finally, we report methylation signatures capable
throughput genome-wide approaches including of distinguishing adenocarcinoma and squamous
methylation-based microarray technology. The cell carcinoma histology (sensitivity = 0.896,
attractiveness of selecting methylation biomakers speciÀcity=0.861, Positive Predictive Value=0.857,
lies in their ability to be easily reactivated or Negative Predictive Value=0.898).
deactivated. The aim of the current study is to Conclusion: DNA methylation proÀles differ
characterize the lung cancer methylome, to identify between normal and tumour lung and are predictive
novel methylated genes and a methylation proÀle for adenocarcinoma and squamous cell carcinoma
to distinguish adenocarcinoma and squamous cell histology. Further validation studies are required
carcinoma subtypes. to conÀrm involvement of candidate genes in lung
Methods: Methylation proÀling by Illumina carcinogenesis. Supported by: The Prince Charles
InÀnium Methylation27 arrays was performed on Hospital Foundation, Queensland Clinical Research
226 primary lung tumours and 80 normal lung Fellowship, NHMRC Biomedical Scholarship,
samples from the TPCH lung tumour bank. Data NHMRC Project Grants 198401 and APP1006695.
was feature extracted using proprietary software Keywords: Epityper, Methylation proÀling, Non-
(GenomeStudio, Illumina, Hayward, CA). We used small cell lung cancer
two separate approaches in gene identiÀcation:
1) we utilised stringent criteria employed by the
The Cancer Genome Atlas (TCGA) project on Genetic Aberrations Thursday, 7 July 2011 12:30-14:00
Glioblastoma performing separate analyses for
training and test sets and 2) we used in-house O40.07 NOTCH ACTIVATION DRIVES
(TPCH) criteria (vis. (1) false discovery rate (FDR) MICRORNA-200-DEPENDENT EMT &
Q<1x10E-7, (2) P-value < 1x10E-7, (3) frequency METASTASIS IN A MURINE MODEL OF
of methylation across samples and (4) magnitude NSCLC
of difference between normal/tumour pairs (at least Don L. Gibbons1, Yanan Yang2, Young-Ho Ahn2,
2-fold)). High priority candidate gene methylation Chad J. Creighton3, Alexander Pertsemlidis4, Philip
levels were validated using Sequenom’s Epityper A. Gregory5, Jennifer Saik6, B. J. Gill6, Zain H.
methodology. Prediction proÀling was performed Rizvi2, Jennifer West6, Jonathan M. Kurie2
1
using BRB Array Tools. Thoracic, Head/neck Medical Oncology &
Results: Unsupervised cluster analyses demonstrated Molecular And Cellular Oncology, University Of
distinct clusters for normal and tumour lung Texas, MD Anderson Cancer Center/United States
and in primary tumours identiÀed six distinct Of America, 2University Of Texas, MD Anderson
clades of tumours which could not be explained Cancer Center/United States Of America, 3Baylor
College Of Medicine, Duncan Cancer Center/ the Notch receptors and multiple ligands. Metastasis
United States Of America, 4University Of Texas, was dependent upon activation of Notch by the
Southwestern, Hammon Cancer Center/United States ligand jagged2, which suppressed microRNA-200
Of America, 5University Of Adelaide/Australia, 6Rice (miR-200) family expression and thereby triggered
University/United States Of America EMT. Jagged2 activated the Notch transcriptional
mediator GATA3, which directly bound to the miR-
Background: Non-small cell lung cancer (NSCLC) 200 promoter and suppressed its activity. Either
is the leading cause of cancer death worldwide, jagged 2 or GATA3 knockdown increased miR-
primarily due to metastatic disease. We lack a clear 200 levels, reversed EMT, abrogated tumor cell
understanding of the molecular and cellular basis for responsiveness to TGFB and suppressed metastasis.
lung cancer metastasis, partly because of the lack of We conclude that jagged2/Notch initiates metastasis
experimental models. by activating GATA3-mediated suppression of miR-
Methods: We have developed an experimental 200 expression.
syngeneic model of metastatic NSCLC using cell Conclusion: New therapeutics to target metastatic
lines derived from a genetic mouse model with NSCLC will emerge from a better understanding
K-rasG12D & p53R172H, which develops spontaneous of the tumor biology. This experimental model
primary lung adenocarcinoma with metastases recapitulates many features of human NSCLC and
similar to the human disease. has revealed a role for EMT in metastasis, the miR-
Results: Combined mRNA/microRNA proÀling 200 family as regulators of the cellular switch, and
of highly metastatic versus non-metastatic a mechanism whereby microenvironmental changes
syngeneic tumors revealed a signature of EMT inÁuence levels of jagged2 and GATA3, altering
and associated loss of the miR-200 family (miR- miRNA expression in the tumor cells and their
141, 200a, 200b, 200c & 429) expression. Forced ability to metastasize. We are currently working to
miR-200 expression abrogated their capacity understand the other factors in microenvironment-
to undergo EMT, invade, and metastasize and dependent regulation of miR-200 members and the
conferred transcriptional features of metastasis- downstream targets of miR-200.
incompetent cells, while forced Zeb expression Keywords: notch, epithelial-mesenchymal
in epithelial cells induced EMT and a metastatic transition, microRNA-200, Metastasis
phenotype, supporting the idea that miR-200
repression is necessary and sufÀcient for tumor
metastasis. Despite signiÀcant genetic alterations, Session O41: Supportive Care
the metastasis-prone tumor cells displayed a marked
plasticity in response to contextual cues, with Thursday, 7 July 2011
the ability to form growth-limited well-polarized
epithelial spheres with high miR-200 family
expression in 3D culture on Matrigel, which were Supportive Care Thursday, 7 July 2011 12:30-14:00
tumorigenic & metastatic upon in vivo injection.
Experiments in a 3D synthetic hydrogel system O41.01 ANALYSIS OF PHASE III
have further demonstrated the regulation of miR- STUDIES FOR PALONOSETRON,
200/Zeb1 levels and cell phenotype by cell-ECM ONDANSETRON, DOLASETRON, AND
interactions. Analysis of a panel of 40 human GRANISETRON IN THE PREVENTION
NSCLC cell lines revealed 2 groups, based upon OF CHEMOTHERAPY-INDUCED
a tight negative correlation between miR-200 and NAUSEA AND VOMITING IN PATIENTS
Zeb1: those with high miR-200/low Zeb1 levels or WITH LUNG CANCER
low/absent miR-200 and high Zeb1 levels. These Lee Schwartzberg1, Gary R. Morrow2, Sally Y.
data strongly suggest that the changes found in the Barbour3, Raza Ahmed4, Gianluca Ballinari5,
experimental model are relevant to human NSCLC. Michael D. Thorn6, David Cox4
1
A metastatic subpopulation of the murine tumors Senior Partner & Medical Director, Acorn And
demonstrated upregulation of the CD133 marker in West Clinic/United States Of America, 2University
cells interacting with adjacent stroma. Expression Of Rochester/United States Of America, 3Duke
proÀling of the metastatic CD133high & non- University Medical Center/United States Of
metastatic CD133low cells revealed high expression of America, 4Eisai, Inc./United States Of America,
5
Helsinn Healthcare Sa/Switzerland, 6Statistical (5.3%; 3.5%; 1.9%, respectively), and increased ALT
Resources, Inc./United States Of America (1.8%; 5.7%; 8.6%, respectively).
Conclusion: In this analysis, palonosetron
Background: Lung cancer is the leading cause demonstrated improved CINV prevention and a
of cancer-related death for both men and women comparable safety proÀle relative to 1st generation
worldwide, with chemotherapy-induced nausea 5HT3-RAs in patients with lung cancer.
and vomiting (CINV) a common side effect of Keywords: Lung cancer, palliative care,
chemotherapeutic treatment. Patients consistently Chemotherapy-induced nausea
report that CINV is amongst the most distressing
aspects of chemotherapy, <<1>> with one or A revised/updated abstract may be included in
two emetic episodes associated with a signiÀcant the Late Breaking Abstract Supplement, available
deterioration in the quality of life – often at the 14th World Conference on Lung Cancer.
resulting in dose delay or refusal of therapeutic
treatment.<<2,3>> Palonosetron is a potent second-
generation 5-HT3 receptor antagonist (5HT3-RA) Supportive Care Thursday, 7 July 2011 12:30-14:00
with a unique pharmacologic proÀle. Palonosetron
has been shown to trigger receptor internalization, O41.02 A 3-DAY ORAL APREPITANT
inhibit in vivo NK1 agonist responses, as well as REGIMEN PROVIDES SUPERIOR
have a higher binding afÀnity for the 5-HT3 receptor PREVENTION OF CINV OVER
and longer half-life when compared to 1st generation STANDARD THERAPY IN CHINESE
5HT3-RAs. PATIENTS RECEIVING HIGH-DOSE
Methods: We conducted a pooled analysis of 4 CISPLATIN.
phase III studies to assess the comparative safety Li Zhang1, Ying Cheng2, Hong-Yu Zhang3, Caicun
and efÀcacy proÀles of palonosetron, ondansetron, Zhou4, Baohui Han5, Yiping Zhang6, Cheng Huang7,
dolasetron, and granisetron in the prevention of Jianhua Chang8, Xiang Q. Song9, Jun Liang10, Houjie
CINV in patients with lung cancer. EfÀcacy data Liang11, Chunxue Bai12, Shiying Yu13, Jia Chen14,
for patients with lung cancer was entered into a Jie Wang15, Hongming Pan16, Alexandra Carides17,
logistic regression model, with the primary outcome Denesh Chitkara18
1
variables being complete response (CR) during the Medical Oncology, Sun Yat-sen University Cancer
0-24hr (acute) period, the 24-120hr (delayed) period, Center/China, 2Tumor Medical, Jilin Province
and the 0-120hr (overall) period. A comparative Cancer Hospital/China, 3Fifth Hospital AfÁiated
descriptive safety assessment was also conducted. Sun Yat-sen University/China, 4Oncology, Tongji
Results: This pooled analysis included 783 patients University AfÀliated Shanghai Pulmonary Hospital/
with lung cancer. The patients were administered China, 5Shanghai Jiaotong University AfÀliated
either palonosetron 0.25mg, n=57; palonosetron Shanghai Chest Hospital/China, 6Zhejiang
0.75mg, n=367; or 1st generation 5HT3-RA, n=360. Cancer Hospital/China, 7Medical Department,
In the acute phase, observed CR rates were 78.3% The Cancer Hospital Of Fujian/China, 8Fudan
for palonosetron and 76.3% for 1st generation 5HT3- University Shanghai Cancer Center/China,
9
RAs (OR=0.88; p=NS from model). SigniÀcantly Medical Oncology, AfÀliated Tumor Hospital Of
higher CR rates were observed for palonosetron Guangxi Medical University/China, 10The AfÀliated
when compared to 1st generation 5HT3-RAs in both Hospital Of Qingdao University/China, 11Southwest
the delayed phase (53.5% vs. 41.8%; OR=0.78, Hospital ,third Military Medical University/China,
12
p=0.0014) and the overall phase (51.2% vs. 39.8%; Zhongshan Hospital Fudan University/China,
13
OR=0.79, p=0.0021). The adverse event (AE) Tongji Hospital/China, 14Jiangsu Cancer Hospital/
proÀle of palonosetron (all doses) was similar to China, 15Peking University School Of Oncology,
1st generation 5HT3-RA across all trials for CINV Beijing Cancer Hospital/China, 16Sir Run Run Shaw
in patients with lung cancer. The incidence of Hospital/China, 17Merck & Co./United States Of
treatment-related AEs was also similar across trials; America, 18Merck & Co/United States Of America
palonosetron 0.25mg, 17.5%; palonosetron 0.75mg,
30.0%; and 1st generation 5HT3-RAs, 31.1%, with Background: Aprepitant (APR) is a Neurokinin-1
notable treatment-related AEs including constipation receptor antagonist that has been shown in clinical
(7.0%; 13.6%; 11.9%; respectively), headache studies to be efÀcacious in preventing CINV and
to be well tolerated. The efÀcacy, safety, and Supportive Care Thursday, 7 July 2011 12:30-14:00
tolerability of APR in Chinese patients has not been
studied. This phase III, multicenter, double-blind, O41.03 PALONOSETRON, APREPITANT
placebo-controlled, randomized study assessed the AND DEXAMETHASONE TO PREVENT
efÀcacy, safety, and tolerability of a 3-day oral APR NAUSEA AND VOMITING DURING
regimen compared with that provided by a standard MULTIPLE CYCLES OF CISPLATIN-
therapy regimen (ST), in Chinese patients. BASED CHEMOTHERAPY FOR LUNG
Methods: Four hundred twenty-one patients, 70% CANCER PATIENTS
of whom were NSCLC, receiving chemotherapy that Flavia Longo1, Giovanni Mansueto2, V. Lapadula1,
included cisplatin 70 mg/m2 were randomized (1:1) G. Del Ben1, L. De Filippis1, E. Del Signore1, B.
to receive the APR regimen (APR 125 mg po d1 and Gori1, L. Stumbo1, R. De Sanctis1, S. Quadrini1, M.
80 mg d2-3, granisetron 3 mg iv d1, DEX 6 mg po Di Seri1
1
d1, and 3.75 mg d2-4) (n=209) or the ST (placebo Medical Oncology A, Policlinico Umberto Primo/
d1-3, granisetron 3 mg iv d1, and DEX 10.5 mg d1 Italy, 2Medical Oncology/Italy
and 7.5 mg d2-4) (n=212). The primary endpoint was
the percentage of patients with complete response Background: With repeated courses of
(CR; no emesis and no use of rescue therapy) in the chemotherapy, chemotherapy-induced nausea and
overall phase (0 – 120 hours after chemotherapy); vomiting (CINV) is progressively more difÀcult to
secondary endpoints were no vomiting (NV), time to be controlled. The aim of our study was to evaluate,
Àrst vomiting episode, and patient-reported impact of for the Àrst time, whether the antiemetic efÀcacy
CINV on daily life. of the triple combination palonosetron, aprepitant,
Results: Overall baseline characteristics were and dexamethasone could be sustained for up to six
balanced between two arms. All 421 patients cycles of highly emetogenic chemotherapy (HEC) in
received at least one dose of treatment drug and lung cancer patients.
had at least one post-treatment assessment. The Methods: Chemotherapy-naïve patients receiving
proportions of patients with CR in the overall cisplatin-based HEC, were treated with palonosetron
phase were 69.6% in the APR regimen and 57.0% 0.25 mg/i.v., dexamethasone 20 mg/i.v. and
in the ST regimen (p=0.007). The proportions of aprepitant 125 mg/p.o., 1-hour before chemotherapy.
patients with NV in the overall phase were 70.6% Aprepitant 80 mg/p.o. and dexamethasone 4 mg
and 57.0%, respectively (p=0.003) Results from the p.o. were administered on days 2-3. The primary
Quality of Life questionnaire showed signiÀcant endpoint was complete response (CR- no vomiting
differences between the APR and ST in two of the and no use of rescue medication), over Àve days
vomiting domains: ‘ability to enjoy a meal’ (76.0% following HEC in up to six cycles. Secondary
vs 66.3%, respectively; p<0.05) and ‘hardship on endpoints were emesis-free and nausea-free rates
others’ (78.0% vs 67.3%, respectively; p<0.05). The during the Àve days following HEC in up to six
incidence of adverse events was generally similar in cycles. Safety was also evaluated
both treatment groups. In addition, the distribution Results: 158 patients with lung cancer were included
of toxicity grades was also generally similar between in the study. Median age was 64 years, 76.6% were
groups. male, 74.7% with stage IV disease. All patients
Conclusion: In our study, the addition of APR to the received cisplatin dose 75mg/sqm. EfÀcacy results
standard antiemetic treatment regimen was superior are reported in table:
in preventing CINV and was well tolerated compared
to the ST alone in Chinese patients undergoing Variable Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycle 5 Cycle 6
cisplatin therapy. CR % 74 77.2 80 79.2 81.8 83.2
Keywords: high-dose cisplatin, Aprepitant, CINV No emesis % 92.4 93 91.6 90.3 91.7 94.1
No nausea % 58.9 67.1 65.2 63.6 66.1 69.7
The most commonly reported side effects were mild

constipation, headache and hickup.
Conclusion: This study shows that, in lung
cancer patients, the antiemetic efÀcacy of the
triple combination palonosetron, aprepitant and
dexamethasone could be sustained for up to Methods: NSCLC patients with radiographic

six cycles of cisplatin-based HEC. These data veriÀcation of BM were treated with at least one
conÀrm that adequate control in the Àrst cycle of kind of BPs in this prospective observational study.
chemotherapy is more likely to be associated with NTX, SRE incidence and adverse event (AE) data
control of CINV in subsequent cycles. were collected at baseline and every 3 months after
Keywords: Highly Emetogenic Chemotherapy, treatment. Treatment continued at least until death.
Palonosetron, Aprepitant NTX levels were characterized as normal (N; <50
nmol/mmol) or elevated (E; 50 nmol/mmol).
A revised/updated abstract may be included in Results: 576 patients were enrolled with a median
the Late Breaking Abstract Supplement, available follow-up of 3.3 months, of whom 574 were eligible
at the 14th World Conference on Lung Cancer. for analysis. 14.0% of patients had BM diagnosed
using only one method (X-ray or CT or ECT). Most
patients had a combination of methods; the most
Supportive Care Thursday, 7 July 2011 12:30-14:00 common combination was CT+ECT, accounting
for 21.1%, and the combination of four (X-ray
O41.05 A MULTI-CENTER, +CT+MRI+ECT) accounted for 9.7%. The E
PROSPECTIVE STUDY ON THE baseline NTX patients were 374 (66.6%). Patients
EFFICACY AND SAFETY OF with multiple BM (465 pts, 81.0%) had signiÀcantly
BISPHOSPHONATE (BP) IN NON- higher NTX baseline level than those with single
SMALL CELL LUNG CANCER (NSCLC) BM (108.9 VS 67.3 nmol/mmol, p=0.0003). In
PATIENTS WITH BONE METASTASES the overall population, progression free survival
(BM) AT DIAGNOSIS (C-TONG-0801) (PFS) and overall survival (OS) were 5.8 and 14.7
Yi-Long Wu1, Li Zhang2, Caicun Zhou3, Shun Lu4, months respectively. There were no differences
Yiping Zhang5, Mei Hou6, Wenchao Liu7, Jie Wang8, between patients with baseline E vs N NTX in both
Gongyan Chen9, Yun Zhou10, Jun Liang11, Shiying PFS (6.1 VS 5.4 months, p=0.26) and OS (16.9 VS
Yu12, Chong-Rui Xu13 13.3 months, p=0.45), however, normalized NTX
1
Guangdong Lung Cancer Institute, Guangdong correlated with improved OS versus persistently
Academy Of Medical Sciences & Guangdong elevated NTX (>19 VS 15.6 months, p=0.04). The
General Hospital/China, 2Medical Oncology, Sun median time to Àrst SRE was 2.86 months. The
Yat-sen University Cancer Center/China, 3Shanghai overall SRE incidence was 21.7%. There was no
Pulmonary Hospital, Tongji University/China, difference in SRE incidence between patients with
4
Shanghai Chest Hospital, Jiaotong University/ E and N baseline NTX (21.1 VS 21.8%, p=0.85),
China, 5Zhejiang Cancer Hospital/China, 6West but zoledronic acid (ZOL) treated patients had a
China Hospital Of Sichuan University/China, 7The signiÀcantly lower SRE incidence than those with
4th Military Medical University Xijing Hospital/ non-ZOL BPs (22.0 VS 38.6%, p=0.01). All BPs
China, 8Department Of Thoracic Oncology, Beijing were generally well-tolerated, and fever was the
Cancer Hospital And Institute/China, 9The Cancer most common AE (4.51%).
Hospital Of Harbin Medical University, Harbin Conclusion: The most common diagnosis method
Medical University/China, 10Henan Provincial of BM is combination of CT and ECT in Chinese
Hospital/China, 11The AfÀliated Hospital Of Qingdao NSCLC patients. The baseline NTX characteristics
University/China, 12Tongji Hospital/China, 13Cancer were nearly consistent with prior retrospective
Center, Guangdong General Hospital/China studies. Elevated baseline NTX indicated high SRE
incidence; normalized NTX after BP treatment could
Background: A retrospective study showed be a prognostic biomarker for a better PFS and OS.
that bone metastatic NSCLC patients with high ZOL could signiÀcantly reduce the SRE incidence
N-telopeptide (NTX) at diagnosis demonstrated a more than other BPs.
higher risk of skeletal related event (SRE) and death Keywords: NSCLC, bone metastases,
than that with lower NTX (Lipton et al. Cancer, bisphosphonate, N-telopeptide
2008). The present study was to observe the efÀcacy
and safety of BPs in Chinese NSCLC patients with A revised/updated abstract may be included in
BM, to investigate NTX changes after treatment and the Late Breaking Abstract Supplement, available
longitudinal evaluation of BM diagnostic methods. at the 14th World Conference on Lung Cancer.
Supportive Care Thursday, 7 July 2011 12:30-14:00 In this pooled analysis of European data, 87 of
214 SREs (40.7%) were associated with inpatient
O41.06 HEALTH RESOURCE stays with a mean duration of 17.7 (SD=14.9) days
UTILISATION ASSOCIATED WITH per inpatient stay for the 92 stays (a SRE could
SKELETAL-RELATED EVENTS IN contribute multiple hospitalisations). The length
LUNG CANCER PATIENTS WITH of inpatient stays varied by facility (i.e., oncology,
BONE METASTASES: A PROSPECTIVE radiation, surgical) and SRE type. The most common
MULTINATIONAL OBSERVATIONAL SRE requiring hospitalisation was spinal cord
STUDY compression (12 of 15 events [80%]) with 14 in-
Vito Lorusso1, Ignacio Duran2, Guy Hechmati3, patient stays requiring an average length of stay
Cristina Garzon-rodriguez4, Diana Lüftner5, John of 18.7 (SD=12.3) days. The least common SRE
Ashcroft6, Amit Bahl7, Prayashi Ghelani8, Rachel requiring hospitalisation, radiation to bone (43 of
Wei9, Emma Thomas10, Herbert Hoefeler11 140 events [30.7%]), was still associated with 44 in-
1
Medical Oncology Unit, Oncology Institute Asl/ patient stays with an average of 19.7 (SD=17.2) days
Italy, 2Centro Integral Oncologico Clara Campal per in-patient stay. Of the 214 SREs, 146 (68.2%)
(ciocc)/Spain, 3Amgen (Europe) Gmbh/Switzerland, required an outpatient visit and 29.5% required >5
4
Instituto Catalán Oncología ICO-IDIBELLl/Spain, visits. As expected, radiation to bone was associated
5
Universitätsmedizin Berlin/Germany, 6PinderÀelds with the highest number of outpatient visits (of the
General Hospital/United Kingdom, 7University 140 SREs, 80.0% were associated with an outpatient
Hospitals Bristol/United Kingdom, 8Ovatech visit). Surgery to bone and spinal cord compression
Solutions/United Kingdom, 9Amgen Inc/United were associated with the least number of outpatient
States Of America, 10ScientiÀc Publications, Amgen visits with 38.1% of 21 SREs and 40% of 15 SREs
(Europe) Gmbh/Switzerland, 11Forschungszentrum requiring a visit, respectively. Only 3.3% of 214
Ruhr/Germany SREs were associated with an emergency room visit.
Conclusion: SREs in patients with advanced lung
Background: Skeletal-related events (SREs) cancer and bone metastases are associated with
are common in patients with bone metastases lengthy hospitalisations and numerous outpatient
secondary to lung cancer and may be associated visits. The need for pain control may also have led
with increased patient morbidity. However, limited to hospitalisation, although these data were not
data on the related economic burden are available in speciÀcally collected. Thus, HRU estimated in this
the literature. This information may assist in future study might underestimate the overall HRU among
resource planning and in estimating the value of lung cancer patients with SREs. The majority
treatment options. of SREs (96.7%) in lung cancer patients are not
Methods: Patients with bone metastases secondary associated with an emergency room visit, likely as a
to breast, lung or prostate cancer or multiple result of emergency care provided by the specialist
myeloma; at least one SRE within 90 days prior to oncology unit. This may also be impacted by the
enrollment; life expectancy >6 months; ECOG2, short residual life expectancy of a lung cancer
were enrolled. Health-resource utilisation (HRU) patient. Preventing SREs may substantially reduce
associated with SREs (spinal cord compression, the burden of costly HRU in different European
surgery to bone, pathologic fracture or radiation healthcare systems.
to bone) was collected retrospectively for 90 days Keywords: Skeletal-related events, Health resource
prior to enrollment and prospectively for up to 18- utilisation, bone metastases
21 months. HRU type included number and length
of inpatient hospitalisations, outpatient visits,
emergency room visits, nursing home/long-term care
facility stays, home health visits, procedures and
medications. Attribution of HRU was determined by
the investigators. This European analysis includes
data for lung cancer patients from centres in
Germany, Italy, Spain and UK.
Results: A total of 135 eligible patients with lung
cancer from the four countries entered the study.
Supportive Care Thursday, 7 July 2011 12:30-14:00 Background: Retrospective subset analyses of
JBR.10 and CALGB-9633 suggest survival beneÀt
O41.07 TESTING THE ROLE OF ADDING from ACT in stage IB NSCLC patients with tumors
AN INFERIOR VENA CAVA FILTER 4cm. However, patients with KRAS mutant tumors
(IVCF) TO ANTICOAGULATION did not appear to beneÀt from ACT. The 7th edition
WITH FONDAPARINUX IN PATIENTS TNM (TNM-7) classiÀcation incorporates new
WITH CANCER AND VENOUS T-size descriptors and upstages N0 patients with
THROMBOEMBOLI (VTE): RESULTS OF tumors >5cm. We previously showed (Chicago
THE CAT (CANCER AND THROMBOSIS) Multidisciplinary Symposium in Thoracic Oncology,
PROSPECTIVE RANDOMIZED 2010) that increasing tumor size, according to
CLINICAL TRIAL (RCT) TNM-7 T-size descriptors, was associated with
Myra F. Barginear1, Richard J. Gralla1, Meredith poor prognosis, and may be predictive of greater
Ackerman2, Martin Lesser2, Thomas Bradley1, ACT beneÀt. Here, the LACE-bio group study the
Iuliana Shapira1, Nanette Nier-Shoulson1, C Greben1, interaction between the prognostic values of T-size
Daniel R. Budman1 and KRAS mutations, and the interaction between
1
Medical Oncology, Hofstra North Shore - Lij School T-size and KRAS mutations in predicting overall
Of Medicine/United States Of America, 2Biostatistics, (OS) and disease-free survival (DFS) beneÀt from
Feinstein Institute For Medical Research/United ACT. We pool data from JBR.10 and CALGB-9633
States Of America as both recorded accurate tumor size.
Methods: Pre-treatment tumor specimens were
Abstract under Embargo - will be presented in a evaluated for KRAS mutations (codons 12, 13,
press conference during WCLC 2011. 61). JBR.10 and CALGB-9633 N0 patients were
reclassiÀed as T2a (>3-5cm), T2b (>5-7cm),
T3 (>7cm) or T3cm (T3cm with other T2
Session O42: NSCLC - Adjuvant Therapy characteristics). T3cm patients (68 with KRAS
data) were excluded from analyses to avoid
Thursday, 7 July 2011 confounding bias. The T2b and T3 subgroups
were pooled due to limited number of events. Cox
models stratiÀed by trial and adjusted for age, sex,
NSCLC - Adjuvant Therapy Thursday, 7 July 2011 12:30-14:00 PS, histology and surgical procedure were used for
survival analyses.
O42.01 A POOLED EXPLORATORY Results: Of 218 JBR.10 and 320 CALGB-9633
ANALYSIS OF THE IMPACT OF TUMOR N0 patients with T-size data, 288 (54%) were T2a,
SIZE AND KRAS MUTATIONS ON 111 (20%) T2b, 62 (12%) T3 and 77 (14%) T3cm.
SURVIVAL BENEFIT FROM ADJUVANT KRAS was evaluable for 207/218 (95%) JBR.10
PLATINUM-BASED CHEMOTHERAPY and 252/320 (79%) CALGB-9633 patients. KRAS
(ACT) IN NODE NEGATIVE (N0) NON- mutations were detected in tumors of 107/391(27%)
SMALL CELL LUNG CANCER (NSCLC) patients included in the Ànal study population.
Sinead Cuffe1, Stephen Graziano2, Abderrahmane Increasing T-size was not associated with an
Bourredjem3, Jean-Pierre Pignon On Behalf Of The increased rate of KRAS mutations (p=0.58). Overall,
Lace-Bio Group3, Monia Ezzalfani3, Lesley Seymour4, a signiÀcant interaction between the prognostic
Elizabeth Strevel5, Ronald Burkes6, Marzia Capelletti7, value of KRAS mutations and that of tumor size was
Pasi A. Janne7, Ming S. Tsao8, Frances A. Shepherd1 observed for OS (p=0.009), but not DFS (p=0.09).
1
Dept. Of Medical Oncology, Princess Margaret The presence of KRAS mutations signiÀcantly
Hospital/Canada, 2Dept. Of Medicine, State increased the risk of death only in T2b-T3 (HR 2.20
University Of New York Upstate Medical University/ [1.27-3.81] p=0.005), but not T2a patients (HR
United States Of America, 3Dept Of Biostatistics 0.87 [0.53-1.41], p=0.56). BeneÀt from ACT was
And Epidemiology, Institut Gustave-Roussy/France, suggested in T2a patients with wild-type tumors
4
NCIC Clinical Trials Group/Canada, 5The Credit (HR 0.82 [0.52-1.29], p=0.39), but not in those
Valley Hospital/Canada, 6Mount Sinai Hospital/ with KRAS mutant tumors (HR 1.81 [0.79-4.16],
Canada, 7Dana-farber Cancer Institute/United States p=0.51); however, signiÀcant differences were not
Of America, 8Princess Margaret Hospital/Canada seen in either subset, and the test for interaction was
non-signiÀcant (p=0.10). Similarly, among T2b-T3 resected in Ontario between 2001 and 2006. We
patients, there was a non-signiÀcant suggestion of linked this data to electronic records of treatment.
beneÀt from ACT in those with wild-type (HR 0.82 We compared the uptake of ACT across the age
[0.45-1.51], p=0.53), but not in those with KRAS groups: <70, 70-74, 75-79 and >80 years. As a
mutant tumors (HR 1.22 [0.52-2.88), p=0.64) surrogate of ACT beneÀt, we compared survival
(interaction p=0.46). Finally, a three-way interaction of patients undergoing surgical resection in 2004-
between KRAS, treatment and tumor size was not 2006 to those treated in 2001-2003. This reÁected
signiÀcant (OS p=0.58, DFS p=0.93). reporting of pivotal ACT studies in 2004. As a proxy
Conclusion: KRAS mutations may identify a subset of treatment related toxicities, we evaluated records
of N0 patients with tumors >5cm who have a worse of hospitalization within 6 months of surgery.
prognosis. In all N0 patients, trends for survival Results: Between 2001-2006, 2763/6304 (44%)
beneÀt from ACT were seen only in KRAS WT NSCLC patients surgically resected in Ontario
patients, but this relatively small study could not were elderly (70 years). Older patients were
demonstrate signiÀcant interaction for ACT beneÀt more often male, had increased co-morbidities and
based on T-size and/or KRAS. Supported by: French longer postoperative hospitalizations. They were
Cancer League, National Cancer Institute, Canadian signiÀcantly less likely to have adenocarcinoma,
Cancer Society. receive treatment at a regional cancer center,
Keywords: KRAS mutation, Tumor size, Non-small or undergo pneumonectomy than their younger
cell lung cancer, Adjuvant chemotherapy counterparts. Among the elderly population,
uptake of ACT signiÀcantly increased from 3.3%
in 2001-2003 to 16.2% in 2004-2006 (p<0.001).
NSCLC - Adjuvant Therapy Thursday, 7 July 2011 12:30-14:00 Age, geographical region, and pathological stage
were independently associated with receipt of ACT
O42.02 UPTAKE OF ADJUVANT in the elderly. Uptake of ACT declined with age:
CHEMOTHERAPY, ITS TOLERABILITY 43% in <70yrs, 23% in 70-74yrs, 13% in 75-79yrs
AND IMPACT ON SURVIVAL AMONG and 5% in 80+yrs during 2004-2006 (p<0.001).
ELDERLY NON-SMALL CELL LUNG Among evaluable cases, 70% of the elderly
CANCER PATIENTS IN ONTARIO: A received cisplatin, 28% carboplatin compared to
POPULATION-BASED OUTCOMES 85% and 14%, respectively, of younger patients
STUDY (p=0.005). Cisplatin/vinorelbine was the regimen
Sinead Cuffe1, Christopher Booth2, Yingwei Peng2, of choice in 66% of elderly patients. Rates of drug
Gail Darling3, Gavin Li2, Weidong Kong2, William J. substitutions, dose reductions or dose omissions
Mackillop2, Frances A. Shepherd1 during chemotherapy did not differ signiÀcantly
1
Dept. Of Medical Oncology, Princess Margaret between the age groups. Over the study period, 4
Hospital/Canada, 2Division Of Cancer Care And year survival of the elderly increased from 47.1%
Epidemiology, Queens University Cancer Research in 2001-2003 to 49.9% in 2004-2006, suggesting
Institute/Canada, 3Dept. Of Surgery, Toronto General a signiÀcant survival beneÀt from ACT (p=0.01).
Hospital/Canada Furthermore, rates of hospitalization within 6 months
of surgery in the elderly declined from 40% in 2001-
Background: Non-small cell lung cancer (NSCLC) 2003 to 38.3% in 2004-2006, suggesting adoption of
is predominantly a disease of the elderly, with a ACT was well tolerated in this population. Finally,
median age at diagnosis of 70 years. Retrospective there were no signiÀcant differences between the age
subgroup analyses of JBR.10 and the LACE meta- groups with respect to rates of hospitalization with
analysis suggest that elderly NSCLC patients beneÀt 6-24 weeks of surgery (p=0.54).
from adjuvant chemotherapy (ACT) with acceptable Conclusion: Uptake of ACT for NSCLC has
toxicity. However, it is known that many elderly increased in the elderly, but continues to lag behind
NSCLC patients are never referred for consideration that of younger patients. Adoption of ACT in the
of ACT. Here, we evaluate the uptake of ACT, its elderly was associated with a signiÀcant survival
tolerability and impact on outcome, by age group, in beneÀt, with similar tolerability and toxicity to that
the general population of Ontario. seen in the younger population. Our Àndings conÀrm
Methods: Using the Ontario Cancer Registry, we that the beneÀts of ACT in the elderly, suggested
retrospectively identiÀed all NSCLC cases surgically by the relevant clinical trials, are being realized in
the general population. Efforts to understand and for this interim toxicity analysis included randomization
improve the underutilization of ACT among elderly at least one year prior to the data pull (February
NSCLC patients should be prioritized in health care 23, 2011). Fisher’s exact test was used to test for
planning. differences in categorical data; Wilcoxon rank sum test
Keywords: Adjuvant chemotherapy, Elderly, Non- was used to test for differences in continuous variables.
small cell lung cancer Toxicities were graded using CTCAE v 3.0.
Results: Included here are 591 patients (enrolled
Aug 2007-Feb 22, 2010) (299 chemotherapy/292
NSCLC - Adjuvant Therapy Thursday, 7 July 2011 12:30-14:00 chemotherapy plus bevacizumab) median age 61 (range
35-86 year old), 360 (61%) ECOG PS 0, 307 (52%)
O42.03 INTERIM REPORT OF ON-STUDY women, 521 (88%) white, 318 (54%) adenocarcinoma,
DEMOGRAPHICS AND TOXICITY FROM 180 (31%) squamous histology. Stages enrolled were:
EASTERN COOPERATIVE ONCOLOGY 137 (23%) IB, 259 (44%) II, 167 (28%) IIIA-N2,
GROUP (ECOG) E1505, A PHASE III 23 (4%) IIIA-T3N1 and only a minority had had a
RANDOMIZED TRIAL OF ADJUVANT pneumonectomy 75 (13%). All demographic features
CHEMOTHERAPY WITH OR WITHOUT were well balanced. Adjuvant chemotherapy regimen
BEVACIZUMAB FOR COMPLETELY was CV- 160 (27%), CD- 196 (33%), CG- 155 (26%),
RESECTED EARLY STAGE NON-SMALL CP- 82 (14% - limited to non-squamous histology),
CELL LUNG CANCER (NSCLC) balanced by arm. There is a signiÀcant increase in
Heather A. Wakelee1, Suzanne E. Dahlberg2, Steven risk of grades 3/4 hypertension (2.0 vs. 19.6%, p less
M. Keller3, David R. Gandara4, Stephen Graziano5, than 0.001), proteinuria (0.7 vs. 3.2%, p equal 0.03),
Natasha B. Leighl6, Alex A. Adjei7, Joan Schiller8 abdomen pain (0.3 vs. 4.6%, p equal 0.001), and overall
1
Medicine/oncology, Stanford University/United grade 3/4 toxicity (68.0% vs. 84.0%, p less than 0.001)
States Of America, 2Dana-farber Cancer Institute associated with bevacizumab. Grade 5 toxicity rates
& Harvard School Of Public Health/United States were not signiÀcantly different at 2.4% vs 3.6% without
Of America, 3Thoracic Surgery, MonteÀore Medical or with bevacizumab, p equal 0.46. Only 1 case each of
Center/United States Of America, 4UC Davis Cancer fatal hemoptysis and non-fatal bronchopleural Àstula
Center/United States Of America, 5Dept. Of Medicine, have been seen in patients receiving bevacizumab.
State University Of New York Upstate Medical Conclusion: This report provides interim
University/United States Of America, 6Medical demographic safety data for E1505, revealing no
Oncology And Hematology, Princess Margaret unexpected toxicities. Enrollment challenges include
Hospital And University Of Toronto/Canada, lack of adequate lymph node sampling in otherwise
7
Medical Oncology, Roswell Park Cancer Institute/ eligible patients. The study remains open to accrual
United States Of America, 8Div. Of Hematology/ with projected enrollment completion in 2013.
Oncology, University Of Texas Southwestern Medical Keywords: Adjuvant chemotherapy, bevacizumab
Background: Adjuvant chemotherapy has been shown NSCLC - Adjuvant Therapy Thursday, 7 July 2011 12:30-14:00
to improve absolute survival after resection of early
stage NSCLC by 5-15%. Encouraging results with O42.05 EVALUATION OF PROGRESSION-
bevacizumab on E4599 in advanced stage NSCLC led FREE SURVIVAL AS A SURROGATE
to trial development of bevacizumab with adjuvant ENDPOINT FOR OVERALL
chemotherapy. SURVIVAL WHEN EVALUATING
Methods: E1505 aims to enroll 1500 patients with THE EFFECT OF CHEMOTHERAPY
resected stage IB (at least 4 cm in size) - IIIA (by AND RADIOTHERAPY IN LOCALLY
AJCC 6) NSCLC. All patients receive 4 x 3 week ADVANCED LUNG CANCER USING
cycles of doublet chemotherapy with cisplatin (C) DATA FROM FOUR INDIVIDUAL
plus vinorelbine (V), docetaxel (D), gemcitabine (G) PATIENT DATA META-ANALYSES
or pemetrexed (P). The pemetrexed option was added Audrey Mauguen1, Stefan Michiels2, Sarah Burdett3,
in 2009. Patients are randomized 1:1 to chemotherapy Jayne F. Tierney3, William Sause4, Sumithra J.
alone or chemotherapy plus bevacizumab Mandrekar5, Suzanne E. Dahlberg6, Frances A.
(bevacizumab continued up to 1 year). Inclusion criteria Shepherd7, Mahesh Parmar8, Michael C. Perry9,
Mary O’Brien10, Cécile Le Péchoux11, Jean-Pierre 0.88 and 0.92) and trial level (R correlations between
Pignon On Behalf Of The Surrogate Lung Project 0.94 and 0.99). Considering PFS events occurring
Collaborative Group1 in the Àrst two years and OS events in the Àrst Àve
1
Service De Biostatistique, Institut Gustave Roussy/ years, trial-level correlations were lower but still
France, 2Institut Jules Bordet/Belgium, 3Meta- strong (R between 0.87 and 0.97).
analysis Group, Mrc Clinical Trials Unit/United
Kingdom, 4Intermountain Medical Center/United Trial level
(R) [95%
States Of America, 5Mayo Clinic/United States Of Number
% of Individual
Trial level conÀdence
events level (Ư)
America, 6Dana-Farber Cancer Institute & Harvard Studied Number of of PFS
occurring [95%
(R) [95% interval]
treatment trial (patients) events, conÀdence For PFS
School Of Public Health/United States Of America, deaths
in the Àrst conÀdence
interval] at 2 years
7 2 years interval]
Medical Oncology, Princess Margaret Hospital/ and OS at
5 years
Canada, 8Clinical Trial Unit London, Medical
1375
Research Council/United Kingdom, 9Cancer And 0.88
Sequential events 0.88 [0.88- 0.98 [0.95-
8 trials(1458) 90% [0.86-
chemotherapy 1333 0.88] 1.01]
Leukemia Group B Statistical Center/United States deaths
0.89]
Of America, 10Lung Unit, Royal Marsden Hospital/ 2391
0.97
United Kingdom, 11Institut Gustave Roussy/France Concomitant
15 trials(2552)
events
90%
0.92 [0.92- 0.99 [0.97-
[0.94-
chemotherapy 2305 0.92] 1.00]
1.00]
deaths
Background: In randomized trials studying the Sequential vs.
1094
0.87
events 0.91 [0.91- 0.94 [0.86-
effect of chemotherapy or radiotherapy in locally concomitant 6 trials(1201)
1065
88%
0.91] 1.03]
[0.67-
chemotherapy 1.07]
advanced lung cancer, the gold standard endpoint deaths
is overall survival, which is simple to measure 2166
0.93
ModiÀed events 0.91 [0.91- 0.98 [0.96-
and reliable. However, a long follow-up period is radiotherapy
10 trials(2279)
2120
84%
0.91] 1.01]
[0.85-
1.01]
required to reach this endpoint. The objective of this deaths
study is to evaluate if progression-free survival could

be used as a surrogate endpoint for overall survival Conclusion: Our large database provides good
in these settings, in order to shorten trial duration. evidence that progression-free survival is a valid
Methods: Individual patient data from three surrogate endpoint for overall survival in locally
meta-analyses (29 trials) studying the effect of advanced lung cancer, when studying both
chemotherapy in patients with locally advanced non- chemotherapy and radiotherapy effects. Supported
small cell lung cancer and one meta-analysis (10 by French Cancer League, PHRC and British
trials) studying the effect of modiÀed radiotherapy in Medical Research Council.
patients with both small cell and non-small cell lung Keywords: surrogate endpoint, Non-small cell lung
cancer were used. Progression-free survival (PFS) cancer, meta-analysis, survival
was deÀned as the time from randomization to the
Àrst event (local or distant recurrence or death from
any cause). Overall survival (OS) was deÀned as the NSCLC - Adjuvant Therapy Thursday, 7 July 2011 12:30-14:00
time from randomization to death from any cause.
Surrogacy ability was validated through a correlation O42.06 FINAL RESULTS AND
approach: at individual level, the coefÀcient Ư PHARMACOECONOMIC ANALYSIS
estimated the association between distributions of OF A TRIAL COMPARING TWO
the two endpoints; at trial level, the coefÀcient R NEOADJUVANT CHEMOTHERAPY (CT)
estimated the association between treatment effect on REGIMENS FOLLOWED BY SURGERY
PFS and OS. Values of Ư and R closer to 1.0 would IN PATIENTS WITH RESECTABLE NON-
indicate strong surrogacy. SMALL CELL LUNG CANCER (NSCLC):
Results: Sequential chemotherapy analysis included A PHASE II RANDOMISED STUDY
8 trials (1458 patients), concomitant chemotherapy BY THE EUROPEAN LUNG CANCER
analysis included 15 trials (2552 patients) and WORKING PARTY.
sequential versus concomitant chemotherapy 6 trials Thierry Berghmans1, Jean-Jacques LaÀtte2,
(1201 patients); modiÀed radiotherapy analysis Vicente Giner3, Marie-Claude Berchier4, Arnaud
included 10 trials (2279 patients). As shown in Scherpereel2, Daniel Lewin1, Marianne Paesmans5,
table below, correlations between PFS and OS were Anne-Pascale Meert1, Thierry Bosschaerts6, Nathalie
strong, both at the individual (Ư correlations between Leclercq1, Jean-Paul Sculier1
1
Intensive Care And Thoracic Oncology, Institut Conclusion: While both neoadjuvant chemotherapy
Jules Bordet/Belgium, 2Pneumology, Chru Lille/ regimens shared similar efÀcacy in patients with
France, 3Oncology, Hospital De Sagunto/Spain, resectable NSCLC, costs were signiÀcantly higher
4
Pneumologie, Centre Hospitalier Alpha Santé/ for second-generation drugs.
France, 5Data Centre, Institut Jules Bordet/Belgium, Keywords: Non small cell lung carcinoma, Surgery,
6
Thoracic Surgery, Hôpital Saint-Pierre/Belgium neoadjuvant chemotherapy, Cost-effectiveness
Background: (Neo)adjuvant cisplatin-based CT

improving survival in resectable NSCLC, we aimed to NSCLC - Adjuvant Therapy Thursday, 7 July 2011 12:30-14:00
determine the respective activity of second-generation
drugs regimen (« GNP ») in comparison with Àrst- O42.07 MAGE-A3 VACCINATION IN THE
generation drugs based CT (« MIP ») as well as the cost- ADJUVANT SETTING FOLLOWING
effectiveness. RESECTION FOR EARLY STAGE LUNG
Methods: Patients with previously untreated CANCER: TOLERABILITY AND LONG-
pathologically proven stage I-IIIA resectable NSCLC, TERM SURVIVAL.
Karnofsky performance status 60, adequate Nasser Altorki1, Jeff Port1, Sacha Gnjatic2, Achim
haematological, hepatic, renal, lung and cardiac Jungbluth2, Yao Chen3, Djordje Atanackovic2, Gerd
functions were eligible. After central randomisation, Ritter2, Farooq Mirza1, Lloyd Old2
1
patients received three courses of MIP (ifosfamide 3g/ Cardiothoracic Surgery, Weill Cornell Medical
m², mitomycin 6 mg/m², cisplatin 50 mg/m²) or GNP Center/United States Of America, 2Ludwig Institute
(gemcitabine 1g/m² D1-8, vinorelbine 25 mg/m² D1- For Cancer Research New York/United States Of
8, cisplatin 50 mg/m²). The conclusion for feasibility America, 3Weill Cornell Medical Center/United
of each regimen will be drawn if, at least, 50 patients States Of America
per arm within a sample size of 67 can be completely
resected (a 5%, b 20%). A cost minimisation analysis, Background: MAGE- A3, a member of the
considering the direct medical costs, was performed cancer testis (CT) antigen super-family, is the most
separately in the Belgian (Bordet Institute) and French commonly expressed CT antigen in non-small-cell
(CHU Lille) social security systems. lung cancer (NSCLC). Given its highly restricted
Results: From 2001 to 2007, 140 eligible patients pattern of expression in normal tissue, it is a prime
were randomised (MIP 69, GNP 71), without any candidate for cancer vaccines. We have previously
signiÀcant imbalance between both arms. The main reported that MAGE- A3 expression is negatively
characteristics were: stage I/II/III in 52, 37 and 51 pts, correlated with survival in patients with resected
squamous histology in 82 pts, male 114 pts, median NSCLC. Here we report the long- term results of
PS 90. Objective response rates to induction CT were a phase 2 trial of MAGE- A3 vaccination in the
60% (MIP) and 65% (GNP) (p = 0.55). 119 patients adjuvant setting after resection of MAGE- A3 positive
underwent surgery. Complete resection rates were 77% NSCLC.
(MIP) and 80% (GNP) (p = 0.62). No difference in Methods: We conducted an open label Àxed- dose
postoperative complications was noted (p = 0.18). At the phase 2 trial of MAGE- A3 vaccination in early
time of analysis (January 2011), 39 (MIP) and 46 (GNP) stage NSCLC. Eligible patients included completely
deaths were documented. Median survival times were resected stage I/II NSCLC patients whose tumors
47.2 months (MIP) and 36.6 months (GNP) (p = 0.41). were MAGE- A3 positive by RT- PCR. MAGE- A3
In the absence of difference between both arms, we (300 g) with (n=12) or without ASO2B (n=7) was
performed a cost analysis in a subgroup of 58 patients: given by alternating IM injection every 3 weeks
for a total of 4 doses. Immunological response, the
Belgium France primary endpoint of the trial, was previously reported.
MIP GNP p MIP GNP p In this report, we present clinical outcome measures
Overall assessment (n=58) including adverse events (AE’s) and long-term
Mean overall cost (€) 9119 11663 0.009 19618 18998 >0.05 survival. Survival was determined by the KM method
Cost assessment for patients receiving full treatment (CT plus surgery)
(n=44)
and was calculated from the date of surgery to the date
Mean overall cost (€) 9471 12815 0.0006 16434 21010 0.047 of last follow-up or death. For comparative purposes,
D8 chemotherapy (€) 0 1677 0 2944 we matched the study group to 38 patients (2:1) from
Chemotherapy drugs (€) 592 1200 0 1677 an institutional lung cancer database based on age,
1
gender, and pathologic stage (table 1). Multidisciplinary Thoracic Oncology Program,
Results: 19 patients were vaccinated between 11/2000 Lineberger Comprehensive Cancer Center/United
and 4/2003. Median age was 64 and the majority States Of America, 2City Of Hope/United States
were women (n=12). Clinical, demographic, and Of America, 3Premiere Oncology/United States
pathologic variables are shown in table 1. Median Of America, 4Piedmont Hematology Oncology
follow- up was 108 months for surviving patients. Associates/United States Of America, 5Vanderbilt
For study patients, Àve- year disease free survival Ingram Cancer Center/United States Of America,
6
(DFS) was 79% and lung cancer- speciÀc survival was Synta Pharmaceuticals/United States Of America,
7
89%. Corresponding Àve- year DFS and lung cancer- Dana-Farber Cancer Institute/United States Of
speciÀc survival in the matched control group were America
55% and 75% (p= 0.16 and 0.05, respectively). The
majority of AEs were CTC grades 0-2. Only 6 AEs Background: Ganetespib, a potent, non-
were CTC grade 3 and none were grade 4. geldanamycin small molecule Hsp90 inhibitor has
shown superior preclinical activity and improved
CASE CONTROL p-value safety proÀle compared to ansamycins (17-AAG).
N 19 38 Ganetespib is broadly active in multiple highly-
age median/range 64 / 49-85 64.5/ 47-83 0.912 resistant cancer models. Preclinical data support
male 7 (36.8%) 14 (36.8%) evaluation of Hsp90 inhibitors in NSCLC driven by
gender 1
female 12 (63.2%) 24 (53.2%) a variety of mutant oncogenic proteins.
IA 7 (36.8%) 15 (39.5%) Methods: Patients (pts) with progressing advanced
pathologic stage
IB 5 (26.3%) 9 (23/7%)
0.996
NSCLC who failed standard of care treatments
IIA 2 (10.5%) 4 (10.5%) received 200 mg/m2 ganetespib as a 1-hr infusion
IIB 5 (26.3%) 10 (26.3%) once weekly for 3 of a 4-wk cycle in a Simon two-
squamous 6 (31.6%) 6 (15.8%) stage study design assessing primary endpoint of
cell type 0.168
non- squamous 13 (68.4%) 32 (84.2%) PFS rate at 16 wks. Patient cohorts were deÀned by
pack year median/range 50/ 30-110 40/ 0-150 0.185 mutation status: A) mEGFR B) mKRAS, C) EGFR
and KRAS wild type (WT). If 2/14 pts in A, B
Conclusion: In this phase 2 trial, MAGE-A3 or C were progression-free at 16 wks, enrollment
vaccination in the adjuvant setting was well-tolerated increased to 23 pts for that cohort. Tumor response
and was associated with encouraging DFS and lung was assessed every 8 wks. Cohort D was later
cancer- speciÀc survival at 5 years. The results of the added to include 35 additional EGFR and KRAS
ongoing international randomized trial (MAGRIT) WT pts with adenocarcinoma histology. Additional
are eagerly anticipated. mutational analysis of BRAF, PIK3CA, ERBB2
Keywords: MAGE-A3, Vaccine, NSCLC and MET, as well as FISH analysis for ALK
translocation, were performed in a subset of patients.
Results: 73 pts (31 M, 42 F; median age 62 yrs,
Session O43: Medical Oncology IV range 28-82; ECOG 0-1; prior therapies range
1-10) received a median of 2 cycles (range 1-12)
Thursday, 7 July 2011 of ganetespib in cohorts A (14), B (17), and C+D
(42). AEs reported in 20% of pts included diarrhea,
fatigue, nausea, anorexia, constipation, and dyspnea
Medical Oncology IV Thursday, 7 July 2011 12:30-14:00 and were generally grade 1-2. Cohort expansion
criteria were met for cohort C, including a durable
O43.01 AN OPEN-LABEL PHASE II partial response (PR) and seven pts with stable
STUDY OF THE HSP90 INHIBITOR disease 16 wks. Cohort D continues recruitment
GANETESPIB (STA-9090) IN PATIENTS with preliminary results of two conÀrmed PRs.
WITH ADVANCED NON-SMALL CELL Genetic proÀling data will be presented.
LUNG CANCER (NSCLC) Conclusion: Ganetespib administered as a single
Mark A. Socinski1, Marianna Koczywas2, Jonathan agent is well tolerated in pts with NSCLC at 200
Goldman3, Eugene Paschold4, Leora Horn5, mg/m2 once weekly with absence of serious liver
Joelle Lufkin6, Ronald K. Blackman6, Florentina or common ocular toxicities seen with other hsp90
TeoÀlovici6, Geoffrey Shapiro7 inhibitors. Clinical activity has been observed in
patients with advanced NSCLC tumors harboring consisted in 5 doses, 1 every 14 days (induction period),
wild-type EGFR and KRAS. followed by a maintenance period (1 dose every 28
Keywords: Non-small Cell Lung Carcinoma, STA- days) until patient refusal or worsening of ECOG status.
9090, Hsp90 inhibitor, Ganetespib Results: Safety: The most common adverse events
were mild and moderate reactions at the injection site
(pain, erythema, induration) and “Áu-like” symptoms,
Medical Oncology IV Thursday, 7 July 2011 12:30-14:00 none unexpected. No differences were observed
between both groups. Overall Survival: Intent to Treat
O43.02 ACTIVE SPECIFIC Analysis (ITT): Data presented corresponds to 132/176
IMMUNOTHERAPY WITH patients (75% of the sample), who had been followed
RACOTUMOMAB IN THE TREATMENT for 8 months. Median OS is 8.23 months in Arm B
OF ADVANCED NON SMALL CELL LUNG and 6.17 months in Arm A (log rank test, p= 0.036).
CANCER (NSCLC). Long- term OS rate (%) at 24 months: 19.4% in Arm B
Amparo Macías1, Saily Alfonso2, Eduardo and 7.7% in Arm A. Per Protocol Population Analysis
Santiesteban3, Darien Toledo4, Carmen Viada4, Ivis (PPP): Shown data only include patients who have
Mendoza5, Pedro P. Guerra5, Maria L. Ardigo6, received 5 doses of vaccine (92/132 patients, 70%
Roberto E. Gómez6, Ana M. Vazquez4, Tania of the patients in the database). Median OS was 10.97
Crombet4, Rolando Pérez4, Agustín Lage4 months in Arm B and 6.27 months in Arm A (log rank
1
Clnical Research Unit, Center Of Molecular test, p= 0.0115). Long- term OS rate (%) at 24 months:
Immunology/Cuba, 2Oncology Unit, University 24% in Arm B and 6.2 % Arm A.
Hospital Celestino Hernández Robau/Cuba, Conclusion:
3
Oncology Unit, Hospital José Ramón Tabranes/ t Immunization with Racotumomab is safe.
Cuba, 4Center Of Molecular Immunology/Cuba, t There is an OS beneÀt for Arm B, both in ITT and
5
National Clinical Trial Coordinator Center/Cuba, PPP analyses.
6
Elea Laboratories/Argentina t Additional data about this trial will be presented at
the IASLC meeting.
Background: Gangliosides are an attractive target for Keywords: Cancer vaccines, NSCLC,
immunotherapy in cancer since they are not expressed in immunotherapy, racotumomab
normal human tissue, are overexpressed in several solid
tumors, including NSCLC, and have been implicated
in tumor development and progression. Racotumomab Medical Oncology IV Thursday, 7 July 2011 12:30-14:00
is an antiidiotype murine monoclonal antibody
speciÀc to P3 Ab1 MAb, an antibody that reacts with O43.03 RANDOMIZED MULTICENTER
NeuGc-containing gangliosides, sulfatides and other PHASE II CLINICAL TRIAL OF A TOLL
antigens expressed in tumors. Phase I trials conducted LIKE RECEPTOR-2 (TLR-2) AGONIST
in advanced melanoma, breast and lung cancer have MYCOBACTERIUM W (CADI-05) IN
demonstrated the low toxicity and high immunogenicity COMBINATION WITH PACLITAXEL
of Racotumomab. PLUS CISPLATIN VERSUS PACLITAXEL
Methods: A phase II multicenter, controlled, PLUS CISPLATIN IN ADVANCED NON-
randomized, double blind trial is ongoing to evaluate SMALL CELL LUNG CANCER (NSCLC)
the effect of Racotumomab in Overall Survival (OS) Chandra P. Belani1, Bhaswat Chakraborty2, Darshini
in patients with advanced (IIIB and IV) NSCLC Desai2, Bakulesh M. Khamar2
1
who have completed onco-speciÀc treatment as Medicine, Penn State Hershey Cancer Institute/
per the Oncology Therapeutic Guidelines (surgery, United States Of America, 2Cadila Pharmaceuticals,
chemotherapy, radiotherapy according to initial staging) Ltd/India
and have achieved partial, complete response or disease
stabilization. ECOG status was < 2 and life expectancy Background: TLR2 agonist, Mycobacterium w
4 months. Vaccination began 4-8 weeks after the end (Cadi-05), an active non-speciÀc immunomodulator
of the onco-speciÀc treatment. Prior chemotherapy and pure Th 1 response enhancer has demonstrated
in most cases was cisplatin/ vinblastin (4 - 6 cycles). synergistic effects with a number of chemotherapeutic
Patients were randomized (1:1) to control group agents. It does not target speciÀc tumor associated
(placebo) or vaccine (Racotumomab). Vaccination antigens. A phase II randomized study was conducted
to test the efÀcacy of the combination of paclitaxel Wilfried Eberhardt12, Andrew Hughes13, Sebastien
plus cisplatin with or without Cadi-05 as Àrst line Lavialle14, Dominique Mery-mignard14, Silvia
treatment of advanced NSCLC. Novello15
1
Methods: Two hundred and twenty-one treatment Department De Medicine Oncologique, Institut
naïve patients (pts) with stage IIIB and IV NSCLC Gustave-Roussy,/France, 2Hospital Vall D’hebron,
were randomized to receive paclitaxel 175mg/m2 Barcelona/Spain, 3Hôpital Sainte Marguerite,
IV 3-hour infusion and cisplatin 100mg/m2 IV with Marseille/France, 4Hôpital Larrey, Toulouse/
or without Cadi-05 administered intradermally, 0.1 France, 5Chu, Côte De Nacre/France, 6Asklepios
ml on each deltoid on the Àrst visit at least 1 week Fachkliniken München-gauting, Gauting/Germany,
prior to 1st cycle and then on day 8 and 15 of each 7
Krankenhaus Großhansdorf Gmbh, Großhansdorf/
cycle of chemotherapy. The cycles were repeated Germany, 8Oncologia Medica, Livorno/Italy, 9New
every 3 weeks for a total of 4 cycles. Cadi-05 was Cross Hospital, Wolverhampton/United Kingdom,
10
administered once a month thereafter until progression Hospital Germans Trias I Pujol, Badalona/
or for a maximum of 12 months from the start of Spain, 11Istituto Clinico Humanitas, Milan/Italy,
12
treatment in the investigational arm. The primary Universitätsklinikum Essen, Essen/Germany,
13
endpoint of the study was overall survival (OS) and Northern Centre For Cancer Care, Newcastle/
the secondary outcome measures were response rate United Kingdom, 14SanoÀ-aventis, Vitry Sur Seine/
(RR) and progression free survival (PFS). France, 15University Of Turin, Turin/Italy
Results: One hundred twelve pts were randomized
to the control arm and 109 pts to the Cadi-05 arm. Background: Iniparib (BSI-201) is a novel
Pt demographics were balanced in both the arms. agent whose mechanism of action is still under
The RR was 36% in the control arm and 47 Cadi-05 investigation. It binds to poly (ADP-ribose)
arm. There were three complete responses all in the polymerase-1 (PARP1) in high micromolar
Cadi-05 arm. Median PFS was 157 days in control concentrations. Additional targets are being
arm and was improved by 96 days to 253 days in investigated. Iniparib has shown activity in some
the Cadi-05 arm [p=0.0446; HR 0.43 (95% CI 0.25- cases of triple-negative breast cancer in combination
0.73)]. Median OS was 236 days in control arm and with gemcitabine and carboplatin with an adequate
was improved by 59 days to 295 days in the Cadi-05 safety proÀle. This is the Àrst completed efÀcacy trial
arm [p=0.0034;HR 0.55(95% CI 0.37-0.82)]. There with iniparib in lung cancer.
were no signiÀcant differences in the adverse events Methods: Eligible subjects had measurable disease
in the control arm vs. the Cadi-05 arm. and received no prior chemotherapy for stage IV
Conclusion: Addition of Cadi-05 to Paclitaxel plus NSCLC (all histologies). Patients were randomized
Cisplatin in patients with advanced NSCLC is safe (2:1) to GCI vs GC. Gemcitabine (1250 mg/m2, IV)
and results in both improvement in PFS and OS. was administered on days 1 and 8, cisplatin (75 mg/
(The study is supported by Cadila Pharmaceuticals m2, IV) on day 1, and iniparib (5.6 mg/kg, IV) on
Ltd and is being presented on behalf of the Cadi-05 days 1, 4, 8 and 11, every 21 days for a maximum of
investigators study group). 6 cycles. The primary objective is overall response
Keywords: Non-small cell lung cancer, rate (ORR, per RECIST 1.1) as assessed by the
Mycobacterium w, Carbotaxol investigator. Secondary objectives included OS,
PFS, safety and biomarker analysis. Patients were
stratiÀed by squamous/non-squamous cell carcinoma
Medical Oncology IV Thursday, 7 July 2011 12:30-14:00 and smoker/never smoker. Baseline biopsy for
translational research was obtained in 66% of
O43.04 RESULTS OF A RANDOMIZED patients, and 17% were re-biopsied at the end of the
PHASE 2 TRIAL OF GEMCITABINE/ Àrst cycle.
CISPLATIN/INIPARIB (GCI) VS Results: A total of 119 patients were randomized
GEMCITABINE/CISPLATIN (GC) IN between May and November 2010: 80 to GCI (77
PATIENTS WITH STAGE IV NSCLC treated) and 39 to GC (all treated). Median age
Benjamin Besse1, Enriqueta Felip2, Fabrice Barlesi3, was 59 years (29–73) and 76% were male. 12%
Julien Mazieres4, Gérard Zalcman5, Joachim Von of patients had squamous cell carcinoma and 70%
Pawel6, Martin Reck7, Federico Cappuzzo8, David adenocarcinoma histologies; 13 pts (11%) were
Ferry9, Enric Carcereny10, Armando Santoro11, never-smokers. PS 0/1 was 49/51% in the GC arm
and 61/39% in the GCI arm. More than 60% of René Gauducheau/France, 9Medical Oncology,
patients are still receiving treatment as of December Princess Margaret Hospital/Canada, 10Thoracic
2010. The full report of efÀcacy data will be Oncology Unit, University Of Turin/Italy
available for the late-breaking abstract presentation.
The 2 arms performed similarly in terms of dose Background: AÁibercept (A), a novel recombinant
reduction, dose intensity and percentage of patients human fusion protein, binds to VEGF-A, VEGF-B,
who discontinued due to tumor progression or and PlGF and prevents interaction with their
adverse events. The median number of cycles is 3 in receptors, thereby acting as a “decoy receptor”.
both arms. Patients with neutropenia leading to dose Preclinical and clinical evidence supports the
reduction were more frequently found with GC than evaluation of the combination of A with docetaxel
with GCI: 23.1% vs 10.4% with 2 events of febrile (D), an effective agent for the treatment of patients
neutropenia in the GC arm. Asthenia was also more with recurrent NSCLC.
common with GC than GCI (All grades: 66.7% vs Methods: Patients with advanced non-squamous
46.8%; Grade 3/4, 15.4% vs 4.9%). 37% of patients NSCLC, PS 0-2, adequate organ function and failure
missed at least one dose of iniparib. Apart from this, of one platinum-based therapy were randomized
the safety proÀle was similar in both arms. (450 planned per arm) to receive D (75 mg/m²) and
Conclusion: In metastatic NSCLC, the combination either A (6 mg/kg) or placebo (Pl) administered
of iniparib with standard doses of gemcitabine and every 3 weeks. The primary endpoint was overall
cisplatin had a safety proÀle similar to that of GC survival (OS). The study had 90% power to detect
alone, and no unexpected toxicities were observed a 22% lower hazard rate for death in the AD group
with the combination. The efÀcacy of GCI vs GC after 687 events (log-rank test, overall 2-sided Ơ=
will be available for the late-breaking abstract 0.05).
presentation in July 2011. (Clinicaltrials.gov number, Results: Results of the Ànal analysis of OS
NCT01086254) comparing the two treatment arms will be presented
Keywords: iniparib, BSI-201, NSCLC, PARP as well as the analysis of secondary endpoints,
including progression-free survival, response rate,
and safety. Between September 2007 and February
Medical Oncology IV Thursday, 7 July 2011 12:30-14:00 2010, 913 patients have been randomized, with a
median follow-up duration of approximately 21
O43.06 AFLIBERCEPT IN COMBINATION months. Final results are expected mid-March 2011.
WITH DOCETAXEL FOR SECOND- As the database is not locked, only preliminary
LINE TREATMENT OF LOCALLY patient and disease characteristics are available:
ADVANCED OR METASTATIC NON- median age 60 yr, male 66%, Caucasians 89%,
SMALL-CELL LUNG CANCER (NSCLC): adenocarcinoma 83%, metastatic 90%, measurable
FINAL RESULTS OF A MULTINATIONAL disease 97%, and PS 0-1 94%.
PLACEBO-CONTROLLED PHASE III Conclusion: Late Breaking Abstract : The
TRIAL (EFC10261-VITAL). conclusion will be provided with the results.
Silvia Novello1, Rodryg Ramlau2, Vera A. Keywords: Angiogenesis inhibitors, Vascular
Gorbunova3, Tudor E. Ciuleanu4, Mustafa endothelial growth factor (VEGF), Phase III clinical
Ozguroglu5, Tuncay Goksel6, Clarissa Baldotto7, trials
Jaafar Bennouna8, Frances A. Shepherd9, Giorgio
Scagliotti10 A revised/updated abstract may be included in
1
U.O. Oncologia Polmonare, Azienda Sanitaria the Late Breaking Abstract Supplement, available
Ospedaliera San Luigi/Italy, 2Wielkopolskie Centrum at the 14th World Conference on Lung Cancer.
Chorob Pluc I Gruzlicy/Poland, 3Chemotherapy,
N.n. Blokhin Russian Cancer Research Center/
Russian Federation, 4Medical Oncology, Institute
Of Oncology/Romania, 5Department Of Medical
Oncology, ústanbul University Cerrahpaüa Medical
Faculty/Turkey, 6Department Of Chest Disease,
Ege University Medical Faculty/Turkey, 7Medical
Oncology, Inca/Brazil, 8Medical Oncology, Centre
Medical Oncology IV Thursday, 7 July 2011 12:30-14:00 size was based on a hazard ratio (HR) of 0.80,
corresponding to a median OS of 9 versus 11.24
O43.07 ATTRACT 1 - PHASE III TRIAL months respectively in the placebo and ASA404
OF CARBOPLATIN/PACLITAXEL (CP) arms, with type I error of 0.025 & 90% power using
WITH OR WITHOUT THE VASCULAR a 1-sided log rank test. Patient reported outcomes
DISRUPTING AGENT ASA404 IN (PRO) were assessed using the EORTC QLQ-C30
ADVANCED NON-SMALL CELL LUNG questionnaire.
CANCER (NSCLC): FINAL EFFICACY Results: 1,299 patients were randomized. Baseline
AND QUALITY OF LIFE (QOL) RESULTS demographics and disease characteristics were well
Primo N. Lara1, Jean yves Douillard2, Kazuhiko balanced. The trial was stopped for futility at interim
Nakagawa3, Joachim Von Pawel4, Mark J. Mckeage5, analysis by the DSMC. EfÀcacy results are shown
Istvan Albert6, Gyorgy Losonczy7, Martin Reck8, below.
Deo Seog Heo9, Hiroshige Yoshioka10, Xiaolin
Fan11, Abderrahim Fandi11, Judith Klimovsky11, Terri Endpoint CP + ASA404 CP + Placebo Hazard Ratio
Goldberg11, Giorgio Scagliotti12 (n=649) (n=650) (HR)
1 Response Rate 25% (21.4, 28.2) 25% (21.3, 28.1) N/A
Hematology/oncology, Internal Medicine, (CR+PR)
University Of California Davis Cancer Center/ Median PFS, months 5.5 (5.2, 5.6) 5.5 (5.4, 5.6) 1.04 (0.91,
United States Of America, 2Centre R. Gauducheau,st. (95% CI) 1.19),
Herblain, Fr/France, 3Kinki University School Of Median OS, months 13.4 (11.4, 16.6) 12.7 (11.3, 14.4) 1.01 (0.85,
(95% CI) 1.19)
Medicine/Japan, 4Asklepios-fachkliniken München-
Median OS, months, 15.0 (13.4, 20.8) 13.5 (11.7, 15.3) 0.98
Gauting/Germany, 5University Of Auckland/ non-squamous (0.8,1.19)
New Zealand, 6Mátrai Gyógyintézet, Mátraháza/ (95% CI)
Hungary, 7Semmelweis Egyetem, Pulmonologiai Median OS, months, 8.9 (8.3, 11.9) 10.7 (9, 14.2) 1.1 (0.7,1.5)
squamous (95% CI)
Klinika/Hungary, 8Krankenhaus Großhansdorf,
Zentrum Für Pneumologie Und Thoraxchirurgie/
Germany, 9Internal Medicine, Seoul National Rate of adverse events (AEs) was comparable
University Hospital/Korea, 10Department Of (ASA404 -98.9%; placebo - 98.2%). The most
Respiratory Medicine, Kurashiki Central Hospital/ common AEs were neutropenia, alopecia, nausea,
Japan, 11Novartis Pharmaceuticals/United States Of and fatigue. Grade 4 neutropenia (27% vs. 19%)
America, 12Thoracic Oncology Unit, University Of and infusion site pain (10% vs. 0.5%) were more
Turin/Italy frequent with ASA404. Number of on-treatment
deaths was also similar (ASA404-28; placebo-24).
Background: Vascular disruption of established PRO analysis showed a signiÀcant decrease in the
tumor blood vessels is a novel anti-neoplastic physical functioning domain across both arms at the
strategy. In a randomized phase II trial (McKeage et end of treatment. However, global health status/QoL
al, Br J Cancer 2008), the vascular disrupting agent domain had no change between arms over time.
ASA404 in combination with CP was found to be Conclusion: The addition of ASA404 to frontline
feasible and to improve several efÀcacy parameters CP, although well tolerated, failed to improve
including overall survival (OS) in patients with efÀcacy or QoL in patients with advanced NSCLC.
advanced NSCLC. A global, randomized, double- Keywords: Vascular Disrupting Agent, Metastatic
blind, placebo-controlled phase III trial of frontline lung cancer, Phase III Clinical Trial
CP +/- ASA404 in advanced NSCLC was therefore
conducted to validate these results.
Methods: Advanced stage IIIB or IV NSCLC
patients, stratiÀed by gender and histology, who
had not previously received systemic therapy for
metastatic disease, were randomly assigned 1:1
to receive paclitaxel (200 mg/m2) and carboplatin
(AUC 6) +/- ASA404 (1,800 mg m2), given IV
q3 weeks for 6 cycles. Primary endpoint was OS;
secondary endpoints included response rate (RR),
progression-free survival (PFS), and safety. Sample
Session O44: NSCLC - Advanced Stage Conclusion: A signiÀcant shift has occurred over
and Statistics the past 3 decades in the design and interpretation
of phase III trials in advanced NSCLC. The use of
median survival as the primary measure of beneÀt is
declining alongside the magnitude of beneÀt deemed
clinically relevant. This suggests a shift in the oncology
NSCLC - Advanced Stage and Statistics Thursday, 7 July 2011 12:30- community towards an increasing willingness to accept
14:00 lesser beneÀt from new treatments.
Keywords: NSCLC, systemic therapy, Phase III
O44.01 EVOLVING PATTERNS IN THE Trials
INTERPRETATION OF PHASE III TRIAL
OUTCOMES IN THE TREATMENT OF
ADVANCED NSCLC NSCLC - Advanced Stage and Statistics Thursday, 7 July 2011 12:30-
Adrian Sacher, Natasha Leighl 14:00
Medical Oncology, Princess Margaret Hospital/
Canada O44.02 A CANADIAN CANCER RISK
MANAGEMENT MODEL: A NEW
Background: The prognosis associated with advanced HEALTH POLICY TOOL USEFUL IN
non-small cell lung cancer (NSCLC) remains grim POLICY DECISIONS RELATED TO LUNG
despite decades of trials involving novel systemic CANCER.
therapies. Over time, there appears to be an increasing William K. Evans1, Michael Wolfson2, William M.
willingness to study and adopt treatments with very Flanagan3, Jillian Oderkirk4, John R. GofÀn5, Janey
modest clinical beneÀt. Here we examine if the primary Shin6, Gina Lockwood7
1
endpoint, outcome and interpretation of large scale Administration, Juravinski Cancer Centre/Canada,
2
clinical trials in advanced NSCLC are changing over Health Modelling/populomics, University Of
time. Ottawa/institute Of Population Health/Canada,
3
Methods: A literature search for all phase III randomized Chief Of Microsimulation/Health Analysis Division,
controlled trials of systemic therapy for advanced Statistics Canada/Canada, 4Health Analysis
NSCLC was performed using Pubmed. Publication Division, Statistics Canada/Canada, 5Oncology,
date, primary endpoint, clinical outcomes, statistical Juravinski Cancer Centre/Canada, 6Analytics &
signiÀcance and conclusions of eligible trials were Surveillance Portfolio, Canadian Partnership
recorded. Aggregate data were compiled by 10-year Against Cancer/Canada, 7Analytics, Canadian
intervals. SigniÀcant differences were determined using Partnership Against Cancer/Canada
an unpaired t-test and chi-squared test as appropriate.
Results: A total of 238 trials were reviewed and 207 Abstract under Embargo - will be presented in a
were eligible for inclusion in this study. The primary press conference during WCLC 2011.
endpoint of these trials shifted signiÀcantly from median
survival in 1980-1990 (97% of trials) and 1991-2000
(96%) towards progression free survival in 2001- NSCLC - Advanced Stage and Statistics Thursday, 7 July 2011 12:30-
2010 (15% progression-free survival, 80% median 14:00
survival; p=0.04 for 1980s vs. 2000s). A similar shift
was noted in trial outcomes (positive vs. negative) from O44.03 SECOND OPINIONS IN AN
uncommonly positive in 1980-1990 (21% of trials) EXPERT CENTER FOR LUNG CANCER
to frequently positive in 1991-2000 (65%) and 2001- PATIENTS AFFECT DIAGNOSIS AND
2010 (78%; p=0.009 for 1980s vs. 2000s). A decrease THERAPY
in the magnitude of median survival gains in positive Romane M. Schook1, Marleen J. Avest, Ter1,
studies between 1980-1990 (4.3 months), 1991-2000 Coralien H. Setten, Van1, Egbert F. Smit1, Pieter E.
(2.6 months) and 2001-2010 (2.4 months) was observed Postmus2
1
(p=0.016 for 1980s vs. 2000s). Lastly, only the pre-1990 Department Of Pulmonary Diseases/Longziekten,
cohort of trials was noted to include studies reported as VU University Medical Center/Netherlands,
2
negative due to insufÀcient magnitude of clinical beneÀt Department Of Pulmonary Diseases, VU University
despite statistical signiÀcance. Medical Center/Netherlands
Background: Lung cancer is the most important showed statistically signiÀcant higher percentages
cause of cancer death in both men and women of discrepancies in stage (p<0.05) compared with
in the western world. Facing a poor survival, patients initiated second opinions. Discrepancies in
patients increasingly ask for a second opinion for diagnosis and therapy were also more frequent when
information, hope and reassurance. Beside this, specialists initiated the second opinions, however
lung specialists also consult expert colleagues for this trend was not signiÀcant.
diagnostics and therapy. The VU University Medical Conclusion: Lung cancer second opinion referrals
Center, Amsterdam, The Netherlands receives a lot to an expert center resulted in more than 2/3 of the
of second opinions. Study objectives: To determine patients in a different therapeutic advice, partially
the characteristics of patients, the outcomes and based on change in stage and/or pathological
supplemental medical information resulting from diagnosis.
second opinions of patients visiting the pulmonary Keywords: second opinion referrals,
oncology outpatient clinic of VU University Medical histopathological diagnosis, therapy advice, expert
Center. center
Methods: In the period of January 2005 to
December 2009, 525 patients from outside the
district of the VU University Medical Center NSCLC - Advanced Stage and Statistics Thursday, 7 July 2011 12:30-
were referred as second opinions to its pulmonary 14:00
oncology outpatient clinic. Demographics, second
opinion initiator and oncology data of second O44.05 DO RESULTS DIFFER BY META-
opinions were collected. Design: Cross sectional, ANALYSIS METHOD: COMPARISON
retrospective and descriptive study OF INDIVIDUAL PATIENT DATA-
Results: Preliminary Results: Of the referred BASED (IPD) WITH LITERATURE-
patients(n=525), 394 patient Àles have been studied BASED ABSTRACTED DATA (AD) IN 10
until date. Forty-Àve of the referred patients were CLINICAL SETTINGS INCLUDING OVER
excluded since they did not Àt our second opinions 35,000 PATIENTS
criteria. Of the included patients (n=349), 57% Emilio Bria1, Richard J. Gralla2, Harry Raftopoulos2,
were male, 78% were diagnosed with NSCLC and Isabella Sperduti1, Michele Milella1, Francesco
8% SCLC, 39% had stage IV, and mean age at Cognetti1, Giampaolo Tortora3, Diana Giannarelli1
1
presentation was 58±11.5 years old. Thirty percent Medical Oncology, Regina Elena National Cancer
of the second opinions was initiated by patient, 66% Institute/Italy, 2Hofstra North Shore-Lij School
by a lung specialist and 4% by both patient and Of Medicine/United States Of America, 3Medical
specialist. At time of referral, the histopathological Oncology, University Of Verona/Italy
diagnosis was unknown in 36 patients (10%). In 43
(14%) patients having a histopathological diagnosis Background: Meta-analyses are considered to be
(n=313), the stage was unknown. Forty-four percent a high level of evidence, especially when based on
of the patients previously had received therapy for multiple large randomized clinical trials. Several
lung cancer. In 228 (65%) patients, supplementary key treatment areas in lung cancer have been studied
diagnostics were needed. Revision of pathologic by different meta-analysis methods. Controversy
material and/or images took place in 241(69%) exists whether the two most frequently used methods
patients. There was a discrepancy between the (IPD or AD) provide equally reliable results. In this
initial and the second pathological diagnosis in 4% analysis we examined the conclusions achieved by
(n=13) of the patients in whom the histopathological each method using the same panel of studies for each
diagnosis (n=313) was already determined. In method. We weighed agreement/discrepancy and
288 patients, lung cancer had been staged prior to evaluated predictivity of AD results with respect to
referral, a discrepancy was found in 14% (n=40). IPD using multiple methods.
In 8 out of 13 patients, changes in histopathological Methods: 10 different settings (including 3 issues
diagnosis had implications for the prognosis, as well in lung cancer, see the table below) which were
as all changes in stages. In 237 cases a therapy had subjected to IPD meta-analysis were selected, and
been suggested, this advice was changed in 164 cases were then evaluated by the AD method, including
(69%). Eighty-eight patients (25%) received therapy the same trials on which the initial IPD was based.
in clinical trials. Specialists initiated second opinions Hazard and Risk Ratios (Rs) with 95% conÀdence
intervals (CI) were derived. Methods agreement NSCLC - Advanced Stage and Statistics Thursday, 7 July 2011 12:30-
was analyzed (Blant-Altman method) as difference 14:00
or ratio and compared using Variance-Ratio (F-test)
and Concordance Correlation CoefÀcient (CCC). O44.06 POOR REPRESENTATION OF
Correlations between AD Risk Ratios and IPD WOMEN, OLDER AGE GROUP AND
Risk Ratios were estimated with linear regression MINORITIES IN US REGISTRATION
[Pearson (r), R2 coefÀcients, Spearman-Rho/ TRIALS FOR NON-SMALL CELL LUNG
Kendall-Tau coefÀcients] to derive a predictive CANCER: FDA REVIEW
estimation of AD on IPD. Shakun Malik, Ann T. Farrell, Richard Pazdur
Results: 14 outcomes in 10 meta-analyses (37,002 OODP/CDER, FDA/United States Of America
patients in total) were analyzed.
Setting Pts [AD/IPD] Rs [AD/IPD] press conference during WCLC 2011.
Bladder 458/491 0.76/0.75
Breast 3672/4006 0.71/0.71
Breast 2805/3034 0.94/0.92 0.99/0.95 NSCLC - Advanced Stage and Statistics Thursday, 7 July 2011 12:30-
14:00
Breast 11163/9856 0.77/0.77 0.98/0.94
Breast 8794/9015 0.73/0.71 0.80/0.79
Breast 2695/2447 0.68/0.64 0.95/0.97 O44.07 RANDOMIZED TRIALS IN
Lung 4658/4584 0.90/0.89
UNSELECTED PATIENTS: MISLEADING
Lung 778/778 0.71/0.73
AND IRRATIONAL?
David J. Stewart
Lung 857/865 1.06/1.09
Thoracic And Head And Neck Medical Oncology,
Emesis 1926/1926 0.998/1.00
M.D. Anderson Cancer Center/United States Of
America
Graphical comparison with the B-A method did not
show meaningful differences between AD and IPD Background: Randomized phase II trials are
(mean difference 0.0075, 95% CI -0.0052, 0.02), used to screen new agents, but if a drug hitting
without signiÀcant discrepancy, with no signiÀcant target present in 40% of patients is compared to
differences in variance (F-test 1.06, p=0.91), and one hitting target present in 10%, it is erroneously
high CCC (0.98, 95% CI 0.59, 0.99). A highly concluded that the drug hitting the more common
signiÀcant correlation by both parametric and non- target is the better drug. The correct conclusion
parametric tests, allowed derivation of a linear is that each agent is best for subpopulations with
regression equation able to predict IPD results from the relevant target. Similarly, there are published
AD data (YAD=[0.04315] + XIPD[0.958]; R2 0.97). examples of drugs that are beneÀcial in one
Conclusion: This study evaluated two meta-analysis subpopulation but harmful in another where
methods (AD or IPD). We found 1) no signiÀcant randomized trials in unselected patients erroneously
differences between the two meta-analysis methods, concluded the drug had no effect.
with very similar risk ratios derived from either Methods: Using actual survival of 334 NSCLC
method. Additionally, 2) AD results predict IPD patients as “controls”, we performed limited
results, without signiÀcant risk of overestimation. simulations to assess performance of randomization
While there may be particular advantages to each in various clinical scenarios.
method (AD can be rapidly and inexpensively Results: For an agent hitting target present in
conducted; IPD may allow greater ability to evaluate 10% of patients in a simulated treatment arm,
issues not originally contemplated in the individual and quintupling survival in patients with target
studies), both give similar and useful results relating (eg, from 2 to 10 months), this simulated study
to the key question analyzed. concluded the drug was ineffective (p=0.16), and an
Keywords: meta-analysis, comparison, methodology agent with marked value in a distinct subpopulation
would be discarded. If the trial was increased to
2,000 patients, then p was <0.03 and the drug
would be approved for use, including in the 90%
of patients deriving no beneÀt. If the target is Àrst
identiÀed in phase I-II trials by correlating tumor Session O45: Pleural and Central
shrinkage with target presence, then a trial with just Airways Management
16 patients selected for target would demonstrate
beneÀt (p<0.02), yielding the correct conclusion
that the drug is effective in patients with target. In
the 668-patient trial, if drug hit common targets and
increased survival of all patients by 33% (just 21 Pleural and Central Airways Management Thursday, 7 July 2011
days) from 2 to 2.7 months, the drug was judged 12:30-14:00
effective (p=0.03). Hence, agents with miniscule
beneÀt in a high proportion of patients may do O45.01 THE FEASIBILITY OF MEDICAL
better in randomized trials than agents with marked THORACOSCOPY FOR DETECTION
impact in subpopulations. In some simulations, OF MALIGNANT EFFUSION IN THE
varying the proportion of patients with target by DIAGNOSIS OF UNDETERMINED
just 2% resulted in drug being declared effective PLEURAL EFFUSION
rather than ineffective. If one drug quintupled Do H. Kim1, Jung J. Hwang2, Kil D. Kim2
1
survival in 10% of patients, and another quintupled Thoracic & Cardiovascular Surgery, Busan
survival in a different subpopulation, the 2 drugs National University Yangsan Hospital/Korea,
2
were declared “equivalent” (p=0.89) despite Cardiovascular Thoracic Surgery, Eulji University
working in completely different subpopulations. Hospital/Korea
Randomized phase II nonparametric comparisons
with respect to % tumor shrinkage would often Background: Thoracoscopic pleural biopsy is
discard agents despite marked beneÀt in a necessary for the conÀrmative diagnosis of malignant
subpopulation, even using a “relaxed” 1-sided pleural effusion. However, the conventional technique
p=0.10. If control patients ranged from tumor is inappropriate as a routine diagnostic tool because it
shrinkage of 15% to growth of 100% and if requires general anesthesia. Medical thoracoscopy is
the new agent shrank tumors by 80% in a 10% thought to be the alternative conventional technique. It
subpopulation of patients carrying a target, 35 is more feasible as a routine diagnostic tool because it is
patients would be required for p<0.10 if control performed only under local anesthesia.
patients with target had 90-100% tumor growth, but Methods: Initially 248 patients were referred to further
300 patients would be required if control patients evaluate undetermined pleural effusions. Excluding the
with target had neither shrinkage nor growth, and 32 patients who refused the medical thoracscopy, the
10,000 patients would be needed if control patients remaining 216 patients underwent cytology, chest CT,
with target had 10-15% tumor shrinkage. and medical thoracoscopy. We analyzed the safety of
Conclusion: Since important new agents often hit medical thoracoscopy and the sensitivity, speciÀcity,
targets present in small subpopulations, it may be and accuracy of the three diagnostic tools respectively
misleading and irrational to conduct randomized Results: There was no mortality, nor any morbidity.
trials in unselected patients. The Ànal diagnoses were malignant effusion
Keywords: NSCLC, Clinical Trials 30.1% (n=65), tuberculosis pleurisy 28.3% (n=61),
parapneumonic effusion 40.7% (n=88), and others
A revised/updated abstract may be included in 0.9% (n=2). The sensitivity of cytology, chest CT and
the Late Breaking Abstract Supplement, available medical thoracoscopy were 22.6%, 78.5%, 93.8%,
at the 14th World Conference on Lung Cancer. respectively, and the speciÀcity were 99.3%, 91.4%,
100% respectively, and the accuracy were 75.9%, 87.5
%, 98.4%respectively. The sensitivity and accuracy
of medical thoracoscopy are signiÀcantly higher than
cytology and radiologic evaluation (p<0.05).
Conclusion: Medical thoracoscopy is a safe and feasible
diagnostic tool for undetermined pleural effusion. The
routine use of medical thoracoscopy is necessary to
prevent misdiagnosis of malignant pleural effusion.
Keywords: Medical thoracoscopy, VATS, malignant
effusion
Pleural and Central Airways Management Thursday, 7 July 2011 rigid thoracoscopy was performed 4.2 (4.8) days
12:30-14:00 after initiation of work-up. In 122 patients pleural
abnormalities were seen. In 118 patients (87%) a
O45.02 ASSESSMENT OF SEMI-RIGID deÀnite diagnosis was established in 10.1 (5.4) days
THORACOSCOPY IN THE DIAGNOSIS after initiation of work-up. In 104 patients the semi-
OF MALIGNANT PLEURAL EFFUSION. rigid thoracoscopy was practice changing compared
Nicole Scheppers, Gerben Bootsma, Michiel to thoracocentesis alone (77%). 85 malignancies
Gronenschild, Erik V. Haren were found; in 76 of these (89%) the origin of the
Pulmonary Diseases, Atrium Mc Parkstad/ malignancy could be determined (deÀnite diagnosis).
Netherlands Other diagnosis revealed Àbrosis, ‘reactive’ and
inÁammation. Five procedures were converted
Background: Almost all malignancies are able to to rigid thoracoscopy, due to insufÀcient biopsy
seed to the pleura. In exsudative pleura effusion, material, all in the Àrst two years of the study. 13
malignancy is the cause in 42-77%. The diagnosis patients received an additional surgical biopsy, 7
of malignant pleural effusion is of major importance revealed malignancy after all (6 mesotheliomas
for staging and therapy. Guidelines recommend and 1 sarcoma). There was 1 haematothorax as a
up to 3 consecutive diagnostic thoracocenteses to complication of the semi-rigid thoracoscopy itself,
diagnose malignant pleural effusion, but even then furthermore 2 patients developed infection of the
sensitivity is limited to 70%. Furthermore only pleural space after pleural drainage.
a cytological diagnosis is yielded and it is a time Conclusion: Semi-rigid thoracoscopy performed
consuming procedure. In our hospital it is practise to immediately after initial thoracocentesis is an easy
perform semi-rigid thoracoscopy immediately after and safe procedure with a high (87%) diagnostic
initial thoracocentesis showing an exsudative non- rate in a limited diagnostic time period. Compared
infectious pleural effusion. We hypothesize that this to thoracocentesis alone, it changes the treatment-
procedure offers a quicker diagnosis and a higher plan in 77% of patients. Furthermore thoracoscopic
diagnostic yield (by addition of (immuno-)histology) assessment yields far more a deÀnite diagnosis of
compared with thoracocentesis, without additional cancer (89% vs 10%).
complications. Keywords: thoracoscopy, malignant pleural
Methods: In a retrospective descriptive study, effusion, diagnostic rate
conducted in our large Dutch teaching hospital, all
patients who underwent semi-rigid thoracoscopy
for the diagnosis of pleural effusion were included Pleural and Central Airways Management Thursday, 7 July 2011
between 2006 and 2010. Semi-rigid thoracoscopy 12:30-14:00
(Olympus® LTF-160) was performed under local
anaesthesia according to standard protocol, a pleural O45.03 EFFECTIVE, EFFICIENT
catheter was left for pleurodesis when necessary. MANAGEMENT OF MALIGNANT
Biopsies of the parietal pleura were taken for PLEURAL EFFUSIONS:
histology. In a standardized protocol, demography, A COLLABORATION OF
(PET-)CT Àndings, aspect of pleural Áuid, results INTERVENTIONAL RESPIROLOGY,
of pleural cytology, time between initiation of PALLIATIVE CARE AND HOME CARE
analysis untill deÀnite diagnosis, thoracoscopic Lynn Kachuik1, Kayvan Amjadi2
1
results including need for conversion (rigid or Palliative Care, The Ottawa Hospital/Canada,
2
surgical), and complications were recorded. Primary Respirology:interventional Pulmonology, The
endpoint is diagnostic rate. Secondary endpoints are Ottawa Hospital / University Of Ottawa/Canada
time to diagnosis, number of decision changes and
complication rate. Background: Malignant pleural effusions are
Results: In 5 years 135 semi-rigid thoracoscopies common complications for patients diagnosed with
were performed in 135 patients, mean (SD) age 68.4 several advanced cancers, but are most commonly
(9.7) years, 92 males, 43 females. Initial pleural associated with bronchogenic carcinoma, found in as
cytology showed a malignancy in 56 patients many as one third of patients. The development of a
(41%). In only 6 out of these 56 patients (10%) malignant effusion portends a poor prognosis with
a deÀnite diagnosis could be established. Semi- an estimated survival of 3 to 6 months. Patients with
malignant pleural effusions experience distressing Pleural and Central Airways Management Thursday, 7 July 2011
symptoms and reduced quality of life in addition to a 12:30-14:00
shortened life expectancy. Management of malignant
pleural effusions varies from inpatient management, O45.05 PHOTODYNAMIC THERAPY
to repeated outpatient or emergency room visits and USING NPE6 FOR MULTIPLE PRIMARY
to formalized outpatient and homecare programs. LUNG CANCERS
In our community, a collaboration of Interventional Jitsuo Usuda, Shuji Ichinose, Tatsuya Inoue, Keishi
Pulmonology, Palliative Care, Oncology and Home Ohtani, Taichirou Ishizumi, Hidetoshi Honda,
Care, facilitated the establishment of a Malignant Naohiro Kajiwara, Tatsuo Ohira, Norihiko Ikeda
Effusion Outpatient Clinic linked to the home Thoracic Surgery, Tokyo Medical University/Japan
Palliative Care program. The management of
these patients was accomplished via the insertion Background: Photodynamic therapy (PDT) is
of a tunneled catheter (PleurX®). The Malignant recommended as a treatment option for centrally
Effusion Clinic provides the expert hub of care for located early lung cancers (CLELCs). Although
insertion, follow up, troubleshooting and community PDT using Photofrin has not been recommended for
education while the home care program provides large tumors or deeply invasive tumors , in the past,
the nursing expertise to conduct ongoing drainages, if their mass is reduced by electrocautery, PDT with
assessment, symptom management and palliative the NPe6 second-generation photosensitizer has been
care. found to be capable of destroying the residual cancer
Methods: A retrospective review of all patients lesion. NPe6 is a second-generation photosensitizer,
treated in the Malignant Effusion Clinic from May and since it has a longer absorption band (664 nm)
2006 to April 2010 was conducted to assess the than Photofrin (630 nm), we hypothesized that
effectiveness and efÀciency of the program. NPe6-PDT would exert a strong antitumor effect
Results: Although the audit included 558 patients against cancer lesions greater than > 1.0 cm in
with all diagnoses who had a total of 643 catheters diameter.
inserted, this presentation will focus only on those Methods: Between June 2004 and December 2009,
patients with a diagnosis of lung cancer (n = 200). 90 patients (109 lesions) with CLELC underwent
Data reported will include patient parameters such as NPe6-PDT after the extent of their tumors had
demographics (age, sex, diagnosis, side of effusion), been assessed by Áuorescence bronchoscopy for
functional status (ECOG), and clinical outcomes photodynamic diagnosis and tumor depth had been
(success of insertion, relief of dyspnea, spontaneous assessed by EBUS
pleurodesis, time to pleurodesis, complications, Results: Eighty six cancer lesions 1.0 cm in diameter
length of time catheter in situ and length of survival). and 31 lesions >1.0 cm in diameter were identiÀed,
We will also discuss process outcomes including and the CR rate was 94.1% (81/86) and 90.3%
numbers of clinic visits, numbers of home care visits (28/31), respectively. After the mass of large tumors
and program costs. and deeply invasive tumors, had been reduced by
Conclusion: There continues to be much variation electrocautery, NPe6-PDT was capable of destroying
in the literature regarding appropriate clinical the residual cancer lesions. Among 90 patients with
management of malignant pleural effusions. The CLELC, multiple lung cancer lesions (MPLC) were
outcomes achieved in a comprehensive outpatient observed in 31 patients (34.4%). Among the patients
program for this group of palliative lung cancer with MPLC, 13 patients underwent surgery for
patients will be presented which may promote further primary lung cancer and then underwent NPe6-PDT
discussion of the role of outpatient management for for the treatment of secondary primary CLELC. In
malignant pleural effusions. 17 of the 31 patients, all 37 lesions were CLELC
Keyword: malignant pleural effusion management were performed PDT alone. Among 31 patients with
MPLC including peripheral type lung cancers which
were resected by surgery, all 51CLELC lesions
exhibited a complete response after NPe6-PDT.
Conclusion: NPe6-PDT has a strong antitumor
effect against CLELCs >1.0 cm in diameter,
thereby enabling the destruction of residual cancer
lesions after mass reduction of large nodular or
polypoid type-lung cancers by electrocautery. The drain insertion. 3 patients had haemoptysis, 2
PDT guidelines for lung cancers should therefore patients developed infection which was treated
be revised, because use of NPe6-PDT will enable with antibiotics. The mean survival was 189 days
expansion of the clinical indications for PDT, and following stent placement,[primary lung cancer
PDT can play an important role for the treatment mean 150 days, secondary cancer mean 406 days]
strategy for MPLC. Conclusion: This technique is useful in palliating
Keywords: early lung cancer, photodynamic life threatening airway obstruction, particularly for
therapy, multiple primary lung cancers secondary cancer, and can be used in any centre
undertaking Àbreoptic bronchoscopy.
Keywords: Airway-stenting, Airway-obstruction
Pleural and Central Airways Management Thursday, 7 July 2011
12:30-14:00
Pleural and Central Airways Management Thursday, 7 July 2011
O45.06 FIBREOPTIC BRONCHOSCOPIC 12:30-14:00
INSERTION OF THE GIANTURCO
STENT FOR TRACHEOBRONCHIAL O45.07 BACTERIAL COLONIZATION IN
OBSTRUCTION IN PATIENTS WITH PATIENTS WITH TRACHEOBRONCHIAL
CANCER AT A LUNG CANCER STENTS
TERTIARY REFERRAL CENTRE: 20 Antoni Rosell, Raquel Pascual Cascon, Rosa Lopez-
YEAR EXPERIENCE Lisbona, Noelia Cubero, Susana Padrones, Pablo
Martin J. Ledson, Andrea Mciver, Jean Hughes, Jo Diaz-Jimenez, Jordi Dorca
Dunbar, Andrea Collins, Colin Smyth Pulmonology, Hospital Universitari De Bellvitge/
Liverpool Heart And Chest Hospital, Liverpool Lung Spain
Cancer Unit/United Kingdom
Background: Interventional bronchoscopic
Background: Large airway obstruction is a procedures are good palliative treatments for
distressing and life threatening complication of locally advanced cancer affecting main airways.
malignant disease, which may not be amenable to Stent colonization by potentially pathogenic
urgent radiotherapy treatment. Palliative protection microorganisms can be a problem in patients
of the airway by stenting is a difÀcult procedure, undergoing chemotherapy. The aim of the study
traditionally carried out under general anaesthesia is to describe the prevalence, incidence and
and Áuoroscopy. Our group has previously shown proÀle of potentially pathogenic microorganisms
that it is possible to place self expanding Gianturco (PPM) colonizating the airways of patients with
metal stents under local anaesthesia using the tracheobronchial stents.
Àbreoptic bronchoscope and direct vision for the Methods: We included consecutive clinically
treatment of malignant airway tumours. We have stable patients attended for palliative treatment of
used this technique routinely for suitable patients cancer in which silicone or metal expandible stents
referred to our regional unit over the last 20 years, were implanted. Previous to endoscopic treatment,
and we now report our experience. bronchial washings (BW) were obtained by Áexible
Methods: A retrospective review of all stenting bronchoscope after the patient was intubated with
procedures carried out in our unit between 1990 and rigid bronchoscope under general anesthesia.
2010 was performed, looking for histological type, Microbiological results were expressed qualitatively.
number and site of stents, any complications of the Results: We retrospectively studied 30 patients with
procedure, other interventions, and survival. a mean follow up of 119 d( 27-300); 73.3% men,
Results: 238 patients (average age 64 years, [range age 62.7 (SD 7), former smokers 56%, smokers
21 to 89]) had 416 stents inserted during 244 26%,never smokers 17%; FEV1% 57.5% (SD
procedures (average 1.72 stents/procedure, [range 17.7%); mean survival time 122 days (95%CI 95-
1 to 4]). 186 patients had malignant primary lung 149), Stents implanted: 60% silicon (Dumon), 26.6%
tumours and 33 secondary malignancy (15 missing metallic (UltraÁex), combines 3.4%. 1 stent 77%, 2
data, 4 patients stented for benign conditions). There stents 23%.
were no operative deaths, but 4 patients developed
a pneumothorax, of which 1 required intercostal
Mean time n PPM (%) PA (%) SA (%) HI (%) MRSA (%) Other
(days) (%)
from
previous
control
0 (basal) 30 23.3 10 6.7 6.7 - -
21 30 66.7 20 26.7 10 3.3 6.7
33 22 77.3 33 28.6 4.8 4.8 4.8
51 19 84.2 26.3 26.3 5.3 - 21.1
29 7 71.4 42.9 14.3 - - 14.3
33 5 80 60 20 - - -
30 3 100 66.7 - - - 33.3
19 2 100 50 50 - - -
PPM: potential pathogenic microorganisms. PA=

Pseudomonas aeruginosa. SA= Staphiloccocus
aureus HI=Haemphilus inÁuenza MRSA=
multiresistent SA
Conclusion: Tracheabronchial stents are associated
with a progressive increase in PPM colonization.
Pseudomonas aeruginosa and Staphiloccocus aureus
are the most common bacteria. Microbiological
sampling during routine bronchosocpy is
recommended. Funded by CIBERES.
Keywords: tracheobronchial stent, bronchoscopy,
bacterial colonization
MINI ORAL SESSIONS survival beneÀt. There were practice variations in

management of patients with advanced stage disease
(n=71). A multimodality approach that included
Session MO01: Mesothelioma and surgery, radiation and chemotherapy correlated with
Thymoma better outcomes. Tri-modality treatment for thymoma
achieved a 5 year OS of 85%; however patients with
advanced thymic carcinoma had poor outcomes
Monday, 4 July 2011
despite aggressive treatment. In multivariate analyses
histology (thymoma vs. thymic carcinoma) and
Mesothelioma and Thymoma Monday, 4 July 2011 14:30-16:00 surgery were signiÀcant predictors of OS. 5 year
progression free survival and overall survival
MO01.01 MANAGEMENT AND
OUTCOMES FOR THYMOMA IN Stage 5 yr PFS 5 yr OS
BRITISH COLUMBIA: A POPULATION- I (n= 13) 91% 91%
BASED ANALYSIS. II (n=84) 83% 86%
Caroline J. Mariano1, Diana Ionescu2, Winson III (n=42) 49% 70%
Y. Cheung1, Rola Ali2, Janessa Laskin1, Hannah IV (n=32) 13% 46%
Carolan3, Kenneth Evans4, Nevin Murray1
1
Medical Oncology, British Columbia Cancer Conclusion: This study is the Àrst population-based
Agency/Canada, 2Pathology, British Columbia series to detail treatment and outcomes for thymoma.
Cancer Agency/Canada, 3Radiation Oncology, Outcomes compare favourably to series from single
British Columbia Cancer Agency/Canada, institutions. Patients with locally advanced disease
4
Thorassic Surgery, University Of British Columbia/ for whom initial surgical resectability is uncertain
Canada should be triaged to a multidisciplinary team for
consideration of multimodality treatment.
Background: The optimal approach to the Keywords: Thymoma, Thymic carinoma,
management of thymoma and thymic carcinomas population-based, locally advanced
is unclear, particularly for advanced stage disease.
Our primary study aim was to analyze treatment A revised/updated abstract may be included in
practices and outcomes in a population-based cohort the Late Breaking Abstract Supplement, available
of thymoma patients. at the 14th World Conference on Lung Cancer.
Methods: All patients with a pathological diagnosis
of thymoma or thymic carcinoma and referred
to the British Columbia Cancer Agency (BCCA) Mesothelioma and Thymoma Monday, 4 July 2011 14:30-16:00
between 1994 and 2009 were reviewed. Kaplan-
Meier curves and Cox proportional hazard models MO01.02 CLINICAL PROGNOSTIC
were used to correlate histology, stage and treatment FACTORS IN THYMIC TUMOURS-8
with outcomes. Pathology review using WHO YEARS FOLLOW UP
classiÀcation is currently underway. Sheng P. Shen1, Shun Lu2
1
Results: 190 patients were identiÀed of which Shanghai Lung Tumor Clinical Medical Center,
171 (90%) were referred to BCCA and eligible Shanghai Chest Hospital,Jiaotong Univercity/China,
2
for analyses. Median was 60 years; 50% of pts Department Of Shanghai Lung Cancer Center,
were male. 26% had paraneoplastic phenomena; Shanghai Chest Hospital, Jiaotong University,
including 21% with myasthenia gravis. Patients with Shanghai/China
thymic carcinoma (n= 23) and thymoma (n=148)
had 5 year overall survival (OS) rates of 38% and Background: To explore the prognostic factor
81%, respectively. Survival by stage is detailed in by analyzing clinical and pathologic features of
table 1. Patients with stage I disease were treated thymoma and thymic carcinoma.
primarily with surgery. Selected stage II patients Methods: 115 cases of thymoma and thymic
received adjuvant radiation therapy, which conferred carcinoma were analyzed based on WHO schema
a signiÀcant improvement in progression free for thymic tumors classiÀcation(2004), and Masaoka
survival (98 vs. 62 months, p<0.01), but no overall stage. The clinical factors include histological
classiÀcation, Masaoka stage, multimodality Mesothelioma and Thymoma Monday, 4 July 2011 14:30-16:00
treatment, and myasthenia gravis (MG). Univariate
survival analysis were done by Kaplan-Meier and MO01.03 DIFFERENT
Log-Rank methods. Multi-analysis was carried out CHARACTERISTICS OF THYMOMAS
by COX regression. WITH AND WITHOUT MYASTHENIA
Results: Histology by WHO was 1 A (0.9%), GRAVIS
15 AB (13%), 7 B1 (6.1%), 22 B2 (19.1%), 27 Lei Yu, Yun-Feng Zhang, Fei Li, Shan Ma
B3 (23.5%), and 43 thymic carcinoma (37.4%), Department Of Thoracic Surgery, Beijing Tongren
respectively. Masaoka staging was stage I, 23 Hospital, Capital Medical University/China
cases (20%), stage II, 35 (30.4%), stage III,
43(37.4%), and stage IV 14(12.2%), respectively. Background: The objective of this study was to
These patients, the median survival time was 84.4 evaluate the different pathological and clinical
months, the 8-year survival rate was 78%. WHO characteristics of thymomas with and without
histologic subtype closely correlated with Masaoka myasthenia gravis (MG) and determine whether
stage (correlation coefÀcient=0.596,P<0.01). The the presence of MG inÁuences the prognosis in
8-year survival rate of type A+AB were 91%, type thymoma patients.
B1+B2+B3 were 94%, thymic carcinoma were 60%, Methods: We retrospectively studied data from 228
respectively(P=0.001). The 8-year survival rate consecutive patients operated on from1992 to 2007
of stage I, II, III and IV were 95%, 97%, 72% and in the department of Thoracic Surgery of Beijing
34%, respectively(P<0.001). MG was present in 96 Tongren Hospital. These thymoma patients have
cases (83.5%). The 8-year survival rate of patients been subdivided into two groups: Group A with MG
with MG was 84%, 77% without MG (p=0.634). 83 (n=125) and Group B without MG (n=103). These
patients received complete resection, and 33(39%) patients underwent extended thymectomy using a
were undergone adjuvant radiotherapy, the other transsternal approach (n=153) or VATS (n=75). All
49(59%) were not. The 8-year survival rate of these thymic epithelial tumors were classiÀed according to
83 patients was 87%, and 88% for the patients the WHO histologic classiÀcation and the Masaoka
treated with adjuvant radiotherapy, 85% for the clinical staging system.
patients without adjuvant radiotherapy, respectively Results: There were no peri-operative deaths.
(p=0.651). Masaoka stage is a signiÀcant 19 cases were inoperable. (6 in the group with
independent prognostic factor in patients with thymic MG, 13 without MG, P=0.035). The proportions
tumors(p=0.019). of type A, AB, B1, B2, B3, and C thymoma in
Conclusion: Myasthenia gravis maybe was not this data were 0%, 22.4%, 26.4%, 30.4%, 20.8%,
the favourable prognosis factor of thymic tumors. and 0% respectively in the group with MG, and
Adjuvant radiotherapy after complete resection 10.5%, 13.4%, 23.6%, 24.5%, 16.4%, and 11.6%
didn’t prolong the survival time. Only Masaoka respectively in the group without MG. According
stage is a signiÀcant independent prognostic factor in to the modiÀed Masaoka’s clinical staging, in the
patients with thymic tumors. group MG, 24.8 % patients were stage III and IV; in
Keywords: Thymoma, Thymic Carcinoma, the group without MG, 33 % patients were stage III
prognostic factor and IV. There was a signiÀcant difference between
hyperplastic paraneoplastic thymus coexisting in
A revised/updated abstract may be included in 28.8% patients with MG and only 5.8% in patients
the Late Breaking Abstract Supplement, available without MG. Microthymoma was identiÀed in
at the 14th World Conference on Lung Cancer. the paraneoplastic thymus of 3 patients with MG.
There were 198 patients followed up. There was
no recurrence in patients with type A and a few
patients with type AB, B1, B2, B3 and C recurred.
The actuarial 5- and 10-year survival rates were
89.3% and 81.2% for patients with MG respectively,
and 90% and 78.9% for patients without MG
respectively. Within 5 years postoperatively, 6 of 9
patients with MG died of myasthenia crisis, while
6 out of 7 deaths in patients without MG were
attributable to inoperable tumors (stage) and type C with Maysthenia Gravis (MG). The median time
thymoma. between onset of MG and the procedure was 15
Conclusion: MG seldom occurs in type A and C months (range 3-72 months). 24 patients were
thymoma. In addition to resection of thymoma, all suspected for a thymoma based on the CT-scan. No
thymic tissue and mediastinal fat should also be surgical mortality was reported and there were no
completely removed to lower possibility of thymoma complications during the procedure. One procedure
recurrence and achieving complete stable remission was performed eventually by sternotomy because of
of MG. The prognosis of thymomas with MG is obesity of the patient. Median hospitalization was
similar to that without MG. The main cause of death 3.8 days (range 3-25 days). The mean procedure
is myasthenia crisis for thymoma patients with MG time was 139 minutes (range 44-260 minutes). Major
and stage IV and /or type C for thymoma patients postoperative complications occurred in 4 patients
without MG. (5.4%) 2 patients experienced a myasthenic crisis
Keywords: characteristics, Prognosis, Thymoma, and 2 patients experienced respiratoiry insufÀciency.
Myasthenia Gravis Histologic analysis of the resected tissue revealed 18
thymomas (3 type AB, 7 type B2, 5 type B1, 1 type
A) and 1 thymus carcinoma. Follow-up evaluation
Mesothelioma and Thymoma Monday, 4 July 2011 14:30-16:00 of 32 patients with MG (mean 22 months) showed
that 2 (6.25%) patients had complete remission
MO01.04 THORACOSCOPIC and 23 (71,9%) patients had clinical improvement,
THYMECTOMY BY A ROBOTIC they were asymptomatic or decreased symptoms
ASSISTED APPROACH and decreased medication. The follow-up of the 18
Marlies Keijzers1, Anne-Marie C. Dingemans1, Hans patients with a thymoom showed no tumour relaps
Blaauwgeers2, Robertjan Suylen Van3, Monique and no tumour related deaths
Hochstenbag1, Leen Van Garsse4, Mark De Baets5, Conclusion: A three-dimensional robotic assisted
Jos Maessen4 videothoracoscopic approach is a safe way to
1
Department Of Pulmonology, Maastricht University remove the thymus. It has a big advantage in tiny
Medical Center/Netherlands, 2Department Of difÀcult areas, the complication rate is low and, most
Pathology, Onze Lieve Vrouwengasthuis, Amsterdam/ important, it is less invasive for the patient.
Netherlands, 3Department Of Pathology, Maastricht Keyword: Robotic surgery
University Medical Center/Netherlands, 4Department
Of Thoracic Surgery, Maastricht University Medical
Center/Netherlands, 5Department Of Neurology, Mesothelioma and Thymoma Monday, 4 July 2011 14:30-16:00
Maastricht University Medical Center/Netherlands
MO01.06 MALIGNANT
Background: Recently, the use of three-dimensional PLEURAL MESOTHELIOMA
robotic assisted videothoracoscopy was suggested IMMUNOHISTOCHEMISTRY IN
to improve the accuracy in radical surgical thymus SEARCH OF THE MOST SUITABLE AND
resection and to reduce operating time. It offers an COST-EFFECTIVE ANTIBODY PANEL.
excellent view and surgical control of the thymus Pier-Giacomo Betta1, Thea Bensi1, Nicol F.
gland and its surroundings. Here we report our 5 Trincheri1, Roberta Libener1, Sara Orecchia1,
year experiences with the Davinci Intuitive Robotic Corrado Magnani2
1
system in thymectomies Pathology, Azienda Ospedaliera Nazionale/Italy,
2
Methods: We retrospectively analyzed the patients University Of Eastern Piedmont/Italy
who underwent a thymectomy from December 2004
to January 2009 using the Davinci surgical robotic Background: Malignant mesothelioma (MM)
system (by a 3 port, right-sides approach). All the exhibits phenotypic versatility with frequent overlap
procedures were performed by two thoracic surgeons with reactive mesothelial proliferations or pleural
who were trained for robotic surgery metastases. Immunohistochemistry is currently an
Results: 74 patients (54 females, 20 males), mean indispensable tool in the histologic diagnosis of
age 39.1 years (range 14-82 years) underwent a MM. No single marker entirely conclusive for MM
thymectomy using the Davinci surgical robotic has yet been established and most commercially
system. 60 (81.1%) patients were diagnosed available antibodies are used in panels, although
no consensus exists about which and how many al Am J Clin Pathol 2000 114: 203) with the resulting
antibodies should be used. To help optimize probability of 0,8183 and 0,00002, respectively.
a combination of antibodies for the histologic Conclusion: This study based on a very large set
evaluation of pleural tumor tissue specimens, the of MMs provides support for a cost-effective panel
use of immunohistochemistry was retrospectively of only three antibodies, without compromising
reviewed in 258 consecutive epithelioid or mixed sensitivity or speciÀcity.
MMs from 2003 to 2009 as well as in 67 carcinoma Keywords: mesothelioma, immunohistochemistry,
metastases in the pleura. logistic regression
Methods: MMs were immunostained with 3 positive
mesothelioma (calretinin, keratin 5, and WT-1)
and 5 positive carcinoma markers [polyclonal Mesothelioma and Thymoma Monday, 4 July 2011 14:30-16:00
carcinoembryonic antigen (pCEA), CD15 (LeuM1),
Ber-EP4, MOC-31, and thyroid transcription factor-1 MO01.07 INTEGRATED ANALYSIS
(TTF-1)], selected following both evaluation of the OF MICRO-RNAS AND GENES IN
literature and experience in the authors’ laboratory. MALIGNANT MESOTHELIOMA
The same antibodies were also applied to the Chuong D. Hoang1, Andrew Gentles2, Yue Xu2,
67 pleural metastatic carcinomas. The relevant Sylvia Plevritis2, Robert E. Merritt2, Richard I.
sensitivities and speciÀcities were calculated for each Whyte2, Joseph B. Shrager2, Robert A. Kratzke3
1
antibody and logistic regression (LR) was applied Cardiothoracic Surgery, Stanford University/United
to determine the optimal combination of antibodies States Of America, 2Stanford University/United
for distinguishing MM from pleural metastatic States Of America, 3University Of Minnesota/United
carcinoma. States Of America
Results: The sensitivities and speciÀcities were as
follows: Background: We hypothesize that certain
microRNA (miRNA)-mRNA interactions are
Sensitivity (%) SpeciÀcity (%) associated with malignant transformation and
Mesothelioma markers - 98 99 98 89 81 72 progression of malignant mesothelioma (MM). To
calretinin - keratin 5 - WT-1 date, no integrated analysis has been performed to
Carcinoma markers - pCEA 100 92 94 100 100 95 74 94 76 65 identify critical interactions between miRNA-mRNA
- CD15 (LeuM1) - Ber-EP4 -
that may drive the MM malignant phenotype.
MOC 31 - TTF-1
Methods: Total RNA was extracted from 24
The combined usefulness of the individual specimens of biopsy proven human MM and
reactivities of the 3 diagnostically best performing 6 specimens of normal pleura. Paired global
antibodies, i.e. calretinin, pCEA and BerEP4, was transcriptional proÀles of miRNA and genes
tested by LR analysis, using an exact logistic model (mRNA) expression were generated using Illumina
with estimate of the intercept (SAS v. 8, Proc microarrays. To optimize detection of causal
logistic, exact conditional analysis). OR values associations, Spearman correlations between miRNA
from multivariate LR were as follows: calretinin and mRNA expression were calculated among MM
[1 (= positive) vs 0 (= negative)] 66,93; CEA (1 vs samples. Correlation p-values were converted to
0) 0,006; and BerEP4 (1 vs 0) 0,0509. This model false discovery rates (FDR q-values) to account for
showed no evidence of lack of Àt based on the multiple comparisons; associations with q<=0.05
Hosmer-Lemeshow statistic (chi-square = 0.027). were considered signiÀcant. To better determine
The likelihood of being an MM for a calretinin- relevant genes for a given process, sets of genes
positive and CEA- and BerEP4-negative case was whose expression levels negatively correlated
very high (pr = 0,9953), whereas a calretinin- with speciÀc miRNAs were identiÀed as likely
negative and CEA- and BerEP4-positive case direct targets of that miRNA. Gene Set Enrichment
had very low probabilities of being an MM (pr = Analysis (GSEA) was used to Ànd target gene sets
0,00097). However, metastatic carcinomas were that were signiÀcantly repressed or overexpressed
greatly underrepresented in the present material with in MM vs normal in the opposite direction to
respect to the expected 1:9 proportion in the general expression of the miRNA itself. Additionally,
population. Therefore, the likelihood estimates were external data sets (n=2) were interrogated with
adjusted according this proportion (Brockstedt U et GSEA to reÀne target gene sets whose behavior
was consistent across the data and identify which Mesothelioma and Thymoma Monday, 4 July 2011 14:30-16:00
were associated with patient survival. Associations
of mRNA expression levels and disease-speciÀc MO01.08 FREQUENT ACTIVATION OF
survival were evaluated by univariate Cox PI3K PATHWAY AND DOWNSTREAM
proportional hazard regression. To improve the SIGNALING ANALYSIS IN MALIGNANT
accuracy of predicted miRNA-mRNA pairs, de novo PLEURAL MESOTHELIOMA (MPM)
DNA motif analysis was performed on the putative Susana Cedrés1, M. A. Montero2, Davis Torrejon2,
targets of a subset of important miRNAs. Pablo Martinez2, Victor Freixinos1, Nuria Mulet-
Results: We found multiple miRNA (total = Margalef1, Isaac Nuñez1, Guillem Argiles1, Maite
12) showing negative correlation in expression Salcedo2, Santiago Ramón Y. Cajal2, Enriqueta Felip1
1
to multiple genes, and having the opposite Medical Oncology, Vall D´hebron University
expression pattern in MM vs normal compared Hospital/Spain, 2Vall D´hebron University Hospital/
to their putative targets. We arrived at this total Spain
by retaining only miRNA whose targets were
consistent across multiple datasets, showed Background: MPM is an aggressive and
signiÀcantly over-represented DNA motifs in their heterogeneous neoplasm with strong variability
3’ untranslated regions, and were signiÀcantly in patient survival that may be due to biological
differentially expressed in tumors (q<0.05). An variability. The AKT/mTOR pathway is frequently
example: expression of miR-1 negatively correlated activated in mesothelioma cell lines. The aim
with expression of 52 mRNA (FDR<0.05). This of this study is to explore the expression and
miRNA was underexpressed in MM by 3-fold phosphorylation status of PTEN, PI3K/AKT and
more (FDR<0.01), while its gene targets showed downstream signaling in MPM and its relationship
an opposite pattern being overexpressed in MM. with the patient´s (pts) prognosis.
Motif analysis of target genes identiÀed a subset of Methods: Thirty-three consecutive MPM pts
biologically plausible miRNA-mRNA interactions. were retrospectively collected from our institution
Ingenuity pathway analysis of these subset genes between 2002 and 2009. Clinical data analyzed
showed enrichment in oncogenic genes (e.g. p21, included sex, age, histology, performance status (PS),
TRAF2, SAA1, and NADSYN1) positively affecting white blood count, and response to chemotherapy
cell growth, survival, anti-apoptosis, immune cell (CT). ParafÀn-embedded biopsies were used for
trafÀcking and inÁammation-related signaling. immunohistochemical proÀle quantiÀed through
Suppressed expression of these genes that are the H-score method. Total and phosphorylated (p)
negatively-correlated with miR-1, associated with proteins analyzed: PTEN, mTOR, MAPK, AKT,
better overall survival in an independent dataset, 4EBP-1, eiF4E, S6 and FOXO3a. Staining results of
indicating that loss of expression of this miRNA each protein were compared with clinical features
affects poorer patient outcomes (FDR<0.01). and the results were calculated according to the
Conclusion: Integrated analysis of miRNA and median H-score.
mRNA expression proÀles in MM revealed novel Results: The total cohort of 33 pts included 25
miRNA associated with MM and identiÀed putative male/8 female; median age 68 (range 52-83);
interactions that may underlie the malignant histology epithelial/no-epithelial (22:11); neutrophil/
phenotype. These miRNA-mRNA are candidates lymphocyte ratio (NLR) >/5 (14:18); stage III/
for functional validation. miR-1 is a putative tumor IV (17:13); PS 0/1(3:24). Patients received either
suppressor miRNA in MM. platinum-pemetrexed (70%) or platinum-gemcitabine
Keywords: microRNA, mesothelioma (25%) and 21.7% of pts had partial response and
43.5% stable disease. Median OS was 16.4months.
Expression of PTEN, pMAPK, mTOR, 4EBP-1,
p4EBP-1, eif4E, peif4E, pAKT, p-S6 and FOXO3a
in MPM was found in 90%, 100%, 93.3%, 100%,
43.3%, 96.7%, 100%, 80%, 63.3% and 100% of
tumors respectively. No correlations were found
between proteins and age, performance status, stage
and response to chemotherapy. Epithelial subtype
histology and NLR less than 5 were associated with
better survival (OS: 23.4 v 2.3 months, p<0.001, CG, Hendriks RW, et al. Consolidative dendritic
for epithelial versus no epithelial and 29.11 v 5.55 cell-based immunotherapy elicits cytotoxicity
months, p=0.001, for pts with NLR less than 5). against malignant mesothelioma. Am J Respir
We found a signiÀcant correlation between low Crit Care Med. [Clinical Trial Research Support,
pS6 protein expression and longer progression free Non-U.S. Gov’t]. 2010 Jun 15;181(12):1383-90).
survival (PFS: 7.88 v 5.55 months; p=0.044) and However, it is known that tumor cells create an
overall survival (OS: 23.36 v 5.59 months; p=0.05). immunosuppressive environment that can lead to a
Among other phosphorylated proteins analyzed no down-regulation of the anti-tumor immunity. Several
differences in survival were detected according to types of suppressive cells (regulatory T cells, M2
median H-score, however, a trend to better results macrophages and myeloid-derived suppressor cells)
in pts with low levels of p4EBP-1 (PFS 7.69 v 5.55 seems instrumental in allowing a growing cancer
months, OS 23.36 v 5.55months; p>0.05) was found. to evade immunological attack and contribute to
In multivariate analysis histology and NLR were the impaired T cell function frequently observed
independent prognostic factors for OS (HR 5.42; in cancer patients. The goal of this study is to
95%CI, 0.44-3.15, p=0.007 and HR 3.43; 95%CI investigate the presence and function of regulatory
1.22-10.79, p=0.018 respectively), but pS6 only T cells (Treg) in tumor bearing animals and cancer
showed a trend (HR 1.22; 95%CI 0.35-4.07; p=0.7) patients. Here we show measures to overcome these
Conclusion: Our results support the prognostic value suppressive mechanisms in combination with DC-
of histologic subtype and NLR in MPM. The PI3K based immunotherapy with the goal to increase the
pathway and downstream proteins are frequently success rate of tumor eradication. New Àndings in
activated. The role of pS6 assessment and its preclinical models have already led to the initiation
prognostic value is worth of prospective validation in of a follow-up clinical study in mesothelioma
future studies on MPM. patients where DC-based immunotherapy is
Keywords: pS6, prognostic factor, malignant pleural combined with low-dose cyclophosphamide to
mesothelioma, PI3K prevent the induction of Treg.
Methods: Tumor bearing mice were treated with
DC-immunotherapy combined with low dose
Mesothelioma and Thymoma Monday, 4 July 2011 14:30-16:00 cyclophosphamide and mean and overall survival
was measured. Treg in blood, lymph nodes and
MO01.09 IMPROVING DENDRITIC spleens were analyzed by Áowcytometry. Patients
CELL-BASED IMMUNOTHERAPY BY with MM are treated with three vaccinations of
MODULATING IMMUNE SUPPRESSIVE clinical-grade ex-vivo generated autologous DC
REGULATORY T CELLS IN at two-week intervals alternating with low-dose
MESOTHELIOMA cyclophosphamide after chemotherapy treatment.
Robin Cornelissen1, Joost Hegmans2, Joris Veltman2, Each vaccine was composed of mature DC pulsed
Marlies Heuvers2, Margaretha Lambers2, Femke with autologous tumor lysate and keyhole limpet
Muskens2, Bart Lambrecht3, Rudi Hendriks2, Henk hemocyanin (KLH) as a surrogate marker. Delayed-
Hoogsteden1, Joachim G. Aerts2 type hypersensitivity activity to tumor antigens
1
Pulmonary Medicine, Erasmus MC/Netherlands, and KLH was assessed, both in vivo and in vitro.
2
Erasmus MC/Netherlands, 3University Of Ghent/ Peripheral blood was analyzed for anti-tumor
Belgium responses and Treg reductions.
Results: The survival of mice increased when
Background: Malignant pleural mesothelioma is a simultaneously metronomic cyclophosphamide
highly aggressive neoplasm. Median survival from was given due to the reduction of Treg in blood
the Àrst signs of illness is 9 - 11 months. Because and lymphoid organs. Until today, eight of the ten
of the limited success of current treatments, novel included patients with MM completed the protocol.
therapeutic regimens are urgently needed. We have Administration of DC pulsed with autologous tumor
previously demonstrated that vaccination with lysate in combination with cyclophosphamice
antigen-pulsed dendritic cells (DC) in mesothelioma was safe with moderate fever as the only side
patients was safe, feasible, and capable of inducing effect. There was no evidence of autoimmunity.
distinct immune and antitumor responses (Hegmans The vaccinations induced distinct immunological
JP, Veltman JD, Lambers ME, de Vries IJ, Figdor responses to KLH. Additional results will be
presented at the congress. patients with high and low SUV and epithelioid and
Conclusion: For the Àrst time, we showed non-epithelioid histotype showed a better prognosis
that immunotherapy combined with low- in both low SUV and epithelioid tumor. The median
dose cyclophosphamide is feasible and safe in follow-up for all surviving patients was 36 months.
mesothelioma patients. At the time of the congress Disease free survival were 11 and 21 months for
results on the presence and function of Treg in the the high and low SUV groups, respectively. Median
blood of patients are available. survivals were 16 and 29 months for the high and
Keywords: mesothelioma, immunotherapy, dendritic low SUV groups, respectively. In a multivariable
cell, regulatory T cell analysis, high SUV tumors were associated with a
4.1 times greater risk of death than low SUV tumors
A revised/updated abstract may be included in (p = 0.04).
the Late Breaking Abstract Supplement, available Conclusion: PET/CT appears to give a good support
at the 14th World Conference on Lung Cancer. in staging and prognosis in MPM. A systematic use
of PET scan could be anticipate the recurrence of
MPM in follow-up period in EPP submitted patients.
Mesothelioma and Thymoma Monday, 4 July 2011 14:30-16:00 Keywords: malignant pleural mesothelioma,
diagnosis, Prognosis
MO01.11 THE ROLE OF PET/CT IN
STAGING AND SURGICAL APPROACH A revised/updated abstract may be included in
FOR MALIGNANT PLEURAL the Late Breaking Abstract Supplement, available
MESOTHELIOMA at the 14th World Conference on Lung Cancer.
Cosimo Lequaglie1, Gabriella Giudice1, Christian
Rolfo2, Daniela R. Marasco1, Aniello Della Morte1
1
Thoracic Surgery, Irccs-crob/Italy, 2Clínica Rotger/ Mesothelioma and Thymoma Monday, 4 July 2011 14:30-16:00
Spain
MO01.12 STAGE-INDEPENDENT PRE-
Background: To show the PET/CT role in reducing OPERATIVE PROGNOSTIC GROUPING
the exploratory procedures with an early diagnosis, OF SURGICALLY-TREATED PATIENTS
in a better staging of disease and in a postoperative WITH EPITHELIAL MALIGNANT
follow-up in MPM. PLEURAL MESOTHELIOMA
Methods: Sixty-seven potentially extrapleural Ritu R. Gill1, Beow Yeap2, Shin Matsuoka1, Andrea
pneumonectomy (EPP) submitted patients (range S. Wolf3, Raphael Bueno3, Hiroto Hatabu1, David J.
age of 31-79 years) were observed between 1999 Sugarbaker3, William G. Richards3
1
and 2009. All patients underwent PET/TC scan: Radiology, Brigham And Women’s Hospital/United
median preoperative SUV was 6.8 (range 3-20). States Of America, 2Cancer Center, Massaschusetts
The same surgeon team operated 45 patients (29 General Hospital/United States Of America,
3
male - 16 female), 23 right-sided lesions and 22 Surgery, Brigham And Women’s Hospital/United
left-sided. Forty patients underwent EPP, 1 pleural States Of America
decortications, 3 exploratory thoracotomies for
chest wall or inferior vena cava invasion, and 1 Background: We sought to derive and validate
laparoscopy for peritoneal metastases. One patient a practical risk model to predict survival
were no surgical proposed for macroscopically following cytoreductive surgery for patients with
evidence of extended diseases and received biopsy diagnosis of epithelial malignant pleural
chemotherapy. Thirty-seven patients had epithelioid mesothelioma (MPM).
subtype, 3 sarcomatous and 6 biphasics. Eighteen Methods: We reviewed 216 (47F:169M)
tumors were pStage I-II, 24 pStage III and 4 pStage MPM patients who underwent extrapleural
IV according IMIG staging system. pneumonectomy (EPP;162) or pleurectomy/
Results: All T4 or M1 cases were detected by PET/ decortication (PD;54) during 2001-2008 and had
CT preoperative scan. The follow-up study reported available preoperative DICOM CT data, from
a PET/TC sensibility of 95% with a diagnostic which tumor volume was calculated. Gender, age,
accuracy of 92% regarding the local recurrences clinical TNM stage and preoperative laboratory
or distant metastases. The analysis correlation in factors (platelet count, hemoglobin, and white blood
cell count) were also assessed. A Cox model was Mesothelioma and Thymoma Monday, 4 July 2011 14:30-16:00
derived based on 102 patients with epithelial Ànal
pathology who underwent EPP 2001-2007 using MO01.13 LUNG SPARING MAXIMAL
factors signiÀcantly related to survival in univariate CYTOREDUCTION FOR PLEURAL
analyses. A preoperative risk assessment algorithm MESOTHELIOMA COMPARES
based on the model was then applied to all 2001- FAVORABLY WITH EXTRAPLEURAL
2007 EPP patients with epithelial biopsy including PNEUMONECTOMY
the patients used to train the model plus 31 who Harvey I. Pass1, S Gadgeel2, Antoinette Wozniak2,
had biphasic histology at Ànal pathology. Algorithm Abraham Chachoua3
1
performance was assessed using a separate cohort of Cardiothoracic Surgery, Nyu School Of Medicine/
54 patients with epithelial biopsy (PD 2001-2008). United States Of America, 2Karmanos Cancer
Results: Multivariate analysis identiÀed tumor Institute/United States Of America, 3Thoracic
volume larger than 500 cm3 and preoperative anemia Oncology, New York University School Of Medicine/
as independently associated with shorter survival United States Of America
duration following EPP for epithelial MPM. A
risk assessment algorithm based on these factors Background: Debate continues regarding the role of
separated biopsy-determined epithelial patients operations other than extrapleural pneumonectomy
(including some with biphasic MPM on Ànal (EPP) for pleural mesothelioma (MPM). There has
pathology) into three distinct prognostic groups. been recent interest in pleurectomy (P) to achieve
Risk groups 1, 2 and 3 (R1, R2, R3; Ns= 62, 51, comparable maximal cytoreduction as an EPP, but
19) had 35.3, 10.4 and 3.7 month median survival, the number of cases reported is small,the magnitude/
respectively. Similarly, in a separate cohort of deÀnition of the operation varies, and overall/
contemporary MPM patients who had epithelial progression free survivals (TTP) are difÀcult to
MPM based on preoperative biopsy (including 14 interpret. Large case series which use consistent
pathologic biphasic) and subsequently underwent criteria for lung sparing in MPM may add insight for
PD (Ns= 28, 21, 5) survival was 33.0, 13.9 and 5.0 future management.
months. Pooled results are depicted in the Àgure. Methods: From 1990 to 2010, 318 MPM
(64F,254M) had either EPP (142), P(102), or Biopsy
only (B, 74) performed by one surgeon, and 30
day mortality was 12 (8%), 2(2%), and 1(1%),
respectively. Our approach has been maximal lung
sparing hemithoracic cytoreduction whenever
possible, especially in low tumor volume MPM.
MPM histology was 182 epithelial, 74 biphasic, 26
sarcomatoid, 36 NOS. All patients had CT scans q
3 months until progression/death, and after 1994
received postoperative or induction chemotherapy.
Recurrence was documented histologically
Conclusion: Radiographic tumor volume and or cytologically when feasible. To achieve
hemoglobin level are measurable preoperatively and cytoreduction, the pericardium, diaphragm, and
provide robust, stage-independent prognostication portions of lung were frequently combined with P.
for patients with apparent epithelial MPM based Results: The MS for B was 5 and 6 months
on pleural biopsy treated with EPP or PD. Most R1 without/with adjuvant therapy. The results of
patients experience extended survival following maximal cytoreductive surgery by EPP or P with
surgery-based multimodality therapy. Surgery for and without chemotherapy are seen below, and
R2 patients and those with biphasic histology on reveal comparable MS of P to EPP in Stage I (and
biopsy should be in the context of clinical trials III) when compared to the literature, a 6 month
investigating novel therapeutic approaches or increase in MS and TTP with chemotherapy, and
strategies to further delineate risk. R3 patients do not a role for EPP in patients with Stage II disease.
demonstrate beneÀt and should be considered for
non-operative treatment or supportive care.
Keywords: Prognosis, mesothelioma, Surgery
in lung function and lung perfusion scans in patients

with MPM before and after RP.
Methods: All patients with histologically proven
MPM were evaluated for trimodality therapy
including RP as surgical procedure in a prospective,
observational study from January to December 2010.
Pulmonary function tests and lung perfusion scans
were obtained before and 2 months after RP. Primary
end-points were pulmonary function by means
Patients who recurred after EPP survived a median of forced vital capacity (FVC), forced expiratory
of 3 months from the time of recurrence, while those volume in 1 second (FEV1) and ipsilateral lung
who recurred after P survived a median of 9 months perfusion, respectively.
from the time of the recurrence (p<0.001). Results: Sixteen patients (age 68.8 ± 8.9 years)
Conclusion: This is one of the largest single-surgeon out of 25 consecutively evaluated patients were
series documenting that (1) maximal lung sparing included in the present study. Exclusion were due
cytoreductive surgery by multivariate analysis is not to metastatic disease (n=1), complete remission
inferior to EPP (2) and may be preferable in patients after induction chemotherapy (n=1), rapid
with Stage I and Stage III disease. EPP appears to progressive disease (n=1), chest wall inÀltration
be associated with a trend towards greater survival (n=2) and impaired cardio-pulmonary reserve (n=3),
and signiÀcantly longer TTP in Stage II disease. respectively. Multimodality treatment was applied
The dramatic differences in survival between EPP in all patients including RP followed by adjuvant
and P need to be explored to determine whether chemotherapy and radiation of the chest wall.
this is due to loss of functional capacity with EPP Macroscopic complete resection could be achieved
which prevents further therapy. Maximal lung in 81.3% (13/16). Diaphragm resection was indicated
sparing cytoreductive surgery should be compared due to inÀltration in 5 patients (31.3%). Statistically
prospectively to EPP after standardization of signiÀcant improvement of pulmonary function was
techniques and deÀnitions, at least in the form of an observed after surgery for FVC (L), FVC (%) and
ongoing IASLC registry. FEV1 (%) as well as ipsilateral lung perfusion after
Keywords: pleurectomy, Extrapleural Bonferroni adjustment (P < 0.05/5). The avoidance
pneumonectomy, adjuvant therapy of diaphragm resection resulted in greater increase
of FVC (=Post-pre FVC (%) +34.6±17.0% vs.
+13.5±5.4%; p=0.002) and FEV1 (=Post-pre FEV1
Mesothelioma and Thymoma Monday, 4 July 2011 14:30-16:00 (%) +29.2±18.1% vs. +12.1±6.4%; p=0.015),
respectively.
MO01.14 PROSPECTIVE EVALUATION
OF THE FUNCTIONAL RESULTS Pre-operative Post-operative p- value Cohen’s Effect
AFTER LUNG-SPARING RADICAL Value Value d size
PLEURECTOMY FOR MALIGNANT FVC (Liter) 2.18± 0.49 2.73± 0.55 0.0060 1.06 large
PLEURAL MESOTHELIOMA FVC (%) 54.7 ± 9.9 68.9 ± 9.1 0.0002 1.49 large
Servet Bölükbas1, Michael Eberlein2, Joachim FEV1 1.79 ± 0.45 2.18 ± 0.50 0.0292 0.81 large
Schirren1 (Liter)
1
Thoracic Surgery, Dr. Horst Schmidt Klinik/ FEV1 (%) 60.2 ± 10.3 73.6 ± 11.4 0.0015 1.23 large
Germany, 2Division Of Pulmonary And Critical Ipsilateral 29.2 ± 6.5 38.5 ± 3.5 0.0001 1.78 large
Care Medicine, Johns Hopkins University School Of Perfusion
Medicine/United States Of America (%)
Background: Lung function can be reduced by Conclusion: SigniÀcant improvement of pulmonary

entrapped lung parenchyma via a rind of tumor of function and lung perfusion can be observed after
malignant pleural mesothelioma (MPM) with or lung-sparing RP and recovery time of two months.
without concurrent effusion. Expansion of trapped Preservation of the diaphragm is associated with
lung can be achieved by radical pleurectomy (RP). better functional results. Lung-sparing RP might
The aim of this investigation was to study changes preserve physiological reserve and allow patients
with MPM to be eligible for further therapeutic Tuesday-Friday each week of concurrent therapy.
options in the long term. After completion of concurrent therapy pts received
Keywords: malignant pleural mesothelioma, radical consolidation therapy (CT) with B+ E for 6 cycles.
pleurectomy, Pulmonary function, Lung Perfusion All histologies were eligible; an early stopping rule
Scan for pulmonary hemorrhage (PH) was included for
the squamous (SQ) pts. The primary end-point was
1-year progression free survival (PFS).
Session MO02: Concurrent Results: 45 patients eligible patients were accrued;
Chemoradiotherapy Combined With median age 61 yrs (range 34 to 74), 33 non-SQ
New Drugs And New Radiotherapy & 12 SQ; 29 stage IIIA & 16 stage IIIB; 33 pts
Schemes and Techniques PS 0 & 12 PS of 1. Cohort 2 was expanded to the
phase II trial. CT was determined to not be feasible
and SQ cohort was closed due to PH. Grade 3
Monday, 4 July 2011 toxicity observed with IND therapy was neutropenia
(42%) and grade 3 hypertension (2%). Grade 3
toxicities observed with CON were esophagitis
Concurrent Chemoradiotherapy Combined With New Drugs And New (29%), pneumonitis (2%); neutropenia (13%), hgb
Radiotherapy Schemes and Techniques Monday, 4 July 2011 14:30- (7%), thrombocytopenia (7%); one trachoesphogeal
16:00 Àstula was observed. In SQ cohort 3 of 12 patients
experienced PH; 1 grade 3, 2 grade 5. 33 pts have
MO02.01 PHASE I/II TRIAL OF experienced disease progression or death; the 1-year
BEVACIZUMAB (B) AND ERLOTINIB PFS rate observed was 44% (95% CI, 29-58%),
(E) WITH INDUCTION (IND) AND median PFS was 10 months (95% CI, 8-22). 27 pts
CONCURRENT (CON) CARBOPLATIN have died, and the median follow-up for survivors is
(CB)/PACLITAXEL (P) AND 74 GY 37 months (range 5-54); median OS was 19 months
OF THORACIC CONFORMAL (95% CI, 13 to 33). The median OS observed in
RADIOTHERAPY (TCRT) IN STAGE the non-SQ and SQ cohorts was 19 and 17 months,
III NON-SMALL CELL LUNG CANCER respectively.
(NSCLC). Conclusion: The PFS and OS with the addition of
Mark A. Socinski1, Thomas Stinchcombe2, Dominic B+E to CbP with 74 Gy TCRT appears similar to
T. Moore2, Scott N. Gettinger3, Roy H. Decker3, previous experience with CbP alone with 74 Gy
William J. Petty4, Aw Blackstock4, Gary Schwartz5, TCRT.
Scott Lankford5, David Morris2
1
Hematology/oncology, University Of North
Carolina/United States Of America, 2University Of Concurrent Chemoradiotherapy Combined With New Drugs And New
North Carolina/United States Of America, 3Yale Radiotherapy Schemes and Techniques Monday, 4 July 2011 14:30-
University/United States Of America, 4Wake Forest/ 16:00
United States Of America, 5Northeast Oncology
Associates/United States Of America MO02.02 DETERMINATION OF
STANDARD DOSE CETUXIMAB
Background: Agents which target the epidermal TOGETHER WITH CONCURRENT
growth factor receptor (EGFR) and inhibit INDIVIDUALISED, ISOTOXIC
angiogenesis have been shown to improve overall ACCELERATED RADIOTHERAPY
survival (OS) in advanced NSCLC and have AND CISPLATIN-VINORELBINE FOR
radiosensitizing properties. PATIENTS WITH STAGE III NON-SMALL
Methods: Patients (pts) received Cb (AUC=6), P CELL LUNG CANCER (NSCLC): A PHASE
(225 mg/m2) and B (15 mg/kg) on days 1 and 22. I STUDY (NCT00522886)
On day 43 patients received Cb (AUC=2) and P (45 Anne-Marie Dingemans1, Gerben Bootsma2, Angela
mg/m2) weekly x 7 weeks (wks) with TCRT to 74 Van Baardwijk3, Bart Reymen3, Rinus Wanders3,
Gy; cohort 1 (n=5) received B 10 mg/kg q 2 wks, Monique Hochstenbag1, Arne Van Belle1, Ruud
cohort 2 (n=5) and cohort 3 (n=5) both received B Houben3, Jacques Borger3, Philippe Lambin4, Dirk
10 mg/kg q 2 wks as well E at 100 mg and 150 mg De Ruysscher4
1
Pulmonology, Maastricht University Medical not reached. The trial was approved by the required
Center/Netherlands, 2Pulmonology, Atrium Mc authorities, all patients gave informed consent.
Parkstad/Netherlands, 3Radiation Oncology, Results: Between 09/2007 and 10/2010 24 patients
MAASTRO Clinic, Grow - School For Oncology (12 males and 12 females, mean age 62.2 years)
And Developmental Biology, Maastricht University were included. The dose could be escalated to the
Medical Centre/Netherlands, 4Department Of third dose level. Full data are available from the
Radiation Oncology (MAASTRO), Grow, Maastricht Àrst 18 patients. ³ Grade 3 toxicity was observed in
University Medical Centre/Netherlands 8/18 patients. Grade 3 toxicities were fatigue 2/18,
oesophagitis 1/18, skin toxicity 1/18, diarrhoea 1/18,
Background: Concurrent chemo-radiotherapy cough 1/18, dyspnea 1/18, vomiting 1/18, pulmonary
is the treatment of choice for patients with stage embolism 1/18. DLT was not reached. One patient
III NSCLC. Survival is far from satisfactory and with a complete metabolic response in dose level 3
strategies to improve outcome are needed. As developed a fatal hemoptoe 4 months after treatment.
cetuximab, a monoclonal antibody against EGFR, Although not in MTD period it was decided to
improves survival in head and neck cancer when include 6 extra patients in the third dose level.
added to radiotherapy and has activity against Metabolic PET responses in the Àrst 18 patients: 8
NSCLC, we investigated the maximum tolerated complete response, 8 partial response, 1 progressive
dose (MTD) of cetuximab with concurrent chemo- disease, 1 missing.
radiation in stage III NSCLC. Individualised, Conclusion: Concurrent isotoxic, accelerated
isotoxic accelerated radiotherapy was chosen to chemo-radiotherapy with cetuximab, cisplatin-
allow the maximal tolerable radiation dose for each vinorelbine seems feasible with acceptable toxicity
individual patient based on normal tissue constraints. and promising metabolic response rates. Final results
Methods: In this open label phase I study patients will be presented.
with stage III NSCLC were included. Main inclusion Keywords: cetuximab, stage III NSCLC, fase I
criteria: WHO-PS 0-1, FEV1>50%, DLCO>50%,
weight loss<10%, no severe cardiac disease, normal
renal function. Patients without progression after Concurrent Chemoradiotherapy Combined With New Drugs And New
2 cycles of gemcitabine 1250 mg/m2 day 1-8 and Radiotherapy Schemes and Techniques Monday, 4 July 2011 14:30-
carboplatin AUC 5 on day 1 every 3 weeks were 16:00
included and treated with cetuximab: 400 mg/kg day
-7 and 250 mg/kg weekly together with concurrent MO02.03 RANDOMIZED PHASE II TRIAL
radiotherapy and cisplatin (50 mg/m2 day 1-8 and 40 OF URACIL/TEGAFUR (UFT) AND
mg/m2 day 22)-vinorelbine for 5 weeks. The dose of CISPLATIN VERSUS VINORELBINE
vinorelbine was escalated in 3 steps: step 1 10 mg/ AND CISPLATIN WITH CONCURRENT
m2 day 1-8 and 8 mg/m2 day 22-29; step 2 20 mg/ THORACIC RADIOTHERAPY FOR
m2 day 1-8 and 8 mg/m2 day 22-29; step 3 20 mg/ LOCALLY ADVANCED UNRESECTABLE
m2 day 1-8; 15 mg/m2 day 22-29. Radiotherapy: 3 STAGE III NON-SMALL-CELL LUNG
weeks 1.5 Gy BID (45 Gy) followed by 2Gy QD to CANCER: NJLCG 0601
a mean lung dose of 19 Gy. Maximum dose 69 Gy in Hiroshi Watanabe1, Shunichi Sugawara1, Makoto
5.5 weeks. Maemondo2, Motoko Tachihara3, Tomohiro
Toxicity (CTCAEv3.0) was scored till 3 months Sakakibara4, Takashi Ishida3, Akira Inoue4, Kazuhiro
after radiotherapy. An FDG-PET-CT was performed Usui5, Osamu Ishimoto1, Nobumichi Matsubara2,
3 months after radiotherapy. The primary endpoint Yasuo Saijo6, Toshihiro Nukiwa4
1
of the study was MTD 3 months after concurrent Pulmonary Medicine, Sendai Kousei Hospital/
chemo-radiotherapy. MTD was deÀned as: ³2/6 Japan, 2Miyagi Cancer Center/Japan, 3Fukushima
patients had ³grade 3 pneumonitis, diarrhoea, liver Medical University/Japan, 4Tohoku University
or renal toxicity or ³ 3/6 patients had ³ grade 3 Hospital/Japan, 5Kanto Medical Center Ntt-ec/
oesophagitis. When 1/6 patients developed grade Japan, 6Hirosaki University Graduate School Of
4 skin or neurological or grade 5 haematological Medicine/Japan
toxicity the dose level was extended with 6 patients.
Patients were included in a next dose level when all Background: A treatment with uracil/tegafur(UFT)
patients were followed for 3 months and MTD was and Cisplatin (UP) in combination with concurrent
thorachic radiotherapy (c-TRT) could have favorable Concurrent Chemoradiotherapy Combined With New Drugs And New
efÀcacy with less toxicity for locally advanced non- Radiotherapy Schemes and Techniques Monday, 4 July 2011 14:30-
small-cell lung cancer (NSCLC). We conducted this 16:00
randomized phase II study to compare this regimen
to a treatment with vinorelbine and cisplatin (NP), MO02.04 MULTIMODALITY
which is a commonly used regimen with c-TRT for TREATMENT WITH RADIO-
locally advaced NSCLC in Japan. CHEMOTHERAPY AND ERLOTINIB IN
Methods: Patients with locally advanced NSCLC ADVANCED NSCLC (MARTE TRIAL)
were randomized to receive UP (UFT400 mg/m2 on Sara Ramella1, Lucio Trodella1, Antonio M. Alberti2,
days 1-14 and 29-42 and cisplatin 80 mg/m2 on days Eugenio Cammilluzzi2, Carlo Greco1, Aurelia Iurato1,
8 and 36) or NP (vinorelbine 20 mg/m2 on days 1, Michele Fiore1, Luca E. Trodella1, Edy Ippolito1,
8, 29, and 36 and cisplatin 80 mg/m2 on days 1 and Barnaba Floreno1, Francesco Cellini1, Rolando M.
29), stratiÀed by age, gender, histology, and stage. D’Angelillo1
1
In both arms, c-TRT began on day 1 (total 60Gy Radiotherapy And Oncology Unit, Campus Bio-
in 30 fractions). The primary endpoint was overall medico University/Italy, 2Oncology Unit, Sandro
response rate (ORR), and secondary endpoints were Pertini Hospital/Italy
progression-free survival (PFS), overall survival,
and toxicity proÀle. Assuming that ORR of 80% in Background: Chemoradiation is the standard of care in
eligible patients would indicate potential usefulness locally advanced NSCLC even if the optimal regimen
while ORR of 60% would be the lower limit of of association is still a matter of discussion. Preclinical
interest, the estimated accrual was 33 patients in data suggest that Erlotinib have radiosensitizing activity.
each arm. Moreover, the correlation between histology and drugs
Results: From February 2006 to May 2009, 70 activity was largely demonstrated in metastatic NSCLC.
patients were enrolled from 5 institutions. Finally We report the results of a phase II trial exploring
66 patients were evaluable for efÀcacy and safety. feasibility and the activity of the Tyrosine Kinase
Patient characteristics were: Male/Female 54/12; Inhibitor, Erlotinib, with concurrent Pemetrexed- or
median age 62 (range 40-75); Performance status 0/1 Gemcitabine-based chemoradiation.
31/35; IIIA/IIIB 24/42. ORRs were 80% (95%CI: Methods: Previous chemotherapy treated patients with
67-93) and 71% (95%CI: 55-87) for the UP arm and histo-citologically conÀrmed NSCLC, stage IIB-IV and
the NP arm, respectively. With a median follow-up local recurrences were treated according to a combined
of 20.2 months, median PFS and median survival chemo-radiation protocol with oral Erlotinib, 150 mg/
in the UP arm were 8.2 and 26.9 months, in the die (E-) and weekly Gemcitabine (GEM) 300 mg/
NP arm were 6.8 and 21.8 months. The 2-/3- year m2 (E-GEM group) or Pemetrexed (PEM) 500mg/m2
survival rates were 51.0/34.3% and 46.9/33.4% for every 3 weeks (E-PEM group). IF radiotherapy was
the UP arm and the NP arm, respectively. Grade 3/4 delivered up to 50,4-59.4 Gy, with standard fractionation.
neutropenia occurred in 20% and 58% of patients Toxicities were assessed according to the NCI CTC
in the arms UP and NP. There was no remarkable 3.0 scale. Clinical response was evaluate with RECIST
difference in other toxicities between both arms. Two criteria at 4-5 weeks after the end of radiochemotherapy
patients in the NP arm died of radiation pneumonitis. by CT scan with or without PET/TC 18 FDG.
Conclusion: Combined with c-TRT, UP achieved Results: From July 2007 to October 2010, 60 patients,
more preferable efÀcacy and safety compared with 20 squamous-cell carcinoma (SCC) and 40 Non-SCC
NP, suggesting a promising candidate as a standard were enrolled. Stages were recorded as follows: 63%
regimen with c-TRT for locally advanced NSCLC. Stage II-III, 10% local relapses after surgery, and
Further evaluation of UP with c-TRT is warranted in 27% oligometastatic stage IV. The median age was 65
a phase III setting in comparison with cisplatin-based years (range 39-83). All but 5 patients (92%) received
third generation chemotherapy with c-TRT. previous chemotherapy (median 4 cycles). 23 patients
Keywords: concurrent thorachic radiotherapy, was treated in E-GEM group while 37 with in E-PEM
locally advanced NSCLC, Vinorelbine, uracil/tegafur one. Two groups did not differ in gender (p=0.093)
and stage (p=0.587). E-PEM group population was
younger and received more cycles of chemotherapy
(p=0.017 and p=0.02, respectively). Chemoradiation
was well tolerated. 4 patients developed a G3 skin
1
rash one and required dose reduction of Erlotinib to Department Of Radiotherapy, West German Cancer
100 mg daily. G3/4 liver enzyme toxicity occurred in Center, University Hospital Essen/Germany, 2Dept.
16.6%, trombocytopoenia in 11.6%, leucopoenia in Of Medicine (cancer Research), West German
30% and anaemia in 5%. In E-PEM group more G3/4 Cancer Center, University Hospital Essen/Germany,
3
leucopoenia was reported (43.2% vs 8.6%; p=0.004). Internistische Onkologie Und Hämatologie,
G3/4 esophagitis and lung toxicity occurred in 2% and Klinikum Herfordt/Germany, 4Thoracic Surgery,
5% of patients, respectively. 1 patients died for ARDS Ruhrlanclinic/Germany, 5Medical Oncology,
and 1 patients had sepsis with positive hemoculture for Huyssen Stiftung/Germany, 6Radiation Oncology,
Staphylococcus Epidermidis . All but 1 patients were Charite/Germany, 7Department Of Medicine (cancer
evaluable for clinical response. Objective response Research), West German Tumor Center, University
was 64% and 68% in E-GEM and E-PEM group, Hospital Essen/Germany
respectively (p=0.412). Skin rash was not associated with
clinical response (p=0.762). Median survival was 14.4 Background: CTx/RTx followed by S
months. E-PEM group reported a statistically signiÀcant (TRIMODALITY = TM) had already been
advantage in survival respect E-GEM one (p=0.036). In successfully piloted as possible treatment strategy
particular, E-PEM Non-SCC patients reported higher (Tx) for patients (pts) with stage IIIA(N2) NSCLC
median survival (14.4 vs 4.9 months; p=0.01) and higher and selected IIIB (Albain, JCO 1995). Here we
progression free survival (7.5 vs 4.6 months; p=0.06) report 15-y VLTS from a large prospective single
versus E-GEM Non-SCC group. Analysis of EGFR center phase-II with TM Tx (Eberhardt, JCO 1998)
mutational status are actually ongoing. that served as predescessor/baseline dataset for our
Conclusion: In the era of the right drug for the right Àrst multicenter randomized trial (KREBSHILFE1;
patients the choice of the concurrent agent to radiation Poettgen, JCO 2007). The long-term F-UP
is a particular interesting topic. Our data conÀrm the information let us perform a detailed CR analysis.
role of histology in the selection of drugs in this setting. Methods: Pts with histopathologically
Addition of Erlotinib to chemo-radiotherapy with (mediastinoscopy) proven IIIA(N2) and selected
Gemcitabine or Pemetrexed is effective and feasible. IIIB NSCLC received three CTx cycles IND P (60
Further investigations are necessary to identify patients mg/m2 d 1+8) and E (150 mg/m2 d 1) qd 22. This
subsets that could beneÀt from addition of target therapy was followed by cc CTx/RTx including P 50 mg/m2
to chemoradiation and could be target in future studies. d 2 + 9 and E 100 mg/m2 d 4-6 cc with 45 Gy (1.5
Keywords: erlotinib, chemoradiation, target therapy, Gy bid). Three to Àve weeks after end of RTx pts
histology-based chemotherapy received S if possible. In pts determined inoperable
NO deÀnitive RTx-boost was added in this trial. We
have investigated long-term F-UP for this cohort
Concurrent Chemoradiotherapy Combined With New Drugs And New (2/11) and have looked for exploratory subgroups.
Radiotherapy Schemes and Techniques Monday, 4 July 2011 14:30- Results: Pts accrual from 3/1991 to 12/1994. Pts
16:00 characteristics: 94 (IIIA(UICC5) 52; IIIB 42); gender
m 75; f 19; PS 0-1; age median 55 range 31-71;
MO02.06 15-YEAR (VERY) LONG-TERM histo: adeno (ADC) 29; squamous cell (SCC) 51;
SURVIVAL (VLTS) AND COMPETING large cell (LCC) 14; 62 pts taken to S: R0 50 (53%);
RISKS (CR) ANALYSIS OF INDUCTION pCR 24 (26%). Exploratory VLTS analysis (med
(IND) CHEMOTHERAPY (CTX) WITH SURV months (m) , 5-y-OS %, 10-y-OS %, 15-y-OS
THREE CYCLES CISPLATIN(P)/ %): med SURV of all pts still alive on F-UP: 98 m;
ETOPOSIDE(E) FOLLOWED BY all pts 20 m 25.0 18.5 9.3; IIIA(N2) 20 m 32.2 22.3
CONCURRENT (CC) CHEMORADIATION 11.3 ; IIIB 19 m 13.8 13.8 6.9 (ns log rank); groups
(CTX/RTX) PE/45 GY (1.5 GY BID) PLUS deÀned by Tx-dependant factors: R0-res 32 m 40.9
SURGERY (S) = TRIMODALITY - PHASE- 31.8 16.0 no-R0 14 m 5.0 0.0 0.0 log rank p = less
II WEST GERMAN CANCER CENTRE than 0.0001. R0-res: pCR 25 m 37.5 37.5 10.7 vital
(WGCC) TRIAL (JCO98). residual TU: 42 m 43.5 24.2 19.3 log-rank ns. No
Rodrigo Hepp1, Thomas C. Gauler2, Christoph signiÀcant impact of age, histopathology, T-status,
Poettgen1, Soenke Korfee2, Stephan Bildat3, Georgios N-status or gender on LTS observed. 25/94 pts
Stamatis4, Siegfried Seeber5, Hansjochen Wilke5, throughout study and F-UP period died of CR (TOX,
Volker Budach6, Martin Stuschke1, Wilfried Eberhardt7 CARDVASC, PULMONARY, CO-MORBIDITIES,
SECOND PRIMARIES, SECOND CANCERS): 6 pts Background: Pneumonectomy after induction

pre/postop TOX (between 1-8 m) ; 2 pts (pneumonia, chemoradiation for lung cancer remains controversial
cerebral infarction) between 12 and 48 m ; 17 pts because of previously reported high postoperative
(cardvasc, pulmon, cerebral infarction, co-morbidities, mortality. We reviewed our 16-year experience to
second cancer, second primary) post 50 and up to 213 determine if induction chemoradiation remains a risk
m. All events post 60 m (5-yrs) were due to CR. With factor for 90-day mortality post-pneumonectomy.
VLTS F-UP brain relapse revealed as a signiÀcant Methods: Data were reviewed for patients who
number of the observed progression sites (21). No underwent pneumonectomy for NSCLC from
brain relapse was noted post 60 m (5-yrs). February 1993 through January 2010 at Fox Chase
Conclusion: VLTS of the WGCC-trial JCO98 Cancer Center. Univariate analysis was done via
deÀned the rationale for our Àrst randomized Fisher’s exact test to compare patients undergoing
multicenter trial with S after induction (TM) pneumonectomy from 1993-2003 and after 2003,
in selected pts with operable IIIA NSCLC. and to identify risk factors for 90-day mortality. A
Interestingly, no pre-treatment factor turned out multiple logistic regression model predicting 90-day
important on 15-y-VLTS in exploratory analysis, survival was Àt using those variables
not even disease stage, T-, N-status, histopathology, Results: 171 patients underwent pneumonectomy,
age or gender. Partly based on selection effects R0- 54/171 (32%) received concurrent induction
res for IIIA and IIIB following induction Tx has chemoradiation. 53/54 (98%) received platinum-
excellent VLTS prognosis. CR analysis revealed based regimens. The most frequent radiation dose
deaths due to CR (cardvasc, pulmon, cerebrovasc, was 50.4Gy (range, 40Gy-66Gy; one patient did
2nd primary, 2nd cancer) as the only events observed not complete RT). Induction patients undergoing
post 60 m (5-yrs). Further aiming to improve VLTS pneumonectomy after 2003 were similar to those
in stage III NSCLC pts treated with TM Tx has undergoing induction and pneumonectomy during
to consider aggressive prevention, treatment and 1993-2003 in terms of median age (65.2 vs. 61.5
management of CR typical in this population. years; P=0.6) gender (61% male vs. 58% male,
Keywords: Stage III, NSCLC, combined modality, P=1.0), overall clinical stage (cStage) distribution
Surgery (P=0.65), Charlson Co-morbidity Index (median 3.0,
range 2.0-7.0 vs. median 3.0, range 2.0-6.0; P=0.1),
preop FEV1 % predicted (median 82, range 47-108;
Concurrent Chemoradiotherapy Combined With New Drugs And New vs. median 80.5, range 42-111; P=0.6) and preop
Radiotherapy Schemes and Techniques Monday, 4 July 2011 14:30- DLCO % predicted (median 68.5, range 38-99 vs.
16:00 median 71.5, range 50-96; P=0.7). From 1993-2003,
26/125 (21%) of pneumonectomy patients received
MO02.07 IS NEOADJUVANT induction chemoradiation compared to 28/46 (61%)
CHEMORADIATION A RISK FACTOR pneumonectomy patients after 2003 (P<0.001).
FOR 90-DAY MORTALITY AFTER For 1993-2003, 90-day mortality for induction
PNEUMONECTOMY FOR LUNG chemoradiation and pneumonectomy was higher than
CANCER IN THE CURRENT ERA? for pneumonectomy alone (23% vs. 8%, P=0.07).
Jacqueline Oxenberg1, Walter J. Scott2, Tianyu Li2, 90-day mortality for all pneumonectomy patients
Eric Ross2, Avi Lebenthal3, Prashant Shah2, Aruna was lower after 2003 compared to 1993-2003 (2.2%
Turaka2, Hossein Borghaei2, Earl King2, Melvyn vs. 11.2%, P=0.07) despite a higher percentage
Goldberg2, Steven Feigenberg4, Benjamin Movsas5, of patients undergoing induction chemoradiation.
Corey J. Langer6 90-day mortality for induction chemoradiation and
1
Philadelphia College Of Osteopatic Medicine/ pneumonectomy after 2003 was 1/28 (3.6%). Causes
United States Of America, 2Thoracic Surgery, Fox of 90-day mortality post-pneumonectomy in all
Chase Cancer Center/United States Of America, patients who underwent induction chemoradiation
3
Brigham And Women’s Hospital/United States Of included ARDS (3), CHF, PE, BPF and unknown
America, 4University Of Maryland Medical School/ (1 each). Chemoradiation prior to pneumonectomy
United States Of America, 5Henry Ford Hospital/ was not a predictor of 90-day mortality by logistic
United States Of America, 6Abramson Cancer regression, whereas operation before 2004 and
Center, University Of Pennsylvania/United States Of postoperative pneumonia were (Table 1).
America
Table.1. Logistic Regression for 90-Day Survival And Neuropathology, University Hospital Essen/
after Pneumonectomy Germany
Variable OR 95% CI P Value Background: IND CTx/RTx followed by S remains

possible treatment (Tx) for pts with stage IIIA(N2)
Induction Therapy 0.380 0.112-1.292 0.1214 NSCLC (Albain, Lancet 2009) and selected IIIB
Pneumonectomy after 2003 9.944 1.126-87.804 0.0387 (Eberhardt, JCO 1998; Stupp, Lancet Oncol 2009).
Pneumonia, None Postop 4.445 1.208-16.348 0.0248 Here we report LTS from a prospective multicenter
phase-II trial with trimodality (TM) Tx (CISTAXOL)
Conclusion: Based on our data, neoadjuvant that served as predescessor/baseline dataset for
chemoradiation is not a risk factor for 90-day our ongoing randomized phase-III (ESPATUE)
mortality after pneumonectomy in the current era. (Poettgen, Int J Radiat Oncol Biol Phys 2010).
Since baseline patient demographics seemed similar, Methods: Pts with histopathologically
we hypothesize that changes in radiation treatment (mediastinoscopy) proven IIIA(N2) and selected IIIB
protocols and surgical management may account for NSCLC received three IND CTx cycles P (50 mg/
these Àndings. m2 d 1+8) and T (175 mg/m2 d 1) qd 22. This was
followed by cc CTx/RTx including cis 50 mg/m2 d
2 + 9 and eto 100 mg/m2 d 4-6 cc with 45 Gy (1.5
Concurrent Chemoradiotherapy Combined With New Drugs And New Gy bid). Three to Àve weeks after end of RTx pts
Radiotherapy Schemes and Techniques Monday, 4 July 2011 14:30- received S if possible. In pts determined inoperable
16:00 at end of RTx, a deÀnitive CTx/RTx-boost (+20
Gy; 2 Gy qd) was added. Here we report ten-year
MO02.08 10-YEAR LONG-TERM (overall) LTS for this cohort and look for exploratory
SURVIVAL (LTS) OF INDUCTION (IND) subgroups.
CHEMOTHERAPY (CTX) WITH THREE Results: Pts accrual from 3/99 to 2/02. Pts
CYCLES CISPLATIN(P)/PACLITAXEL(T) characteristics: 64 (IIIA(N2) 24; IIIB 40); gender m
FOLLOWED BY CONCURRENT (CC) 48; f 16; PS 0-1; histo: adeno (ADC) 17; squamous
CHEMORADIATION (CTX/RTX) P/ cell (SCC) 28; large cell (LCC) 17; NOS 2; age:
ETOPOSIDE (ETO)/45 GY (1.5 GY BID) median 52.5 (range 28-69). 36 pts taken to S: R0 32
PLUS SURGERY (S) - A MULTICENTER (50%); R1/R2 3; exploratory 1; pCR 16. Exploratory
PHASE-II TRIAL (CISTAXOL). LTS analysis (5y-OS %, 10y-OS %): med SURV of
Christoph Poettgen1, Cecile Le Pechoux2, Thomas all pts still alive on F-UP: 8 yrs 10 mo; all pts 30.1
C. Gauler3, Martin Stuschke1, Dominique H. 27.8; IIIA(N2) 34.3 34.3; IIIB 27.7 23.8 (log-rank
Grunenwald4, Georgios Stamatis5, Stephan Bildat6, ns); groups deÀned by pre-Tx factors: histo SCC
Thomas Krbek7, Daniel C. Christoph8, Stefan 46.2 41.0 ; LCC 23.5 23.5 ; ADC 11.8 11.8 log-rank
Welter5, Berthold Fischer9, Rodrigo Hepp1, Dirk p = 0.0075 ; age less 50 45.9 45.9 age greater/equal
Theegarten10, Wilfried Eberhardt3 50 23.1 20.3 log-rank p = 0.035; groups deÀned by
1
Department Of Radiotherapy, West German Cancer Tx-dependant factors: R0-res 46.4 46.4 ; no R0 14.6
Center, University Hospital Essen/Germany, 2Institut 9.7 log-rank p = 0.0013 ; R0/pCR 66.0 66.0 R0/vital
Gustave Roussy/France, 3Department Of Medicine TU 27.0 27.0 log-rank p = 0.03.
(cancer Research), West German Tumor Center, Conclusion: LTS of CISTAXOL deÀnes the
University Hospital Essen/Germany, 4Thoracic rationale for our ongoing randomized trial with
Surgery, Hopital Tenon. University Of Paris Vi/ S after induction (TM) in selected pts with stage
France, 5Thoracic Surgery, Ruhrlanclinic/Germany, IIIA/IIIB. Interestingly, histo and age turn out to
6
Internistische Onkologie Und Hämatologie, be important factors in exploratory analysis. ADC
Klinikum Herfordt/Germany, 7Thoracic Surgery, and older pts demonstrate poor prognosis even with
Ruhrlandklinik/Germany, 8Department Of Medicine, aggressive TM. We will prospectively validate these
Division Of Medical Oncology, University Of Àndings in ESPATUE and perform competing risk
Colorado Denver/United States Of America, 9Iii. analysis.
Medizinische Klinik Und Poliklinik, University Keywords: NSCLC, Stage III, combined modality,
Medical Center Of The Johannes Gutenberg Surgery
University/Germany, 10Department Of Pathology
Concurrent Chemoradiotherapy Combined With New Drugs And New This was followed by cc CTx/RTx including P 50 mg/
Radiotherapy Schemes and Techniques Monday, 4 July 2011 14:30- m2 d 2 + 9 and E 100 mg/m2 d 4-6 cc with 45 Gy (1.5
16:00 Gy bid). 3-5 weeks after end of RTx S was performed
if possible and supplemented by PCI given thereafter.
MO02.09 LONG-TERM SURVIVAL (LTS) In case of non-operability no RTx boost was planned/
AND COMPETING RISKS WITHIN scheduled in this trial. Arm A had local treatment
A PROSPECTIVE MULTICENTER alone (S + RTx) and no PCI.
GERMAN RANDOMIZED TRIAL Results: Pts accrual 1/95 to 10/01; eligible 106/112
COMPARING INDUCTION (IND) randomized; Pts characteristics: gender m 90; f 16;
CHEMOTHERAPY (CTX) FOLLOWED BY age median 57 (37-71); PS 0-1; histo: adeno (ADC)
CONCURRENT (CC) CHEMORADIATION 35; squamous cell (SCC) 55; large cell (LCC) 16;
(CTX/RTX) PLUS SURGERY (S) (= ADSCC 5 TN-groups: T3N0-1 6 (IIIA UICC5 IIB
TRIMODALITY) SUPPLEMENTED BY UICC6/7) T1-2N2 83 T3N2 17. Med SURV of pts
PCI VERSUS LOCAL TREATMENT still alive on F-UP: 130 mo. LTS exploratory analysis
ALONE (S + RTX) IN OPERABLE IIIA (2-y-OS %; 5-y-OS %, 10-y-OS %); B: 54.6 20.0
NSCLC. 12.5; A: 44.2 23.5 10.0 (ns log rank, Wilcoxon); PFS:
Thomas C. Gauler1, Christoph Poettgen2, Soenke B: 36.4 14.6 12.7 A: 29.4 17.3 10.4 (p = 0.30/0.14
Korfee3, Horst Wagner4, Rodrigo Hepp2, Georgios log rank/Wilcoxon) Disease-speciÀc survival: B; 40.5
Stamatis5, Daniel C. Christoph6, Bernward Passlick7, 25.0 25.0 A: 32.5 23.1 18.5 (p = 0.16/0.059 log rank/
Volker Budach8, Siegfried Seeber9, Hansjochen Wilcoxon), Cumulative 10-y prob %: non-disease-
Wilke9, Martin Stuschke2, Wilfried Eberhardt1 related events (tox, comorbidity, second cancer): B:
1
Department Of Medicine (Cancer Research), West 56.3 A: 67.7 (ns); brain relapse as Àrst site of failure:
German Tumor Center, University Hospital Essen/ B: 16.6 A: 30.4 (p = 0.059/0.020 log rank/Wilcoxon).
Germany, 2Department Of Radiotherapy, West Conclusion: LTS after Tx in operable stage IIIA is
German Cancer Center, University Hospital Essen/ signiÀcantly hampered by cumulative competing risks
Germany, 3Dept. Of Medicine (Cancer Research), (toxicities, comorbidities, second cancers) regardless
West German Cancer Center, University Hospital of Tx intensity. Even if LT-disease-speciÀc SURV
Essen/Germany, 4Pneumological Oncology, may be optimized by aggressive multimodality Tx
Asklepios Clinics Gauting/Germany, 5Thoracic these effects may be ultimately dilluted (in LTS) by
Surgery, Ruhrlanclinic/Germany, 6Department Of the competing risks/events in later F-UP. Initial pts
Medicine, Division Of Medical Oncology, University selection based on comorbidity proÀles and aggressive
Of Colorado Denver/United States Of America, handling of comorbidities (smoking stop, pulmonary,
7
Thoracic Surgery, University Of Freiburg/Germany, cardiac, long-term cancer F-UP) may be most
8
Radiation Oncology, Charite/Germany, 9Medical important in improving LTS with aggressive protocols
Oncology, Huyssen Stiftung/Germany based on TRIMODALITY (+/- PCI) in the future.
Keywords: NSCLC, combined modality, Surgery,
Background: We have already reported cumulative prophylactic cranial irradiation
probability (prob) of brain relapse as Àrst site of
failure within our multicenter German randomized
trial that investigated TRIMODALITY + prophylactic Concurrent Chemoradiotherapy Combined With New Drugs And New
cranial irradiation (PCI) versus S + RTx alone in Radiotherapy Schemes and Techniques Monday, 4 July 2011 14:30-
operable IIIA NSCLC (Poettgen, JCO 2007). Here 16:00
we report LTS for these arms, look for exploratory
subgroups and investigate competing risks observed MO02.11 SOCCAR TRIAL: COMPARING
on long F-UP.. TOXICITY AND EFFICACY OF
Methods: Pts with histopathologically HYPOFRACTIONATED CONCURRENT
(mediastinoscopy) proven operable IIIA (1-2 LN CHEMORADIATION TO PUBLISHED
involved, no clinical N2, no bulky/extranodal disease, TRIALS
central T3N0-1, WHO 0,1) NSCLC were stratiÀed Noelle O’Rourke1, Joe Maguire2, Rhona
(TN-group, center) and randomized. Arm B received Mcmenamin3, Michael P. Snee4
1
three CTx cycles induction (IND) cis (P) (60 mg/m2 Beatson Cancer Centre, Gartnavel General
d 1+7 or 8) and eto (E) (150 mg/m2 d 3,4,5) qd 22. Hospital/United Kingdom, 2Clatterbridge Oncology
Centre/United Kingdom, 3Newcastle Cancer Centre/ 30 fractions over six weeks ranged from 18-37%.
United Kingdom, 4Oncology, St James Institute Of Complete table of all trials will be presented.
Oncology/United Kingdom Conclusion: Toxicity of 55Gy in 20 fractions over
four weeks with concurrent cisplatin and vinorelbine
Background: The optimal management of locally is similar to other published regimens but is
advanced NSCLC remains uncertain. Although associated with substantially improved survival.
concurrent chemoradiation is now widely used, it This is the Àrst randomised trial of a concurrent
is not clear what radiation dose and fractionation chemoradiation regimen to achieve two year survival
are most effective and with which chemotherapy above 50%. We believe future research should
these should be combined. The introduction of pursue the rationale of hypofractionated radiotherapy
concurrent regimens has resulted in higher levels in combination with chemotherapy.
of acute oesophagitis and increased treatment Keywords: hypofractionated radiotherapy,
related mortality (TRM) but although survival concurrent chemoradiation, favourable toxicity
is increased, the rates of local control remain
disappointing. Accelerated repopulation during
radiotherapy diminishes efÀcacy of treatment as Concurrent Chemoradiotherapy Combined With New Drugs And New
treatment duration increases. Hypofractionated Radiotherapy Schemes and Techniques Monday, 4 July 2011 14:30-
therapy offers the potential to improve local control 16:00
and survival by completing treatment in a shorter
time but there have been concerns this may increase MO02.12 PROTON BEAM THERAPY
toxicity. The recently completed SOCCAR trial VS. INTENSITY-MODULATED (X-RAY)
used hypofractionated radiotherapy (55Gy/20f/4w) RADIATION THERAPY FOR LOCALLY
concurrent with cisplatin and vinorelbine at systemic ADVANCED NON-SMALL CELL LUNG
therapy doses. We report here the toxicity data from CANCER
this study comparing the toxicity of the concurrent James D. Cox1, Xiong Wei1, Pamela K. Allen1,
treatment arm with the concurrent treatment Richard Amos2, Radhe Mohan2, Joe Y. Chang1,
schedules used in previously published trials. Zhongxing Liao1, Lei Dong2, Ritsuko Komaki1
1
Methods: Literature search was conducted for Radiation Oncology, UT MD Anderson Cancer
randomised trials using concurrent chemoradiation Center/United States Of America, 2Radiation
for stage III NSCLC in one arm of the trial. Trials Physics, UT MD Anderson Cancer Center/United
were included if a minimum of 50 patients in the States Of America
concurrent treatment arm and toxicity data available.
We recorded radiotherapy dose and fractionation for Background: The current standard of care for
each study with details of chemotherapy schedule. locally advanced non-small cell lung cancer
We compared rates of grade 3 and 4 toxicity and (NSCLC) in patients with good performance status
TRM from these trials with the SOCCAR data and is concurrent chemotherapy and radiation therapy
we recorded 2 year survival for all studies. (RT). We previously found that using 3D conformal
Results: 16 randomised trials were identiÀed for (X-ray) RT (CRT) cut the risk of severe esophagitis
comparison with SOCCAR. These included 1733 in half relative to 2D RT and that using intensity-
patients treated with concurrent chemoradiation. modulated (X-ray) RT (X-IMRT) further reduced
10 trials used 60-66 Gy in 2Gy fractions. TRM in the risk of pneumonitis, but not that of esophagitis,
SOCCAR was 4% and in the other trials ranged relative to 3D CRT. Hypothesizing that the physical
from 0-10%. G3 oesophagitis in SOCCAR was dose characteristics of proton particles would
17%, with no G4. In other trials G3/G4 oesophagitis allow proton beam therapy (PBT) to spare critical
ranged from 3-66% (median 17%). G3/G4 acute lung structures such as esophagus, lung, and bone marrow
toxicity in SOCCAR was 4% compared to range from incidental irradiation to a greater extent than
of 1-16% (median 5%) in other trials. Leucopenia X-ray-based therapy, we evaluated the rates of
rate was 4% in SOCCAR and ranged from 2-99% severe esophagitis, pneumonitis, and bone marrow
in other trials, depending when assessed. Two year suppression in patients with locally advanced
survival for concurrent SOCCAR group was 54% NSCLC treated with concurrent chemotherapy and
with 2ys across the other 16 trials ranging from 13- either PBT or X-IMRT.
43%. Two year survival for the trials using 60Gy in Methods: Patients with locally advanced NSCLC
were treated with chemotherapy+PBT (62 patients) Concurrent Chemoradiotherapy Combined With New Drugs And New
or chemotherapy+X-IMRT (66 patients) from Radiotherapy Schemes and Techniques Monday, 4 July 2011 14:30-
January 2003 through June 2008; all had concurrent 16:00
chemotherapy, none had had prior thoracic RT, and
all were treated to at least 60 Gy (X-IMRT) or 60 MO02.13 EVALUATION OF
CGE (cobalt-60Gy-equivalent) (PBT). Patients who SEQUENTIAL CHEMORADIATION
had both IMRT and 3D CRT or PBT were excluded. WITH HYPERFRACTIONATED
Toxicity was graded according to the Common RADIOTHERAPY FOR UNRESECTABLE
Terminology Criteria for Adverse Events version 3.0. NON SMALL CELL LUNG CANCER: AN
Results: Median follow-up times were similar for INDIAN EXPERIENCE.
the two groups (PBT 15.2 months [range, 3.1–25.7 Subrata Saha1, Prasenjit Chatterjee2
1
months] and X-IMRT 17.4 months [range, 1.4–37.6 Radiotherapy, Medical College Hospital, Kolkata/
months]). Patients in the PBT group were older than India, 2Radiotherapy, Amri Hospitals/India
those in the X-IMRT group (median 67 years vs.
62 years, P<0.04). Median Karnofsky performance Background: It is now well established that
scores for both groups were 80. The incidence concomitant chemoradiation for unresectable non
of nodal involvement was similar in both groups small cell lung cancer (NSCLC) offer superior
(X-IMRT 91% vs. PBT 81%, P>0.05). Median dose outcome to sequential chemoradiotherapy, but at the
was 74 CGE (range, 63-80.5 CGE) for the PBT cost of signiÀcantly increased grade 3-4 esophagitis.
group vs. 63 Gy (range, 60-76 Gy) for the X-IMRT To Ànd an edge over sequential chemoradiation
group (P<0.001). Severe (grade 3+) esophagitis result without added toxicity as often observed
occurred in 44% of patients treated with X-IMRT vs. with concomitant treatment, this prospective
5% with PBT. Severe (grade 3+) treatment-related randomized trial aims to explore the beneÀt and
pneumonitis was observed in 9% of the X-IMRT toxicity of hyperfractionated radiotherapy preceeded
group vs. 2% of the PBT group. Patients treated with by neoadjuvant chemotherapy and to compare
PBT experienced signiÀcantly smaller reductions in with conventionally fractionated concomitant
hemoglobin levels (P<0.001), neutrophils (P<0.008), chemoradiation. Study end pints are local control,
lymphocytes (P<0.001), and leukocytes (P <0.001) progression free survival, systemic failure, acute and
than those treated with X-IMRT. Reductions in late toxicity.
platelet counts were the same for both groups. Methods: This is a multicentric 2-arm prospective
Conclusion: This preliminary analysis suggests that randomized trial initiated in April 2008. A total
concurrent chemotherapy and PBT was less toxic of 112 patients with unresectable IIIB NSCLC
to normal esophagus, lung, and bone marrow than with measurable disease with KPS > 60 have been
concurrent chemotherapy and X-IMRT; this lesser enrolled (after informed consent) to either 60 Gy
toxicity could allow use of more aggressive systemic in 30 Fractions over 6 weeks radiotherapy with
regimens. These treatments are being compared concomitant weekly paclitaxel (45 mg/ m2) and
directly in a prospective randomized trial, funded carboplatin (AUC 2) (Arm 1, Control arm : n = 57)
by the U.S. National Cancer Institute and conducted or induction chemotherapy with Paclitaxel 180 mg/
jointly by MD Anderson and Massachusetts General m2 plus carboplatin AUC 6, 3-weekly for 2 cycles
Hospital, to compare high-dose radiation (66-74 followed by hyperfractionated thoracic radiation for
Gy) given by PBT or X-IMRT in conjunction with a dose of 72Gy/ 6 weeks, 5 days a week, using twice
carboplatin and paclitaxel chemotherapy for NSCLC. daily fractions of 120 cGy each at 6 hours interval
Tumor motion is being accounted for with 4D CT (Arm 2, Study Arm: n=55).
simulation. Endpoints are local tumor control and Meticulous CT scan guided radiotherapy planning
pneumonitis. was done for each patient in 3D- Treatment Planning
Keywords: proton therapy, radiation modality System. V20 varied between 24-28%, mean total
comparison, pneumonitis, esophagitis lung dose was between 6.6 – 13.4 Gy and mean
esophageal dose was 26.5-33.8 Gy as recorded from
DVH analysis, During treatment all patients were
reviewed weekly for assessment of acute reactions
and nutritional status. After completion, patients
are on monthly follow up to detect tumor response,
recurrence (local or distant), acute and late reactions used during treatment planning at the NKI is V35
(recorded as per RTOG criteria). Minimum duration (volume receiving at least 35Gy) <65%, predicting
of follow up is 30 months. a 47% chance to develop AET grade 2 [1]. The
Results: Overall response rate was 52/57 patients purpose of this study was to investigate the dose-
in Arm 1 and 53/55 of Arm 2. But median time to effect relation between AET and dose-volume
progression was 275 days in Arm 1 and 306 days parameters of the esophagus after IMRT and
in Arm 2. Systemic failure was recorded in 18/57 concurrent chemotherapy for lung cancer patients.
(31.5%) in Arm 1 and 11/55 (20%) in Arm 2. Methods: 185 inoperable stage II and III Non-
Median duration of survival was 14 months in Arm Small Cell Lung Cancer patients treated with IMRT
1 and 15.5 months in Arm 2. One year survival was and concurrent chemotherapy were prospectively
41/57 (72%) for Arm 1 vs. 40/55 (73%) in Arm 2. analyzed. The fractionation scheme was 24 x 2.75
Corresponding data for 2-year OS were 14/57 (24%) Gy. All pts received concurrent daily dose Cisplatin
and 16/55 (29%) for Arm 1 and 2 respectively. (6 mg/m²). Maximum AET was scored according
Grade 3-4 esophagitis was in 16/57 (28%) of Arm to CTC 3.0. Dose-volume parameters V5 to V70,
1, whereas only 4/55 (7.22%) in sequential chemo- Dmean and Dmax of the esophagus were calculated
hyperfraction arm (P = 0.005).Corresponding data taking biological fractionation effects into account
for grade 3-4 neutropenia was 29/57 (51%) for Arm for acute reacting tissue (Ơ/ơ of 10 Gy). A logistic
1 and 14/55 (25%) of Arm 2 (P=0.006). Radiation regression analysis was performed to analyze the
pneumonitis was recorded in 12% of Arm 1 and 15% dose-effect relation between these parameters and
of Arm 2. AET grade2 and grade3. The outcome was
Conclusion: Sequential chemo radiotherapy using compared to the clinically used esophagus constraint:
twice daily fractionation resulted comparable V35 [1].
treatment outcome with concomitant chemoradiation Results: The Dmax ranged from 20 and 84 Gy,
with conventional fractionation in terms of both while Dmean ranged from 4 and 68 Gy. 7.6% of
progression free survival as well as over all survival, these patients did not develop AET, 33.5% developed
but treatment toxicity was signiÀcantly less with grade1, 36.2% grade 2 and 22.7% grade 3. At
sequential chemo-hyperfractionated radiotherapy. univariate analysis, the V40 and V50 turned out
Keywords: chemoradiation, Hyperfractionation, to be the most signiÀcant dosimetric predictor for
sequential, concomitant grade 2 AET (p= 0.001) and grade 3 (p= 0.006)
respectively, although Dmean and V35~V55 were
all statistically signiÀcant predictors. Comparing our
Concurrent Chemoradiotherapy Combined With New Drugs And New new V35 model to the old V35 model [1] derived for
Radiotherapy Schemes and Techniques Monday, 4 July 2011 14:30- the current clinical use, the current clinical constraint
16:00 (V35<65%) underestimated the risk to develop AET
grade 2 by 27% (74% instead of 47%). For the
MO02.14 ACUTE ESOPHAGUS TOXICITY new parameter, when the V40 is 30% there is an
IN LUNG CANCER PATIENTS TREATED estimated risk of 50% developing grade 2 AET.
WITH INTENSITY MODULATED Accepting a risk of 25% grade 3, V50 should be
RADIOTHERAPY (IMRT) AND 40%.
CONCURRENT CHEMOTHERAPY Conclusion: For NSCLC patients treated with IMRT
Margriet Kwint1, Wilma Uyterlinde2, Wilma and concurrent chemotherapy, the V40 was identiÀed
Heemsbergen1, Josien De Bois1, Chun Chen1, as most accurate predictor for AET grade 2 and the
Michelle M. Van Den Heuvel2, Jan Jakob Sonke1, V50 for AET grade 3. A signÀcant higher incidence
Joost Knegjens1, Marcel Van Herk1, José Belderbos1 was observed, especially of grade 3 toxicity, in these
1
Radiotherapy, NKI-AVL/Netherlands, 2Thoracic patients treated with concurrent chemo radiation
Oncology, NKI-AVL/Netherlands and IMRT, compared to previous series of patients
treated with radiotherapy alone and 3D conformal
Background: Currently used models to predict acute radiotherapy. This increased risk is probably due to
esophageal toxicity (AET) in lung cancer after IMRT the concurrent use of chemotherapy as well as due
and concurrent chemotherapy were derived from to more modulated dose distributions typically given
patients treated with 3D conformal radiotherapy with IMRT. 1: J Belderbos et al. Acute esophageal
techniques [1]. The esophagus constraint clinically toxicity in non-small cell lung cancer patients after
high dose conformal radiotherapy. Radiother Oncol size, histopathological type, grade, pleural, perineural
2005;75:157-164 and vascular invasion) were extracted. Forty-three
Keywords: esophagitis, imrt, concurrent tissue micro-arrays (TMAs) were constructed using
chemoradiation, Radiotherapy four 1mm in diameter donor cores of tumour and two
donor cores of non-neoplastic matching lung from
formalin-Àxed parafÀn-embedded tissue blocks. TMAs
Session MO03: Prognostic Factors and were processed for immunohistochemical staining for
Stage phosphorylated-Akt (P-Akt). Two pathologists, blinded
to patient outcomes, independently reviewed the
immunohistochemical staining and scored according to
Monday, 4 July 2011
intensity. Kaplan-Meier and Cox Proportional Hazards
analyses were used to analyse the relationship between
Prognostic Factors and Stage Monday, 4 July 2011 14:30-16:00 cliniocpathologic factors, immunohistochemical
intensity of phosphorylated-Akt and survival outcome
MO03.01 MARKERS OF PROGNOSIS in patients with stage IB disease.
IN RESECTED STAGE IB NON-SMALL Results: We identiÀed 527 patients (median age 69)
CELL LUNG CANCER (NSCLC) with stage IB NSCLC. Our overall Àve year survival
Po Yee Yip1, Wendy Cooper2, Annabelle Mahar2, rate was 55%. 378 (72%) were male. 392 (74%) had
James Kench2, Maija R.J. Kohonen-Corish3, Mark lobectomy, 70 (13%) underwent pneumonectomy and
ChatÀeld4, Alice Boulghourjian3, Catherine W. the remainder had lesser resections. The tumour size
Kennedy5, Brian Mccaughan5, Michael Boyer1, Lisa ranges from 0.6 to 18cm. The proportion of squamous
Horvath1 cell carcinoma (41%) and adenocarcinoma (40%) were
1
Medical Oncology, Sydney Cancer Centre, similar. Pleural invasion was consistently reported (477;
Royal Prince Alfred Hospital/Australia, 2Tissue 91%) but vessel (214; 41%) and perineural invasion
Pathology And Diagnostic Oncology, Royal Prince (161; 31%) were not. Univariate analysis demonstrated
Alfred Hospital/Australia, 3Cancer Research Àve signiÀcant prognostic factors: age (p<0.001);
Program, Garvan Institute Of Medical Research/ gender (p=0.008); histopathological grade (p=0.02);
Australia, 4Nhmrc Clinical Trial Centre/Australia, vessel invasion (p=0.01); pleural invasion (p=0.02).
5
Cardiothoracic Surgery, Royal Prince Alfred Multivariate analysis demonstrated that age (p <0.001)
Hospital/Australia and pleural invasion (p=0.003) are independent
prognostic factors. The immunohistochemical result of
Background: Adjuvant cisplatin-based chemotherapy phosphorylated-Akt is ongoing.
has been shown to improve survival in resected Conclusion: Pleural invasion is a potential prognostic
NSCLC. However, much of this beneÀt seems to histopathologic marker for overall survival in patients
be due to an effect on stage II and IIIA disease, with stage IB disease. Its presence may deÀne a
although retrospective analyses of randomized group of high risk patients with stage IB disease who
trials suggest that a subgroup of patients with stage could be assessed for possiible beneÀt from adjuvant
IB disease (those with tumours >4cm diameter) chemotherapy.
may also beneÀt. Because of the uncertainty of the
degree of beneÀt for patients with stage IB disease,
current guidelines advise against providing adjuvant Prognostic Factors and Stage Monday, 4 July 2011 14:30-16:00
chemotherapy to these patients. Therefore, there is
a need to identify prognostic markers that deÀne MO03.02 FEATURES AND PROGNOSTIC
high risk stage IB patients who may beneÀt from FACTORS OF THE “NEW” STAGE II
adjuvant chemotherapy. We aimed to identify clinico- NON-SMALL CELL LUNG CANCER
pathologic and molecular markers of prognosis in POPULATION
resected stage IB non-small cell lung cancer. Francesca Toffalorio1, Davide Radice2, Lorenzo
Methods: Using our patient database, we identiÀed Spaggiari2, Valentina Sinno2, Massimo Barberis2,
patients diagnosed between January 1990 and May Gianluca Spitaleri2, Giovannini Monica2, Angelo
2008 with pathological stage IB disease and who Delmonte2, Chiara Catania2, Crisitina Noberasco2,
had undergone surgical resection. Pathology reports Daniela Brambilla2, Filippo De Braud2, Tommaso De
were reviewed and clinicopathologic details (tumour Pas2
1
Medical Oncology Unit Of Respiratory Tract Prognostic Factors and Stage Monday, 4 July 2011 14:30-16:00
And Sarcomas, New Drug Development Division,
European Institute Of Oncology/Italy, 2European MO03.03 RECURRENCE RISK
Institute Of Oncology/Italy FACTORS FOCUSED ON CLINICAL,
RADIOLOGICAL AND PATHOLOGICAL
Background: The 7th TNM edition has raised new FEATURES IN RESECTED STAGE IA
clinical issues, as the role of adjuvant therapy for ADENOCARCINOMA OF THE LUNG
tumours larger then 5 cm without lymph node invasion. Hee Chul Yang1, Eoksung Park1, Jung-Moon Lee1,
In the 6th TNM, these tumours were classiÀed as stage Eunee Sim1, S.-W. Sung2, Sanghoon Jheon1
1
Ib and international guidelines provided no need for Thoracic And Cardiovascular Surgery, Seoul
adjuvant treatment. In the 7th TNM these tumours National University Bundang Hospital/Korea,
2
have shifted to stage II, opening the perspective of Thoracic Surgery, The Catholic University Of
post-surgery chemotherapy. To challenge this issue, Korea/Korea
we evaluated the rate of tumours shifting from stage
Ib (6th TNM) to stage IIa/b (7th TNM) and analyzed Background: Prediction of recurrence of early
the relationship between their biological characteristic stage lung cancer is very important issue. The aim
and the clinical outcome, in order to identify putative of this study was to retrospectively evaluate clinical,
prognostic factors of this subset of patients. radiological and pathological factors on recurrence in
Methods: We retrospectively collected tumor related resected stage IA adenocarcinoma.
and demographics data (histological type, grading, Methods: From June 2003 to December 2010, 271
vascular invasion, gender, age smoking status and type patients were diagnosed with pathologic stage IA
of surgery) from 467 patients who underwent radical adenocarcinoma after complete pulmonary resection.
surgery with total linfoadenectomy for primary 6th Among them, 52 patients were diagnosed with
TNM-T2N0 NSCLC in our Institute from 1998 to adenocarcinoma in situ. T1a and Tlb was 70.5% and
2009. Categorical variables were cross-tabulated by 29.5%. In these patients the impact of the following
tumor staging according to the 7th TNM edition and factors on recurrence was evaluated: clinical factors
tested both for association (Fisher’s exact test) with (gender, age, and smoking history), computed
stage and survival (Kaplan-Meier method). tomography (CT) and positron emission tomography
Results: According to the 7th TNM, 87 (19 %) cases (PET) Àndings (diameter of tumor including
shifted from stage Ib to stage IIa and 31 (7%) to stage or excluding ground glass opacity (GGO) and
IIb. No patients received induction/adjuvant chemo maximal standardized uptake value (SUVmax)) and
and/or radiation therapy. Patients who shifted to pathologic Àndings (presence or absence of tumor
stage IIb were signiÀcantly older (69.9 ± 8.9) and the necrosis, vascular invasion, lymphatic invasion, and
grading of the tumor was higher compared to the total histologic subtype).
population (p = 0.039) and the stage IIa (p = 0.013). Results: Mean age was 64 years (R: 31-85) and 140
Median overall survival times were signiÀcantly worse (51.7%) patients were female. The follow-up period
for patient shifted to stage II (4.6 years) than patients was median 26 months and 3 year survival was
not shifted (9.3 years, p = 0.018). Among the factors 97.8%. During the period, recurrence occurred in 16
investigated, our data suggest a relationship between patients (6.3%) who were 5 patients with T1a and
smoking habitus and grading with a worse prognosis, 11 with T1b. There was no recurrence in the group
even if not statistically signiÀcative. of pure GGO. Univariate analyses demonstrated
Conclusion: A high rate (26%) of patients with recurrence risk factors in male (p=0.03), smoking
T2N0 NSCLC shift from stage I (6th TNM) to stage history (p=0.03), 2cm diameter of tumor including
II (7th TNM), raising a major need for information GGO in CT (p=0.002), 15mm of CT solid portion
on the effects of adjuvant chemotherapy in this (p<0.001), SUV max 2 (p<0.001), presence of tumor
population. Smoking status and grading, but not necrosis (p<0.001), acinar subtype (p=0.006), invasion
histological type, vascular invasion, gender, age of lymphatics (p<0.001) and vessel (p<0.001), and
and type of surgery, could be explored as possible moderate to poorly cell differentiation (p<0.001).
prognostic factors in the adjuvant chemotherapy Male, 15mm of CT solid portion, lymphatic
decision-making process. invasion, moderate to poorly cell differentiation,
Keywords: 7th TNM, prognostic factors, adjuvant acinar subtype were signiÀcant (p<0.05) recurrence
treatment risk factors in multivariate analyses.
Conclusion: Invasiveness of early stage The median value of plCEA was 65.2 ng/g protein
adenocarcinoma might be strongly associated with (range, 0-7331.7). plCEA signiÀcantly correlated
solid portion of the tumor, cutoff value of which with pleural invasion and serum CEA, but did
was 15mm. Male, lymphatic invasion, moderate to not correlated with PLC. Analysis of ROC curve
poorly cell differentiation, and acinar subtype are identiÀed an optimal plCEA cut-off value to predict
also at high risk for recurrence. These subgroup may recurrence of 38 ng/g protein (area under the curve,
be considered as risk group for recurrence and may 0.663; sensitivity, 92.3%; speciÀcity, 43.7%; 95%CI:
need adjuvant therapy or closed follow up. 0.538-0.788, p = 0.021). Five-year DFS rates were
91.1% in patients with plCEA < 38 ng/g protein and
47.8% with plCEA > 38 ng/g protein (p = 0.0005).
Prognostic Factors and Stage Monday, 4 July 2011 14:30-16:00 Even in 51 patients with stage I lung cancer, 5-y DFS
signiÀcantly differed between patients with plCEA
MO03.04 PROGNOSTIC VALUE OF < 38 and > 38 ng/g protein (94.1% vs. 59.3%, p =
CARCINOEMBRYONIC ANTIGEN FROM 0.0068). Based on the multivariate Cox analyses,
PLEURAL LAVAGE FLUID IN NON- plCEA was a signiÀcant independent factor for DFS.
SMALL CELL LUNG CANCER Conclusion: Intraoperative plCEA was a powerful
Yasuhiro Tsutani, Yoshinori Yamashita, Keizo prognostic determinant for patients with NSCLC.
Misumi, Takuhiro Ikeda, Yoshihiro Miyata, Morihito Keywords: Non-small cell lung cancer, CEA,
Okada pleural lavage Áuid, prognostic factor
Surgical Oncology, Hiroshima University/Japan
Background: Little is known about the signiÀcance Prognostic Factors and Stage Monday, 4 July 2011 14:30-16:00
of carcinoembryonic antigen (CEA) from pleural
lavage Áuid (plCEA) in patients with operable MO03.06 PREOPERATIVE
non-small cell lung cancer (NSCLC). This study SERUM CARCINOEMBRYONIC
evaluates the prognostic signiÀcance of plCEA in ANTIGEN LEVEL AND COMPUTED
patients with completely resected NSCLC. TOMOGRAPHIC FINDINGS ARE
Methods: We examined 74 curatively resected PREDICTORS OF PATHOLOGICAL
patients whose pleural lavage Áuid were collected N0 IN CLINICAL STAGE IB LUNG
at thoracotomy, and pleural lavage cytology (PLC) ADENOCARCINOMA
and plCEA were determined. The relationships Shinya Neri1, Junji Yoshida1, Genichiro Ishii2, Yoichi
between plCEA and clinicopathological factors were Ohtaki1, Keiju Aokage1, Tomoyuki Hishida1, Mitsuyo
analyzed. Frequencies were compared using the Ƶ2 Nishimura1, Kanji Nagai1
1
test for categorical variables and Fischer’s exact Department Of Thoracic Surgery, National Cancer
test was applied to small samples. Mann-Whitney U Center Hospital East/Japan, 2Pathology Division,
tests were performed when comparing continuous Research Center For Innovative Oncology, National
variables. Receiver operating characteristic (ROC) Cancer Center Hospital East/Japan
curves of the plCEA for the prediction of recurrence
were generated to determine the cut-off value that Background: The standard intervention for
yielded optimal sensitivity and speciÀcity. The resectable non-small cell lung cancer (NSCLC)
patient population was subdivided based upon the has been lobectomy and systematic lymph node
cut-off value of plCEA derived from ROC curves, dissection. Recently, limited surgery with/without
and the duration of disease-free survival (DFS) lymphadenectomy has been repeatedly evaluated
was analyzed using the Kaplan-Meier method. in clinical stage IA NSCLC, and a clinical trial of
Differences in DFS were assessed using the log-rank wedge resection without lymph node dissection is
test. To assess the potential independent effects of now ongoing in Japan for clinical T1aN0M0 sub-solid
plCEA on DFS, we performed multivariate analyses tumors, organized by the Japan Clinical Oncology
using the Cox proportional hazards model with Group. However, few reports have analyzed the
variables with a p value of < 0.05 in the univariate validity of limited surgery in clinical stage IB (cIB)
analyses, and p < 0.05 was considered to be NSCLC. We reviewed cIB pulmonary adenocarcinoma
statistically signiÀcant. patients in an attempt to identify clinical and radiologic
Results: Ten patients (13.5%) had positive PLCs. predictors of pathological N0 (pN0) disease.
Methods: From 2002 through 2009, 224 consecutive D´Hebron University Hospital/Spain, 3Medical
patients with cIB adenocarcinoma who underwent Oncology, Vall D´Hebron University Hospital/Spain
complete resection with systematic lymph node
dissection were enrolled. We reviewed their Background: To evaluate if a more extensive
preoperative clinical data and computed tomographic lymphadenectomy provides a better staging and
scans, and evaluated the correlations between improves survival depending on the number of
nodal involvement and the following factors: lymph nodes (LN) obtained.
age, gender, smoking history, preoperative serum Methods: Retrospective study of 784 lung cancer
carcinoembryonic antigen (CEA) level (normal patients operated between 1995 and 2008. Groups
range: 5.0 ng/mL), and tumor disappearance based on factor T are divided according to the
ratio (TDR: 1- DM/DL; DM: maximum tumor number of LN resected (0-6, 7-12, 13) .
diameter on mediastinal settings, DL: maximum Results: We analyzed a total of 5.237 lymph nodes
tumor diameter on lung settings). Univariate and resected, with an average of 6.68 (0-48). (0-48). 688
multivariate analyses were performed using logistic were men and 96 women with and average age of
regression models. 62.48. Almost the 50% were diagnosed of squamous
Results: There were 115 men and 109 women. The cell carcinoma.
median age was 67 years (range: 37 – 85). There We present the results of the 163 T1 and 621 T2
were 164 pN0 patients and 60 pN1-2 patients. In patients.The analysis shows that the probability
univariate analysis, a lower preoperative CEA level to detect positive LN increases when more lymph
and a higher TDR were signiÀcant predictors of pN0 nodes are obtained during the lymphadenectomy
disease. In multivariate analysis, preoperative CEA (Table 1) and these Àndings are also seen when
level (OR: 0.032, 95%CI: 0.002 – 0.340) and TDR considering T stages separately (25%, 18,75%
(49.32, 10.94 – 285.5) were signiÀcant independent and 56,25% vs 78,91%, 14,97% and 6,12%,
predictors of pN0 disease. All of the 18 patients with p<0.3897 in T1 and 13,64%, 36,36%, and 50%
a 0.9 had pN0 disease. Among 45 patients with vs 65,44%, 16,16% and 18,40% p<0.0001 in T2).
a TDR 0.7 (pN0/pN1: 44/1), 33 patients with a
normal preoperative CEA level had pN0 disease.
Conclusion: Lymph node metastasis was not
observed in cIB patients with a TDR 0.9 or in
those with a normal preoperative serum CEA level
and TDR 0.7. These patients may be successfully
managed without systematic lymph node dissection.
Keywords: clinical stage IB, Adenocarcinoma,
lymph node dissection, carcinoembryonic antigen
A revised/updated abstract may be included in We also found that median survival with more lymph
the Late Breaking Abstract Supplement, available nodes resected were better in T1 and T2 (Table 3)
at the 14th World Conference on Lung Cancer. patients (statistically signiÀcant differences).
Prognostic Factors and Stage Monday, 4 July 2011 14:30-16:00
MO03.07 LYMPH NODE DISSECTION IN

EARLY STAGE NON SMALL CELL LUNG
CANCER
Laura Romero Vielva1, Amaia Ojanguren Arranz1,
Maria Deu Martin1, M. A. Montero2, Javier
Perez Velez1, Joan Sole Montserrat1, Joel Rosado
Rodriguez1, Iker Lopez Sanz1, Enriqueta Felip3,
Mercedes Canela1
1
Thoracic Surgery, Hospital Universitario Vall
D’Hebron/Spain, 2Pathology Department, Vall
Conclusion: The probability of Ànding positive preoperative high-resolution computed tomography

mediastinal LN increases with a more extensive (HRCT) imaging in adenocarcinoma cases. First,
lymphadenectomy. A complete lymphadenectomy we measured the longest diameter of the tumor in
provides a better staging and improves survival, and lung window and deÀned it as “lung diameter (L).”
therefore it should be performed in all lung cancer Second, we measured the length of the consolidation
patients even in those with an early stage. of “lung diameter” in mediastinal window and
Keywords: Lymphadenectomy, Lung cancer, deÀned it as “mediastinal diameter (M).” Then
survival we calculated the ratio (M/L) and analyzed the
correlation between M/L and the existence of
A revised/updated abstract may be included in pathological vessel invasion.
the Late Breaking Abstract Supplement, available Results: Mean follow-up period was 40.5 months.
at the 14th World Conference on Lung Cancer. During this period, 76 patients relapsed. Univariate
analyses revealed sex, high level of CEA,
histological type other than bronchioloalveolar
Prognostic Factors and Stage Monday, 4 July 2011 14:30-16:00 carcinoma, smoking, interstitial pneumonia, COPD,
history of other cancer, pathological stage IB or
MO03.08 CORRELATION BETWEEN higher, and vessel invasion as statistically signiÀcant
RADIOLOGICAL COMPUTED prognostic factors. On multivariate analysis, vessel
TOMOGRAPHY FINDINGS AND invasion, high level of CEA and history of other
PATHOLOGICAL VESSEL INVASION: cancer had signiÀcant impact on disease-free
ANALYSIS OF PROGNOSTIC FACTORS survival and their hazard ratios were 3.14, 2.51 and
FOR RELAPSE IN CLINICAL STAGE IA 1.94, respectively. In HRCT imaging analysis of 198
NON-SMALL CELL LUNG CANCER adenocarcinoma cases, when we set the cutoff value
Takuya Ito1, Tomohiro Murakawa1, Hajime Sato2, of M/L at 0.64, the sensitivity and speciÀcity of
Aska Tanabe2, Masaki Maekawa2, Akiteru Goto3, detecting pathological vessel invasion existence were
Shigeki Morita3, Takehiro Tsuchiya1, Yukihiro about 0.8 and 0.7, respectively.
Yoshida1, Atsushi Sano1, Masashi Fukayama3, Jun
Nakajima1
1
Department Of Cardiothoracic Surgery, University
Of Tokyo/Japan, 2University Of Tokyo/Japan,
3
Department Of Pathology, University Of Tokyo/
Japan
Background: There have been reports stressing

the importance of pathological vessel invasion
as a prognostic factor for relapse in primary lung
cancer. In this study, we analyzed prognostic impact
of vessel invasion on relapse in clinical stage
IA non-small cell lung (NSCLC), and examined
possible correlation between preoperative computed Conclusion: The existence of pathological vessel
tomography (CT) Àndings and pathological vessel invasion had the most signiÀcant impact on
invasion. relapse of primary non-small cell lung cancer. It
Methods: For examining prognostic factors, we may be possible to predict the existence of the
retrospectively analyzed 421 patients with primary most important prognostic factor associated with
non-small cell lung cancer who were diagnosed relapse preoperatively by using this quite simple
as clinical stage IA and underwent surgery from measurement of HRCT imaging.
1999 to 2009 at our department. The prognostic Keywords: pathology, computed tomography,
factors affecting disease-free survival were assessed Survival analysis, Non-small cell lung cancer
by Kaplan-Meier survival analysis, Log rank and
Wilcoxon test as univariate analyses and Cox’s
proportional hazards analysis as multivariate
analysis. Additionally, as a sub-analysis, we analyzed
Prognostic Factors and Stage Monday, 4 July 2011 14:30-16:00 less than 90% in clinical N0 patients, suggesting that
improvement of accurate N staging is warranted
MO03.09 MEDIASTINAL LYMPH NODES by incorporating PET with other minimal invasive
STAGING BY 18F-FDG PET/CT FOR approaches, including EBUS and EUS
EARLY STAGE NON-SMALL CELL LUNG Keywords: 18F-FDG PET/CT, Non-small cell lung
CANCER: A MULTICENTER STUDY cancer, Mediastinal lymph nodes stage
Xiaolin Li1, Huaqi Zhang2, Ligang Xing2, Lin
Zhang3, Wengui Xu4, Guoren Yang5, Jinming Yu2
1
Department Of Radiation Oncology, Shandong Prognostic Factors and Stage Monday, 4 July 2011 14:30-16:00
Tumor Hospital And Institute/China, 2Department Of
Radiation Oncology, Shandong Tumor Hospital And MO03.11 PROTON BEAM THERAPY
Institute/China, 3Deparment Of Thoracic Surgery, FOR STAGE I NON-SMALL-CELL LUNG
Shandong Province Hospital/China, 4Department CANCER
Of Nuclear Medicine, Tianjin Tumor Hospital And Chiyoko Makita, Tatsuya Nakamura, Haruo
Institute/China, 5Department Of Nuclear Medicine, Inokuchi, Takuya Tomoda, Akinori Takada, Kanako
Shandong Tumor Hospital And Institute/China Takayama, Miho Shiomi, Takahiro Kato, Nobuyuki
Fuwa
Background: Accurate staging of mediastinal lymph Radiation Oncology, Southern Tohoku Proton
nodes is a critical factor determining operability Therapy Center/Japan
and stereotactic body radiation therapy (SBRT) in
patients with non-small cell lung cancer (NSCLC). Background: Proton beam has an excellent dose
This multicenter study is to evaluate the accuracy of distribution called Bragg-peak that enables us to
18
F-FDG PET/CT to detect mediastinal lymph nodes deliver higher doses to the tumor without increasing
(MLN) metastases for T1-2 NSCLC doses to the surrounding normal tissues. We
Methods: The data of patients with T1-2 NSCLC retrospectively evaluated the safety and efÀcacy of
who received preoperative CT staging, FDG PET/ proton beam therapy (PBT) for Stage I non-small-
CT staging and radical surgery were retrospectively cell lung cancer (NSCLC).
reviewed in three centers between Oct. 2004 and Methods: Between 2009 and 2010, 128 NSCLC
Jan. 2009. The MLN metastatic was conÀrmed patients were treated in Southern TOHOKU proton
histopathologically after thoracotomy and lymph therapy center. There were 39 patients in clinical
node dissection. The sensitivity, speciÀcity, accuracy, Stage I ( IA: 30, IB: 9). A total dose of 66-84 GyE
PPV and NPV were calculated and compared for was delivered in 10-33 fractions(2.4, 3.2 and 6.6
PET and CT. Clinical and pathological factors were GyE per fraction, respectively) over 2-7 weeks with
analyzed for the correlation with MLN metastases. 2 or 3 portals of 150 or 210 MeV proton beam. The
Results: Eighty-six patients were enrolled. The relative biological effectiveness (RBE) of our proton
sensitivity, speciÀcity, accuracy, PPV and NPV for beam was deÀned as 1.1. Local control and disease
MLN metastasis on CT were 49%, 93%, 89%, 59% free were measured by serial chest CT and/or FDG-
and 92% respectively, with 80%, 90%, 90%, 62% PET/CT scans after PBT treatment. CTC version 4.0
and 93% on PET. (P=0.023, 0.07, 0.87, 0.89, 0.17). was used to assess toxicity.
There were 50 patients with clinical T1-2N0 NSCLC. Results: Patient characteristics are as follows:
In these patients, the NPV for MLN metastasis with median age 75 (range, 48 to 89 years), male/
FDG PET were 82% (41 of 50). It was showed that female: 25/14, Performance status 0/1/2: 27/7/5,
FDG uptake of primary tumor (P=0.006) and T adenocarcinoma/squamous/unknown: 22/11/6, T1a/
stage (P=0.007) were correlated with lymph node T1b/T2a: 15/15/9, medically in operable/refusal
involvement. Only 1 patients were found MLN of surgery: 27/12, total dose 66/80/72-84GyE:
metastasis in 26 patients with primary tumor FDG 18/15/6. With median follow-up period of 12 months
PET SUV<6.67, whereras 8 patients had MLN (range, 3 to 24 months), the local progression-free
metastases in 24 patients with SUV>6.67, P<0.01. and disease-free rates were 100% and 82% ( IA:
There were 6 and 3 patients found MLN metastasis 80%, IB: 89%), respectively. 7 patients showed
in T1 (n=44) and T2 (n=6) NSCLC, respectively recurrences in regional lymph node and/or distant
Conclusion: FDG PET/CT improves the sensitivity metastases or pleuritis carcinomatosa between 3 and
of N staging in T1-2 NSCLC. However, the NPV was 22 months after treatment. No serious acute toxicity
was observed. Late pulmonary toxicities were Conclusion: Brain MRI should be considered
observed in 5 patients with Grade 2 and 1 patient as initial screening procedure in neurologically
with Grade 3. asymptomatic node-negative patients with >3cm
Conclusion: Though further investigation of PBT sized non-small cell lung cancer.
for Stage I NSCLC is warranted, PBT is a promising Keywords: NSCLC, brain MRI, Brain Metastasis
treatment modality for Stage I NSCLC, producing
favorable results and low toxicity. A revised/updated abstract may be included in
Keywords: Stage I, Proton beam therapy, Non- the Late Breaking Abstract Supplement, available
small-cell lung cancer at the 14th World Conference on Lung Cancer.

the Late Breaking Abstract Supplement, available Session MO04: Biomarkers VI
Monday, 4 July 2011
Prognostic Factors and Stage Monday, 4 July 2011 14:30-16:00
Biomarkers VI Monday, 4 July 2011 14:30-16:00
MO03.12 PREVALENCE OF
ASYMPTOMATIC BRAIN METASTASIS MO04.01 P95HER2 TRUNCATED FORM
IN PATIENTS WITH NODE-NEGATIVE AND HER2 GENE COPY NUMBER IN
EARLY STAGE NSCLC NON-SMALL-CELL LUNG CANCER
Eun Young Heo1, Sang-Min Lee2, Jae-Joon Yim2, (NSCLC)
Seok-Chul Yang2, Chul-Gyu Yoo2, Sung-Koo Han2, Federico Cappuzzo1, Yong Gon Cho2, Greta
Young-Whan Kim2 Alì3, Matteo Incarbone4, Annarita Destro5, Luigi
1
Internal Medicine, Boramae Medical Center/Korea, Terracciano6, Gabriella Fontanini3, Antonio
2
Seoul National University Hospital/Korea Marchetti7, Massimo Roncalli5, Marileila Varella-
Garcia8
1
Background: Routine screening for brain metastases Oncology, Istituto Toscano Tumori-ospedale Civile/
in asymptomatic patients has not yet reached a Italy, 2Medicine/medical Oncology And Pathology,
consensus in practice guidelines. .In this study, we University Of Colorado/United States Of America,
3
evaluated the prevalence of asymptomatic brain Pisa University/Italy, 4Multimedica/Italy, 5Istituto
metastasis in patients of T1 or T2, node negative Clinico Humanitas-milan University/Italy, 6Basel
non-small cell lung cancer at the time of initial University/Switzerland, 7Chieti University/Italy,
8
staging and the efÀcacy of brain MRI as screening in Medical Oncology, University Of Colorado/United
patients with node-negative early stage NSCLC. States Of America
Methods: We retrospectively reviewed medical
records of 132 patients who were diagnosed of Background: Anti-HER2 therapies demonstrated to
clinical T1 or T2 node-negative NSCLC and signiÀcantly improve the outcome of patients with
underwent brain MRI at initial staging work-up breast and gastric cancer. In metastatic NSCLC,
between January 2005 to April 2010 at Seoul anti-HER2 monoclonal antibodies (HER2-mab)
National University Hospital. failed to demonstrate any beneÀt. Recent studies in
Results: Ninety two out of 132 patients (69.7%) breast cancer suggested that p95HER2, the NH2-
were diagnosed as adenocarcinoma. Seventy seven terminally truncated form of HER2, could confer
(58.3%) were clinical T1N0(T1a : 39, T1b: 38) and resistance to HER2-mab. HER2 gene ampliÀcation
55 (41.7%) were clinical T2N0(T2a: 41, T2b : 14). is considered a negative prognostic factor in many
Of 132 patients, brain MRI detected asymptomatic human malignancies. In NSCLC a recent meta-
brain metastasis in 13 (9.8%) at initial diagnosis. analysis suggested that HER2 overexpression but not
Patients of clinical T2 stage had signiÀcantly ampliÀcation is a poor prognostic factor, especially
higher prevalence of brain metastasis than patients in adenocarcinomas. Aim of the present study was
of clinical T1 stage (18.2% vs. 3.9%, P=0.013). to investigate the role of p95HER2 and HER2 gene
Histologic subtypes of tumor didn’t affect the copy number (GCN) in NSCLC.
prevalence of brain metastasis signiÀcantly. Methods: The present study included 447 surgically
1
resected NSCLC patients with known MET GCN Department Of Oncology, The Royal Marsden
status and 8 additional parafÀn-embedded tumor Hospital/United Kingdom, 2Molecular Diagnostics,
specimens from NSCLC patients harbouring exon Institute Of Cancer Research/United Kingdom,
3
20 HER2 mutations. P95HER2 status was evaluated Department Of Cytogenetics, Royal Marsden
by immunoÁuorescence in tissue microarray sections Hospital/United Kingdom, 4Histopathology, Royal
and data were correlated with HER2 GCN evaluated Brompton Hospital/United Kingdom
by Áuorescence in situ hybridization (FISH) and
HER2 mutations. Tumors were scored as positive for Background: ALK rearrangement is a transforming
p95HER2 expression if any cytoplasmic staining was event in NSCLC carcinogenesis, particularly observed
detected. in the rare signet-ring sub-type of adenocarcinoma.
Results: HER2 GCN was evaluable in 439 patients We aimed to characterize the predictive utility of
and increased GCN (at least 4 copies in at least tumour morphology and ALK immunoreactivity
40% cells) was found in 60 cases, of which 22 to identify ALK rearrangements in a cohort of
(5.0%) displayed true gene ampliÀcation (GA). adenocarcinomas with signet-ring morphology,
No difference in survival was observed between compared with primary lung adenocarcinoma of other
patients with or without HER2 GA (median 38 morphology.
versus 41 months, p=0.46). Interestingly, HER2 Methods: Adenocarcinomas from the Royal
GA was signiÀcantly associated with MET GA (p Brompton and HareÀeld Hospitals diagnostic archives
value inferior to 0.001), with no effect on patient reported with signet-ring morphology were identiÀed
survival (median survival: 36 versus 21 months in and assessed for pattern extent. Adenocarcinomas
MET GA/HER2 GA and MET GA/ HER2 negative, without signet-ring features over the same time
respectively, p=0.3). P95HER2 was successfully period were chosen for comparison. Tumours were
evaluated in 431 patients and the result was positive reviewed by 2 thoracic pathologists independently
(p95HER2+) in 33 (7.6%) cases. No association for percentage of signet-ring and other growth
was detected between P95HER2+ and increased patterns, and then classiÀed into signet-ring, and non-
HER2 GCN. Among the 22 patients with HER2 signet-ring groups. ALK expression was assessed by
ampliÀcation and among the 8 patients with HER2 immunohistochemistry using the ALK1 clone (Dako,
mutation, only one resulted P95HER2+. In the whole UK; 1 in 20 dilution) and a semi-quantitative scoring
population, p95HER2- patients had numerically system. ALK rearrangements were assessed in all
higher risk of death than p95HER2+ (HR=1.4, tumours by FISH using a commercially available
IC95%:1.08-1.82) even if the difference was not break-apart probe set. Associations were calculated
statistically signiÀcant (p=0.2). using Fisher’s exact test.
Conclusion: HER2 is not prognostic in NSCLC Results: Eighteen adenocarcinomas were assessed.
even in a context of MET co-ampliÀcation. All but three were surgical resections. Median age
P95HER2 plays a limited prognostic role in resected did not differ between signet-ring vs non-signet-
NSCLC. Although p95HER2 is present in a fraction ring groups (67 vs 57 years, p=0.32). Seven patients
of NSCLC, it is unlikely that this event is responsible had a signet-ring cell component, ranging from 20-
for the lack of efÀcacy of HER2-mab therapies 100%; six (86%) were TTF-1 positive. Two cases
observed in clinical trials. demonstrated diffuse moderate cytoplasmic ALK
Keywords: HER2, p95HER2, NSCLC immunoreactivity (2+), and were excision biopsies.
Both showed pure (100%) signet ring morphology,
and both harboured ALK rearrangements (29%
Biomarkers VI Monday, 4 July 2011 14:30-16:00 translocation prevalence, 95%CI: 4-71%). The other
5 mixed-signet-ring and 9 of 11 non-signet-ring
MO04.02 ALK TRANSLOCATION adenocarcinomas showed no immunoreactivity with
IS ASSOCIATED WITH ALK one each of the non-signet-ring tumours showing
IMMUNOREACTIVITY AND EXTENSIVE weak nuclear ALK positivity in 5% of cells and
SIGNET-RING MORPHOLOGY IN very weak cytoplasmic ALK immunoreactivity
PRIMARY LUNG ADENOCARCINOMA. respectively. All 16 showed no ALK rearrangements.
Sanjay Popat1, David Gonzalez2, Toon Min3, John ALK expression was not associated with ALK copy
Swansbury3, Melissa Dainton3, James Croud4, number. Pure signet ring morphology was strongly
Alexandra Rice4, Andrew G. Nicholson4 associated with ALK rearrangements (break-apart,
1
p=0.007) and ALK immunoreactivity (p=0.007), Oncology, Hospital Del Mar/Spain, 2Pathology,
unlike mixed signet-ring (p=1.0) or non-signet ring Hospital Del Mar/Spain
adenocarcinoma (p=0.135).
Conclusion: Adenocarcinomas with signet ring Background: ALK copy number aberrations have
morphology are strongly associated with ALK been previously described by our group and others
rearrangements, showing good correlation with in Non-Small Cell Lung Cancer (NSCLC). We have
cytoplasmic ALK immunoreactivity, in this small expanded the series of cases evaluated for ALK
series. TTF-1 positivity was 86% in primary copy number and analyzed the correlation with
lung signet-ring adenocarcinomas, and can aid in other relevant biomarkers and clinico-pathological
distinction from tumours spreading from other more characteristics.
common sites of origin. Methods: A series of non-small cell lung carcinomas
was evaluated for ALK gene status by Áuorescence
Signet
ALK
in situ hybridisation (FISH) and all non-squamous
Sample ring/solid ALK cases had EGFR and KRAS mutational analysis by
ID Age Sex ALK FISH Copy
type inÀltrate immunoreactivity
number sequencing and RT-PCR. Clinico-pathological data
(%)
1 68 F Resection 20 Negative Negative up to 7 and follow-up was available for these patients.
2 46 F Resection 30 Negative Negative 3-4 Results: Two hundred and twenty seven patients
Excision
Moderate
abnormal were included in this study. Patients’ characteristics
3 45 M 100 cytoplasmic translocation
biopsy
immunoreactivity
+split are presented in Table 1. Of these, 152 tumors
Excision were evaluable for ALK by FISH. We found 6
4 67 F 80 Negative Negative 3-4
biopsy cases of ALK translocation (4%). None of these
Moderate cases had KRAS or EGFR mutations. ALK copy
Excision abnormal
5 54 M 100 cytoplasmic translocation
biopsy
immunoreactivity
+split number status and its association with EGFR and
6 78 M Resection 60 Negative Negative 3-4 KRAS are detailed in Table 2. Interestingly, we
7 71 F Resection 30 Negative Negative 3-5 found a 15% of cases with ALK ampliÀcation or
8 53 F Resection 0 Negative Negative 3-4 presence of ALK clusters in <10% of cells. In non-
9 57 F Resection 0
<5% nuclear
Negative 3-5 squamous specimens we observed 17% and 19%
immunoreactivity
of EGFR and KRAS mutations, respectively. ALK
10 73 M Resection 0 Negative Negative 3-6
5 or
ampliÀcation (and clusters) was associated with
11 53 M Resection 0 Negative Negative
more early stage (p=0.048), better performance status (0-
12 43 F Resection 0 Negative Negative 3-5 1vs2-3) (p=0.016) and a trend to improved survival
Very weak
3-4 or (p=0.1). This last association was lost in multivariate
13 71 M Resection 0 cytoplasmic Negative
immunoreactivity
more analysis. Table 1. Patients’ characteristics
15 46 F Resection 0 Negative Negative up to 7 Patients characteristics (N:227) Number (%)
16 82 M Resection 0 Negative Negative Median age (range) 65 (36-88)
3-4
Gender Male 172 (76)
Female 75 (24)
5 or
18 76 F Resection 0 Negative Negative Smoking habit Current 99 (44)
more
Former 81 (36)
Keywords: ALK, FISH, immunohistochemistry, Never 44 (20)
Signet-ring Stage I 54 (24)
II 23 (10)
III 44 (20)
Biomarkers VI Monday, 4 July 2011 14:30-16:00 IV 103 (46)
PS 0-1 158 (70)
MO04.03 ALK COPY NUMBER CHANGES 2-3 35 (30)
IN NON-SMALL CELL LUNG CANCER Histology Adenocarcinoma 153 (67)
Edurne Arriola1, Álvaro Taus1, Marta Salido2, Ana Squamous cell carcinoma 38 (17)
B. Galván2, Luz Martínez-Avilés2, Javier Gimeno2, LCC + LCNEC + BAC 15 (7)
NOS 21 (9)
Sergio Serrano2, Beatriz Bellosillo2, Francesc Solé2,
Joan Albanell1
Table 2. ALK, EGFR and KRAS status outcomes per RECIST. Linear associations between
EGFR KRAS the percentage of ALK positive cells and signal copy
ALK n (%) Mutant WT Mutant WT number or response to therapy were summarized by
Disomic 28 (18) 1 19 3 18 Spearman correlations (two-sided p-values).
Gain 96 (63) 11 68 17 59 Results: Mean percentage cells positive was 56%
AmpliÀcation 12 (8) 0 6 2 4 (n = 90, range: 18-100%). Isolated red signal copy
Clusters < 10% 10 (7) 1 8 0 9 number (contributing to both single red (n = 33,
Translocation 6 (6) 0 6 0 6 mean cell positivity = 74%) and split positive
152 (100) 13 107 22 96 patterns (n = 49, mean cell positivity = 48%)
strongly correlated with a higher percentage of
Conclusion: ALK copy number gain and positive cells (r = 0.743, p <0.0001). Isolated green
ampliÀcation are relatively frequent in NSCLC, signal copy number (contributing to the split positive
although its biological role remains to be deÀned. pattern and the single green negative pattern) was
Keywords: ALK, Kras, EGFR, NSCLC weakly associated with a lower percentage of
positive cells (r = -0.264, p = 0.012). However, when
only those tumors with a split pattern of positivity
Biomarkers VI Monday, 4 July 2011 14:30-16:00 were assessed this correlation strongly reversed (r =
0.909, p < 0.0001). Fused signal copy number was
MO04.04 THE PERCENTAGE OF moderately negatively associated with the percentage
TUMOR CELLS SHOWING AN ALK of positive cells (r = -0.466, p <0.0001), but was also
GENE REARRANGEMENT IN ALK negatively associated with isolated red signal copy
FISH POSITIVE LUNG CANCER number (r = -0.409, p <0.0001). Neither percentage
CORRELATES WITH SIGNAL COPY cells positive (r = 0.192, p = 0.3), nor isolated red
NUMBER, BUT NOT WITH RESPONSE (r = 0.274, p = 0.195), isolated green (split pattern)
TO CRIZOTINIB THERAPY. (r = 0.438, p = 0.117) or fused signal (r = -0.247, p
David R. Camidge1, Mariana Theodoro1, Delee A. = 0.187) copy number correlated with the maximal
Maxson1, Margaret Skokan1, Tara O’Brien1, Xian percentage tumor shrinkage on crizotinib.
Lu2, Robert C. Doebele1, Anna E. Baron2, Marileila Conclusion: FISH analyses are conducted on
Varella-Garcia1 sectioned cells. The positive association between
1
Medical Oncology, University Of Colorado/United increases in rearranged signal copy number and
States Of America, 2Biostatistics And Informatics, percentage of ALK FISH positive cells supports
University Of Colorado/United States Of America the hypothesis that some signals are missed due to
nuclear truncation. The higher percentage of positive
Background: ALK gene rearrangements occur cells with single red, compared to split patterns,
in 3-5% of NSCLC. Increased copy numbers of suggests that difÀculties in detecting the narrow
native (fused) and rearranged signals have also been probe separation in the dominant EML4-ALK
reported. FISH using break-apart probes consistently paracentric inversion may also contribute towards
shows ALK rearrangements in < 100% of tumor ‘missed’ true positive cells. These data suggest that
cells. ALK positivity is usually deÀned as >15% of ALK FISH negative cells in otherwise ALK positive
tumor cells showing split red (3’) and green (5’) and/ tumors may not represent true biological negatives.
or single red patterns. Fused or single green patterns The lack of correlation between either percentage
are reported as negative. We explored correlations cells positive, or fused/rearranged signal copy
between the percentage of ALK positive cells and number and crizotinib response in tumors bearing
signal copy number and whether either variable is >15% ALK FISH positive cells suggests that these
associated with response to ALK inhibition. are not relevant biological variables with respect to
Methods: 90 consecutive ALK FISH positive beneÀt from ALK inhibition.
NSCLC patient samples were identiÀed. Keywords: ALK, FISH
The percentage of tumor cells positive for a
rearrangement, pattern of positivity (split, single red
or both) and copy number of the fused, isolated red
and isolated green signals were recorded. 30 of the
90 patients had received crizotinib with available
Biomarkers VI Monday, 4 July 2011 14:30-16:00 8.9%, never versus former versus current] did
not indicate any signiÀcant differences based on
MO04.06 UPDATE OF THE SOMATIC ethnicity. With respect to treatment with TKI mono-
MUTATIONS EGFR DATABASE (WWW. therapy (irrespective of line or stage) stratiÀed by
SOMATICMUTATIONS-EGFR.NET) mutation indicated signiÀcant differences according
Samuel Murray1, Helena Linardou2, Issa Dahabreh3, to response measures [mutant versus wild type,
Christos Papadimitriou4, Dimitrios Bafaloukos2, CR+PR: 69.9% versus 11.6%, SD: 14.6% versus
Paris Kosmidis5 20.4%, and PD: 15.6% versus 68.0%]. The database
1
Oncology, Genekor/Greece, 21st Department Of also details all reported mutations and supports links
Oncology, Metropolitan Hospital/Greece, 3University to all published datasets.
School Of Medicine, Boston/United States Of Conclusion: Inclusion of over 500 reported datasets
America, 4Alexandras Hospital/Greece, 5Hygeia allows investigation of several trends associated with
Hospital/Greece this particular somatic mutation. The cumulative
nature of the data is a singular limitation; however,
Background: Somatic mutations particularly in information extractable per Àeld is paramount to
exons 18-21 of the epidermal growth factor receptor patient stratiÀcation. Although the spectrum of
(EGFR) have been correlated with improved EGFR mutations is slowly increasing (n>300),
response outcomes in NSCLC patients treated with several distinct mutational hotspots (n=9) account for
tyrosine kinase inhibitors (TKIs). The frequency 82% of all mutational carriers. Screening practices
and spectrum of these mutations differs depending will be formulated on such data. We are currently
on ethnicity, wherein the incidence in Asians is assessing correlative Àelds and incidence using
approximately 30% compared to 15% in Whites. In Baysian statistics to generate predictive algorithms.
addition several clinicopathological factors (gender, We implore authors to support this data-source
smoking status and histological type) demonstrate primarily through submission of independent patient
correlation with their presence. Aim: To update our data that will allow more robust analyses to be
existing comprehensive database through collation conducted.
of all published data reporting on somatic EGFR Keywords: incidence, EGFR mutation, Smoking,
mutational analysis. Using this resource it should be Predictive
possible to investigate several trends associated with
several of the correlative factors and also address
aspects associated with screening issues. Biomarkers VI Monday, 4 July 2011 14:30-16:00
Methods: Using a broad search string including
“EGFR”, “geÀtinib”, “NSCLC”, “erlotinib” and MO04.07 COMPREHENSIVE ANALYSIS
associated synonyms we identiÀed 9895 abstracts OF MECHANISMS ON ACQUIRED
from inception through to 01/01/2011 in MEDLINE RESISTANCE OF LUNG CANCER
(PubMed). One additional Àeld was added into our AGAINST EGFR-TKI WITH SPECIAL
existing database, former smoker, thus splitting REFERENCE TO ROLE OF PTEN
smoking status into current-former-never. Data EXPRESSION LOSS
extraction was conducted by two investigators Kosei Yasumoto1, Hidetaka Uramoto2, Takashi
and all manuscript reference lists were scoured Yoshimatsu1, Tetsuya So1, Naohiro Nose1, Takamitsu
for potentially eligible manuscripts. A total of 545 Onitsuka2, Fumihiro Tanaka2, Mayumi Ono3
1
manuscripts (data sets) have been identiÀed and Respiratory Disease Center, Tiyuukai Hospital
included into the compendium (increasing the Groop/Japan, 2Second Dept Surg, Univ Occupat
number from 202). Environment Health/Japan, 3Dept Pharmaceutical
Results: With a total of 31,749 screened patients Oncol, Kyushu Univ/Japan
9,032 have been identiÀed to harbor a mutation
(28.4%) [33.9% versus 17.3%; asians and whites Background: Acquired resistance against EGFR-
respectively]. Cumulative data split by correlating TKI may be ascribed to T790M secondary
factors of histology [34.6% versus 8.2%; mutation(50%) and to MET ampliÀcation(20%).
adenocarcinoma versus other histologies], gender However, the mechanisms of remaining 30% of
[17.8% versus 41.9%, males versus females], acquired resistance of EGFR-TKI has remained
and smoking status [50.0% versus 16.9% versus to be elucidated. Recently, we have reported that
loss of PTEN expression is a crucial mechanism unresponsiveness to EGFR-TKI. In conclusion, 4

of experimental acquired resistance induced by out of 11 resistant tumors remain to be elucidated the
exposing PC9 cells(EGFR-mutated lung cancer mechanism of acquired resistant to EGFR-TKI.
cell line harboring activating mutation of EGFR( Keywords: EGFR-TKI, PTEN expression, Acquired
delE746-A750)) in vitro to stepwise increasing resistance to EGFR-TKI
concentrations of EGFR-TKI(geÀtinib)(from
005 ƫmol/L to 15 ƫmol/L) over 7months which
does not exhibit T790M ( Cancer Res 70(21), Biomarkers VI Monday, 4 July 2011 14:30-16:00
8715-8725,2010). Therefore, we evaluated
PTEN expression in 11 cases showing acquired MO04.08 HIGH PREVALENCE OF
resistance to EGFR-TKI. Also, overexpression of GERMLINE EGFR T790M MUTATIONS
MET ligand:HGF is thought to be one of crucial IN LUNG CANCER PATIENTS WHOSE
mechanisms of acquired resistance of lung cancer TUMORS HARBOR BASELINE T790M
against EGFR-TKI. Geoffrey R. Oxnard1, Maria E. Arcila2, Mark G.
Methods: We have evaluated comprehensively such Kris1, Marc Ladanyi2, Vincent A. Miller1
1
mechanisms as T790M acquired mutation, MET Medicine, Memorial Sloan-Kettering Cancer
ampliÀcation, HGF overexpression and loss of PTEN Center/United States Of America, 2Pathology,
expression in 11 Japanese patients with acquired Memorial Sloan-kettering Cancer Center/United
resistance to EGFR-TKI whose pretreatment tumors States Of America
harbor sensitive mutation for EGFR-TKI. Mutations
of EGFR-TKI and MET ampliÀcation were Background: EGFR T790M mutations are found in
evaluated based on PCR methods. PTEN and HGF up to 68% of lung cancers with acquired resistance to
expressions were evaluated by immunohistochemical EGFR tyrosine kinase inhibitors (TKIs; Arcila, CCR,
staining. 2011), and can also be detected prior to TKI (1% of
Results: Seven had T790M in resistant tumors, no adenocarcinomas; Kris, ASCO, 2010). Additionally,
MET ampliÀcation was detected, and 6 exhibited lung cancer patients with germline T790M and a
strong expression of HGF. All of these 6 tumors had family history of lung cancer have been described.
T790M. PTEN was down-regulated in 3 resistant- A study screening for germline T790M in blood
tumors in which all had T790M and responses to samples of never-smokers with lung cancer (Girard,
EGFR-TKI of pretreatment tumors were PR in 2 CCR, 2010) found a prevalence of only 0.5%. We
with TTP of 5.8 and 11.7m,and SD in one with TTP hypothesized that one way of identifying patients
of 7.4m. Moreover, loss of PTEN expression was with germline T790M mutations would be to study
observed in 3 pretreatment tumors having activating those whose lung cancers were found to harbor
EGFR mutation. These 3 tumors exhibited CR in baseline T790M.
one, PR in one and SD in one during the treatment Methods: All patients at our institution with lung
with EGFR-TKI( geÀtinib) with TTP of 7.0, 7.8 and cancer harboring baseline EGFR T790M, prior
7.4m, respectively. to TKI exposure, were included in this analysis.
Mutations had been identiÀed in tumor tissue
through direct sequencing, mass spectroscopy, or
a locked-nucleic-acid (LNA) assay. Sequencing
tracings were reviewed to exclude patients with
false positive T790M results. With IRB approval,
patient charts were reviewed and benign tissue was
collected, which was then anonymously tested for
T790M by direct sequencing.
Results: 11 patients with baseline T790M were
Conclusion: identiÀed; all harbored a concurrent sensitizing
Thus, the loss of PTEN expression seems not to be mutation (5 exon 19, 6 exon 21). Median survival
an independent mechanism of acquired resistance was 39 months for the 9 patients with advanced
to EGFR-TKI in clinical setting in contrast to the disease, though 0 of 5 patients treated with single-
experimental resistance. Furthermore, Loss of PTEN agent TKI had a radiographic response. 9 patients
expression in pretreatment tumors does not predict had benign tissue tested for germline T790M, which
was present in 4 (44%); analysis of benign tissue at diagnosis ranging from 26 to 89 years (median 65
from 2 additional cases is pending. Median age at years). Seventy-nine patients had stage I disease, 11
diagnosis for the 4 germline T790M patients was 51; had stage II, 22 had stage III, and 3 had stage IV. In
2 had a family history of lung cancer. 65 of 115, environmental tobacco smoke (ETS) data
Conclusion: Germline T790M mutations are were available.
common in lung cancer patients with tumors Results:
harboring baseline EGFR T790M, and can occur EGFR mutations (72 patients), KRAS mutations
with or without a family history of lung cancer. (6 patients), HER2 mutations (4 patients), and
These patients are ideal candidates for germline ALK translocations (6 patients) were identiÀed in
testing; affected probands and their family members 77% of all 115 patients and these were mutually
could then be studied prospectively. A study of CT exclusive each other. Strikingly, all but one (18/19)
screening in family members with germline T790M of male never-smoking patients harbored one of
is under development. Study supported by the NIH these alterations, in contrast, 27% (26/96) of female
(P01-CA129243). never-smoking patients did not have any of these
Keywords: EGFR, genetics alterations, and this difference was statistically
signiÀcant (Fig.1, left; p=0.042). When we combined
our data with those of Sun, et al. (JCO. 28: 4616-
Biomarkers VI Monday, 4 July 2011 14:30-16:00 4620, 2010), the similar results were obtained;
i.e., 97% (29/30) of male never-smoking patients
MO04.09 ANALYSES OF MUTUALLY harbored one of these alterations, while 23%
EXCLUSIVE DRIVER MUTATIONS IN (31/137) of female never-smoking patients did
LUNG ADENOCARCINOMAS FROM not have these alterations (p=0.019). To explain
NEVER-SMOKING PATIENTS this difference, we explored the inÁuence of ETS,
Kenichi Suda1, Kenji Tomizawa1, Keitaro Matsuo2, because of suspected higher rate of household
Yasushi Yatabe3, Tetsuya Mitsudomi1 ETS exposure in elderly Japanese female never-
1
Department Of Thoracic Surgery, Aichi Cancer smokers. Interestingly, 32% (6/19) of patients with
Center Hospital/Japan, 2Division Of Epidemiology ETS exposure did not have either of the alterations,
And Prevention, Aichi Cancer Center Research in contrast, 85% (39/46) of patients without ETS
Institute/Japan, 3Pathology And Molecular exposure had any of these four alterations (Fig.1,
Diagnostics, Aichi Cancer Center Hospital/Japan right).
Background: It is known that EGFR, KRAS,

HER2, or ALK oncogenic alterations occur in
lung adenocarcinomas in mutually exclusionary
fashion. Therefore, lung adenocarcinomas can be
subdivided based on these alterations, and this sub-
classiÀcation would be important in understanding
lung carcinogenesis and in developing treatment
strategies. The prevalence of these alterations,
except for KRAS, is higher in never-smokers, and
a very recent paper that analyzed 52 never-smoking
Chinese patients (Sun, et al. JCO. 28: 4616-4620,
2010) showed that about 90% harbor one of these Conclusion: In lung adenocarcinoma from never-
alterations. In the present study, we performed smoking patients in East Asia, virtually all male
similar and further analyses using much larger cohort patients and about 80% of female patients can be
of never-smoking Japanese lung adenocarcinoma explained by oncogenic activation of one of EGFR,
patients. KRAS, HER2, or ALK genes. ETS may be one of the
Methods: One hundred Àfteen never-smoking reasons for this gender difference.
patients with lung adenocarcinoma had enough Keywords: driver mutations, lung adenocarcinoma,
tumor samples for analyses of all four genes never-smoking patients, EGFR mutations
described above, and were included in this study.
Nineteen were men and 96 were women, with ages
Biomarkers VI Monday, 4 July 2011 14:30-16:00 were analyzed for response and progression-free
survival (PFS). A subpopulation of 18 evaluable
MO04.11 PRECLINICAL MODELING OF KRAS-mutant NSCLC patients who had failed prior
SUSCEPTIBILITY OF NSCLC CELLS docetaxel therapy were evaluated for the time on
WITH RAS MUTATIONS TO GSK1120212, treatment for docetaxel and the subsequent time on
A POTENT AND SELECTIVE MEK1/ treatment for GSK212 therapy.
MEK2 INHIBITOR: IMPLICATION FOR Results: GSK212 monotherapy had a response rate
CLINICAL DEVELOPMENT (RR) of 24% (6/25) in the NSCLC cell line panel,
Li Liu1, Tona M. Gilmer1, Hong Shi1, Vivian deÀned by both cell growth inhibition and apoptosis
Zhang1, Jennifer Park2, Leslie A. Fecher3, Wells induction assays. In contrast, everolimus or erlotinib
A. Messersmith4, Jeffrey R. Infante5, Gerald S. alone showed little or no activity. Interestingly,
Falchook6, Vijay Peddareddigari7 docetaxel had a RR of 40% (10/25) alone and 84%
1
Oncology Translational Research, Glaxosmithkline/ (21/25) in combination with GSK212. Furthermore,
United States Of America, cell lines that were sensitive to GSK212 alone
2
Oncology,Glaxosmithkline/United States Of were less responsive to both docetaxel and
America, 3Medicine, University Of Pennsylvania, paclitaxel alone. In vitro response to GSK212
Abramson Cancer Center/United States Of America, was associated with a distinct proÀle of molecular
4
Medicine/division Of Medical Oncology, University markers including: lower levels of AKT/FOXO3a-
Of Colorado Cancer Center/United States Of phosphorylation, higher expression levels of genes
America, 5Drug Development Unit, Sarah Cannon involved in EGFR signaling, adhesion or endocytosis
Research Institute/United States Of America, such as TGFA, EREG, EPCAM, CTNND1, STN2,
6
Investigational Cancer Therapeutics, University and lower expression levels of genes involved in
Of Texas MD Anderson Cancer Center/United transcription regulation or cell cycle such as TWIST,
States Of America, 7Research And Development, TYMS, CDKN2C compared with GSK212-resistant
Glaxosmithkline/United States Of America NSCLC cell lines. Of the 18 evaluable KRAS-
mutant NSCLC patients treated with GSK212
Background: Activating mutations of the KRAS monotherapy on the ongoing MEK111054 Phase
oncogene are the most frequent mutations in non- I study, two experienced a partial response for a
small cell lung cancer (NSCLC) and may correlate preliminary RR of 11% and yielded a preliminary
with a poorer prognosis, in part due to limited PFS for 3.8 months (95% CI: 1.9-5.5). Interestingly,
beneÀt from systemic treatments. Targeting the there was an inverse correlation (Pearson correlation
activated RAS/RAF/MEK pathway in NSCLC with coefÀcient = -0.3, p value >0.3) between GSK212
the potent, selective MEK1/MEK2 small molecule treatment duration and prior docetaxel treatment.
inhibitor GSK1120212 (GSK212) is an innovative Conclusion: Similar to the preclinical observations,
approach to potentially improve the clinical outcome the sensitivity to GSK212 monotherapy may be
for patients with KRAS-mutant tumors. In this restricted to a distinct subpopulation of KRAS-mutant
study, we assessed the in vitro susceptibility of NSCLC patients, although these results were not
RAS-mutant NSCLC cell lines to GSK212 alone statistically signiÀcant. The speciÀc molecular and
or in combination with other therapeutic agents, to genetic proÀle established in vitro in the 25 NSCLC
identify predictive markers of response and provide cell line panel will be analyzed in KRAS-mutant
a scientiÀc rationale for the clinical development of NSCLC tumor samples obtained from the clinic to
GSK212. explore possible predictive markers that may guide
Methods: A panel of 25 RAS-mutant NSCLC cell future GSK212 treatment strategies as monotherapy
lines was subjected to genomic alterations, gene or in combination with other standard or novel
expression and cell signaling proÀling. Susceptibility therapies.
to GSK212, docetaxel, erlotinib and everolimus Keywords: Kras, NSCLC, MEK, Biomarkers
alone or in combinations was determined by cell
growth inhibition (CellTiter-Glo® assay, Promega)
and apoptosis induction (caspase 3/7 activation)
assays. Additionally, data from 22 KRAS-mutant
NSCLC patients on the ongoing MEK111054
Phase I study who were treated with GSK212 alone
Biomarkers VI Monday, 4 July 2011 14:30-16:00 Biomarkers VI Monday, 4 July 2011 14:30-16:00
MO04.12 ELECTRONIC NOSE MO04.13 DETECTING LUNG CANCER

DISTINGUISHES LUNG CANCER FROM FROM VOLATILE ORGANIC
HEALTHY EVER SMOKERS. COMPOUNDS WITH AN ELECTRONIC-
Annette G. Dent, Rayleen Bowman, Paul NOSE (E-NOSE)
Zimmerman, Ian A. Yang, Kwun M. Fong Calum E. Macaulay1, Stephen Lam2, Annette M.
Department Of Thoracic Medicine, The Prince Mcwilliams2
1
Charles Hospital And The University Of Queensland/ Integrative Oncology, BC Cancer Research Centre/
Australia Canada, 2British Columbia Cancer Agency/Canada
Background: The measurement of volatile organic Background: This ongoing study is investigating
compounds (VOCs) in exhaled breath using an the ability of an array of 32 nanosensors (Cyranose
electronic nose may prove to be a novel, effective and E-nose) to discriminate between breath volatile
simple technique for screening and diagnosing lung organic compounds (VOC) that characterise
cancer. subjects at risk of developing lung cancer from
Methods: Aims: To determine whether VOC proÀle in subjects harbouring an early lung cancer. The
individuals with lung cancer can be differentiated from operating hypothesis is that the altered metabolic
that of healthy ever smokers with at least a 30 pack year and physiologic characteristics of lung cancer
smoking history. 2. To determine whether the VOC tissue result in the release of VOC in amounts or
proÀle differs between lung cancer histologies. Method: composition different than normal tissues. The goal
Subjects performed two exhaled vital capacities (10 is that the reliable detection of these changes could
min apart) into a Tedlar sample bag after breathing be used as part of a lung cancer screening program.
tidally through an inspiratory port Àlter for 5 minutes. Methods: To date VOC data in 139 exhaled breath
Samples were analysed using a Cyranose 320. Means samples from control subjects who are high risk
of the two tests for each of the 32 sensors were reduced smokers and 18 exhaled breath samples from Stage
to principal components and canonical discrimination I/II lung cancer patients has been collected using the
analyses were performed to determine signiÀcance of E-nose system. These subjects are between 50-79
difference between subject groups and cross validated years of age and have a smoking history of at least
accuracy (CVV) of the groups using the leave one out 20 pack years. Control subjects are from a local lung
classiÀcation method (SPSS V17.0). Spirometry and cancer screening study, and cancer patients from
gas transfer measurements were also performed. local referrals
Results: The VOC proÀles of lung cancer subjects Exhaled breath samples are collected from each
(n=26) were correctly differentiated from healthy subject while breathing medical air to control for
subjects with a smoking history (n=61) with CVV local ambient VOC. The breath collection is then
accuracy of 82% (p<0.0001). The VOC proÀles did not sampled by the E-nose device. This is a relatively
differ with the type of cancer. inexpensive organic polymer sensor that changes
Conclusion: SigniÀcant differences in exhaled breath resistance in the presence of certain VOCs. These
VOC proÀles between subjects with lung cancer and systems measure a differential signal between a
healthy ever smokers indicate that the eNose (Cyranose reference gas (medical air) and the sample being
320) does have the potential to be a clinically useful tested. In addition to examining the system’s
diagnostic and screening tool for lung cancer however response to subject samples we have assessed the
may not be able to discriminate between cancer types. variability of its response to differing supplies of
Supported by The Prince Charles Hospital Foundation, medical gas as well as compared the inter system
The Prince Charles Hospital Private Practice Trust variability between two systems.
Fund, NHMRC Career Development Award (IY), Results: The E-nose system is very sensitive to
NHMRC Practitioner Fellowship (KF). ConÁict of changes in temperature and humidity. We developed
Interest: None algorithms which remove baseline data drift and
have Àt individual sensor response to a 5th order
A revised/updated abstract may be included in polynomial and a double exponential to maximize
the Late Breaking Abstract Supplement, available sensor sensitivity while minimizing the effects of
at the 14th World Conference on Lung Cancer. noise. Individual sensor data was found to have very
little classiÀcation ability. However combinations for about 80% of cases of which adenocarcinoma
of pairs of sensors data were found to be quite represents the majority. The appearance of distant
discriminating. For the 157 samples aquired, using metastasis is one of the main reasons for failing to
data from only 2 of the 32 sensors optimized for a cure patients with this disease. Thus, understanding
speciÀcity of 90%, the observed sensitivity was 50% the biological processes underlying lung cancer cell
and similarly for a speciÀcity of 50% we observed motility, invasion and metastasis should highlight
a sensitivity of 94%. Through the measurement of novel therapeutic biomarkers to improve the poor
many samples in parallel by the two systems, we clinical outcome.
observed that they are substantially equivalent with a Methods: We performed an automated kinome-
sensor by sensor average linear correlation R2 value based RNA interference screen for cell migration
of 0.994 with a range of 0.999 to 0.972 across the using the A549 non-small cell lung cancer (NSCLC)
32 sensors. The E-nose system could detect subtle cell line. We studied changes in cell migration
differences between medical air supply batches, patterns in response to RNAi treatment using time-
however these differences were signiÀcantly smaller lapse microscopy and automated tracking.
than subject to subject differences. The E-nose We then tested the capacity of our motility hits
systems performance is encouraging and active to regulate cell invasiveness in a 96-well plate
recruitment is ongoing. 3-dimensional invasion assay where cells invaded
Conclusion: Our results suggest that measurement upward from the bottom of the well through a
of VOC in exhaled breath is a promising method to collagen matrix. Using a human protein-protein
identify subjects with early lung cancer in a high risk interactome database we identiÀed novel interactor
population. of RSK and conÀrmed that RSK1 interact with
vasodilator-stimulated phosphoprotein (VASP) by
co-immunoprecipitation. IdentiÀcation of the VASP
Biomarkers VI Monday, 4 July 2011 14:30-16:00 residues phosphorylated by RSK1 was performed
using mass spectrometry analysis and phospho-
MO04.14 IDENTIFICATION OF RSK1 AS speciÀc antibody. We further extended our Àndings
A KEY MODULATOR OF LUNG CANCER in vivo using A549 xenograft model in zebraÀsh.
METASTASIS Finally, RSK1 expression was tested in a tissue
Romain Lara1, Francesco Mauri2, Harriet Taylor3, microarrays containing matched primary non-small
Rita Derua4, Alice Shia3, Colin Gray5, Alastair cell lung cancers (adenocarcinomas) and adjacent
Nicols5, Robert J. Shiner2, Edward Edward normal lung.
SchoÀeld6, Paul Bates6, Etienne Waelkens4, Maggie Results: Our cell motility screen identiÀed 48
Dallman3, Jonathan Lamb3, Daniel Zicha5, Julian previously unknown to regulate cell motility.
Downward7, Michael Seckl1, Olivier Pardo1 Among our candidates, were several members
1
Oncology, Imperial College London/United of the ribosomal S6 kinase (RSK) family. In
Kingdom, 2Histopathology, Imperial College particular, RSK1 silencing increased, while RSK2
London/United Kingdom, 3Imperial College London, and 4 downregulation decreased, cell motility. In
Division Of Cell And Molecular Biology, Department a secondary screen, more than 50% of our hits
Of Life Sciences, Faculty Of Natural Sciences/ similarly modulated A549 cell invasion in vitro.
United Kingdom, 4Labo Proteïne Fosforylatie Amongst these, RSK1 downregulation, in keeping
En Proteomics, Katholieke Universiteit Leuven/ with its effect on cell migration, strongly increased
Belgium, 5Cancer Research Uk - London Research cell invasiveness. In silico analysis and biochemical
Institute, Light Microscopy Department/United experimentation revealed that RSK1 interacted with
Kingdom, 6Cancer Research Uk - London Research the actin regulators VASP and Mena. This correlated
Institute, Biomolecular Modelling Laboratory/United with the ability of RSK1 to phosphorylate VASP
Kingdom, 7Cancer Research Uk - London Research on Thr-278, a site regulating VASP-mediated actin
Institute, Signal Transduction Laboratory/United dynamics. Moreover, RSK1 silencing enhanced
Kingdom the metastatic behaviour of A549 cells in vivo
using a zebraÀsh xenograft model. Importantly,
Background: Lung cancer is the commonest cancer immunohistochemical staining showed decreased
killer worldwide with a 5-year survival rate <5%. RSK1 expression in metastatic lung cancer lesions
Non-small cell lung cancer (NSCLC) accounts as compared to their isogenically matched primary
tumours. Furthermore, loss of RSK1 expression in comorbidity. Volunteers received one prevalence
lung primary tumours correlated with an increased scan and two annual incidence scans using a Phillips
number of metastatic lesions. Brilliance 64-slice multidetector scanner at 0.9mm slice
Conclusion: Our screen revealed 48 previously thickness. Two radiologists independently reported
unpublished regulators of lung cancer cell migration. scans with the Ànal report agreed by consensus. Any
In particular, we identiÀed RSK1 as a key regulator non-calciÀed nodule 4mm diameter was deÀned as a
of lung cancer cell metastasis. Importantly, positive scan. Generally, nodules 4-8mm diameter were
immunohistochemical staining demonstrated that followed with interval scans whereas larger nodules
RSK1 was downregulated in metastatic compared to underwent further investigation. Health status follow-up
primary tumours establishing RSK1 as a determinant will continue for Àve years from study entry.
of lung cancer cell metastasis and a potential Results: From December 2007 to December 2010,
predictive marker for disease progression. 958 persons enquired about enrolment. In total,
256 volunteers were screened (Table 1). The mean
estimated Effective Dose was 1.5mSv/scan. 305
Session MO05: CT Screening of nodules 4mm were detected (35% were in the right
Individuals At Risk and Epidemiology upper lobe, 72.5% had a smooth margin and 87.9%
were of soft tissue density). 607 micronodules (<4mm)
were detected. 53% of participants had positive
Monday, 4 July 2011
scans; 15% of participants had neither nodules nor
micronodules; 32% had micronodules only and were
CT Screening of Individuals At Risk and Epidemiology Monday, 4 July followed up at a 12 month interval. 8 participants
2011 14:30-16:00 (5.8% of those with positive scans) underwent one
or more invasive diagnostic procedures (CT-guided
MO05.01 LUNG CANCER SCREENING: biopsy and/or bronchoscopy). Three out of eight did
BASELINE RESULTS FROM not have malignant disease diagnosed and two of these
AUSTRALIAN LOW DOSE COMPUTED suffered signiÀcant pneumothorax requiring intercostal
TOMOGRAPHY STUDY chest drainage. No participants underwent a surgical
Henry M. Marshall1, Rayleen Bowman2, Jane procedure for benign disease. Five cancers were
Crossin3, Melanie Fuentes3, Richard Slaughter3, diagnosed. The cancer prevalence was 1.95% [95%CI
Linda Passmore1, Elizabeth Mccaul1, Deborah 0.26 - 3.64] or 3.68% of positive scans. All cancers
Courtney1, Morgan Windsor4, Ian A. Yang2, Terry were stage I or II. Four participants had surgery, one
Hayes3, Paul Zimmerman1, Stanley Redmond3, Ian had radical chemoradiotherapy. Table 1.
Smith5, B J. Keir6, Kwun M. Fong2
1
Thoracic Medicine, The Prince Charles Hospital/ Male Female All participants
Australia, 2Department Of Thoracic Medicine, The n (%) 171 (66.8) 85 (33.2) 256
Age, years Median (range) 64.5 (59-75) 64.6 (60-74) 64.5 (59-75)
Prince Charles Hospital/Australia, 3Department Of
Age groups 60-64, n (%) 93 (54.4) 47 (55.3) 140 (54.7)
Medical Imaging, The Prince Charles Hospital,/ 65-69, n (%) 59 (34.5) 30 (35.3) 89 (34.8)
Australia, 4Thoracic Surgery, The Prince Charles 70-74, n (%) 19 (11.1) 8 (9.4) 27 (10.5)
Hospital/Australia, 5St Andrew’s Medical Institute, FEV1 %
Spirometry predicted, 95.7 (52.1-155.5) 94.2 (46.6-129.4) 95.0 (46.6-155.5)
St Andrew’s War Memorial Hospital/Australia, median (range)
6
Biomedical Technology Services, Royal Brisbane Obstructive
ventilatory Mild 45 (26.3) 21 (24.7) 66 (25.8)
And Women’s Hospital/Australia defect
Moderate 9 (5.3) 4 (4.7) 13 (5.1)
Background: The National Lung Screening Trial Moderately

severe
10 (5.8) 3 (3.5) 13 (5.1)
reports that LDCT screening can reduce lung cancer Severe 0 1 (1.2) 1 (0.4)
mortality. The Queensland Lung Cancer Screening Smoking Current, n (%) 74 (43.3) 42 (49.4) 116 (45.3)
Study (QLCSS) is an observational study based on the Pack-year

history, median 58 (24 -235) 46 (22 -220) 54 (22-235)
NLST protocol. We report our interim baseline Àndings. (range)
Methods: Using advertisement and press release, we Nodules per

participant
Median (range) 1 (0-13) 1 (0-9) 1 (0-13)
recruited healthy volunteers aged 60-74 years with Micronodules
Median (range) 1 (0-18) 2 (0-15) 2 (0-18)
per participant
a smoking history 30 pack years (current or quit
within 15 years), FEV1>50%predicted and no major
Conclusion: The prevalence of lung cancer in our Àfth year. One hundred seventy-Àve primary lung
cohort is similar to other studies. High rates of tumors were detected. One hundred thirty six cases
false positive scans and the subsequent potential (78%) were initial stage (N0M0). Interval cancers
for adverse events following biopsy need to be the occurred in 6 patients. Resectability rate was 88%
focus of future studies in order to improve screening with 0.5% postoperative mortality. Five-year overall
efÀcacy. Supported by a Queensland Smart State and cancer speciÀc survival were 76% and 81%
Grant, NCARD and NHMRC. respectively. Recall rate was 10.2% at baseline and
Keywords: lung cancer screening, low dose ranged from 4.2% to 6.4% at subsequent screening
computed tomography rounds. Delayed diagnosis occurred in 16 patients
(16/186) (Table 1). Causes of misdiagnosis can be
resumed as follow: protocol failure (nodule < 5 mm
CT Screening of Individuals At Risk and Epidemiology Monday, 4 July one year before) in 7 cases; LD-CT failure (central
2011 14:30-16:00 position) in 6; human failure (misinterpretation) in
3. Metachronous second primaries were diagnosed
MO05.02 DIAGNOSTIC PERFORMANCE at follow-up CT in 11 cancer patients. Sensibility
OF ANNUAL LD-CT SCREENIGN FOR of protocol was 168/193 (87.0%); speciÀcity was
LUNG CANCER AFTER FIVE YEARS 4976/5001 (99.5%); and PPV was 168/202 (83.2%).
Giulia Veronesi1, Lorenzo Spaggiari1, Ptrik Benign diseases diagnosed with surgical biopsy were
Maisonneuve1, Cristiano Rampinelli2, Alessandro 34 (34/220=15.5%).
Pardolesi1, Raffaella Bertolotti2, Alessandro Borri1, Conclusion: The diagnostic performance of our
Francesco Petrella1, Stefania Rizzo2, Massimo CT protocol was high with acceptable number of
Bellomi2 benign disease requiring surgical biopsy, limited
1
Division Of Thoracic Surgery, European Institute Of recall rate and high long term survival. Number of
Oncology/Italy, 2Division Of Radiology, Europena interval cancers, advanced stage at diagnosis and
Institute Of Oncology/Italy misdiagnosis will probably be further reduced by
future application of risk modeling and lung cancer
Background: CT screening is an effective tool to serum markers.
reduce lung cancer mortality however to increase Keyword: lung cancer, screening, early stage
diffusion and acceptance of screening programmes
it is essential to identify standardised diagnostic A revised/updated abstract may be included in
protocols and make evidence-based decisions on the Late Breaking Abstract Supplement, available
nodule management. We report the long term results at the 14th World Conference on Lung Cancer.
of a single center low-dose CT screening trial and
analyze the performance, invasiveness and side
effects of the diagnostic protocol. CT Screening of Individuals At Risk and Epidemiology Monday, 4 July
Methods: Between October 2004 and October 2011 14:30-16:00
2005, 5203 asymptomatic high-risk individuals
(20 pack-years, age >50 years) were enrolled in a MO05.03 PREDICTORS OF EARLY
single centre trial and followed annually for 5 years. CT-DETECTED LUNG CANCERS IN
Nodules 5 mm were scheduled for repeat CT a year DUTCH-BELGIAN RANDOMIZED LUNG
later. Nodules between 5.1 and 8 mm were checked CANCER SCREENING TRIAL (NELSON)
with LD-CT 3-6 months later. Nodules >8.1 mm or Eleonora Baecke1, Rob J. Van Klaveren2, C.W.N.
growing lesions were scheduled for CT-PET. True Looman2, J.W.J. Lammers3, Harry J.M. Groen4, C.
positives were deÀned as any stage prevalent lung Weenink5, K. Nackaerts6, Matthijs Oudkerk4, H.J. De
cancer, nodules in progression diagnosed as stage Koning2
1
I lung cancers or new nodules diagnosed as lung Public Health, Erasmus MC/Netherlands, 2Erasmus
cancers; false negatives, as nodules in progression MC/Netherlands, 3Umc Utrecht/Netherlands, 4Umc
diagnosed as lung cancer in stage >1; false positives Groningen/Netherlands, 5Kennemer Gasthuis/
as benign nodules resected surgically; and true Netherlands, 6Umc Leuven/Belgium
negatives as patients with no evolving nodules at
baseline and subsequent LD-CTs. Background: Although smoking and age are well-
Results: Compliance was 82% at the end of the known risk factors for lung cancer, less evidence
is available about other predictors and the role of initial, low-dose CT scan and their implications on
gender, particularly not for early CT-detected lung the delays in diagnosis of lung cancer.
cancers. We investigated predictors of CT-screen- Methods: We determined all instances of non-
detected lung cancers among participants of the calciÀed nodule(s) in the initial, low-dose CT scans
Dutch-Belgian randomized lung cancer screening performed in 2006-2009 in the International Early
trial (NELSON), who are high-risk current and Lung Cancer Action Program (I-ELCAP), Using
former smokers. the current deÀnitions of positive result for baseline
Methods: We evaluated data, obtained from and annual repeat and more restrictive ones, we
questionnaires sent before randomization, of 6294 determined the frequencies of positive results and
male and 1247 female screen arm participants, aged how often the diagnosis of lung cancer would have
50-75, who underwent at least the baseline CT scan. been delayed using the more restrictive deÀnition.
Cox proportional Hazard regression was performed, The current deÀnitions of a positive result of the
in which screen-detected lung cancer was the initial, low-dose CT in the lung parenchyma are as
dependent variable. The mean follow-up was 35.8 follows. In baseline screening, a positive result is
months. the identiÀcation of at least 1 of: solid or part-solid,
Results: Till 2010, lung cancer had been detected non-calciÀed nodule 5.0 mm or more in diameter,
in 159 male and 29 female participants. Age, level or nonsolid non-calciÀed nodule 8.0 mm or more in
of education, smoking history, prior diagnosis of diameter; or a solid endobronchial lesion 5.0 mm or
cancer < 5 years ago and perceived health were all more in diameter (14). In annual repeat screenings,
signiÀcantly associated with lung cancer detection. a positive result is the identiÀcation of at least 1
After correcting for these predictors, the Hazard ratio previously unidentiÀed, non-calciÀed parenchymal
comparing women with men was 1.39 (95% CI: 0.93 nodule, larger than before, regardless of consistency
to 2.08). The estimated discriminative value of the and size, or a solid endobronchial nodule, regardless
NELSON model was 0.72 (95% CI: 0.68 to 0.75). of size. A nodule is classiÀed as solid, part-solid, or
Conclusion: The NELSON model is the Àrst lung nonsolid, and as calciÀed or non-calciÀed according
cancer risk model based on early CT- detected to speciÀed criteria, and its ‘diameter’ is taken to
lung cancers and includes age, level of education, be the average of its ‘length’ and ‘width’. The more
smoking, prior diagnosis of cancer < 5 years ago, restrictive alternatives are: In baseline screening,
perceived health and gender. The calculated Hazard a positive result is the identiÀcation in the lung
ratio suggests a possibly higher risk for women. parenchyma of at least 1 of: solid non-calciÀed
After validation, the model is likely to be useful for pulmonary nodule 7.0 mm or more in diameter,
risk stratiÀcation, especially in the context of a lung or part-solid non-calciÀed nodule 7.0 mm or more
cancer screening program. in diameter; or at least 1 nonsolid, non-calciÀed
Keywords: NELSON, lung cancer risk, lung cancer pulmonary nodule 15.0 mm or more in diameter,
screening, risk model or solid endobronchial lesion 7.0 mm or more in
diameter. In annual repeat screenings, a positive
result is the identiÀcation of least 1 previously
CT Screening of Individuals At Risk and Epidemiology Monday, 4 July unidentiÀed solid non-calciÀed nodule 3.0 mm
2011 14:30-16:00 or more in diameter that was larger than before,
part-solid non-calciÀed nodule 5.0 mm or more in
MO05.04 CT SCREENING FOR LUNG diameter, or nonsolid non-calciÀed nodule 15.0 mm
CANCER: UPDATE OF THE DEFINITION or more in diameter, or solid endobronchial lesion
OF POSITIVE RESULT 5.0 or more in diameter.
Claudia I. Henschke1, Rowena Yip1, James P. Smith2, Results: For baseline screening using the current
Olli S. Miettinen2 deÀnition, the frequency of positive result was 18%
1
Radiology, Mount Sinai School Of Medicine/United (3,180/17,858), while using the more restrictive
States Of America, 2Pulmonary Medicine, Weill deÀnition it would have been 8% (1,347/17,858), a
Cornell Medical College/United States Of America 58% reduction. Using the more restrictive deÀnition,
the number of lung cancers diagnosed within 1 year
Background: Given concerns about ‘false positives’ of the initial CT scan would have been 111 instead
of CT screening for lung cancer, we considered of 118, 6% fewer. For annual repeat screening, the
alternative deÀnitions of positive results of the corresponding frequencies were 8% (1,587/20,347)
and 5% (992/20,347), a 37% reduction and the biennial (CT2, 1182) LDCT, within the MILD trial.
number of lung cancers diagnosed within 1 year of Follow-up was obtained on December 2010 from
the initial CT scan would have been 40 instead of 41, the Lombardy Cancer Registry, and the analysis was
2% fewer. performed by the Istituto Mario Negri, in Milan.
Conclusion: Continuing technologic advances Results: The two arms were superimposable in terms
in imaging and image interpretation increase the of known risk factors: median age was 57 years in
frequency of positive results that can be identiÀed both arms, males were 68% in CT1 vs. 69% in CT2,
on CT scans. The frequency of positive results, pack/years 40 vs. 38, former smokers 33% vs. 36%.
however, can be markedly reduced using a more Follow-up was 5,020 vs. 5,011 person years, median
restrictive deÀnition without undue delay in the 4.25 years in both arms. The total number of lung
diagnosis of lung cancer. cancers was 33 in CT1 vs. 17 in CT2 (p=0.06), lung
Keywords: Screening, positive result of screening, cancer deaths were 10 vs. 5 respectively (p=0.20),
CT, Lung cancer and the total number of deaths was 28 vs. 17
(p=0.10).
Conclusion: A less intensive screening modality
CT Screening of Individuals At Risk and Epidemiology Monday, 4 July such as LDCT every two years was associated with
2011 14:30-16:00 a substantially lower lung cancer detection rate, but
no difference was observed in terms of lung cancer
MO05.06 A LESS INTENSIVE SCREENING or total mortality between the two arms. A longer
MODALITY, SUCH AS CT EVERY 2 follow-up is needed to assess the relative beneÀt of
YEARS INSTEAD OF ANNUAL CT, IS the two screening modalities in comparison to the
NOT HARMFUL FOR HEAVY SMOKERS observational control arm.
Ugo Pastorino1, Alfonso Marchianò2, Nicola Keyword: lung cancer screening
Sverzellati3, Francesco Leo1, Alessandra Fabbri4,
Carlo Morosi2, Elisa Calabrò1, Carlotta Galeone5,
Eva Negri5, Giuseppe Pelosi4, Carlo La Vecchia5 CT Screening of Individuals At Risk and Epidemiology Monday, 4 July
1
Thoracic Surgery Dept, National Cancer Institute/ 2011 14:30-16:00
Italy, 2Radiology Dept, National Cancer Institute/
Italy, 3Clinical Sciences Dept, Section Of Radiology, MO05.07 LONG-TERM OUTCOMES OF
University Of Parma/Italy, 4Department Of A PILOT CT SCREENING FOR LUNG
Pathology And Laboratory Medicine, National CANCER: 10-YEARS RESULTS
Cancer Institute And University Of Milan School Of Giulia Veronesi1, Rui Kuenzer Silva1, Ptrik
Medicine/Italy, 5Epidemiology Dept, Mario Negri Maisonneuve1, Cristiano Rampinelli2, Alessandro
Institute/Italy Pardolesi1, Raffaella Bertolotti2, Francesco Petrella1,
Lorenzo Spaggiari1, Massimo Bellomi2
1
Background: The National Lung Screening Division Of Thoracic Surgery, European Institute Of
Trial (NLST), that randomised 53,456 former or Oncology/Italy, 2Division Of Radiology, Europena
current smokers to annual low-dose computerized Institute Of Oncology/Italy
tomography (LDCT) or chest x-ray (CXR) screening
for three years, has been prematurely stopped Background: Low-dose computed tomography (CT)
on October 2010 due to a signiÀcant mortality screening seems effective to reduce mortality of lung
reduction (-20% for lung cancer, -6.9% overall) in cancer in high risk populations however no data on
the LDCT arm. In order to assess the potential harm long term results of continuous annual screening is
related to different screening modalities in high risk available in literature. We assessed the long term
individuals, we analysed the outcome of the two overall survival, the lung cancer detection rate and
interventional arms of the Multicentric Italian Lung stage distribution according to year of screening over
Detection (MILD) trial. a 10 years period.
Methods: From January 2005, 2367 current or Methods: We analysed outcomes in high-risk
former smokers of 20 pack/years and aged 49 years asymptomatic volunteers (smokers and former
or older, have been randomly assigned to active smokers, >50 years) enrolled in a pilot study over
screening at the Istituto Nazionale Tumori of Milan, one year from 2000, who received annual low-dose
and further randomized to annual (CT1, 1185) or CT for 10 years. Nodules 5mm underwent repeat
LD-CT at 1 year; nodules 5.1—8mm underwent LD- Background: The technological development of
CT 3 months later; lesions >8mm received combined multidetector row CT scanners has reduced slice width
CT-positron emission tomography (CT-PET). and improved spatial resolution providing excellent
Cumulative lung cancer survival were represented by image quality with reduced radiation dose. Their use in
Kaplan-Meier curves. clinical practice and lung cancer screening trials has led
Results: Compliance was 65% at the end of the tenth to the detection of large numbers of small pulmonary
year in 1035 recruited volunteers (71% men, mean nodules of uncertain signiÀcance. Published guidelines
age 58 years). Ten years after baseline CT, seventy- exist to assist in the management of these lesions, but
two lung cancers were diagnosed (0.83% year), 12 there is no available published evidence based longterm
at baseline (prevalent) and 60 at subsequent rounds clinical data and, therefore, the optimum management
(incident) . Cell types were as follows: squamous remains controversial. Therefore we aim to assess
cell tumor, 14 (19.4%); adenocarcinoma, 44 (61.1%); the longitudinal behaviour and malignant risk of all
large cell tumor, 1 (1.4%); non–small cell tumor, 1 screening detected noncalciÀed pulmonary nodules of
(1.4%); small cell tumor, 7 (9.7%); carcinoid tumor, any size in a high risk smoking cohort.
5 (6.94%). The mean size of NSCLC was 12.5 mm. Methods: Volunteer current or former smokers in an
The stages were as follows: I, 54 (75%); II, 7; III, 6; early lung cancer detection program received a baseline
IV, 5; limited SCLC, 3. Among the operated patients, thoracic CT scan and those with nodules were followed
10 (12.1%) were benign lesions. Complete resection with serial CT. We systematically recorded and
was achieved in 58 (80.5%) lung cancers. The 5 and analysed the longitudinal behaviour of all pulmonary
10-year survival were respectively: 64% and 57% nodules of any size found using the endpoints of:
overall, 84% and 65% for stage I cases. diagnosis of lung cancer, stability over 24 months,
Conclusion: Cancer detection rate and rate of stage I resolution or calciÀcation.
disease did not decrease over the all observed period. Results: A total of 1123 subjects had reached the
This study conÀrmed that most screen-detected endpoints and were included in the analysis. A total
cancers were in early stage and survival of screen- of 9110 nodules were detected and 76% (6958/9110)
detected cancer patients was high. The number of were <5 mm. The majority were solid in appearance
invasive procedure for benign disease was limited. (80%) and overall 0.9% were malignant. Of note,
Keyword: Lung Cancer, Screening, Computed 7.5% of malignant nodules were <5mm when Àrst
Tomography, Surgery visible, and 34% of observed malignant nodules did
not exhibit growth for at least 24 months followup.
A revised/updated abstract may be included in The combination of nodule appearance and size were
the Late Breaking Abstract Supplement, available important predictors of malignancy and signiÀcant
at the 14th World Conference on Lung Cancer. differences were seen when lesions were evaluated
according to these factors (p< 0.0001). Malignancy
risk in lesions 8mm was 12% if solid and increased
CT Screening of Individuals At Risk and Epidemiology Monday, 4 July to 70% if semisolid in appearance. Growth of a solid
2011 14:30-16:00 lesion on two sequential scans or increase in the solid
component of a nonsolid/semisolid lesion were also
MO05.08 PREDICTING THE TRUE associated with an increase in malignancy risk (70%).
NATURE OF PULMONARY NODULES Conclusion: This longitudinal nodule evaluation
IN HIGH RISK SMOKERS: THE is useful to predict malignant risk of CT detected
SCREENING DILEMMA pulmonary nodules in a high risk smoking cohort.
Annette M. Mcwilliams1, Stephen Lam2, John C. It challenges existing guidelines regarding the
English3, Richard J. Finley4, John Mayo5 management of very small < 5mm nodules and the
1
Respiratory Medicine, British Columbia Cancer duration of longitudinal observation. This data conÀrms
Agency/Canada, 2British Columbia Cancer Agency/ that immediate evaluation of semisolid lesions
Canada, 3Pathology And Laboratory Medicine, 8mm is required due to a very high malignancy risk.
Vancouver General Hospital/Canada, 4Surgery/ Evidence of persistent growth or increase in a solid
thoracic Surgery, Vancouver General Hospital/ component also requires prompt investigation.
Canada, 5Radiology, Vancouver General Hospital/ Keyword: Pulmonary Nodule, Lung cancer
Canada screening, Computed tomography, early lung cancer
CT Screening of Individuals At Risk and Epidemiology Monday, 4 July Moreover, 1 type E adenocarcinoma showed
2011 14:30-16:00 lymphatic invasion.
Pure GGO lesions showing pleural indentation
MO05.09 DOES A PURE GROUND- on HRCT or those mildly positive on positron
GLASS OPACITY LESION ALWAYS emission tomography/CT tended to be invasive
REPRESENT NONINVASIVE adenocarcinomas and not BAC or AAH (odds ratio
BRONCHIOLOALVEOLAR 2.8 and 3.7, respectively).
CARCINOMA? Conclusion: Pure GGO lesions do not always
Junji Ichinose1, Tadasu Kohno1, Sakashi Fujimori1, represent noninvasive BAC. One in four pure GGO
Rie Tagaya1, Takeshi Fujii2 lesions represent invasive adenocarcinomas. Pure
1
Department Of Thoracic Surgery, Toranomon GGO lesions should be monitored carefully by
Hospital/Japan, 2Department Of Pathology, periodic chest CT and resected at an appropriate
Toranomon Hospital/Japan time.
Keywords: ground-glass opacity, bronchioloalveolar
Background: Although it is well known that carcinoma, high-resolution computed tomography
localized ground-glass opacity (GGO) lesions on
high-resolution computed tomography (HRCT) are
one of the characteristic Àndings of noninvasive CT Screening of Individuals At Risk and Epidemiology Monday, 4 July
bronchioloalveolar carcinoma (BAC), the 2011 14:30-16:00
relation between malignancy of tumors and their
radiological Àndings on HRCT has not yet been fully MO05.11 GENOME-WIDE ASSOCIATION
investigated. ANALYSIS OF LUNG CANCER IN
Methods: From January 2008 to December 2010, KOREAN NEVER-SMOKERS
1065 patients underwent pulmonary resection at Myung-Ju Ahn1, Jong-Mu Sun1, Hong-Hee Won2,
Toranomon Hospital. Out of these, 160 patients who Seung-Tae Lee2, Jin Seok Ahn2, Jong-Won Kim2,
underwent resection of 20-mm GGO lesions were Keunchil Park2
1
included in this study. Internal Medicine, Samsung Medical Center/Korea,
2
GGO is deÀned as a hazy increase in lung Samsung Medical Center/Korea
attenuation without obscuring underlying vascular
markings on the lung window of HRCT. Tumor Background: Although several studies were
disappearance rate (TDR) is deÀned as the ratio of conducted to Ànd susceptibility loci for lung cancer
tumor area of the mediastinal window to that of the in never-smokers, no regions were replicated except
lung window on HRCT. GGO lesions that measured for 5p15.33, suggesting locus heterogeneity and
20 mm in diameter as measured by HRCT and different environmental toxic effects. To identify
those with a GGO ratio of 50% were included in genetic loci associated with susceptibility of lung
this study. They were divided into two groups: pure cancer in never-smokers, we performed genome-wise
GGO lesions, deÀned as tumors in which both the association (GWA) analyses using the Affymetrix 6.0
GGO ratio and TDR are 100%, as well as mixed SNP array (Affymetrix, Inc., Santa Clara, CA).
GGO lesions. Methods: For discovery GWA set, we recruited
Results: Out of 191 resected GGO lesions, 114 446 never-smoking Korean patients with lung
were pure GGO lesions and 77 were mixed GGO cancer and 497 normal subjects. Genomic DNA
lesions. Histological diagnosis of pure GGO lesions was extracted from peripheral whole blood and
revealed BAC in 69, adenocarcinoma in 31, atypical normalized to 50 ng/ul. After calling genotypes
adenomatous hyperplasia (AAH) in 6, and benign using the Birdseed algorithm of the Affymetrix
tumors in 8. Histological diagnosis of the mixed Genotyping Console 3.0.2 software, we excluded
GGO lesions revealed BAC in 7, adenocarcinoma in two case samples with missing genotypes >5%. The
58, lymphoma in 5, and benign tumors in 7. SNPs with missing genotypes >1% or minor allele
Among the 31 invasive adenocarcinomas that frequency <5% were removed. We also excluded
manifested as pure GGO lesions, 27 were type C SNPs showing deviations from Hardy-Weinberg
BAC and papillary mixed-type adenocarcinomas equilibrium in control samples (P<0.001). Finally,
as per Noguchi’s classiÀcation, and 4 were type E we tested association of 474,503 autosomal SNPs
adenocarcinomas containing an acinar component. with lung cancer susceptibility in 444 patients and
497 controls using the Cochran-Armitage trend test. characteristics such as tumor histology (Bev and
For validation, 39 SNPs were selected from the top Pem), anticoagulant use (Bev), hypertension
50 SNPs and Àve additional SNPs were selected in (Bev) and presence of CNS metastases (Bev).
the DAB1 gene region which showed signiÀcant 2) To describe the clinical and demographic
associations in the GWA analysis. The validation characteristics of patient who receive Àrst-line
SNPs were genotyped in an independent validation NSCLC treatment containing Bev and Pem as well
sample including 434 patients and 1000 controls as those demographics associated with receipt of
using the MassARRAY® system (Sequenom, Inc., subsequent maintenance treatment. Records of
San Diago, CA). advanced NSCLC pts receiving active care at US
Results: Among the 44 validation SNPs, two SNPs Oncology practices were assessed utilizing the
(rs11080466 and rs11663246) in the 18p11.22 iKnowMed electronic medical record system with
region harboring the APCDD1, NAPG and FAM38B documentation of 1st line chemotherapy regimen
genes were replicated. P value of rs11080466 was (and any subsequent maintenance therapy) initiated
1.08×10–6 in the combined sets (2.68×10–5 in the from January 1, 2007 – February 28, 2010.
discovery set and 2.60×10–3 in the validation set) and Results: Based on the clinical proÀle of the cohort
odds ratio was 0.68 (0.58–0.79). We observed similar of 5,313 pts receiving Àrst-line systemic treatment,
association for rs11663246. the distribution of Bev eligibility was: 31%
Conclusion: Our result suggests the 18p11.22 region eligible, 51% ineligible, and 17% unknown. The
as a novel lung cancer susceptibility locus in never- distribution of Pem eligibility was: 52% eligible,
smokers. 22% ineligible, and 26% unknown. Of all pts
Keywords: Lung cancer, never smoker, SNPs receiving treatment, the percentage of pts receiving
the observed initial regimens were: 49% Paclitaxel
+ Carboplatin (Carbo-Pac), 15% Paclitaxel+Carbop
CT Screening of Individuals At Risk and Epidemiology Monday, 4 July latin+Bevacizumab, 2% Cisplatin+Pemetrexed , 2%
2011 14:30-16:00 Carboplatin+Pemetrexed, 8% Erlotinib, 13% other
mono therapy and 10% other combination therapy.
MO05.12 TREATMENT PATTERNS IN A Receipt of Carbo-Pac as an initial regimen varied
COHORT OF ADVANCED NON-SMALL by histology (squamous (SQ)=62%, non-squamous
CELL LUNG CANCER PATIENTS (NS)=38%, not otherwise speciÀed (NOS)=44%;
(PTS) TREATED IN THE COMMUNITY p<0.0001). Characteristics with a statistically
SETTING signiÀcant association with Bev-containing regimen
Mitra Corral1, Eric S. Nadler2, Clara Chen2, Michael were: histology (SQ=2%, NS=21%, NOS=14%;
Forsyth2, John R. Penrod1, Mark E. Salvati3 p<0.0001), younger age (<65), ECOG performance,
1
Bristol-myers Squibb/United States Of America, and payer status. Surprisingly, use of anti-coagulants
2
Us Oncology/United States Of America, 3Medical or hypertension were not statistically signiÀcant
Services, Bristol-myers Squibb/United States Of predictors of Bev use in the regimen. Of the 999
America pts receiving a Bev-containing initial regimen, 48%
were eligible, 34% ineligible and 18% unknown.
Background: According to NCCN guidelines, A Pem-containing regimen had a statistically
platinum-containing chemotherapy doublets form the signiÀcant association with: tumor histology
backbone treatment for eligible pts with advanced or (SQ=1%, NS=6%, NOS=4%; p<0.0001), younger
metastatic Non-Small Cell Lung Cancer (NSCLC). age (< 65), male gender, ECOG performance, and
Recently, newer agents such as bevacizumab (Bev) payer status. Of the 656 pts treated with a Pem-
and pemetrexed (Pem) have been demonstrated to containing initial regimen, the distribution of
be effective in combination with platinum based eligibility was: 66% eligible, 8% ineligible and 25%
regimens for the treatment of NSCLC in eligible unknown. 59% of pts receiving Carbo-Pac did not
patient subgroups. Maintenance regimens beyond receive maintenance, while 50% or more of the pts
the initial treatment have also been shown to offer with the other initial regimens received maintenance.
clinical beneÀt. Patient characteristics with a statistically signiÀcant
Methods: 1) To describe the % of pts eligible/ association with maintenance therapy were: younger
ineligible for Bev and Pem regimens, as deÀned age (<65), prior early stage NSCLC, high ECOG
by NCCN guidelines, based on baseline clinical performance status, and payer status.
Conclusion: This examination of a recent cohort of seen before being referred, when Àrst seen and when
pts receiving 1st L treatment for advanced NSCLC referred.
shows that a substantial number are eligible for Results: 2 patients declined, so 257 were
recently-introduced initial regimens and maintenance evaluable. 145 patients (56%) were initially mono-
therapy, however, there still exists a signiÀcant need symptomatic, with cough (25%), dyspnoea (25%),
for new agents for ineligible pts. Choice of initial haemoptysis (10%), chest pain (10%), sputum (7%)
therapy and maintenance treatment were related to or other symptom (24%). 105 (41%) initially poly-
patients’ clinical proÀle and payer status. symptomatic patients had symptoms of cough (36%),
Keyword: NSCLC, Treatment, Bev, Pem, regimen, dyspnoea (39%), haemoptysis (12%), chest pain
maintenance, therapy (9%), sputum (21%), and other (19%). By the time
patients were seen at the oncology department, the
frequency of chest symptoms had risen to 78%, 76%,
CT Screening of Individuals At Risk and Epidemiology Monday, 4 July 60%, 30% and 42% respectively. The remaining
2011 14:30-16:00 7 patients (3%) were asymptomatic. Mean time
from start of Àrst symptom to seeing the GP was
MO05.13 A STUDY OF SYMPTOMS AND 81 days, with a median of 24, range 0-710 days.
DURATION OF PATHWAYS IN LUNG Mean delay from Àrst seeing GP to MDT decision
CANCER PATIENTS to refer to oncology was 115 days, median 70, range
Zacharias Tasigiannopoulos1, Andrew Wilson2, Allan 2-945 days. Mean delay from that time to starting
Clark3, Rachel Banham1, Tom Roques1, Thankamma treatment was 25 days, median 15, range 0-37
Ajithkumar1, Craig Martin1 days. Within-patient delay is considerably longer
1
Oncology, Norfolk And Norwich University than within oncology delay (p<0.0001). 98 patients
Hospital/United Kingdom, 2Medicine, University Of (38%) admitted delaying going to see the doctor.
East Anglia/United Kingdom, 3Medical Statistics, Of these, 38% said they were worried, 18% did not
University Of East Anglia/United Kingdom wish to know, 14% were too busy and 10% said
delay was for family reasons. Patients went to their
Background: Lung cancer is the commonest cause GP 1 to 8 times before being referred for chest X
of cancer death worldwide. National UK targets ray or to secondary care, (one 49%, 2-3 42%, 4-8
actively promote shorter times from secondary 9%). Staging was IA, IB,IIA, IIB,IIIA, IIIB and IV
care to starting treatment, but earlier delays in the in 5,10,15,6,55,46,and 118 patients respectively.
patient’s pathway are signiÀcant. Most previous Analysis of variance showed no relation between
studies of symptomatology or the length of patient stage and time to presentation.
pathways from primary care to treatment have Conclusion: Within-patient delay is signiÀcantly
used hospital notes methodology rather than asking longer than within-oncology delay. The causes of
patients themselves to describe their symptoms and within-patient delay are complex. The frequency
identify delays. of chest symptoms increases considerably during
Methods: 259 patients diagnosed with lung cancer the pathway to oncological treatment. Over 50% of
after a multidisciplinary team (MDT) meeting and patients visited their GP more than once in order to
presenting to the oncology department were asked be referred for investigation or to secondary care.
to complete a questionnaire modiÀed from the Increased patient and GP awareness could lead to
EORTC QLQ C-30 and LC-13, including NICE- earlier treatment with reduced symptoms and thus
guidance urgent symptoms. The patient was asked beneÀt quality of life.
especially about the symptom or symptoms which Keywords: Symptoms, Lung cancer, Delay, Patient
represented the start of the illness, and subsequent pathway
symptoms, and to date these to the nearest week, to a
total of 27 questions. The questionnaire asked about
common chest symptoms, MRC dyspnoea score,
pain, analgesia, systemic symptoms, hoarseness,
neck lumps, Ànger discomfort, xerostomia and
abnormal taste, when they Àrst saw their GP, whether
they delayed and if so the reason. The GP was
independently asked how many times the patient was
CT Screening of Individuals At Risk and Epidemiology Monday, 4 July 1-year relative survival has slightly increased from
2011 14:30-16:00 14% to 19% for males and from 18% to 24% for
females. However, survival for the total group of
MO05.14 DESPITE NEW TREATMENT SCLC remained stable.
MODALITIES, SURVIVAL OF Conclusion: The diverging trends in incidence
UNSELECTED SMALL CELL LUNG of SCLC between Dutch males and females have
CANCER PATIENTS HAS NOT followed the trends in smoking behaviour in the past.
IMPROVED SINCE THE EARLY 1990S Improved staging has resulted in better selection
Maryska Janssen-Heijnen1, Henrike Karim-Kos2, for treatment and improved survival in both stage
Miep Van Der Drift3, Harry J.M. Groen4, Vincent groups. However, survival of the total group of
Ho5, Caro Koning6, Esther De Vries2 unselected patients with SCLC has not further
1
Research, Eindhoven Cancer Registry/Netherlands, improved since the 1990s (stage migration, Will
2
Public Health, Erasmus MC University Medical Rogers phenomenon). This means that prevention
Center/Netherlands, 3Pulmonary Diseases, Radboud remains important, especially primary prevention
University Nijmegen Medical Centre/Netherlands, of youth smoking, smoking cessation of current
4
Pulmonary Diseases, University Medical Center smokers, and early detection programs for former
Groningen/Netherlands, 5Registration And Research, smokers.
Comprehensive Cancer Centre The Netherlands Keywords: Small cell lung cancer, trends, incidence,
(iknl)/Netherlands, 6Radiation Oncology, Amc/ survival
Netherlands
Background: Lung cancer was one of the major Session MO06: PET, SPECT and CT
epidemics observed in the last decennia of the In The Initial Staging and Response
former century. There is a strong relationship with Assessment in NSCLC
smoking habits. Fifteen to twenty percent of lung
cancer consists of small cell lung cancer (SCLC).
Several changes in the diagnostic and treatment Monday, 4 July 2011
procedures took place during the last 20 years. This
paper focuses on trends in incidence, treatment and PET, SPECT and CT In The Initial Staging and Response Assessment in
survival of SCLC. NSCLC Monday, 4 July 2011 14:30-16:00
Methods: All cases with primary SCLC diagnosed
in 1989-2009 in the Netherlands were included MO06.01 THE UK TWO WEEK RULE
(N=34,100). Follow-up was complete until February INITIATIVE IN LUNG CANCER - FIRST
1st 2010. REPORT OF IMPACT ON DISEASE
Results: The age-standardised incidence rate (ESR) STAGE AND 5-YEAR SURVIVAL
of SCLC among men has decreased from 19 per Tom S. Waddell1, James Myerson1, Alison Reid1,
100,000 in 1989 to 10 in 2009. Among women the Sue Ashley2, Naureen Starling1, Ju-Ee Seet3, KoÀ
ESR has increased from 4.3 per 100,000 to 7.0. The Nimako1, Sanjay Popat4, Mary E.R. O’Brien1
1
proportion of patients with extensive disease (ED) Lung Unit, Royal Marsden Hospital/United
has increased to 65%. The proportion of patients Kingdom, 2Dept Of Clinical Research And
with limited disease (LD) receiving chemoradiation Development, Royal Marsden Hospital/United
has increased from 20-30% in 1989-2003 to 65-70% Kingdom, 3Pathology Department, St George’s
in 2004-09 among those younger than 60, from 15% Hospital/United Kingdom, 4National Heart And Lung
to 58% among those aged 60-74, and from 7% to Institute, Imperial College/United Kingdom
27% among those aged 75 or older. Among patients
with ED the proportion receiving chemotherapy Background: UK survival rates from cancer remain
remained stable over time (85-90%, 75% and almost worse than in other westernised countries. In 2000,
50% for those younger than 60, 60-74 and 75 or the UK government introduced the ‘Two Week
older, respectively). One-year relative survival for Rule (TWR)’ for suspected cancer to streamline
patients with LD was better in 2004-09 as compared pathways and reduce delays. This initiative advised
to earlier periods (54% versus 44% for males and that patients with suspected malignancy should be
61% versus 50% for females). For those with ED, seen by a specialist within two weeks of GP referral,
with maximum 62 days between GP referral and Àrst the 2 groups. Amongst patients with NSCLC, TWR
treatment. This audit aimed to retrospectively assess patients were of lower average stage than non-TWR
the impact of the TWR in lung cancer on disease patients (p=0.04). There was no difference in overall
stage, time to treatment and 5-year survival rates. survival rates (adjusted for age, sex, stage and PS)
Methods: All new lung cancer patients referred between the 2 groups.
in 2005 were identiÀed from the Royal Marsden Conclusion: TWR was associated with a stage
Hospital (RMH) Electronic Patient Records (EPR). shift at diagnosis in NSCLC patients. These small
The date and type of referral (TWR versus other) as improvements could lead to more patients having
well as relevant demographics, treatment and follow- radical treatment, but will take many years and large
up data were collected from EPR. numbers of patients to show population changes.
Results: 349 new lung cancer referrals were made Nevertheless it is possible to audit and monitor this
in the study period, including 106 patients referred in individual centres as above. However, this audit
via the TWR pathway and 243 patients referred via suggests that additional measures are necessary in
alternative routes (61 routine GP referrals, 182 others the UK to increase resection rates and signiÀcantly
e.g. from another hospital specialist) Table 1 - Patient improve lung cancer outcomes.
Demographics and Treatment Information (n=349) Keywords: Two week rule, Lung cancer, TWR
TWR - n(%) Non-TWR - n(%)

Patients 106 (30) 243 (70)
Gender Male 61 152
PET, SPECT and CT In The Initial Staging and Response Assessment in
Female 45 91 NSCLC Monday, 4 July 2011 14:30-16:00
Age (yrs) Median 70 70
Range 35-88 37-94
Diagnosis SCLC 14 (13) 38 (16) MO06.02 INVESTIGATION OF
NSCLC 79 (75) 166 (68) SENTINEL LYMPH NODES USING
Histo subtype
unknown
10 (9) 18 (7) SPECT/CT AND PERIOPERATIVE
Mesothelioma 2 (2) 19 (8) GAMMA ASSAY COMBINED WITH
Other 1 (1) 2 (1)
PS 0/1/2 3(3) / 36(34) / 17(16) 7(3) / 82(34) / 37(15) IMMUNOHISTOCHEMISTRY IN NSCLC
3/4 8(8) / 0 35(14) / 1(1) PATIENTS UNDERGOING LUNG
Not documented at
referral
42 (40) 81 (33) RESECTION
Median Time to
Treatment (days)
50 40 Pinar Cagan Varer1, Okan Falay2, Tugba Coskun1,
First Treatment Surgery 14 (13) 28 (12) Ferda Aksoy3, Guven Olgac4, Cemal Asim Kutlu4
1
Radiotherapy 36 (34) 83 (34) Department Of Thoracic Surgery, Dr. LutÀ
Chemotherapy 40 (38) 88 (36)
Active Monitoring 3 (3) 10 (4) Kirdar Kartal Teaching And Research Hospital/
Palliative Care 11 (10) 30 (12) Turkey, 2Department Of Nuclear Medicine,
Other 2 (2) 4 (2)
Medica Diagnostic Center/Turkey, 3Department
Of Pathology, Sureyyapasa Chest Diseases And
Thoracic Surgery Teaching And Research Hospital/
Turkey, 4Department Of Thoracic Surgery,
Sureyyapasa Chest Diseases And Thoracic Surgery
Teaching And Research Hospital/Turkey
Background: Skip metastasis in NSCLC is more

common than other organ malignancies. To date,
the actual usefulness of sentinel lymph node (SLN)
has not been clearly deÀned for NSCLC. This study
addresses the clinical beneÀt of a SLN that was
detected by SPECT/CT combined with perioperative
gamma probe assays in node negative NSCLC
patients undergoing lung resection.
Methods: Twenty consecutive NSCLC patients
with proven cN0 disease on PET-CT and undergoing
There were no signiÀcant differences in age, gender, lung resection were included. All patients scanned
diagnosis, PS, or Àrst treatment received between with SPECT/CT following peritumoral injection of
99mTc colloidal human albumin via transthoracic with perioperative gamma assays can be more
or transbronchial route a day before the operation. advantageous in identifying intraparenchymal
Sentinel nodes were also sought using a gamma SLNs by guiding both the surgeon and the
probe perioperatively. All dissected lymph histopathologist as to which lymph nodes should
nodes were histopathologically analyzed using be further investigated with immunohistochemistry.
Hematoxylin-Eosin stain. Of them without tumor The interim results of our study are promising and
invasion on Hematoxylin-Eosin and all SLNs warrant further studies containing larger number of
regardless of their involvement were also examined patients in order to validate actual clinical beneÀt of
with immunohistochemistry. these diagnostic tools.
Results: SPECT/CT Àndings combined with Keywords: NSCLC, Sentinel lymph node, SPECT/
perioperative gamma probe assays yielded a SLN in CT, skip metastasis
all patients. SLN was located within the boundaries
of pulmonary parenchyma in majority (n=18;
90%) of patients. Half of the upper lobe tumors PET, SPECT and CT In The Initial Staging and Response Assessment in
(n=8) drained into the #11s as a SLN. Second NSCLC Monday, 4 July 2011 14:30-16:00
most common SLN for upper lobe tumors (n=7)
was located at #12 station that appeared in 5 and 2 MO06.03 OCCULT NODAL
patients for the left and right sides, respectively. Two METASTASIS IN POSITRON EMISSION
patients with right lower lobe and one patient with TOMOGRAPHY AND COMPUTED
left lower lobe tumors Àrst drained into #7, #11i and TOMOGRAPHY DIAGNOSED STAGE I
#12 SLN stations, respectively. Eight (40%) patients NON-SMALL CELL LUNG CANCER: A
presented with nodal metastasis. Two (25%) patients POOLED ANALYSIS OF MULTICENTER
presented with metastasis in only their corresponding STUDIES
SLN stations. However, tumor cells skipped Jingbo Wang1, Luhua Wang2, Feng-Ming (Spring)
SLNs and invaded more proximal pulmonary Kong1
1
and/or mediastinal nodes in 6 (75%) of them. A Radiation Oncology, University Of Michigan/United
metastatic SLN at #11s location was discovered States Of America, 2Radiation Oncology, Cancer
with immunohistochemistry that was missed on Hospital, Chinese Academy Medical Sciences &
Hematoxylin-Eosin examination in one patient. Two Peking Union Medical College/China
patients demonstrated an unusual skip metastasis.
Background: Nodal staging of non-small cell lung
Clinical and Pathological Characteristics of Node cancer (NSCLC) is crucial in prognosis evaluation
Positive Patients and therapeutic strategy determination. Combined
HE=Hemotoxylin-Eosin; PET and CT (PET-CT) has remarkably improved
IHC=Immunohistochemistry; LUL=Left upper lobe; the accuracy of nodal staging in NSCLC. This
RUL=Right upper lobe; AC=Adenocarcinoma; pooled analysis aimed to evaluate the occult nodal
SqC=Squamous cell carcinoma; PleoC=Pleomorphic metastasis in patients with stage I (T1-2N0) NSCLC
carcinoma determined by positron emission tomography and
computed tomography (PET-CT) and study the
Tm. Location Cell Type cTNM-Stage #SLN HE IHC Skip Met. possible risk factors for occult nodal disease.
LUL-Central AC T2bN0M0-IIA 11s 11s 11s None Methods: Studies investigating the diagnostic
LUL-Central SqC T3N0M0-IIB 11s 11s 11s None
performance of PET incorporated with CT, either
LUL-Central SqC T3N0M0-IIB 12 11s (-) N1
LUL-Peripheral AC T3N0M0-IIB 12 6 (-) N2
integrated or visually correlated, for stage I
LUL-Peripheral PleoC T3N0M0-IIB 12 11s, 5 (-) N1+N2 NSCLC were identiÀed in the MEDLINE database.
RUL-Central AC T2aN0M0-IB 11s 11i 11s N1 Computerized search was performed according to
RUL-Central SqC T2aN0M0-IB 12 11i (-) N1 the following key words: . Pathological assessments
RUL-Central SqC T3N0M0-IIB 11s 7 (-) N2
through mediastinoscopy or thoracotomy were
required as the gold standard for assessment of
Conclusion: Contrary to other similar studies, PET-CT accuracy. The standard for reporting of
most of our patients had an intrapulmonary SLN diagnostic accuracy (STARD) was used to ensure
that are not easily assessable with other imaging quality of studies included in this analysis. Negative
techniques. In this respect, SPECT/CT combined predictive value (NPV) and incidence of occult nodal
metastasis were calculated on a per-patient basis. in patients with NSCLC treated with chemotherapy.
Results: Nine studies with a total of 1025 stage I Only scarce data are available for radiotherapy alone
(T1-2N0) NSCLC patients were eligible for analysis. or concurrent chemo-radiation (e.g. van Baardwijk
STARD quality scores of the included series ranged et al; Eur J Cancer 2007). In the present study, we
from 10 to 16 (maximum score). The NPV of investigated the correlation between FDG changes
combined PET and CT across studies varied from early during treatment and survival.
82% to 97% for hilar metastasis (N1 alone) and 86% Methods: Prospectively, FDG-PET/CT imaging
to 100% for N2 mediastinal metastasis. All studies was performed at two time-points for 39 consecutive
were eligible for N2 analysis, yielding a 7.6% (95% lung cancer patients (4 SCLC, 35 NSCLC) treated
CI: 6.1%, 9.5%) incidence of occult N2 mediastinal with radical concurrent chemo-radiotherapy
metastasis. On the basis of corresponding studies (N=18), sequential chemo-radiotherapy (N=19) or
with available sub-stage (T1 vs. T2) data, PET-CT no chemotherapy prior to radiotherapy (N=2). One
based false negative N2 nodal disease occurred imaging time-point was prior to treatment and the
in 7.6% (95% CI: 5.7%, 9.9%) of T1 patients and second during week 2 of radiotherapy. The FDG
12.3% (95% CI: 7.4%, 19.5%) of T2 patients (P = uptake in the gross tumour volume (GTV) of the
0.068). Six studies (527 patients) also eligible for N1 primary tumour was analysed. The maximum SUV,
analysis revealed that 16.0% of patients had overall mean SUV and the area-under-the-curve (AUC) for
occult nodal metastases, consisting of 10.1% (95% a cumulative SUV histogram (SUVAUC; calculated
CI: 7.7%, 13.0%) stage N1 disease alone and 5.9% using SUVmean normalized to the SUVmax of the
(95% CI: 4.1%, 8.3%) stage N2 disease. There was Àrst scan) was tested for correlation with 2-year
signiÀcant difference between the prevalence of overall survival. The SUVAUC is a measure of
occult N1 and N2 metastases (P = 0.02). T2 stage, intra-tumour heterogeneity. Multiple testing was
central location, adenocarcinoma histology and high accounted for using a Bonferroni correction.
FDG uptake in primary lesion were associated with Results: Minimum follow-up was 2.2 years; overall
greater risk of occult nodal metastasis (P<0.05). survival at 2 years was 52%. One patient had no
Conclusion: Incidence of N2 mediastinal metastasis visible tumour at the repeated PET/CT scan and
in PET-CT staged T1N0 patients is relatively low, was excluded from further analysis. A decrease
though overall occult nodal metastasis in unselected in mean SUV was signiÀcantly correlated with
staged I NSCLC is not infrequent. This data may higher survival rates: mean±SD (range) decrease
help our daily practice of additional invasive staging in SUVmean of 20.7±16.6% (-2.5 to +48%) for the
for this group of patients. patient group alive after 2 years was signiÀcantly
Keywords: 18-FDG PET, Non-small cell lung different (p=0.03) compared to the patients not
cancer, Stage I, Occult nodal metastasis surviving 2 years: 2.9±15.8% (-25 to +45%). For the
changes in maximum SUV or SUVAUC, no signiÀcant
correlations were found (p>0.2) The maximum,
PET, SPECT and CT In The Initial Staging and Response Assessment in mean SUV or SUVAUC on either of the time points
NSCLC Monday, 4 July 2011 14:30-16:00 prior and during treatment was also not correlated
with 2-year overall survival. We deÀned a cut-off
MO06.04 EARLY TREATMENT point for a reduction in SUVmean of more than 10%,
RESPONSE ASSESSMENT IN LUNG the survival curves were then signiÀcantly different
CANCER: REPEATED FDG-PET (p=0.01) between both groups, see Figure. No
IMAGING OF THE PRIMARY TUMOUR correlations were found between the extracted SUV
DURING TREATMENT IS CORRELATED parameters and the use of chemotherapy, volume of
TO 2-YEAR OVERALL SURVIVAL the primary tumour or prescribed radiotherapy dose.
Wouter Van Elmpt, Dirk De Ruysscher, Hugo Aerts,
Philippe Lambin
Department Of Radiation Oncology (MAASTRO),
Grow, Maastricht University Medical Centre/
Netherlands
Background: It is known that early changes of the

FDG uptake in the tumour correlates with survival
Methods: Retrospective, single institution study of

413 consecutive patients with non-small cell lung
cancer who underwent potentially curative surgical
resection after PET/CT had been obtained in the
same PET center between August 2004 and January
2010. The SUVmax was calculated drawing region of
interest (ROI) around the primitive tumour, the liver
and the aortic arch in PET images (i.e. the plane with
the hottest tumour voxel was found and SUVmax for
that plane was measured), using the formula: SUV
= activity (MBq/mL) x body weight (kg) / injected
dose (MBq). The same procedure was performed
for two adjacent planes and the average of these
measures was considered in the statistical analysis.
Kaplan-Meier method, log-rank test, and Cox model
Conclusion: Early treatment response assessment were used in the statistical analysis.
in lung cancer is possible using repeated FDG-PET/ Results: Nine patients were considered 30-day
CT imaging. These results should be conÀrmed in an postoperative deaths and were excluded from the
external dataset. analysis. At the end of the study in December 2010,
Keywords: FDG-PET, response assessment, survival 312 (77.2%) out of the 404 remaining patients were
prediction, imaging biomarkers living (median follow-up, 24.7 months; range,
1.4 - 71.9) and 92 had died (median survival,
15.7 months; range, 1.2 – 64.6). Median (range)
PET, SPECT and CT In The Initial Staging and Response Assessment in SUVmax of primary tumor, median (range) SUVmax
NSCLC Monday, 4 July 2011 14:30-16:00 primary tumor/SUVmax blood pool ratio, and median
(range) SUVmax primary tumor/SUVmax liver ratio
MO06.06 THE PROGNOSTIC were 8.6 (1.1-54), 5 (0.6-30), and 3.7 (0.5-16.9),
SIGNIFICANCE OF MAXIMUM respectively. Using univariate analysis, sex (p=0.03),
STANDARDIZED UPTAKE VALUE OF T stage (p=0.00004), N stage (p<0.000001), TNM
PRIMARY TUMOR IN NON-SMALL CELL stage (p<0.000001), primary tumor characteristics
LUNG CANCER PATIENTS SURGICALLY including presence of necrosis (p=0.004), presence
TREATED: ANALYSIS OF 413 CASES. of vascular invasion (p=0.0012) and grading
Andrea Billè1, Andrea Skanjeti2, Luca Errico1, (p=0.001), primary tumor SUVmax (p=0.00016),
Vincenzo Arena3, Mara Gisabella1, Elena Lisi1, primary tumor SUVmax/SUVmax blood pool ratio
Ettore Pelosi3, Francesco Ardissone1 (p=0.0005), and primary tumor SUVmax/SUVmax
1
Department Of Thoracic Surgery, University Of liver ratio (p=0.00017) were found to be signiÀcant
Turin, San Luigi Hospital/Italy, 2Nuclear Medicine Ii prognostic factors. At multivariate analysis, T stage,
Unit, University Of Turin, Molinette Hospital/Italy, N stage, TNM stage, primary tumor grading and
3
Pet Center Irmet/Italy SUVmax were the parameters that retained signiÀcant
independent prognostic impact. All the remaining
Background: Integrated positron emission variables did not enter the model.
tomography and computed tomography (PET/ Conclusion: Maximum standardized uptake value
TC) is widely used in the preoperative staging of primary tumor is an independent predictor for
and prognostic assessment of non-small cell survival in non-small cell lung cancer patients
lung cancer patients. Aims of this study were to undergoing surgery and might be helpful in
evaluate the prognostic signiÀcance of maximum identifying patients at increased risk of death so as
standardized uptake (SUVmax) of primary tumor to guide adjuvant treatment strategies. Maximum
in patients undergoing surgical treatment and, in standardized uptake value of primary tumor
order to minimize technical interferences, to verify normalized by SUV blood pool or SUV liver does
whether SUVmax normalized by SUVmax liver and not provide additional prognostic information.
SUVmax blood pool provided additional prognostic Keywords: Maximum Standardized Uptake Value,
information. prognostic value, Non small cell lung cancer, PET/CT
PET, SPECT and CT In The Initial Staging and Response Assessment in between the levels of residual MRglc after RT and
NSCLC Monday, 4 July 2011 14:30-16:00 the TCP at 12 m. From this inverse relationship,
residual MRglc values 0.031, 0.041, and 0.093
MO06.07 METABOLIC RESPONSES mmol/min/gm by SKM at S2 were associated with
MEASURED WITH SIMPLIFIED TCP 95%, 90%, and 50% respectively. Among SUV
KINETIC METHOD AND STANDARD values, SUVmax(bsa.g) showed strongest correlation
UPTAKE VALUE OF 18F-FDG PET with the SKM (R2>0.90). SUV with no correction
SHORTLY AFTER RADIOTHERAPY showed lowest correlation (R2<0.80).
OR RADIOTHERAPY OF Conclusion: The nadir values of MRglc at S2
CHEMORADIOTHERAPY: ROBUST measured with SKM and SUVmax(bsa.g) are robust
BIOMARKERS FOR PREDICTING bioimaging biomarkers capable for predicting
THERAPY OUTCOME IN LUNG CANCER TCP and survival. Therefore, residual MRglc at S2
Noah C. Choi1, Tristen Chun1, Andrzej Niemierko1, corresponding to TCP ³95%, £90%, £75% and £50%
Marek Ancukiewicz1, Alan Fischman2 are surrogate biomarkers useful for developing a
1
Radiation Oncology, Massachusetts General new model of personalized RT. SUVmax (bsa.g)
Hospital, Harvard Medical School/United States performed as well as SKM in measuring metabolic
Of America, 2Radiology, Shriners Burns Institute, response and predicting therapy outcome.
Harvard Medical School/United States Of America
Background: To evaluate early metabolic responses the Late Breaking Abstract Supplement, available
measured with SimpliÀed kinetic method (SKM) at the 14th World Conference on Lung Cancer.
and standard Uptake value (SUV) of 18F-FDG
PET shortly after radiotherapy (RT) or RT of
chemoradiotherapy (CRT) for their robustness in PET, SPECT and CT In The Initial Staging and Response Assessment in
predicting local tumor control and survival for NSCLC Monday, 4 July 2011 14:30-16:00
patients with lung cancer.
Methods: Patients with inoperable stages I - III MO06.08 CT-BASED AUTO-
lung cancer were enrolled into a prospective study SEGMENTATION OF LUNG TUMORS
in which 18F-FDG PET was obtained before, 10- SHOWS HIGH OVERLAP WITH
12 days (S2), 3 months (S3), 6 months (S4) and 12 ONCOLOGIST DELINEATIONS AND
months (S5) after RT or RT of CRT. To meet the PATHOLOGY
study endpoints, patients were to have survived Emmanuel Rios Velazquez, Hugo Aerts, Dirk De
12 months (m) without local recurrence or to have Ruysscher, Philippe Lambin
developed local failure within 12 m. The association Radiation Oncology (MAASTRO), Maastricht
between residual glucose metabolic rates (MRglc) University Medical Center/Netherlands
measured with SKM and SUV at S2 and tumor-
control probability (TCP) at 12 m was modeled Background: In radiotherapy, CT data is acquired
using logistic regression and evaluated with Mann- immediately before dose delivery. It is known that
Whitney test. tumor delineation has a high inter-observer variability.
Results: We accrued 112 patients and 64 of these An automated delineation method would enable a
met study endpoints. The baseline values of more reproducible tumor deÀnition, to optimize the
maximum MRglc were 0.23 mmol/min/gm by SKM daily workÁow and would facilitate multi-centric trials.
and 0.19 by SUVmax(bsa.g) [SUVmax corrected for Here we present and compare an automatic CT-based
body surface area and plasma glucose] respectively. segmentation method, based on region growing and
The nadir of MRglc was realized at S2. Residual context, with pathology and with CT/PET manual
MRglc (median) representing metabolic response delineations by Àve independent oncologists in non-small
for patients with local control vs. local failure were cell lung cancer (NSCLC).
0.06, 0.06, 0.07 and 0.07 vs. 0.12, 0.14, 0.18 and Methods: For nineteen NSCLC patients the gross tumor
0.33 mmol/min/gm by SKM and 0.03, 0.03, 0.03 and volume was delineated manually on CT/PET scans by
0.03 vs. 0.07, 0.07, 0.09 and 0.16 by SUVmax(bsa.g) Àve independent oncologists and segmented using a
at S2, S3, S4 and S5 respectively (p<0.0001 for CT based automatic tool. Tumor volume and overlap
each time-point). An inverse relationship was noted fractions between the intersection and union of the
1
manual delineations and the auto-segmentation tool were Genentech/United States Of America, 2Genentech/
compared. All measurements were correlated with the United States Of America
maximal diameter on macroscopic examination of the
surgical specimen. Background: The discovery of a non-invasive
Results: High overlap fractions were observed between and early marker of response to targeted therapy
the auto-segmentation tool and the intersection (94.52 ± could avoid unnecessary toxicity and ineffective
6.38) and union (91.75±9.16) of the manual delineations. treatment. Results from the phase II study testing
Differences in tumor volume were not observed between erlotinib plus MetMAb or placebo in advanced
the automatic segmentation (median, 30.83 cm3) and NSCLC (OAM4558g) revealed that the addition of
manual delineations (35.89 cm3; p = 0.98). The maximal MetMAb to erlotinib resulted in an overall survival
tumor diameter of the auto-segmented tumor mask (OS) beneÀt in Met Diagnostic (Dx)+ patients (OS
correlated strongly with the macroscopic diameter of the HR 0.37); but an OS detriment in Met Dx- patients
primary tumor (correlation coefÀcient = 0.93). (OS HR 3.02). This study prospectively evaluated
whether early modulation of 18F-FDG correlated with
the observed clinical outcomes.
Methods: A standardized imaging protocol was
implemented at 24 global sites; scan quality metrics
were compiled to monitor adherence during the
study. FDG-PET scans were acquired at baseline
(within 14 days of randomization) and between days
10 and14 following Cycle 1. Changes in 18F-FDG
uptake were assessed prospectively by a single
reference radiologist. PET partial metabolic response
(PMR) was deÀned as a mean decrease in SUVmax
20% and no new lesions. Progressive metabolic
disease (PMD) was deÀned as either a mean increase
in SUVmax >20%, or the presence of new lesions.
Conclusion: Tumor volume measurement and 3D PET responses were compared to PFS, OS, and CT
deÀnition using a CT-based auto-segmentation algorithm responses observed in the Phase II trial.
demonstrated high agreement with CT/PET manual Results: Of the 121 FDG-PET patient datasets
delineations and showed a high correlation with the acquired, 84% were considered evaluable. Technical
macroscopically dimensions on pathology considered imaging protocol adherence was comparable to
the “gold standard”. This method may be used routinely that described in our previous benchmark study
in clinical practice and could be employed as a validated (OSI3926g). 30 PMRs were observed; 9 were in
segmentation method for multi-centric clinical trials or patients with an EGFR mutation. No correlation was
high-throughput data mining research. observed between PMRs and OS, or CT RECIST
Keywords: NSCLC, CT Imaging, Tumor responses in the two treatment arms; no correlation
segmentation was observed between PMRs and clinical outcomes
in the two diagnostic subgroups, Met Dx+ and Met
Dx-. However, more Met Dx+ patients on placebo
PET, SPECT and CT In The Initial Staging and Response Assessment in had PMD on PET compared to Met Dx+ patients
NSCLC Monday, 4 July 2011 14:30-16:00 treated with MetMAb: 45% (9/20) vs. 18% (3/17);
this was mostly driven by the presence of new PET
MO06.09 RESULTS FROM FDG- lesions.
PET IMAGING IN OAM4558G, Conclusion: Quantitative FDG-PET was
A RANDOMIZED, PLACEBO- successfully and consistently implemented in a
CONTROLLED, MULTI-CENTRE PHASE randomized, global Phase II study. Metabolic
II TRIAL OF ERLOTINIB ± METMAB IN responses, as measured by changes in SUVmax, did
SECOND- AND THIRD-LINE NSCLC. not reÁect the survival beneÀt observed in Met
Premal Patel1, John Bothos2, Jill Fredrickson2, Dx+ patients on MetMAb+erlotinib therapy; nor
Thomas Bengtsson2, Amy Peterson2, Alex De did they explain the detriment observed in Met
Crespigny2 Dx- patients on MetMAb+erlotinib. The lower
PMD rate observed in MetMAb+erlotinib treated A and arm B, respectively) and OS (18.2 vs. 14.2
Met Dx+ patients is intriguing and warrants further months) were not signiÀcantly different (p=0.354
investigation (see Bengtsson, et al abstract). and p=0.282, respectively). Incidence of grade 3 or
Keywords: cMet, MetMAb, erlotinib, NSCLC 4 hematologic and non-hematologic toxicities were
12.8% and 18.8% (p=0.575) and 26.5% and 20.4%
(p=0.631) in arm A and B, respectively. Sensitivity
PET, SPECT and CT In The Initial Staging and Response Assessment in and speciÀcity for prediction of best response was
NSCLC Monday, 4 July 2011 14:30-16:00 81.8% (95% conÀdence interval [CI], 52.3 – 94.9%)
and 47.1% (95% CI, 26.2 – 69.0%), respectively.
MO06.11 CHANGING CHEMOTHERAPY Conclusion: In present study, changing
STRATEGY AS TO FDG-PET RESPONSE chemotherapy according to response of PET after
AFTER 1ST CYCLE OF STANDARD Àrst cycle of chemotherapy numerically improved
CHEMOTHERAPY FOR ADVANCED ORR without statistical signiÀcance but PFS and
NSCLC OS were not improved. High sensitivity with 81.8%
Jeong Eun Kim1, Kyu-Pyo Kim1, Chang-Min Choi1, of PET for prediction of best response suggests that
Dae-Ho Lee2, Dae-Hyuk Moon3, Jin-Sook Ryu3, reduction of metabolic activity observed in PET is
Seung Jun Oh3, Jung-Shin Lee1, Sang-We Kim1 closely correlated with Ànal outcome of therapy, but
1
Oncology, Asan Medical Center/Korea, 2Asan the speciÀcity was poor.
Medical Center, University Of Ulsan College Of Keywords: Non small cell lung cancer, FDG-PET,
Medicine/Korea, 3Nuclear Medicine, Asan Medial Response
Center/Korea
Background: The aim of this study was to evaluate PET, SPECT and CT In The Initial Staging and Response Assessment in
whether changing chemotherapy according to NSCLC Monday, 4 July 2011 14:30-16:00
response of positron emission tomography (PET)
after 1st cycle of chemotherapy improve overall MO06.12 PET/CT FOR EARLY
response rate (ORR) of chemotherapy in non-small DETECTION OF RECURRENCE AFTER
cell lung cancer (NSCLC) patients. LUNG RESECTION IN PATIENTS WITH
Methods: This is an open-label, randomized, NSCLC
prospective study. Between December 2008 and Didier Lardinois1, Mark Wiese1, Flavio Forrer2,
July 2010, 100 patients were randomly assigned Daiana Stolz3, Michael Tamm3
1
two groups; 4 cycles of GPMP (GenexolPM 230 Surgery, Division Of Thoracic Surgery University
mg/m2 and Cisplatin 60 mg/m2 on Day 1, every Hospital Basel/Switzerland, 2Division Of Nuclear
3 weeks) in arm A; without metabolic response Medicine University Hospital Basel/Switzerland,
3
(reduction of tumor FDG uptake more than 20% in Division Of Pneumology University Hospital Basel/
PET) after 1st cycle of GPMP, change to 4 cycles Switzerland
of GemOx (Gemcitabine 1000 mg/m2 on Day 1
and 8 and Oxaliplatin 130 mg/m2 Day 8, every 3 Background: Despite a curative approach and
weeks) in arm B. ORR, progression free survival complete removal of the tumour the recurrence rate
(PFS), and overall survival (OS) were compared. of NSCLC is very high following lung resection for
Sensitivity and speciÀcity of PET to predict response NSCLC especially in the Àrst two to three years.
to chemotherapy could be evaluated in 36 patients in Over the last years the percentage of pneumectomy
group A, who performed baseline and follow up PET has steadily decreased because experienced thoracic
after 1st cycle of chemotherapy. surgeons perform parenchyma sparing procedures
Results: Out of 100 patients, 49 patients were such as sleeve resections whenever possible.
included in arm A and 51 patients in arm B. Age, Follow up of operated patients with NSCLC is
gender, performance status and smoking history were not standardized and there are no conclusive
not different between groups. ORR was 26.8% in recommendations in guidelines. Therefore follow-up
arm A and 47.1% in arm B (p=0.090). In arm B, 11 investigations vary considerably from centre to centre
patients received GemOx without metabolic response and might include only clinical control or radiological
after 1st cycle and 3 partial response, 5 stable disease examinations such as conventional chest x-rays
were achieved. PFS (4.6 versus 4.9 months in arm or computed tomography. Integrated whole-body
1
Positron Emission Tomography (PET/CT) has become Genentech/United States Of America, 2Genentech/
a routine investigation for the staging of NSCLC. United States Of America
Because of the high sensitivity of PET/CT to detect
mediastinal and distant metastases we perform PET/ Background: As an exploratory biomarker and
CT 6 and 12 months after curative lung resection. potential predictor of clinical outcome, tumor
Methods: In this study we analysed the diagnostic changes as measured by FDG-PET were evaluated as
yield of PET/CT for detection of early recurrence in predictors of OS in two global, multi-center, Phase II
patients with stage I to IIIA disease, who underwent studies of second- and third-line NSCLC.
anatomical lung resection and mediastinal lymph Methods: Combined data from two NSCLC trials
node dissection. Data of 60 patients, with a mean age were used to evaluate the use of new lesion (NL)
of 62 years (39-77y) were analysed. status as determined by FDG-PET at 2 weeks
Results: Pathological stage of NSCLC was IA, following treatment initiation. 125 second- and
IB, IIA, IIB, IIIA in 15, 13, 5, 7, and 20 patients third-line NSCLC patients were examined by
respectively. Histology revealed adenocarcinoma FDG-PET at baseline and following 2 weeks of
(31), squamous cell carcinoma (21) and large daily erlotinib (OSI3926g and OAM4558g). An
cell carcinoma (8). Follow up PET/CT showed a additional 61 patients treated with MetMAb +
solitary FDG uptake in a total of 29 patients (48%), erlotinib (OAM4558g) were similarly assessed.
19 at 6 months and 10 at 12 months after surgery. The predictive value of NL status by FDG-PET at 2
Recurrence of the disease was cytologically and/ weeks with respect to OS was evaluated by survival
or histologically proven in 16/60 asymptomatic analysis. (For details on OSI3926g, see Mileshkin, et
patients (27%), consisting of mediastinal lymph node al JCO 28:15s, 2010 and for the imaging protocol in
metastases (4), local recurrence in the remnant lung OAM4558g, see Patel et al., submitted.)
(4) and distant metastases (8). A second carcinoma Results: Positive NL status by FDG-PET at 2 weeks
of the esophagus was found in one patient, the other was found to be associated with a large reduction
12 PET/CT positive lesions were of benign origin in survival. In the combined data, the median OS
(9 inÁammatory; 3 colon adenoma). Recurrence of for patients with no NL by FDG-PET at 2 weeks
the disease was diagnosed in 4, 3, and 9 patients was 8.0 mo vs. 2.4 mo for patients with NL, with a
with stage I, II, and IIIA NSCLC respectively. corresponding hazard ratio (HR)=0.40 (p <1.4e-4).
Therapy of the recurrences included reoperation (6), The analysis of the OAM4558g trial demonstrated
radiotherapy (5) and chemotherapy (5). the median OS was 12.2 mo for patients with no NL
Conclusion: PET/CT at 6 and 12 months vs. 2.2 mo for patients with NL (HR=0.24, p <1.4e-
postoperatively allowed to early diagnose recurrence 07). Separate Cox regression analysis conÀrmed
of NSCLC in a considerable number of patients, who that the result holds even when ECOG is accounted
underwent curative resection for NSCLC. If early for, discounting the confounding effect of baseline
diagnosis of recurrence improves patient survival has performance status. The overall rate of new lesions
to be addressed in a prospective randomised trial. in this sample was found to be 18.8% (95% CI:
Keywords: Non small cell lung cancer, early 13.1–24.6%), while the rate of new lesions among
recurrence, lung resection, PET/CT patients with longest expected survival was observed
to be lower. In particular, in OAM4558g, the new
lesion rate for treated, Met-positive patients was
PET, SPECT and CT In The Initial Staging and Response Assessment in <10%, compared with 30% in the control group.
NSCLC Monday, 4 July 2011 14:30-16:00 Conclusion: NL status by FDG-PET is found to be
a strong predictor of OS in second- and third-line
MO06.13 NEW LESION (NL) STATUS BY NSCLC patients treated with erlotinib and MetMAb.
FDG-PET IS A STRONG PREDICTOR OF A suppressed NL rate among patients with long OS
SURVIVAL DURATION (OS) IN SECOND- (relative to the overall median) suggests that NL
AND THIRD-LINE NON-SMALL-CELL rates could potentially be used to detect an early
LUNG CANCER (NSCLC) PATIENTS therapeutic effect in this patient population.
TREATED WITH ERLOTINIB AND Keywords: MetMAb, erlotinib, FDG-PET, NSCLC
METMAB + ERLOTINIB.
T. Bengtsson1, J. Fredrickson2, P. Patel2, R. Port2, B.
M. Fine2, Alex De Crespigny2, Amy Peterson2
PET, SPECT and CT In The Initial Staging and Response Assessment in radiographer/radiologist should explain the risk”.
NSCLC Monday, 4 July 2011 14:30-16:00 49% (n=74) of respondents correctly estimated the
approximate dose associated with each investigation,
MO06.14 RADIATION DOSE: 62% (n=94) signiÀcantly underestimated the dose
PERCEPTIONS OF INFORMED and 14% (n=21) overestimated the dose signiÀcantly.
CONSENT AND CANCER RISK FROM Over 60% (n=91) of respondents requested further
MEDICAL IMAGING. educational activities regarding risks of radiation.
James D. Runciman, Tom Brett, Diane Arnold-Reed Conclusion: Ionising radiation dose from medical
School Of Medicine, University Of Notre Dame imaging potentially poses a small but discernable
Australia - Fremantle Campus/Australia risk of cancer. Experts state that “informed consent
must include statements alluding to the high
Background: A growing body of literature supports background risk of cancer, some risk of cancer
the association of exposure to ionizing radiation from with low-dose radiation, and the beneÀt of having
medical imaging with a small but statistically signiÀcant the imaging test performed” (9). This study has
incidence of cancer (3, 4, 5, 15, 16). Generally the risks observed that general practitioners do value the risk
associated with clinical decisions are managed by the of cancer but that this is not reÁected in their practice
practice of informed consent. A recent study of specialists of informed consent. It is also seen that while
across three tertiary hospitals in the United States found most general practitioners correctly approximate
most believed informed consent should be obtained prior radiation dose, there is a signiÀcant minority
to medical imaging however few knew if this practice that underestimate the risk. Numerous barriers
occurred at their institution (9). Further studies have to obtaining consent are described and general
found that radiation dose and risks from imaging are practitioners are open to further education. Future
generally underestimated, especially in regards to CT, studies measuring the effectiveness of educational
but that doctor insight is improved by further education interventions would be of beneÀt.
(12, 21). This study explores the perceptions of general Keywords: Cancer, Consent, RADIATION, Imaging
practitioners in regards to patient consent and the risks
from ionising radiation associated with medical imaging.
Methods: An anonymous questionnaire was distributed Session MO07: Biomarkers,
to 485 general practitioners in Western Australia. Chemotherapy and Radiotherapy in
Participants were asked to comment on the practice Mesothelioma
of informed consent, barriers to gaining consent and
their perception on the radiation dose associated
with commonly requested imaging investigations. Tuesday, 5 July 2011
International Commission for Radiological Protection
standards for radiation dose were used for reference Biomarkers, Chemotherapy and Radiotherapy in Mesothelioma
(14). Data was analysed utilizing SPSS (13). The study Tuesday, 5 July 2011 10:30-12:00
was approved by the University of Notre Dame Human
Research Ethics Committee. MO07.01 THE COMBINATION
Results: A response rate of 31.13% (n=151) of the OF MESOTHELIN AND CEA
total population 485 was achieved. An overwhelming SIGNIFICANTLY IMPROVES THE
96% (n=144) of respondents agreed that radiation DIFFERENTIATION BETWEEN
risks from medical imaging were important. In MALIGNANT PLEURAL
contrast only 53% (n=80) actually informed all MESOTHELIOMA, BENIGN ASBESTOSIS
their patients of the risks prior to undergoing a CT. AND LUNG CANCER
There is a large correlation between the belief that Thomas R. Muley1, Hans Hoffmann1, Hendrik
patients should be informed of the risks of CT and Dienemann1, Felix J. Herth1, Michael Meister1,
the reported practice of actually doing so (Pearson Joachim Schneider2
1
correlation coefÀcient of 1.0 to +/- 0.5 and p < 0.05). Translational Research Unit, Thoraxklinik,
51% (n=77) of participants commented on barriers to University Of Heidelberg/Germany, 2Institute And
obtaining consent. These included “time constraints”, Policlinic For Occupational And Social Medicine,
that “I don’t understand the risks”, that “the Justus-liebig University/Germany
patient is too unwell to comprehend” and that “the
Background: Soluble mesothelin related proteins Conclusion: The diagnostic yield of the Mesomark-
(SMRP) have been reported as potential markers test can be improved when combined with a CEA
for the diagnosis of malignant pleural mesothelioma test in regard to the differential diagnosis between
(MPM). We wondered, whether a combination MPM and lung cancer and between MPM and benign
with a CEA-test might improve the relatively low asbestosis. For diagnosis/differential diagnosis the
diagnostic yield of the SMRP-test. use of both tests should be recommended.
Methods: 93 newly diagnosed histologically proven Keywords: MPM, mesothelin, CEA, differential
MPM patients were compared to 75 patients with diagnosis
benign asbestosis and 139 patients with lung cancer.
SMRP serum concentrations were measured with
MesomarkTM-Kit (Fujirebio Diagnostics, Malvern, Biomarkers, Chemotherapy and Radiotherapy in Mesothelioma
USA). CEA was measured with Advia Centaur Tuesday, 5 July 2011 10:30-12:00
immunoassay (Siemens, USA). Statistical analyses
were done with SPSS 18.0 (Chicago, Illinois, USA). MO07.02 SOLUBLE MESOTHELIN,
Results: The results of the SMRP-test alone have MEGAKARYOCYTE POTENTIATING
been recently published (Schneider et al., 2008). The FACTOR AND OSTEOPONTIN AS
combination of Mesothelin and CEA increased the MARKERS OF PATIENT RESPONSE AND
power to differentiate between MPM, lung cancer, OUTCOME IN MESOTHELIOMA
and benign asbestosis. Whereas CEA was found to Kevin Hollevoet1, Kristiaan Nackaerts2, Robert
be low expressed in MPM (median: 0.3 ng/ml) and Gosselin3, Walter De Wever4, Lionel Bosquée5,
therefore nonspeciÀc for the detection of MPM, most Paul De Vuyst6, Paul Germonpré7, Eliane Kellen4,
lung cancer patients had elevated CEA serum levels Catherine Legrand8, Yoshiro Kishi9, Joris R.
(median: 3.9 ng/ml). The area under curve (AUC) Delanghe3, Jan P. Van Meerbeeck1
1
of the receiver operator characteristics (ROC) curve Respiratory Medicine, Ghent University Hospital/
for Mesothelin alone was found to be only 0.71 Belgium, 2Respiratory Medicine, University Hospital
comparing MPM and lung cancer (Àg. left). When Gasthuisberg/Belgium, 3Ghent University Hospital/
Mesothelin was combined with CEA (Mesothelin/ Belgium, 4University Hospital Gasthuisberg/
CEA) the AUC of the resulting ROC- curve Belgium, 5Chu Sart Tilman/Belgium, 6Erasme
increased to 0.987. The sensitivity rate was 93.5% Hospital Ulb/Belgium, 7Antwerp University Hospital/
at 95% speciÀcity (68.8% at 100% speciÀcity) for Belgium, 8Université Catholique De Louvain/
the differentiation between MPM and lung cancer. Belgium, 9Ina Institute, Medical & Biological
The AUC of the ROC-curve for the differentiation Laboratories/Japan
between MPM and benign asbestosis (Àg. right)
was 0.887 for the quotient of Mesothelin/CEA. The Background: Radiological response evaluation
sensitivity rate was 55.9% at 95% speciÀcity (47.3% is notoriously difÀcult in patients with
at 100%). In contrast, the AUC for the Mesothelin- malignant pleural mesothelioma, an asbestos-
test alone was only 0.715, and for the CEA-test alone related malignancy. Soluble mesothelin (SM),
0.15. megakaryocyte potentiating factor (MPF), and
osteopontin (OPN) are blood biomarkers of
mesothelioma. This study evaluates their use as
markers of response to therapy and outcome.
Methods: 62 patients with malignant pleural
mesothelioma were surveilled in a Belgian
observational multicenter study. Blood samples and
CTs were collected at diagnosis and, when possible,
during and after therapy, until disease progression
or death. SM and MPF levels were measured in
serum with the MesomarkTM ELISA and the non-
commercial Human MPF ELISA, respectively. OPN
levels were measured in plasma with the Human
Osteopontin ELISATM. For each patient, the best
overall radiological response was compared with
the change in serum SM, MPF and plasma OPN Hospital/Australia, 7Medical Oncology, Sydney
levels across the corresponding time points. Survival Cancer Centre/Australia, 8Royal North Shore
analysis was performed with Cox proportional Hospital/Australia
hazard regression and log-rank statistics.
Results: In Àve patients who underwent extrapleural Background: MPM patients show widely variable
pneumonectomy, SM and MPF markedly survival following EPP and there are no validated
decreased after surgery, whereas OPN showed a prognostic/predictive factors that could be used
median increase. Of the 57 patients who received preoperatively. We investigated the expression
chemotherapy, 27 (47%) had radiological stable of calretinin and D2-40 as well as the neutrophil-
disease (SD), 14 (25%) partial response (PR), and to-lymphocyte ratio (NLR), an index of systemic
16 (28%) progressive disease (PD). In patients with inÁammation as potential preoperative prognostic
SD, biomarker levels did not change signiÀcantly factors in patients undergoing EPP.
(SM and MPF), or decreased (OPN). For PR and PD, Methods: All MPM patients who underwent EPP
biomarker levels typically decreased and increased, from 1994 to 2008 at participating institutes were
respectively. A change 15% in all three biomarkers included in this retrospective study. Potential
was signiÀcantly associated with patient response, prognostic factors such as age, gender, histological
whereas SM and MPF were more accurate than subtype, baseline laboratory parameters including
OPN. Low baseline OPN levels were independently NLR, and immunohistochemical staining of
associated with favorable overall and progression calretinin and D2-40 (scored based on percentage
free survival. Neither SM nor MPF were informative of cells labelled) were examined. Overall survival
for patient outcome. (OS) from the date of surgery was determined by the
Conclusion: SM and MPF levels were more Kaplan Meier method. The prognostic value of the
closely associated with disease course than OPN, variables was examined using the Cox regression
and might prove useful in monitoring patients and signiÀcant factors (p<0.05) were entered into
with mesothelioma. Baseline OPN levels were an a multivariate model all together to determine their
independent negative predictor of survival. Furhter independent effect.
valdiation of these promising results remains Results: A total of 85 patients were included in
necessary. this retrospective evaluation: median age 58 years
Keywords: mesothelin, mesothelioma, biomarker, (range: 22-74); 80% male; 77% epithelial and 23%
monitoring biphasic MPM. The median OS was 19.7 months.
The following variables were predictive of longer
OS: female gender (p=0.02), epithelial histological
Biomarkers, Chemotherapy and Radiotherapy in Mesothelioma subtype (p=0.04), low NLR (p<0.01), and high
Tuesday, 5 July 2011 10:30-12:00 calretinin score (p<0.001). After multivariate
analysis, NLR 3 (HR 1.79; 95% CI, 1.04-3.07;
MO07.03 CALRETININ EXPRESSION p=0.04), and calretinin score 33% vs. >67%
IMPROVES THE PREDICTIVE (HR 4.72; 95% CI, 1.97-11.32; p<0.01) remained
ACCURACY IN SURVIVAL IN PATIENTS independent predictors. The addition of calretinin
WITH MALIGNANT PLEURAL score increased the explained variation by 10.1%.
MESOTHELIOMA (MPM) UNDERGOING Conclusion: Both low calretinin expression and
EXTRAPLEURAL PNEUMONECTOMY high NLR were independently associated with poor
(EPP) prognosis in MPM patients undergoing EPP and the
Steven C. Kao1, Sonja Klebe2, Douglas W. calretinin score appeared to inÁuence the accuracy
Henderson2, Glen Reid3, Mark ChatÀeld4, Nicola of the prognostic model. Given that calretinin is
Armstrong5, Tristan Yan6, Janette Vardy7, Stephen routinely used in daily practice, our Àndings can be
Clarke8, Nico Van Zandwijk3, Brian Mccaughan6 easily validated in a prospective manner.
1
Medical Oncology, Asbestos Diseases Research Keywords: malignant pleural mesothelioma,
Institute/Australia, 2Anatomical Pathology, Flinders calretinin, neutrophil-to-lymphocyte ratio, prognostic
Medical Centre/Australia, 3Asbestos Diseases factor
Research Institute/Australia, 4Nhmrc Clinical Trial
Centre/Australia, 5Garvan Institute/Australia,
6
Cardiothoracic Surgery, Royal Prince Alfred
Biomarkers, Chemotherapy and Radiotherapy in Mesothelioma had persisting stable disease (SD) (+270 d), and 8 pts
Tuesday, 5 July 2011 10:30-12:00 PD. DCR was 27.7%. As of January 2011, 4 of the
alive 6 pts remain on treatment. At a median follow-
MO07.04 A PHASE II STUDY WITH THE up of 8 months, median OS was 8 months (95% CI,
ANTI-CTLA-4 MAB TREMELIMUMAB 6.11-9.89). Grade 1-2 AE occurred in 90% of pts;
IN CHEMOTHERAPY-RESISTANT one pt had hepatic and pancreatic grade 4 AE that
ADVANCED MALIGNANT resolved with steroid therapy. Among investigated
MESOTHELIOMA: SAFETY, markers, a signiÀcant increase in the absolute
TOLERABILITY, CLINICAL AND number of CD4+HLA-DR+, CD4+CD45RO+,
IMMUNOLOGIC ACTIVITY CD4+ICOS+, CD8+HLA-DR+, and CD8+ICOS+
Luana Calabrò1, Anna Maria Di Giacomo2, Aldo T cells was detected at d 14, 30 and 60 after the Àrst
Morra3, Ornella Cutaia2, Ester Fonsatti1, Riccardo dose of tremelimumab, it slowly declined thereafter,
Danielli1, Maresa Altomonte1, Luciano Mutti4, and resumed upon re-dosing.
Michele Maio1 Conclusion: CTLA-4 blockade in MM pts is safe
1
Dept Oncology, Medical Oncology And and shows promising clinical activity. A sizeable
Immunotherapy Unit/Italy, 2Dept Of Oncology, proportion of pts experienced clinical beneÀt and
Medical Oncology And Immutherapy/Italy, 3Dept prolonged disease stabilization. Treatment associates
Of Radiology, Euganea Medica Diagnostic Center/ with major changes in activated and memory T cell
Italy, 4Dept Of Medicine, Laboratory Of Clinical subpopulations. As of February 2011, 16 pts have
Oncology, Hospital Of Vercelli/Italy been enrolled in the study.
Keywords: Malignant mesothelioma,
Background: Anti-CTLA-4 monoclonal antibodies Immunotherapy, Anti-CTLA-4 mAb
(mAb) are showing signiÀcant activity in different
tumor types; however, no data are available in
malignant mesothelioma (MM) patients (pts). We Biomarkers, Chemotherapy and Radiotherapy in Mesothelioma
report preliminary results of a phase II, single Tuesday, 5 July 2011 10:30-12:00
Institution, study investigating safety, clinical
and immunologic efÀcacy of the fully-human MO07.06 MALIGNANT (DIFFUSE)
anti-CTLA-4 mAb tremelimumab as second-line MESOTHELIOMA IN WOMEN: A STUDY
treatment for MM pts who failed a platinum-based OF 355 CASES
regimen. Elizabeth N. Pavlisko, Thomas A. Sporn, Victor L.
Methods: Of the 29 foreseen pts, 6 stage III and 5 Roggli
stage IV MM pts (7 males, 4 females), median age Department Of Pathology, Duke University Medical
66 (51-76) years, ECOG performance status 0-2, Center/United States Of America
received tremelimumab at 15 mg/Kg i.v on day (d) 1
and 90 for 4 cycles or until progressive disease (PD). Background: Malignant mesothelioma has
Primary endpoint was objective response (OR); long been accepted as a consequence of
safety, disease control rate (DCR) (PR+SD), overall asbestos exposure. The Àrst literature regarding
survival (OS), and immunologic activity were mesothelioma in women, especially asbestos
secondary. As per Simon’s design at least 1 OR was exposure as a household contact, was in 1965
required in the Àrst 11 pts, to continue enrolment. (Newhouse and Thompson). Since then others
Tumor assessment at baseline, and at each cycle have reported signiÀcant exposure to asbestos from
utilized modiÀed RECIST Criteria. Adverse events nonoccupational sources. This is supported by the
(AE) were collected according to the Common 1995 NIOSH Home Contamination Study Report
Terminology Criteria v3.0. Peripheral blood and the 1997 Helsinki Criteria. Few have correlated
mononuclear cells collected at baseline, d 14, 30, and nonoccupational exposure with Àber analysis data
60 of the 1st and 2nd cycle, were analyzed by Áow or presence or absence of pleural plaques and
cytometry for an extensive panel of phenotypic and asbestosis.
activation markers. Methods: Our database included cases obtained
Results: All pts received at least 1 dose of from the consultation Àles of one of the authors
tremelimumab (median 3; range 1-4). One patient (VLR) between 1983 and 2010. There were 2858
(pt) achieved partial response (PR) (+180 d); 2 pts cases of histologically conÀrmed malignant (diffuse)
mesothelioma, and 355 of those (12.4%) occurred had elevated chrysotile above background range,
in women. Cases of well-differentiated papillary all of which also had elevated amphiboles. Of 287
mesothelioma were excluded. Data collected cases without Àber analysis, only 38 had evidence
included tumor location, morphology, exposure of asbestos exposure as indicated by plaques or
history, presence of asbestosis and/or pleural plaques asbestosis.
and survival. Exposure information was categorized Keywords: Àber analysis, mesothelioma, asbestos
using 23 previously established exposure groups.
Fiber analysis was performed in 68 cases according
to previously described methodology followed by Biomarkers, Chemotherapy and Radiotherapy in Mesothelioma
light and scanning electron microscopy. Energy Tuesday, 5 July 2011 10:30-12:00
dispersive x-ray analysis was used to determine Àber
type. MO07.07 ASSESSING SURVIVAL
Results: Of the 355 cases, 275 (77%) were located AND TIME TO TREATMENT (TT)
in the pleura and 80 (23%) within the peritoneum. FOR PATIENTS DIAGNOSED
The ratio of epithelial, biphasic and sarcomatoid WITH MALIGNANT PLEURAL
variants for pleural mesothelioma was 8:2:1, and for MESOTHELIOMA (MPM) IN ONTARIO,
peritoneal was 17:3:1. The median age of women CANADA.
with pleural mesothelioma was 65 years (range Arman Hasani1, Bin Sun2, Geoffrey Liu1, Wei Xu3,
19-93 years) and for peritoneal was 52 years (20- Ronald Feld1, Natasha B. Leighl1
1
84 years). There were 326 cases with informative Medical Oncology And Hematology, Princess
data regarding exposure. The largest category Margaret Hospital And University Of Toronto/
was nonoccupational with household contacts Canada, 2Biostatistics, Princess Margaret Hospital
accounting for 60% of cases with single exposure And York University/Canada, 3Biostatistics, Princess
and an additional 9% of cases with more than one Margaret Hospital And University Of Toronto/
documented exposure. The relationship between Canada
case and contact(s) was wife (46%), daughter (27%)
and both (8%). The largest industry/occupation Background: Systemic therapy (ST) is the only
for the contact was insulation (16%) followed by treatment modality with proven survival beneÀt
shipyard (13%), construction (12%) and oil/chemical for advanced MPM. There is no proven survival
(9%). Fiber analysis data showed elevated asbestos advantage to commencing ST earlier rather than later
bodies by light microscopy in 29/67 cases. Twenty for patients diagnosed with MPM. We hypothesised
had elevated commercial amphibole Àbers, 23 had that delay in administration of ST would result in
elevated noncommercial amphiboles, and 4 had shorter overall survival from diagnosis.
elevated chrysotile. Thirty-three had levels which Methods: Information for patients diagnosed with
were within our background range. Of 287 cases MPM between 2005-2010 were obtained from
without Àber analysis, 35 had pleural plaques, one administrative databases at University Health
asbestosis and two both. Survival data was available Network, Cancer Care Ontario and WSIB. Date of
on 276 cases. Median survival was 12 months (range diagnosis was deÀned as the date of the procedure
0.25 – 268). For pleural tumors by morphologic from which a deÀnitive diagnosis of MPM was
variant, survival was 15 (0.25-268), 9 (0.25-170) able to be made pathologically. Overall survival
and 4 (0.25-65) months and for peritoneal tumors, (OS) was calculated from date of diagnosis by the
survival was 16 (0.75-120), 5 (0.75-25), and 4 (1- Kaplan-Meier method, differences between the
12) months for epithelial, biphasic and sarcomatoid, survival curves were analyzed by the log-rank test.
respectively. Analysed cases for TT analysis were restricted to
Conclusion: Peritoneal tumors occurred in a those receiving chemotherapy who did not undergo
somewhat younger age group. Nonoccupational extrapleural pneumonectomy (EPP).
exposures to asbestos predominated with household Results: 557 patients were diagnosed with MPM
contact exposure accounting for over half, most in Ontario between 2005 and 2010. Of these, most
often as wives of men who worked with insulation, were male (82.4%), had right sided tumors (61.7%),
in shipyards or in construction. Fiber analysis and epithelioid histology (77.8%). The average
demonstrated elevated asbestos bodies in 43%, with age was 70.5 years (range 29.3-94.7). Treatment
amphiboles the dominant Àber type. Only 4 cases consisted of extrapleural pneumonectomy (EPP) in
57 (10.2%); and Àrst line ST was conÀrmed in 232 C, an oral tyrosine kinase inhibitor of VEGFR 1, 2, 3
(41.7%) patients. Median OS for those treated with and PDGFR-a, in MM pts.
ST compared with those not treated with ST was Methods: Eligible pts had unresectable,
13.3 and 5.5 months respectively (p<0.001). Data for histologically-conÀrmed MM, measurable disease,
TT was available for 186 patients, and the median and performance status 0-1. No more than 1 prior
TT was 2.4 months (range 0.3-35.3). Patients in the chemotherapy regimen was permitted. The initial
lower, middle and upper tertiles for TT had a median dose of C was 45 mg orally daily. Because of toxicity
OS from diagnosis of 8.2, 11.4, and 15.5 months observed in other studies of C, an amendment in
respectively (p=0.0011). June 2007 decreased the starting dose to 30 mg daily.
Conclusion: Most patients with MPM did not CT scans were obtained every two 28-day cycles.
receive ST. Of those treated with ST without The primary endpoint was objective response rate
EPP, prolonged TT correlated with increased OS, per modiÀed RECIST. Using an alpha level of 0.10
possibly as a result of lead time bias and delayed ST and 90% power, the Simon, optimal, 2-stage design
administration in patients with indolent disease. required 3 responses in the Àrst 21 pts to proceed to a
Keywords: mesothelioma, Chemotherapy 2nd stage, and 8 responses in 50 MM pts for further
investigation.
Results: 50 pts enrolled from March 2006 to
Biomarkers, Chemotherapy and Radiotherapy in Mesothelioma September 2010 at 9 centers. Pt characteristics: male
Tuesday, 5 July 2011 10:30-12:00 84%; median age 64 (range 44-81); PS 0 30%, PS
1 70%; disease site: pleural 94%, peritoneal 6%;
MO07.08 FINAL RESULTS OF A pathologic subtype: epithelial 72%, sarcomatoid 4%,
UNIVERSITY OF CHICAGO PHASE II biphasic 12%, unknown 12%; prior chemotherapy
CONSORTIUM TRIAL OF CEDIRANIB 88%; thrombocytosis 26%. The initial dose was 45
(C) IN PATIENTS (PTS) WITH mg in 15 pts and 30 mg in 35 pts. A median of 2
MALIGNANT MESOTHELIOMA (MM) cycles was delivered (range 1-14). Dose reductions
Nicholas P. Campbell1, R. Kunnavakkam2, Natasha were required in 48% of all pts, and in 60% of pts
Leighl3, M. D. Vincent4, David R. Gandara5, at the 45 mg dose. C was discontinued for toxicity
Marianna Koczywas6, Barbara J. Gitlitz7, E. in 26% of all pts, and in 47% of pts at the 45 mg
Agamah8, S. P. Thomas9, W. M. Stadler1, Everett dose. Partial responses (PR): 10% (3/15 pts at 45
Vokes10, Hedy Lee Kindler1 mg, 2/35 pts at 30 mg). The median duration of
1
Oncology, University Of Chicago/United States response was 8.3 months (range 7.3-12.9 months).
Of America, 2Statistics, University Of Chicago/ All PR occurred in pts with epithelial histology.
United States Of America, 3Princess Margaret Stable disease (SD): 34% (7/15 pts at 45 mg, 10/35
Hospital/Canada, 4Oncology, London Regional pts at 30 mg). The disease control rate (PR + SD)
Cancer Program/Canada, 5Oncology, Uc Davis was 44% (67% at 45 mg, 34% at 30 mg). Median
Cancer Center/United States Of America, 6Medical progression-free survival was 1.9 months (95% CI:
Oncology And Therapeutic Research, City Of Hope/ 0.1, 14.2). Median overall survival was 4.4 months
United States Of America, 7Medicine, University (95% CI: 0.9, 41.7). One-year survival was 15%.
Of Southern California Keck School Of Medicine/ One patient with a partial response continues on
United States Of America, 8Central Illinois Hem/onc study in cycle 10. Grade 3/4 toxicity: fatigue 24%,
Center/United States Of America, 9Illinois Cancer hypertension 22%, diarrhea 8%, hyponatremia 6%,
Care/United States Of America, 10University Of thrombosis 6%, acute renal failure 4%, mucositis
Chicago/United States Of America 4%, angioedema 2%, arrhythmia 2%, headache 2%,
posterior leukoencephalopathy 2%, seizure 2%.
Background: Vascular endothelial growth factor Conclusion: Although some prolonged partial
(VEGF) signaling is thought to play an important responses were observed, the trial did not meet its
role in MM biology. In preclinical models, MM pre-speciÀed response endpoint. The 45 mg dose
growth is inhibited by agents that target VEGF. In of C was poorly tolerated. Supported by NCI grant
MM patients, high serum VEGF levels correlate N01-CM-62201
inversely with survival. Phase II trials of several Keywords: mesothelioma, cediranib, VEGF
VEGF inhibitors have demonstrated modest activity
in MM. We performed a multi-center phase II trial of
Biomarkers, Chemotherapy and Radiotherapy in Mesothelioma thrombocytopenic bleeding during radiotherapy

Tuesday, 5 July 2011 10:30-12:00 1.5%, making total treatment induced mortality 14%.
Median survival rates for cohorts 1 and 2 were 24.3
MO07.09 SCANDINAVIAN and 33.6 months, respectively (p=0.22), while cohort
TRIMODAL STUDY OF INDUCTION 2 had 1-, 2-, 3-, and 4-years survival rates of 84%,
CHEMOTHERAPY (IC), EXTRAPLEURAL 62%, 42%, and 20%, respectively.
PNEUMONECTOMY (EPP), AND Conclusion: EPP is a safe procedure when
POSTOPERATIVE INTENSITY- performed in high-volume institutions but especially
MODULATED RADIOTHERAPY postoperative radiotherapy is high-risk procedure.
(IMRT) IN MALIGNANT PLEURAL The survival for cohort 2 is among the best results
MESOTHELIOMA (MPM). published with 4-year survival rate of 20% but fatal
Jens B. Sorensen1, Jesper Ravn2, Claus A. radiation pneumonitis remains a serious problem
Kristensen1, Annika Loft3, Anne K. Berthelsen3, which should be further explored.
Gunnar Hillerdal4, Mikael Johansson5, Paal Keywords: Extrapleural pneumonectomy, Intensity
Brunsvig6, Stein Sundstrøm7, Ulf Aasebø8 Modulated Radiotherapy, mesothelioma, trimodality
1
Oncology, Finsen Centre/National University treatment
Hospital/Denmark, 2Thoracic Surgery, National
University Hospital/Denmark, 3National University
Hospital/Denmark, 4Karolinska Hospital/Sweden, Biomarkers, Chemotherapy and Radiotherapy in Mesothelioma
5
Umeå Hospital/Sweden, 6Radiumhospital Oslo/ Tuesday, 5 July 2011 10:30-12:00
Norway, 7Sct. Olav Hospital Trondheim/Norway,
8
University Hospital Tromsø/Norway MO07.10 PHASE II STUDY
OF THE COMBINATION OF
Background: Trimodality treatment combining BEVACIZUMAB PLUS PEMETREXED
chemotherapy, surgery, and radiotherapy has AND CARBOPLATIN AS FIRST-
yielded 5-year survival in some MPM patients LINE THERAPY IN PATIENTS
though prognosis is generally poor. Results from a WITH MALIGNANT PLEURAL
PanScandinavian trimodality study in MPM patients MESOTHELIOMA (MPM)
from Denmark, Norway, and Sweden is presented. Giovanni L. Ceresoli1, Paolo A. Zucali2, Adolfo G.
Methods: IC was 3-6 courses of platinum-based Favaretto3, Fabio De Vincenzo2, Manlio Mencoboni4,
doublet chemotherapy. Subsequent restaging Mario Botta5, Francesco Grossi6, Paolo Bidoli7, N.
using F18-FDG-PET/-CT scan fused imaging and Zilembo8, Matteo Simonelli2, Letizia Gianoncelli2,
mediastinoscopy was subsequently performed at Elena Lorenzi2, Armando Santoro2
1
Rigshospital, Copenhagen, Denmark, followed by Oncology, Cliniche Humanitas Gavazzeni/Italy,
2
EPP in epithelial MPM patients having T1-3N0-1M0, Ist. Clinico Humanitas/Italy, 3Ist. Oncologico
performance status 0-1, age 70 years, and no major Veneto/Italy, 4H. Villa Scassi/Italy, 5H. Casale/Italy,
6
comorbidities. Postoperative radiotherapy was 56- National Institute For Cancer Research/Italy, 7S.
60 Gy in 30 fractions, 5F/W. Patients were divided Gerardo Hospital/Italy, 8Istituto Nazionale Tumori/
into cohort 1 (2003-2006, 26 patients) and cohort 2 Italy
(2006-2010, 38 patients). Radiotherapy constraints for
contralateral lung in cohort 1 was V20<20% and mean Background: The carboplatin/pemetrexed combination
lung dose (MLD) <15 Gy, while in cohort 2 it was showed activity in MPM patients (pts). Vascular
V20<15%, V10<50%, and MLD<12 Gy. endothelial growth factor (VEGF) is highly expressed
Results: Characteristics among all 64 patients in MPM; in pre-clinical models, anti-VEGF antibodies
were: Males 88%, right hemithorax disease 61%, were shown to decrease MPM cells growth. The aim
median age 61 years (range 45-69 years), and IMIG of this multicenter, open label phase II study was to
preoperative stages I, II, III, and IV (port metastases) assess the activity of bevacizumab in combination with
in 16%, 66%, 16%, and 3%, respectively. carboplatin/pemetrexed (BPC regimen) as Àrst-line
Frequencies of fatal radiation pneumonitis were therapy in MPM pts.
15% and 8% in cohorts 1 and 2, respectively. Methods: Chemotherapy-naive pts, not candidates
Overall, 30-days postoperative mortality was for curative surgery, received pemetrexed 500 mg/
1.5%, fatal radiation pneumonitis 10.9%, and fatal m2, carboplatin AUC5 and bevacizumab 15 mg/kg,
administered intravenously every 21 days for 6 cycles, a standardized multimodality treatment concept
followed by maintenance bevacizumab. Main endpoint and to investigate the effectiveness of this approach
of the study was progression free survival (PFS). It using lung-sparing Radical Pleurectomy (RP) for
was planned to achieve a median PFS of 9 months in the treatment of malignant pleural mesothelioma
comparison to a null hypothesis of 6 months. (MPM).
Results: Seventy-seven pts were enrolled. Their Methods: In a prospective, observational study,
characteristics were: M/F 50/27, median age 67 all patients with histologically proven MPM were
(range 27–78), EORTC prognostic score good/ evaluated for trimodality therapy: lung-sparing
poor 66/11. Histology was epithelial in 61 pts, RP (visceral and parietal pleurectomy, as well as
sarcomatoid or biphasic in 11, and not speciÀed resection of pericardium and diaphragm as indicated)
in 5. A partial response was achieved in 31/77 pts followed by 4 cycles of Cisplatin/Pemetrexed
(40%). Thirty-seven pts (48%) had stable disease, and tangential radiation of the chest wall at the
for an overall disease control rate of 88%. Median incision sites (21 Gy in 3 fractions) from November
PFS and overall survival (OS) were 7.9 and 14.3 2002 to December 2008. Patients with prior
months, respectively. Disease control rate, PFS and treatment for MPM were excluded. The primary
OS were not correlated to baseline serum VEGF and secondary end-points were overall survival, as
levels. Haematological toxicity was low, with well as progression-free survival (PFS), patterns of
grade 3/4 adverse events observed in 7 pts (9%). recurrence, morbidity and mortality.
Non-haematological toxicity was generally mild; Results: Fifty-two out of 135 consecutive patients with
however, 2 toxic deaths (one bowel perforation, one a median age of 65.3 years were enrolled in the study.
pneumonitis) were reported. Forty-nine patients (94.2%, 42 males) completed the
Conclusion: First-line treatment with BPC regimen trimodality therapy. Surgical morbidity and mortality
in MPM pts was feasible, with acceptable toxicity. were 23.1% (12/52) and 1.9% (1/52), respectively.
Bevacizumab-related adverse effects should be Epithelial histology was detected in 42 study subjects
strictly monitored. Although the survival outcomes (80.8%). Macroscopic complete resection (MCR)
compared favorably with historical controls of could be achieved in 34 patients (65.4%). Thirty
platinum/pemetrexed regimens, the primary endpoint patients (57.7%) had advanced stages III/IV applying
of the trial was not reached. the International Mesothelioma Interest Group (IMIG)
Keywords: mesothelioma, Chemotherapy, staging system. Median follow-up was 24.2 months.
bevacizumab Cumulative survival, 1- and 5-year-survival were 34.8
months (95% ConÀdence Interval [CI] 24.6-44.9), 69%
and 29%, respectively. Mean PFS was 21.5 months
Biomarkers, Chemotherapy and Radiotherapy in Mesothelioma (95%CI 16.1-26.8). Recurrence were locoregional (27/51,
Tuesday, 5 July 2011 10:30-12:00 52.9%), distant (10/51, 19.1%) and both (2/51, 3.9%),
respectively. Comparisons of MCR vs. incomplete
MO07.12 MULTIMODALITY resections (P < 0.001), IMIG stages I/II vs. III/ IV (P
TREATMENT OF MALIGNANT PLEURAL = 0.013) and nodal disease N0 vs. N1-2 (P = 0.005)
MESOTHELIOMA: LUNG-SPARING resulted signiÀcant survival differences. On contrary,
RADICAL PLEURECTOMY FOLLOWED no signiÀcant impact on survival were seen analyzing
BY ADJUVANT CHEMOTHERAPY histology (P = 0.8), gender (P = 0.4) and age (P = 0.4),
(CISPLATIN/PEMETREXED) AND respectively. MCR was the single signiÀcant prognostic
TANGENTIAL RADIATION OF THE factor (hazard ratio 0.14, 95% CI 0.058-0.335; P < 0.001)
CHEST WALL when the Cox proportional hazards model was applied.
Servet Bölükbas1, Michael Eberlein2, Thomas Conclusion: Trimodality therapy concept including
Bergmann1, Annette Fisseler-Eckhoff3, Joachim lung-sparing RP as surgical modality is associated
Schirren1 with promising long-term survival, morbidity and
1
Thoracic Surgery, Dr. Horst Schmidt Klinik/ mortality. MCR is the only prognostiÀcator within this
Germany, 2Division Of Pulmonary And Critical multimodality treatment. Further investigation for the
Care Medicine, Johns Hopkins University School Of locoregional control of the disease is warranted because
Medicine/United States Of America, 3Pathology And of the high rate of locoregional failure.
Cytology, Dr. Horst Schmidt Klinik/Germany Keywords: Chemotherapy, RADIATION, malignant
Background: The aim of the study was to present pleural mesothelioma, radical pleurectomy
Biomarkers, Chemotherapy and Radiotherapy in Mesothelioma Methods: Patients with untreated, stage I-III MPM
Tuesday, 5 July 2011 10:30-12:00 receive up to 4 cycles of pemetrexed and platinum
chemotherapy. If feasible, P/D is performed. IMRT is
MO07.13 CREATING A NEW MULTI- then administered in 28 fractions for a total planned
MODALITY TREATMENT PARADIGM dose of 50.4 Gy. There is a two-stage design: if <3
FOR MALIGNANT PLEURAL cases of severe pneumonitis occur among the Àrst 9
MESOTHELIOMA (MPM) USING patients, the cohort will expand to 28. The primary
INTENSITY MODULATED RADIATION endpoint is the incidence of severe pneumonitis.
THERAPY (IMRT) TO THE PLEURA Secondary endpoints include response rate,
Marjorie G. Zauderer1, Andreas Rimner2, Kenneth progression free survival, and overall survival.
Rosenzweig3, Valerie Rusch4, Prasad Adusumilli4, Results: 13 patients have enrolled. Patient
Samantha Kass5, Lee M. Krug6 characteristics include: median age 65 (range 48-79);
1
Thoracic Oncology Service, Memorial Sloan- 15% women, 85% men; median Karnofsky PS 90%
Kettering Cancer Center/United States Of America, (range 70-90%). Four patients came off-study prior to
2
Radiation Oncology, Memorial Sloan-Kettering receiving IMRT (2 experienced progression of disease,
Cancer Center/United States Of America, 3Radiation 1 died from progressive disease, and 1 experienced
Oncology, Mount Sinai Medical Center/United grade 4 toxicity with the Àrst cycle of chemotherapy).
States Of America, 4Thoracic Surgery, Memorial 7 patients have completed IMRT; 2 patients are
Sloan-Kettering Cancer Center/United States Of completing their other treatment modalities. There has
America, 5Medicine, Memorial Sloan-Kettering been 1 case of grade 3 pneumonitis and the patient
Cancer Center/United States Of America, 6Thoracic was weaned from oxygen after a course of steroids.
Oncology, Memorial Sloan-Kettering Cancer Center/ Conclusion: At our institution, we have compiled
United States Of America an extensive experience using IMRT to the pleura
in patients with two intact lungs and shown it to be
Background: Local disease progression is the safe, with an incidence of severe pneumonitis 20%,
primary cause of morbidity and mortality in MPM, and promising with high survival rates. We are
and radiation has been added to surgery and currently studying induction chemotherapy, P/D when
chemotherapy to improve outcomes. Hemithoracic feasible, and IMRT to the pleura in a prospective
radiation has become widely used as adjuvant study. Given the waning enthusiasm for performing
therapy after extrapleural pneumonectomy (EPP). EPPs, this approach has the potential to establish a
IMRT can also be used in this setting although, if new multi-modality paradigm for the treatment of
not performed within strict parameters, it can be locally advanced MPM. Supported, in part, by Lilly
associated with fatal pneumonitis. Also, the survival Oncology.
beneÀt of EPP over pleurectomy/decortication Keywords: imrt, multi-modality, mesothelioma
(P/D) has been questioned by a large retrospective
review (Flores, J Thorac Cardiovasc Surg 2007)
and many fewer EPPs are now being performed. Biomarkers, Chemotherapy and Radiotherapy in Mesothelioma
Retrospective reports of IMRT to the pleura without Tuesday, 5 July 2011 10:30-12:00
surgery or after P/D have demonstrated much less
severe toxicity. We identiÀed 36 patients with MPM MO07.14 CONTROVERSIES IN THE
who received IMRT to the pleura after P/D (20) or MANAGEMENT OF MALIGNANT
without any surgery (16) treated at Memorial Sloan- PLEURAL MESOTHELIOMA: THE
Kettering Cancer Center between 2005 and 2010 CASE FOR CONSERVATIVE SURGERY
(Zauderer, IMIG 2010). There was a 20% incidence AND HIGH-DOSE HEMITHORACIC
of severe pneumonitis among these patients and RADIOTHERAPY
almost all patients improved with steroids. Overall Malcolm Feigen1, Simon Knight2, Paul Mitchell3,
survival was encouraging at 26 months in the Gavin M. Wright4, Sze Ting Lee5, Chris Hamilton1
1
P/D patients, and 17 months in those who did not Radiation Oncology Centre, Austin Health/
undergo surgery. Based on these Àndings, we have Australia, 2Thoracic Surgery Dept, Austin Health/
launched a phase II trial to prospectively characterize Australia, 3Medical Oncology, Austin Health/
the safety of IMRT to the pleura in the multi- Australia, 4Thoracic Surgery, St Vincent’s Hospital/
modality treatment paradigm for MPM patients. Australia, 5Centre For Pet, Austin Health/Australia
Background: In the absence of deÀnitive medical local control can be achieved with radiation doses
trials, patients diagnosed with mesothelioma face above 50 Gy. The introduction of advanced radiation
difÀcult decisions with limited treatment options and technologies, including intensity-modulated and
many unresolved questions. This disease is almost image-guided radiotherapy, allows adequate sparing
always fatal, has a median survival of only nine of adjacent normal tissues. Complete macroscopic
months and there is no proven beneÀt from standard resection is no longer mandatory and radical
therapies. Hemithoracic radiotherapy is regarded diaphragmatic and pericardial reconstructions,
by most institutions as unsafe unless the lung has together with mediastinal lymphadenectomy, can
been resected. There is an increasing reluctance to be avoided since we have shown that high radiation
recommend extrapleural pneumonectomy (EPP), doses can sterilize gross residual disease without
supported by the MARS trial results. Multimodality producing signiÀcant pulmonary, hepatic or cardiac
treatment programs must balance the potential risk of toxicity, even in patients who retain the affected
major toxicity with palliative beneÀts. It is imperative lung. These techniques can be safely delivered to
that clinical research should focus on reducing the selected patients following suboptimal surgery and
high rate of locoregional progression that is the chemotherapy and are recommended to provide
overwhelming cause of morbidity and death. palliation and locoregional control to patients with
Methods: We have delivered high dose intensity- advanced mesothelioma. Further studies with high
modulated radiotherapy (IMRT) to the whole dose radiotherapy are warranted.
hemithorax in mesothelioma patients with good Keywords: mesothelioma, intensity-modulated
performance status and incompletely resected radiotherapy, conservative surgery, PET scanning
localized disease. All patients had PET/CT scans
performed to exclude distant metastases, deÀne
residual gross tumour volume (GTV), quantify Session MO08: Radiation Oncology
metabolic responses by serial total glycolytic volume
(TGV) analysis, and assess locoregional control. A Tuesday, 5 July 2011
daily online cone beam CT imaging protocol was
implemented. Strict radiation dose constraints were
observed and all toxicities were recorded and graded Radiation Oncology Tuesday, 5 July 2011 10:30-12:00
according to CTCAE 4.0.
Results: From July 2007 to February 2011, twenty MO08.01 THE RELATION BETWEEN
patients with incompletely-resected mesotheliomas RADIATION PNEUMONITIS AND MEAN
received IMRT to the whole hemithorax. All patients LUNG DOSE IN PATIENTS TREATED
received radiotherapy at a single institution to doses WITH LUNG SBRT
of 55 - 60 Gy as outpatients over six weeks. Based on Alize Scheenstra, Maddalena M.G. Rossi, Eugène
planning PET scans, 80% had advanced clinical stage Damen, José Belderbos, Heike Peulen, Jan Jakob
disease (stage II 4, III 9, IV 7). Only one patient had Sonke
an EPP and all the others had conservative procedures Radiation Oncology, The Netherlands Cancer
including 1 radical pleurectomy, 4 pleurectomy/ Institute - Antoni Van Leeuwenhoek Hospital/
decortications, 10 pleurodeses or, in 3 cases, biopsy Netherlands
only. Chemotherapy was given to 18 patients, all
of whom had progressed prior to commencing Background: Both the mean lung dose (MLD) and
radiotherapy. IMRT was well tolerated and we the percentage of lung volume receiving doses more
found no acute or late grade 4-5 radiation toxicities. than a certain threshold dose (Vx) are known to be
Assessable TGVs were reduced to 40% of the pre- related to the incidence of radiation pneumonitis
irradiation values. Median followup was 8 months (RP) in conventionally fractionated radiotherapy
(range 2 to 44 months) and 13 patients remain alive, (RT). This work investigates the relation of RP to the
8 disease-free. Relapses have occurred outside the MLD and the Vx for stereotactic body radiotherapy
GTV in 11, including only 3 with concurrent in-Àeld (SBRT) in NSCLC patients.
relapse, a locoregional control rate of 85%. There Methods: A total of 187 patients with peripheral
were no cases of relapse conÀned only within the lung tumors <5cm were treated with SBRT between
irradiated volume. June 2006 and March 2010: 174 patients received
Conclusion: Mesothelioma is radiosensitive and 3x18Gy, 4 patients had other fractionation schemes
and 9 patients were treated with SBRT for 2 lung Radiation Oncology Tuesday, 5 July 2011 10:30-12:00
tumors. During follow up (FU) RP grade2 was
scored according to the CTCAE 3.0. Dose volume MO08.02 LATE OUTCOMES OF
histograms (DVH) of the biologically equivalent STEREOTACTIC ABLATIVE
dose given in fractions of 2 Gy (EQD2) were RADIOTHERAPY (SABR) FOR
generated using the LQ model with Ơ/ơ=3Gy. From CENTRALLY LOCATED STAGE I LUNG
the DVHs the MLD and the Vx with threshold CANCER
doses of 5Gy-15Gy, 20Gy, 30Gy, 40Gy, and 50Gy Cornelis J. Haasbeek, Frank J. Lagerwaard, Ben
were calculated. A sigmoid dose-effect model with Slotman, Suresh Senan
parameters d50 or V50 (the dose or volume with Radiation Oncology, VU University Medical Center/
a 50% probability on RP) and m (steepness of the Netherlands
curve) was Àtted to estimate the probability on RP
as function of the MLD and each Vx separately. The Background: In centrally located lung tumors, the
optimal Àt for each model was determined by the use of stereotactic ablative radiotherapy (SABR) has
maximum likelihood (ML). been associated with increased toxicity. We studied
Results: Median FU-time was 17 months outcomes after delivery of risk-adapted SABR to
(range:2-54 months). The crude incidence of RP central tumors in patients who were followed-up for
grade 2 was 4.25%, no grade 3 was observed. All at least 1 year.
RP were reported at 3-4 months after SBRT, except Methods: Between 2003 and 2009, SABR was
in one patient that experienced RP 1 month after delivered in 8 fractions of 7.5Gy in 63 patients,
SBRT. Statistics and optimized parameters for the using a median of 10 non-coplanar radiation beams
MLD, the V5, V10, V13, V15, V20, and V50 are given on a Novalis linear accelerator. Target volumes
in Figure 1a. Figure 1b plots the dose-effect models were based on 4D-CT scans incorporating tumor
MLD and the V10. As the MLD is highly correlated movement. Thirty-seven patients had a stage
to the Vx, there were insufÀcient patients to assess I lung tumor at a central hilar location (RTOG
which model best predicts RP. The Àtted model criteria), while 26 patients had a tumor abutting the
for the MLD is similar to the reported function for pericardium or mediastinal structures. Follow-up
conventionally fractionated RT (d50=30.8, m=0.37) CT scans were performed at 3, 6 and 12 months
which was assessed on 382 patients [1]. following SABR, and yearly thereafter. Toxicity was
scored according to CTC-AEv4 guidelines. Survival
outcomes were compared to patients with peripheral
stage I SABR patients treated during the same
time period with identical treatment techniques.
Peripheral tumors were treated to 3 fractions of 20Gy
for T1 tumors, and to 5 fractions of 12 Gy for T2
tumors and T1 tumors directly adjacent to the chest
wall.
Results: Acute grade III chest wall pain was
observed in 1 patient. Late grade III toxicity was
limited to chest wall pain (n=2) and increased
dyspnoea (n=2). No grade 4/5 toxicity was observed,
but grade V toxicity could not be excluded in 9
patients with a cardiopulmonary cause of death.
Distant failure was the predominant cause of death,
and cardiovascular death was not associated with
Conclusion: For lung SBRT the incidence of RP a tumor location near the heart. No signiÀcant
grade2 is correlated to the MLD. Whether the Vx is differences were observed in survival outcomes
a more sensitive predictor for RP is subject to further between the 63 patients with central and the 445
study in a larger patient cohort. [1] Seppenwoolde et patients with peripheral tumors. The 3-year overall
al. IJROBP 55(3):724-35(2003) survival rates were 64.5% and 51.1%, with median
Keywords: stereotactic body radiotherapy, NTCP survival rates of 47 and 36 months, respectively
function, radiation pneumonitis, mean lung dose (p=0.09). The median follow-up was 34 months for
both groups (range 13-86 months). Three-year local (56%) patients had COPD GOLD III/IV. Scans were
control rates were 92.6% and 90.2% (p=0.9), and reviewed by 3 radiation oncologists experienced
also no signiÀcant differences were seen for regional in lung SABR; toxicity scores and attributes were
control, distant control and disease free survival assigned by consensus.
rates. Results: Within 6 months post-SABR, 54% of
Conclusion: Risk-adapted stereotactic radiotherapy patients exhibited acute radiological abnormalities,
in 8 fractions of 7.5Gy did not lead to an increase mainly patchy or diffuse consolidation. The
in toxicity for centrally located stage I lung tumors. incidence of CT changes at 6, 12, 24 and 36 months
Clinical outcomes were comparable to patients with was 56%, 73%, 87% and 99%, respectively, most
peripheral lesions after SABR. often categorized as modiÀed conventional pattern.
Keywords: Stereotactic radiotherapy, outcomes, Approximately 25% of changes Àrst appeared 1
toxicity, early stage lung cancer year post-SABR and the morphology and/or severity
continued to evolve after >2 years in 47% of lesions.
Nearly all changes observed were considered mild
Radiation Oncology Tuesday, 5 July 2011 10:30-12:00 (50%) or moderate (47%). 55% of patients with
moderate/severe acute changes had moderate/severe
MO08.03 LATE RADIOLOGICAL late changes compared with 39% of patients with no/
CHANGES AFTER STEREOTACTIC mild acute changes (p=0.002). Treatment volume,
ABLATIVE RADIOTHERAPY OF GOLD score and number of fractions were not
PRIMARY LUNG TUMORS correlated with maximum severity of lung changes.
Max Dahele, David Palma, Frank J. Lagerwaard, ClassiÀcation of late radiological changes (modiÀed
Ben Slotman, Suresh Senan from Koenig)
Netherlands Term Description
ModiÀed Consolidation, volume loss, and bronchiectasis similar
conventional to, but usually less extensive than, conventional
Background: Stereotactic ablative radiotherapy pattern radiation Àbrosis. Larger than the original tumor size.
(SABR) for early-stage peripheral non-small cell Occasionally with associated GGO
lung cancer has achieved local control rates above Mass-like Àbrosis Well-circumscribed focal consolidation limited to area
surrounding the tumor. The abnormality must be larger
90%. Post-treatment, radiological changes on than the original tumor
computed tomography (CT) are common, and can Scar-like Àbrosis Linear opacity in the region of the tumor associated
sometimes be difÀcult to distinguish from tumor with volume loss
progression. With limited follow up in many reports, No evidence of No new abnormalities. Includes patients with tumors
increased density that are stable, regressing or resolved, or Àbrosis in the
and varying terminology used to describe post- position of the original tumor that is not larger than the
SABR changes, we report the incidence, radiological original tumor
severity and long-term morphology of CT changes
in patients followed for at least 2 years after SABR, Conclusion: Post lung SABR radiological
and considered free of local tumor progression at the changes are observed in nearly all patients. Their
time of the analysis. morphology, severity and size continues to evolve
Methods: CT-scans were evaluated from patients long after treatment. Careful and continued follow
treated at VUmc between 2003 and June 2008 up using standardized descriptions is therefore
provided that (1) radiological follow-up had been necessary to monitor local tumor control. When
performed at our center for at least two years post- there is concern over local progression the decision
SABR and (2) there was no deÀnite evidence of local between interval imaging and invasive investigations
progression. Patients had been treated with 8-12 non- will be inÁuenced by salvage options.
coplanar beams. Follow-up CT was obtained 3, 6 and Keywords: Lung changes, computed tomography,
12-months post-SABR and then every 6-12 months Stereotactic ablative radiotherapy
or more frequently depending on CT Àndings and
clinical status. We standardized the description of
lung changes (Table), and evaluated severity, timing,
incidence, and morphology. 325 CT scans (median 5/
patient) were evaluated from 61 patients (68 lesions)
with median follow-up 2.5 years (2-6.7 years). 34/61
Radiation Oncology Tuesday, 5 July 2011 10:30-12:00 doses at the edge of the PTV in SBRT series were
about 73 Gy, which was sufÀcient to achieve
MO08.04 WHAT IS THE RADIATION about 90% local tumour control in stage I. More
DOSE NEEDED TO ERADICATE STAGE fractionated and accelerated schedules with equal
I NSCLC WITH STEREOTACTIC BODY biological doses achieve the same tumour control
RADIOTHERAPY (SBRT)? rates as SBRT. Lower, but more homogeneous
Angela Van Baardwijk1, Wolfgang Tomé2, Wouter doses to the whole PTV may be sufÀcient to achieve
Van Elmpt1, Søren M Bentzen2, Bart Reymen1, Rinus similar control rates, with the possibility to deliver
Wanders1, Michel Öllers1, Philippe Lambin1, Dirk De SBRT in adapted schedules, beneÀcial to centrally
Ruysscher1 located tumors in the vicinity of critical stuctures like
1
Radiation Oncology, MAASTRO Clinic, Grow - oesophagus and great vessels.
School For Oncology And Developmental Biology,
Maastricht University Medical Centre/Netherlands,
2
Department Of Human Oncology, University Of
Wisconsin/United States Of America
Background: For SBRT, usually a scheme of 60 Gy

in 3 to 5 fractions is applied, with local control rates
around 90%. However, this dose speciÀcation is in
one point only, and ignores possible underdosages
at the edge of the Planning Target Volume (PTV).
Indeed, in many series older techniques and
calculation algorithms have been used, leading to
real doses at the edge of the PTV of only 36 Gy in
3 fractions. We therefore investigated the doses at Radiation Oncology Tuesday, 5 July 2011 10:30-12:00
the edge of the PTV and correlated this with local
tumour control with the aim to shed light on the MO08.05 FDG-PET SUV UPTAKE AS
radiation dose needed to eradicate stage I NSCLC. A PREDICTOR OF OUTCOME IN
Methods: Freedom from local progression (FFLP) STEREOTACTIC BODY RADIOTHERAPY
data from SBRT series for stage I NSCLC with a (SBRT) FOR NON – SMALL CELL LUNG
follow up of at least 30 months were obtained from CANCER(NSCLC)
literature and compared to accelerated high-dose Katy Clarke1, Mojgan Taremi2, Marc Freeman2,
conventional radiotherapy series from CALGB 39904 Sharon Fung3, Max Dahele2, Andrea Bezjak2,
(Bogart, J Clin Oncol 2010) and MAASTRO Clinic Anthony Brade2, John Cho2, Andrew Hope2,
(van Baardwijk, J Clin Oncol 2010). The biological Alexander Sun2
1
equivalent dose corrected for time (EQD2,T), Radiation Oncology, Princess Margaret Hospital/
assuming an Ơ/ơ of 10 Gy and Tk of 21 days, was Canada, 2Department Of Radiation Oncology,
calculated from the dose at the edge of the PTV. Princess Margaret Hospital/Canada, 3Department
Results: Nineteen studies for SBRT were identiÀed; Of Biostatistics, Princess Margaret Hospital/Canada
15 studies (901 patients) provided FFLPs for various
prescription schemes. For each scheme the dose at the Background: To identify FDG-PET imaging metrics
edge of the PTV was calculated. The two fractionated that may predict for outcomes following SBRT for
trials delivered a mean dose of 70 Gy/24 fractions early stage NSCLC.
(CALGB) and 75.6 Gy/42 fractions (MAASTRO). Methods: Inoperable patients with early stage
The mean ± SD (range) FFLP for SBRT was 83.6 ± NSCLC undergoing SBRT who had a pre treatment
13.4% (49.0-100%), with a mean EQD2,T of 73.0 ± FDG-PET scan between Aug 2004-Jan 2009 were
13.2 Gy (50.4-99.6 Gy). The FFLP was 92.3% in the included. Information on histology, stage, dose,
CALGB trial and 83.8% in the MAASTRO study, GTV volume, performance status, SUVmax pre-and
with an EQD2,T of 64.7 Gy and 61.9 Gy, respectively. 3 months post-treatment, maximum response to
No signiÀcant correlation was found between FFLP treatment, and patterns of failure were prospectively
and the EQD2,T (p=0.16; Fig 1). collected and analyzed. SUVmax was analyzed as a
Conclusion: The biological equivalent radiation continuous and dichotomized variable.
Results: 82 pts (40 male, 42 female, median age the high rates of relapse in this group may have
71.5 median follow up 2.0 yr (range 0.74-4.64)) implications for adjuvant treatment.
with 58 T1 lesions and 24 T2 lesions were analyzed. Keywords: SBRT, NSCLC, [18F] FDG PET,
Local, regional, distant and overall relapse-free SUVmax
rates at 2 years were 90%, 92%, 83% and 72%
respectively. Disease free survival (DFS), overall
survival (OS) and cause speciÀc survival (CSS) at Radiation Oncology Tuesday, 5 July 2011 10:30-12:00
2 yrs was 51%, 67% and 91% respectively. Median
SUVmax at baseline was 4.75 (range 0.5-23.3). In MO08.07 THE INCIDENCE OF
those patients with diagnostic pathology (n=61/82, HIPPOCAMPAL METASTASES IN NON-
74.4%), median SUVmax was 4.8 (range 0.5-23.3), SMALL CELL LUNG CANCER (NSCLC):
in 21 pts without diagnostic pathology (15 biopsy A CONSECUTIVE POPULATION-BASED
contraindicated, 6 biopsy non-diagnostic) median SERIES OF PATIENTS PRESENTING TO
SUVmax was 4.5 (range 0.5-16). Post treatment PET THE BRITISH COLUMBIA (BC) CANCER
was obtained in 62 pts with a median SUVmax of 2 AGENCY
(range 0.3-5.2). Median change between the pre/ Chad R. Lund1, Monty Martin2, Christopher W. Lee3,
post SUVmax was -2.55 (range-13.1 to +1.73). On Devin Schellenberg1
1
univariate analysis pre-SBRT FDG-PET SUVmax Radiation Oncology, British Columbia Cancer
predicted for local relapse (p=0.04), distant relapse Agency/Canada, 2British Columbia Cancer Agency/
(p=0.001) and relapse free survival (RFS) (p=0.04). Canada, 3Medical Oncology, British Columbia
We dichotomized our sample around the median Cancer Agency/Canada
and found baseline SUVmax 4.75 (median) was
correlated with a higher risk of distant relapse Background: Brain metastases from NSCLC are
(p=0.01) and poorer RFS (p=0.04). Multivariate common, but randomised trials of prophylactic
analysis was carried out for RFS and only stage cranial irradiation (PCI) have failed to accrue due to
(HR 3.4, p<0.01) and only pre-treatment SUVmax concerns about the effect of radiation on cognitive
(HR1.09, p=0.03) remained statistically signiÀcant. function. Recent radiotherapy advances permit
Patients who developed any relapse (n=22) had a hippocampal sparing (HS), which may reduce
median SUVmax on pre treatment scan of 7.7 vs. memory impairment. However, the incidence of
4.2 months for patients without relapse. When hippocampal metastasis will dictate interest in HS-
analyzed as a dicotomized variable patients with PCI. Previous research suggests the incidence of
a post-SBRT SUVmax median (2) had a higher failure to be 0% within the hippocampus proper
rate of distant relapse (p=0.005). As a continuous and 8.6% within a larger hippocampus + 5mm
variable the SUVmax on post treatment PET scan (perihippocampal) volume in patients with a variety
did not predict for local or distant failure but was of primary tumours. The rate of hippocampal failure
predictive for regional relapse (HR 1.75, p=0.03). in NSCLC is unknown.
Change in SUVmax showed a trend for predicting Methods: All patients diagnosed with NSCLC
for RFS (p=0.06) when analyzed as a continuous in 2005 who underwent brain irradiation were
variable; patients with a larger reduction in SUVmax identiÀed in the BC Cancer Registry. A single
had lower rates of distant relapse (HR 0.76, p=0.03). radiation oncologist reviewed all reports and images
We also evaluated change in SUVmax (from pre- to of initial diagnostic brain scans, while a single
post-SBRT FDG-PET-CT scan) as a dichotomized neuroradiologist evaluated scans of all temporal lobe
variable, employing the median change of -2.55 as a metastases. Metastases were categorised as being
cut off. There was statistically signiÀcant association within the hippocampus, perihippocampal volume or
between greater decrease in SUVmax and lower rates elsewhere.
of distant metastatic relapse (p= 0.03). Results: Of 119 patients identiÀed, 19 were excluded
Conclusion: This study showed that FDG-PET for either receiving PCI or absence of veriÀable
SUVmax may have a role in predicting risk of reports and/or images. There were 100 patients with
relapse, particularly distant metastases following localizable brain metastases. Twenty-one patients
SBRT in NSCLC. How inoperable early stage had a CT scan and MRI, 1 had only MRI and 78
NSCLC patients with high SUV values should best patients underwent a CT scan only. In almost all
be managed remains an area of investigation, but cases the indication for imaging was to investigate
neurological symptoms. The mean and median in regional lung perfusion at 6 months post-RT,
number of metastases per patient was 2.8 and 2, and related the degree of change to regional dose
respectively. Six percent of patients had metastases to generate a dose response curve (DRC). Each
within the hippocampus proper and 12% within the patient’s DRC was Àt to a linear model and thus
perihippocampal volume. described by its slope (% reduction in regional lung
Conclusion: The high rate of hippocampal and perfusion / Gy). Data from multiple patents were
perihippocampal metastases in patients with NSCLC combined via volume-weighted average to generate
may preclude clinical studies of HS-PCI. a population DRC. The slope of the population
Keywords: Non-small cell lung cancer, DRC was compared for the population of 4 patients
Hippocampus, prophylactic cranial irradiation treated with a single suite of beams throughout (e.g.
variable fraction size) vs. 51 historical patients with
sequential Àelds, using a two-sided student’s t-test.
Radiation Oncology Tuesday, 5 July 2011 10:30-12:00 Results: The slope of the population DRCs for
reductions in regional lung perfusion for the study
MO08.08 THE IMPACT OF FRACTION group (variable fraction daily size) was 0.39, vs. 1.08
SIZE ON RADIATION-INDUCED in the historical patients (p=0.0004).
REDUCTIONS IN REGIONAL LUNG Conclusion: Patients treated with techniques that
PERFUSION expose the lung to lower daily fractions (e.g. the use
Michael V. Lawrence1, David Fried1, Dorothy of a single suite of beams throughout therapy) appear
Riguera1, Terence Wong2, Ronald Jaszczak2, Shiva to have lesser degrees of dose-dependent radiation-
Das2, Sumin Zhou3, Lawrence B. Marks1 induced reductions in regional perfusion.
1
Radiation Oncology, University Of North Carolina Supported in part by NIH grant RO1-CA69579.
At Chapel Hill/United States Of America, 2Duke Keywords: RADIATION, Perfusion
University/United States Of America, 3University Of
Nebraska Medical Center/United States Of America
Radiation Oncology Tuesday, 5 July 2011 10:30-12:00
Background: Radiation (RT)-induced lung injury
is common in patients with thoracic tumors. Our MO08.09 INDIVIDUALISED
previous studies have shown that radiation causes a ACCELERATED RADIOTHERAPY
reduction in regional lung perfusion at 6 months post- (INDAR) IMPROVES SURVIVAL OF
radiotherapy. The vast majority of patients in prior PATIENTS WITH STAGE III NSCLC: A
studies were treated conventionally with sequential PROSPECTIVE POPULATION-BASED
“shrinking Àeld boosts”; e.g. 44 Gy via large AP/PA STUDY
Àelds followed by reduced off-cord oblique boosts to Dirk De Ruysscher1, Jessie Steevens2, Anita
60-70Gy. Thus, most of the affected lung was exposed Botterweck3, Bart Reymen4, Angela Van Baardwijk4,
to daily fractions of ~ 2 Gy. With the movement away Rinus Wanders3, Jacques Borger3, Anne-Marie
from elective nodal irradiation, patients are often Dingemans5, Gerben Bootsma6, Cordula Pitz7, R
treated with a single suite of beams (conformal or Lunde7, Wiel Geraedts8, Philippe Lambin1
1
IMRT) throughout the course of RT. This results in the Department Of Radiation Oncology (MAASTRO),
lung exposed to a more variable daily dose (e.g. 0.2- Grow, Maastricht University Medical Centre/
2 Gy). We herein quantify the degree of RT-induced Netherlands, 2Comprehensive Cancer Center The
reductions in regional lung perfusion in patients Netherlands, Location Maastricht/Netherlands,
3
treated with these newer approaches, and compare the MAASTRO Clinic/Netherlands, 4Radiation
results to that of our prior experience. Oncology, MAASTRO Clinic/Netherlands,
5
Methods: Patients receiving thoracic RT were Pulmonology, Maastricht University Medical
enrolled onto an IRB-approved clinical study (all Center/Netherlands, 6Pulmonology, Atrium Mc
provided informed consent) that included pre- and Parkstad/Netherlands, 7Pulmonology, Laurentius
6 months post-RT thoracic single photon emission Ziekenhuis/Netherlands, 8Pulmonology, Orbis Mc/
computed tomography (SPECT) scans to assess Netherlands
pulmonary perfusion. Pre-RT computed tomography
(CT) scans were used to calculate radiation dose. Background: Sequential chemotherapy and INDAR
Using image registration, we quantiÀed changes resulting in promising survival with low toxicity
(van Baardwijk, J Clin Oncol 2010), was introduced Conclusion: A clear increase in survival occurred
in clinical routine from 2006. The same concept in with sequential INDAR alone and concurrent chemo-
concurrent chemo-radiotherapy schedules became INDAR.
standard in 2008. We hypothesised that these more Keywords: Non-small cell lung cancer,
intensive treatment schedules should lead to improved Individualised treatment, Radiotherapy, Stage III
overall survival (OS) rates and that this should be
reÁected in the population of South- and Middle
Limburg (Maastricht Cancer Registry, MCR), The Radiation Oncology Tuesday, 5 July 2011 10:30-12:00
Netherlands.
Methods: All patients with a pathological diagnosis MO08.11 COMPARISON OF ELECTIVE
of NSCLC in the MCR and with a stage III (UICC NODAL IRRADIATION (ENI) VS.
6th Edition) from 2002 to 2008 were included. MCR INVOLVED-FIELD RADIOTHERAPY
covers > 98 % of all lung cancer cases. Staging: whole (IFRT) FOR STAGE III NON-SMALL-
body FDG-PET scan and brain CT or MRI. Treatment: CELL LUNG CANCER: CLINICAL
Period 1: 2002-2005: sequential 3 cycles cisplatin/ OUTCOMES AND TOXICITIES
carboplatin-gemcitabine and chest radiotherapy (60 Gy/ Su Ssan Kim1, Geumju Park1, Si Yeol Song1,
30 fractions/ 6 weeks); Period 2: 2006-2007 3 cycles Jungshin J. Lee2, Eun Kyung Choi1
1
cis(carbo)platin-gemcitabine followed by IDAR (mean Radiation Oncology, Asan Medical Center/Korea,
2
dose of 64.8 Gy/ 36 fractions/ 3.6 weeks = biological Medical Oncology, Asan Medical Center/Korea
equivalent of 82 Gy/ 41 fractions/ 8.2 weeks); Period 3:
2008 concurrent cisplatin-vinorelbine and IDAR (mean Background: To investigate the clinical outcomes
dose of 65 Gy/ 40 fractions/ 5.5 weeks = biological and toxicities of involved-Àeld radiotherapy (IFRT)
equivalent of 74 Gy/ 36 fractions / 7.4 weeks). Minimal compared with elective nodal irradiation (ENI) in
follow-up of all patients is 2 years. patients with stage III non-small-cell lung cancer
Results: 1002 patients with stage III were diagnosed, (NSCLC).
24.3 IIIA and 47.3 % IIIB. Mean age: 68 ± 10.3 years Methods: A total of consecutive 263 patients (133
(SD) (r34-90); 71.1 % men, 28.9 % females. The ENI vs. 130 IFRT) of stage
number of patients per year diagnosed with stage III III NSCLC who received deÀnitive RT with or
NSCLC remained constant over de years : 2002 : without chemotherapy from 1999 to 2007 were
146, 2003 : 144, 2004 : 144, 2005 : 147, 2006 : 137, reviewed. 3D-CRT was delivered 1.8 Gy per fraction
2007 : 140, 2008 : 144. Age, histology and Charlson to 64 to 70 Gy for ENI, and 2.2 Gy per fraction to
co-morbidity distribution remained constant over the 66 Gy for IFRT. Only the primary gross tumor and
time periods. The proportion of patients referred for lymph nodes involved with tumor either by biopsy or
treatment with curative intent increased over time: radiologic criteria were included in the clinical target
2002 47.3 %, 2003 48.6 %, 2004 50.7 %, 2005 51.7 volume for IFRT. Isolated elective nodal failure
%, 2006 54.7 %, 2007 51.4 %, 2008 56.3 %. Taken all (ENF) was deÀned as recurrence in an initially
three periods together, the median OS of all patients uninvolved lymph node in the absence of in-Àeld
was 11.6 months (10.5-12.7), for curative intent therapy progression or distant failure.
17.3 months (15.6-19.0) and for palliative treatment 6.8 Results: The 2-year overall survival, progression-
months (5.6-7.7), p<0.001. Median and two-year OS free survival, and local control rates were 35.3%,
increased over the different time-periods: Period 1: 16.4 35.2%, 48.7% for ENI and 32.3%, 36.5%, 58.2%
months (14.3-18.5), 2-year 24 %; Period 2: 18.1 months for IFRT, respectively. This differences were not
(13.9-22.6), 2-year 40.8 %; Period 3: not reached statistically signiÀcant. No isolated ENF was
median OS, 2-year 51.9 %; p<0.001 (Figure 1). identiÀed in IFRT. The grade 3 radiation esophagitis
in patients with IFRT was lower than in patients with
ENI (8% ENI vs. 1% IFRT, p=0.005).
Results: The 2-year overall survival, progression-
free survival, and local control rates were 35.3%,
35.2%, 48.7% for ENI and 32.3%, 36.5%, 58.2%
for IFRT, respectively. This differences were not
statistically signiÀcant. No isolated ENF was
identiÀed in IFRT. The grade 3 radiation esophagitis
in patients with IFRT was lower than in patients with have malignant pleurisy. A predictive model was
ENI (8% ENI vs. 1% IFRT, p=0.005). developed using backwards Cox regression analysis
Conclusion: IFRT did not result in a signiÀcant (excluding variables with p >.20) with R 2.12.0 and
amount of elective nodal failure. IFRT also did the Design library. The Ànal model was internally
not compromise survival and local control while validated using a 100 times bootstrap procedure, to
signiÀcantly decreasing esophageal toxicity when check whether variables were consistently selected.
compared to ENI. Therefore, IFRT may help Potential predictors for survival were sex, age, T
improve local control and survival by allowing and N-stage, intake WHO-PS, number of positive
higher dose to the primary tumor and involved nodal lymph nodes on PET, smoking status, lung function,
regions while minimizing the toxicity and increasing chemotherapy, gross tumor volume, radiotherapy
patients’ compliance to concurrent chemotherapy. dose and overall treatment time. Missing values were
Keywords: Non-small cell lung cancer, generally less than 10% and patients with missing
Radiotherapy, elective nodal irradiation values had mostly 1 or 2 values missing. These
values were replaced with regression based multiple
imputation.
Radiation Oncology Tuesday, 5 July 2011 10:30-12:00 Results: Of all patients, 374 had died at the time
of the analysis. Median survival time was 16
MO08.12 A PRACTICAL PREDICTION months, survival at 2 years was 33%. Backwards
MODEL FOR OVERALL SURVIVAL Cox regression of possible predictors resulted in
FROM STAGE III LUNG CANCER: the elimination of age, smoking status, N-stage and
A FIRST STEP TOWARDS DOSE lung function from the model. GTV could only be
INDIVIDUALIZATION modeled non-linearly. Concordance statistic for the
Cary Oberije1, Ruud Houben1, Dirk De Ruysscher1, Ànal model was 0.63. A nomogram was constructed
Anne-Marie C. Dingemans2, Gerben Bootsma3, based on the model in order to predict an individual
Wiel Geraedts4, R. Lunde5, Cordula Pitz5, Philippe patient’s probability for 2, 3 and 5-year survival
Lambin1 (Àgure 1).
1
Department Of Radiotherapy, Maastricht
Radiation Oncology (MAASTRO), Grow - School
For Oncology And Developmental Biology,
2
Department Of Pulmonology, Grow - School
For Oncology And Developmental Biology,
3
Department Of Pulmonology, Atrium Mc Parkstad/
Netherlands, 4Department Of Pulmonology, Orbis
Mc/Netherlands, 5Department Of Pulmonology,
Laurentius Ziekenhuis/Netherlands
Background: Most models regarding outcome of Conclusion: The predictive model for overall
treatment for lung cancer are prognostic in nature. survival of stage III lung cancer patients highlights
Recently, a practical and validated prediction the importance of patient, clinical and treatment
model for radiation-induced dysphagia has been variables. A nomogram for prediction of overall
published (Dehing-Oberije, 2010). We aim to design survival has been developed. This tool could be
a predictive model for overall survival for patients useful for treatment individualization and design
with stage III lung cancer. of clinical trials. References: Dehing-Oberije
Methods: Patient, clinical, treatment and survival C, De Ruysscher D, Petit S, Van Meerbeeck J,
data for 492 stage III (according to UICC version Vandecasteele K, De Neve W, Dingemans AM,
6) lung cancer patients were available for analysis. El Naqa I, Deasy J, Bradley J, Huang E, Lambin
Patients were included in the analysis if they P. Development, external validation and clinical
(1) were treated with radiotherapy with curative usefulness of a practical prediction model for
intent, (2) had not received surgery, (3) had no radiation-induced dysphagia in lung cancer patients.
other tumours in the past 5 years and (4) did not Radiother Oncol. 2010 Dec;97(3):455-61.
Keywords: Treatment individualization, nomogram, Results:

Overall survival, Prediction model
ROC area ClassiÀer Training Cross- Prospective
dataset Validation Validation
Radiation Oncology Tuesday, 5 July 2011 10:30-12:00 procedure Set
Naïve Bayes .815 .777 .69
Bagging .997 .79 .727
MO08.13 COMBINING THE
Bayesian Networks .813 .764 .756
PREDICTIONS FOR RADIATION-
Boosting .824 .614 .756
INDUCED DYSPHAGIA IN LUNG-
Penalized Logistic .82 .772 .752
CANCER PATIENTS FROM MULTIPLE regression
MODELS IMPROVES THE PROGNOSTIC Radial Basis Function .83 .739 .722
ACCURACY OF EACH INDIVIDUAL (RBF) network
MODEL Random Forest .997 .653 .721
Georgi Nalbantov, Cary Oberije, Philippe Lambin, Linear Support Vector .771 .783 .722
Dirk De Ruysscher, André L.A.J. Dekker Machines (SVM)
Dept. Of Radiation Oncology (MAASTRO), Grow - LASSO .82 .76 .732
School For Oncology And Developmental Biology/ Equal-voting of all .77
Netherlands Physicians’ predictions .53
Background: Acute dysphagia is a distressing

dose-limiting toxicity occurring frequently
during concurrent chemo-radiation or high-dose
radiotherapy for lung cancer. It can lead to treatment
interruptions and thus jeopardize survival. A number
of predictive factors have been identiÀed. It has been
suggested in the statistical literature that combining
the predictions of multiple prediction models into
one Ànal model could improve the accuracy of each
individual model. We have therefore developed and
validated such a combined model to predict severe
acute dysphagia.
Methods: Clinical data from 469 inoperable lung
cancer patients, treated with curative intent, were The ten predictive models (classiÀers) performed
collected prospectively. Input variables included relatively similar on the prospective dataset (see
age, gender, World Health Organization performance Table 1 and Figure 1). However, the combined model
status, mean and maximum esophagus dose, performed better than any individual model and
overall treatment time and concurrent/sequential achieved an area under the curve of .77. Physicians’
chemotherapy. The endpoint for analysis was acute predictions resulted in area-under-the-curve of .53.
dysphagia (grade >= 3 according to CTCAEv3.0). Conclusion: Combining different prediction models
We have developed and validated ten prediction into one Ànal model worked well and produced
models for severe acute radiation-induced dysphagia, superior performance than any individual model. The
which are based on ten popular data-analysis approach was successfully validated and predicted
methods. We subsequently combined the predictions acute dysphagia better than physicians. Therefore,
of these models into one Ànal model using the equal- this approach could be used to identify patients at
voting rule. Model evaluation was based on the area high/low risk for developing dysphagia and provide
under the receiver-operator-characteristic (ROC) assistance in treatment decision making in daily
curve, which was estimated via a cross-validation clinical practice.
procedure. Model performance was validated on a
prospective dataset of 138 patients and compared to
physicians’ predictions.
Radiation Oncology Tuesday, 5 July 2011 10:30-12:00 average PD of 75.1Gy. The table shows the impact of
treatment technique and PD on mean doses to PTVinc
MO08.14 PET-BASED PLANNING IN LA- and PTVtot, on corresponding TCPs and p-values
NSCLC: SHOULD WE RE-CONSIDER comparing (MLD-escalated ) IMRT to baseline
ELECTIVE NODAL IRRADIATION IN 3D-CRT.
THE IMRT ERA?
An Nulens1, Amr G. Mousa2, Gilles Defraene1, Sigrid Baseline MLD-escalated
Stroobants3, Walter De Wever4, Frank Van Den 3D-CRT IMRT p-values IMRT p-values
Heuvel1, Yolande Lievens1, L. Leuven Lung Cancer PTVinc
Group1 Dmean 45.5 Gy 40.2 Gy 0.003 45.6 Gy 0.96
1
Radiation Oncology, University Hospitals Leuven/ D95 17.7 Gy 11.3 Gy 0.053 12.6 Gy 0.12
Belgium, 2Radiation Oncology, KFSH&RC/ TCP 31% 21% 0.008 25% 0.06
Saudi Arabia, 3Radiation Oncology, Universitair PTVtot
Ziekenhuis Antwerpen/Belgium, 4Radiology, Dmean 62.4 Gy 62.3 Gy 0.76 71.0 Gy <0.0001
University Hospitals Leuven/Belgium D95 38.3 Gy 34.8 Gy 0.041 39.0 Gy 0.740
TCP 57% 55% 0.044 61% 0.055
Background: To compare involved-Àeld
radiotherapy (IF-RT) in locally-advanced non-small The 10% higher risk of isolated nodal failure after
cell lung cancer (LA-NSCLC), delivered with 3D IMRT is highly statistically signiÀcant, but the
conformal (3D-CRT) and intensity-modulated decrease in local control becomes of borderline
(IMRT) radiotherapy. The risk of loco-regional signiÀcance when considering the TCPs for PTVtot.
relapse was analysed using incidental nodal MLD-escalated IMRT results in signiÀcantly higher
irradiation (INI) parameters and tumour-control Dmean and potentially superior chance of local control.
probability (TCP) models. Conclusion: In one out of three LA-NSCLC
Methods: Thirty-one LA-NSCLC patients with patients, PET underestimates the actual nodal disease
pathology-proven mediastinal involvement were extension. Due to reduced INI, using IMRT for IF-
retrospectively retrieved from the Leuven Lung RT entails a statistically signiÀcantly higher risk of
Cancer Group database. Involved nodes were isolated local recurrence. Our data however suggest
compared on mediastinoscopy and 18F-deoxyglucose that this negative impact may be counteracted by the
positron emission tomography (PET) scans. Patients potential of isotoxic dose escalation, which in turn
with one or more nodes positive on pathology may positively inÁuence loco-regional control rates.
but (falsely) negative on PET were selected for Further prospective evaluation of IF-RT using IMRT
further analysis. False-negative nodes on PET were is warranted.
deÀned ‘incidental nodes’ and used to delineate Keywords: intensity-modulated radiotherapy,
the incidental clinical and planning target volumes locally-advanced non-small cell lung cancer,
(CTVinc, PTVinc). The sum of PET-based PTV and involved-Àeld radiotherapy, 18F-deoxyglucose
PTVinc formed the total PTV (PTVtot). Prescribed positron emission tomography
dose (PD) in baseline 3D-CRT and IMRT plans was
66Gy/2Gy, isotoxic escalated IMRT plans delivered A revised/updated abstract may be included in
the same mean lung dose (MLD) as the baseline the Late Breaking Abstract Supplement, available
3D-CRT plan. Mean dose (Dmean), dose to 95% of at the 14th World Conference on Lung Cancer.
the volume (D95) and TCPs were analysed for PTVinc
and PTVtot. All plans were calculated using Eclipse
(Varian) software with a pencil beam (PB) algorithm
and recalculated using a collapsed cone algorithm
(AAA). TCP models being available for PB only,
these data are presented. A two-parameter (D50 and
Ƣ50) TCP model based on Poisson statistics was used.
Results: In 11 patients (35%), false negative
nodes were detected, resulting in a sensitivity and
speciÀcity for PET at the nodal level of 69% and
89% res. MLD-escalated IMRT-plans resulted in an
Session MO09: Medical Oncology I PFS was 9m (95% CI:3.5-11), and the median OS
has not been reached. No grade 2 neuropathy
Tuesday, 5 July 2011 or hematologic/gastrointestinal toxicities were
observed. One pt experienced transitory cerebral
ischemia, and one had a colon perforation. High, but
Medical Oncology I Tuesday, 5 July 2011 10:30-12:00 reversible, BP ( 150/100 or 20 mmHg increase in
diastolic BP from baseline) was observed in 70% of
MO09.01 PRELIMINARY RESULTS OF the evaluable pts. SigniÀcant proteinuria (3+ or 4+)
A PHASE II STUDY OF METRONOMIC was observed in 2 pts.
CHEMOTHERAPY (MC) WITH Conclusion: Adding bevacizumab to metronomic
BEVACIZUMAB (B) IN ADVANCED (ADV) chemotherapy is well tolerated in adv NSCLC pts.
NON-SMALL CELL LUNG CANCER Preliminary efÀcacy data is encouraging. Updated safety
(NSCLC) and efÀcacy data of this ongoing trial will be presented.
Francisco Robert, Mark Womack, Mollie Deshazo, Keywords: Advanced NSCLC, Metronomic
Alan Cantor, Mary Jerome, Debi Miley chemotherapy with bevacizumab, Phase II clinical trial
Comprehensive Cancer Center, University Of
Alabama At Birmingham/United States Of America
Medical Oncology I Tuesday, 5 July 2011 10:30-12:00
Background: Preclinical studies have demonstrated
dramatic control of tumor growth using protracted MO09.02 SUNITINIB PLUS ERLOTINIB
low dose chemotherapy (MC), also resulting in FOR THE TREATMENT OF ADVANCED
signiÀcant apoptosis of endothelial and tumor NSCLC: SUBSET ANALYSIS OF EAST
cells. In order to enhance the antiangiogenic effect ASIAN PATIENTS PARTICIPATING IN A
of MC, we initiated a phase II study using MC PHASE III TRIAL
doses of gemcitabine (G) and paclitaxel (P) in Sumitra Thongprasert1, Yuk Tung2, Joo-Hang
combination with B, with the primary objective Kim3, Gee-Chen Chang4, Keunchil Park5, Wu-
of having a progression-free survival (PFS) of Chou Su6, Sang-We Kim7, Tony S.K. Mok8, Virote
30% over historical data (ECOG 4599-6.4m). Sriuranpong9, Aron Thall10, Lesley Tye11, Ke
Secondary objectives include: safety, objective Zhang10, Richard C. Chao10, Giorgio V. Scagliotti12,
response rate (ORR) and overall survival (OS). Ramaswamy Govindan13
1
Exploratory correlations of the kinetics of several Faculty Of Medicine, Chiang Mai University,
angiogenic biomarkers and clinical parameters Division Of Medical Oncology,/Thailand, 2Clinical
(tumor cavitation, blood pressure [BP], proteinuria) Oncology, Tuen Mun Hospital,/Hong Kong, 3Medical
are evaluated. Oncology, Yonsei Cancer Center, Yonsei University
Methods: Chemo-naive, stage IIIb/IV, non- College Of Medicine/Korea, 4Department Of
squamous NSCLC patients (pts) with performance Internal Medicine, Division Of Chest Medicine,
status 0-1, and without active brain metastases Taichung Veterans General Hospital,/Taiwan,
5
(mets) were treated with MC doses (weekly x 3, Division Of Hematology/oncology, Dept Of
4-week cycle) of P (80 mg/m2/wk) and G (200- Medicine, Samsung Medical Center, Sungkyunkwan
300 mg/m2/wk) and B (10 mg/kg q 2 wks). After 6 University School Of Medicine,/Korea, 6Internal
cycles, pts were placed on B maintenance. Response Medicine, National Cheng Kung University
was determined by CT scans after every 2 cycles Hospital,/Taiwan, 7Oncology, Asan Medical Center,
(RECIST), and toxicity was assessed with CTCAE. University Of Ulsan College Of Medicine,/Korea,
8
Results: Four of the 26 pts enrolled are not evaluable Clinical Oncology, Prince Of Wales Hospital,/
(1- transferred care; 1- ineligible, and 2- too early Hong Kong, 9Chulalongkorn University, Faculty
for evaluation), and one pt was not evaluable for Of Medicine,/Thailand, 10PÀzer Oncology,/United
response because of early death due to a fatal colonic States Of America, 11Oncology, PÀzer Oncology,/
perforation. Baseline characteristics include: median United States Of America, 12Department Of Clinical
age, 57 years; female, 64% never smokers, 16%; loss And Biological Sciences, University Of Turin,
of weight, 40%; and brain mets, 16%. Sixteen pts Department Of Clinical And Biological Sciences/
had an objective response (CR-1; PR-15), and 3 pts Italy, 13Washington University School Of Medicine,/
each had stable and progressive disease. The median United States Of America
Background: Sunitinib is an oral multitargeted [grade 3/4: 2.0%]) and rash (61.5% [grade 3/4:
tyrosine kinase inhibitor of VEGFRs, PDGFRs, KIT 9.6%] vs. 54.9% [grade 3/4: 3.9%], in the sunitinib
and other receptors. A recent phase III double-blind plus erlotinib vs. erlotinib alone arms, respectively).
trial (SUN 1087) investigated sunitinib plus erlotinib Hematologic serious AEs were uncommon (1 case
vs. placebo plus erlotinib in NSCLC patients after of anemia in each study arm). Post-study treatments
failure of chemotherapy. A signiÀcant increase were balanced between study arms. Updated data
in overall survival (OS) was not demonstrated. will be presented.
However, a signiÀcant improvement in progression- Conclusion: Sunitinib plus erlotinib vs. erlotinib
free survival (PFS) and a greater objective response alone was associated with signiÀcantly longer OS,
rate (ORR) were observed in the sunitinib plus greater ORR, and a trend toward longer PFS in the
erlotinib arm vs. erlotinib alone. Since subset subgroup of East Asian patients participating in
analyses in several trials indicate tumors in Asian this trial. AEs were more frequent and severe in the
patients may be more responsive to antiangiogenic sunitinib arm and reÁect the known toxicity proÀles
agents, we investigated the outcome for the subset of of erlotinib and sunitinib. These data indicate that
patients of East Asian descent participating in SUN additional studies of sunitinib plus erlotinib in
1087. patients with advanced NSCLC may be warranted.
Methods: Patients (18 years; ECOG PS 0 or Keywords: erlotinib, Non-small cell lung cancer,
1, previously treated with 1 or 2 chemotherapy phase III, sunitinib
regimens, including 1 platinum-based) had
recurrent NSCLC and were eligible for erlotinib
treatment. Patients were randomized (1:1) to Medical Oncology I Tuesday, 5 July 2011 10:30-12:00
sunitinib 37.5 mg/day plus erlotinib 150 mg/day,
or placebo plus erlotinib 150 mg/day, stratiÀed by MO09.03 THE COMBINATION OF
prior bevacizumab use, smoking history, and EGFR ERLOTINIB/BEVACIZUMAB IN NEVER-
expression. The primary endpoint was OS. Key SMOKERS WITH ADVANCED LUNG
secondary endpoints included PFS, ORR, safety, and ADENOCARCINOMA: SOUTHWEST
patient-reported outcomes. ONCOLOGY GROUP (SWOG) TRIAL 0636
Results: Of the 960 patients randomized, 103 Howard West1, James Moon2, Fred R. Hirsch3,
(10.7%) were of East Asian descent: 52 in the Phillip Mack4, Antoinette Wozniak5, Mary W.
sunitinib plus erlotinib arm and 51 in the placebo Redman2, David R. Gandara4
1
plus erlotinib arm (n=92 [9.6%] randomized in East Medical Oncology, Swedish Cancer Institute/
Asia, n=7 [0.7%] in North America and n=4 [0.4%] United States Of America, 2Southwest Oncology
in EU/South America); 67.0% were male, 40.8% Group/United States Of America, 3Cancer Center,
were never smokers, 69.9% had non-squamous University Of Colorado/United States Of America,
4
histology, and 90.3% had stage IV disease. Mean Oncology, Uc Davis Cancer Center/United States
number of cycles started (range) was 6.0 (1–26) for Of America, 5Karmanos Cancer Institute/wayne State
sunitinib plus erlotinib and 4.0 (1–30) for erlotinib University/United States Of America
alone. Interim median OS was signiÀcantly longer
with sunitinib plus erlotinib vs. erlotinib alone: NR Background: Never-smokers with advanced lung
months (95% CI 13.4, NR) vs. 9.4 months (95% CI adenocarcinoma have emerged as a potentially
7.2, 15.4), P=0.0042. The data did not indicate that relevant clinical subpopulation enriched for a higher
the difference in never smokers between study arms probability of clinical beneÀt from epidermal growth
(sunitinib plus erlotinib n=23, erlotinib alone n=19) factor receptor (EGFR) tyrosine kinase inhibitors
confounded the treatment effect on OS (Cox model). (TKIs). Such patients have a high proportion
ORR was markedly greater in the sunitinib arm of activating mutations and/or copy number
(38.5% vs. 13.7%, P=0.0083), and one conÀrmed abnormalities in the EGFR gene associated with
complete response was observed with sunitinib. favorable clinical outcomes with EGFR TKI-based
Median PFS also favored the sunitinib plus erlotinib: therapy. Based on these results and the potential for
31.2 weeks vs. 15.2 weeks (HR [95%CI]: 0.723 increased clinical activity conferred by addition of
[0.451, 1.161], P=0.0889). The most frequent all- bevacizumab to erlotinib, SWOG initiated a phase
causality non-hematologic adverse events (AEs) II trial (S0126) to test this combination in never-
were diarrhea (94.2% [grade 3: 15.4%] vs. 52.9% smokers with advanced lung adenocarcinoma.
Methods: A total of 85 eligible patients were Medical Oncology I Tuesday, 5 July 2011 10:30-12:00
enrolled and received protocol-based treatment.
Patients received erlotinib 150 mg PO daily MO09.04 CEDIRANIB, A VEGF
and bevacizumab 15 mg/kg IV q21 days until RECEPTOR 1, 2 AND 3 INHIBITOR, AND
progression or prohibitive toxicity. Tumor tissue PEMETREXED IN PATIENTS (PTS) WITH
submission for assessment of molecular markers RECURRENT NON-SMALL CELL LUNG
was mandated. EGFR mutations were assessed by CANCER (NSCLC)
microdissection and sequencing; EGFR copy number Shirish Gadgeel1, John Ruckdeschel2, Antoinette
abnormalities were assessed using the Colorado Wozniak3, Deborah Hackstock3, Wei Chen3, Cathy
FISH scoring system. Galasso3, Angelika Burger3, Patricia Lorusso3, Percy
Results: The median age was 61.3 (range 31.2- Ivy4, Martin J. Edelman5
1
84.1); 87% treatment-naive; 66% are female; 97% Oncology, Karmanos Cancer Institute/wayne State
had a performance status of 0/1; 66% of patients University/United States Of America, 2Nevada
were Caucasian, and 25% were Asian. The RECIST Cancer Institute/United States Of America,
3
response rate among 53 patients with measurable Karmanos Cancer Institute/wayne State University/
disease was 47%. With a median follow-up in United States Of America, 4National Cancer
patients still alive of 12 months (mo) (range 0-35 Institute/United States Of America, 5Cancer Center,
mo), the estimated progression-free survival (PFS) is University Of Maryland/United States Of America
8 mo. Toxicity consisted primarily of rash, diarrhea,
and hypertension; there have been no treatment- Background: The role of anti-VEGF therapy in
related deaths and a single case of grade 3 pulmonary recurrent NSCLC is unclear. We are currently
hemorrhage. In preliminary biomarker analysis, 49% conducting a phase II trial evaluating cediranib, an
of patients were EGFR FISH-positive (17 of 35). oral inhibitor of VEGFR 1,2 and 3, and pemetrexed
EGFR mutations were observed in 30% (10 of 33). in recurrent NSCLC pts who may or may not have
EGFR FISH-positivity correlated with improved previously received bevacizumab.
PFS (p=0.01, HR 0.35 [90% CI: 0.16-0.75]. EGFR- Methods: Pts with progressive NSCLC following
mutation-positive patients had a signiÀcantly better 1 or 2 prior regimens and with any histologic
RECIST response rate (47% vs 26%; p = 0.03). sub-type were eligible. Pts on anti-coagulants and
Patients with a favorable marker (FISH-positivity with treated brain mets were allowed. Pts received
and/or EGFR mutation) had a median PFS of 20 cediranib 30mg daily. 1 week after starting cediranib,
months compared 6 months for those with no pts received pemetrexed 500 mg/m2 every 21 days.
favorable marker (p=0.02) The study consists of two cohorts- A (no prior
Conclusion: The combination of erlotinib bevacizumab) and B (prior bevacizumab). Planned
with bevacizumab in never-smokers with lung accrual is 37 pts each cohort. Accrual to cohort A is
adenocarcinoma is associated with a very completed. Consenting pts underwent blood draw
encouraging clinical efÀcacy and modest toxicity in for circulating tumor cells (CTCs) and circulating
a population that was not molecularly selected. The endothelial cells (CECs) before therapy, 1 week after
addition of bevacizumab did not appear to adversely cediranib was commenced, and after 1 cycle of the
affect erlotinib activity in patients subsets (EGFR combination.
mutant; EGFR FISH+) expected to beneÀt from an Results: 38 pts were enrolled in cohort A. Median
EGFR-TKI. age- 62, males- 50%, ever smokers- 92%, squamous-
Keywords: Adenocarcinoma, Never-smoker, 18% (7 patients), brain mets- 34%, 2 prior regimens-
bevacizumab, erlotinib 42%. Median cycles- 4 (range- 0-26). Grade 3/4
toxicities- neutropenia- 14%, febrile neutropenia-
5%, fatigue-22%, diarrhea- 14%, infection- 8%.
One patient each developed pulmonary hemorrhage,
cardiac ischemia and cerebrovascular event. Three
deaths were deemed related to drug related toxicities.
Response rate is 29% (95% CI- 17%-45%) and
disease control rate (response+stable disease) is 74%
(95% CI- 58%-85%). Median PFS is 5.6 (95% CI-
4.4- 6.8) months and median survival is 11 (95% CI-
5.8- 16.6) months. EfÀcacy parameters for squamous And Innovation Hospital/Japan, 12Osaka Medical
versus non-squamous patients were- Response rate- College Hospital/Japan, 13Jcog Data Center,
0% vs. 35%, PFS- 3.7 vs. 5.7 months, survival 5.2 National Cancer Center/Japan, 14Data Center,
vs. 11.5 months. Among 18 pts with available data, West Japan Oncology Group (wjog)/Japan,
15
60% had decrease in CTCs and 31% of the patients Kyoto University School Of Public Health/Japan,
16
had declines in CECs. There was no signiÀcant Department Of Medical Oncology, Kinki University
association between declines in CTCs or CECs and Faculty Of Medicine/Japan, 17National Cancer
PFS. Center Hospital/Japan
Conclusion: 1.The combination of cediranib and
pemetrexed is tolerable. 2. The response rate of 29% Background: Tri-weekly DTX is considered one
(35% in non-squamous patients) and the median PFS of the standard treatment regimens for elderly
of 5.6 (5.7 in non-squamous patients) months are patients with advanced NSCLC, previously reported
very promising. 3. Though the numbers are small, in WJTOG9904 trial. To investigate whether the
the addition of a VEGF inhibitor cediranib does not addition of a modiÀed administration schedule of
reverse the resistance of squamous cell NSCLCs to CDDP might improve the survival in these patients,
pemetrexed 4. Enrollment to cohort B is ongoing. we previously conducted a phase III trial comparing
Keywords: cediranib, Pemetrexed, recurrent weekly DP with weekly DTX (JCOG0207).
NSCLC Concerning ethically, the trial was terminated early
due to the strong interaction that weekly DP might
be beneÀcial for subgroup of age between 70-74
Medical Oncology I Tuesday, 5 July 2011 10:30-12:00 years. Therefore, we brushed up on a phase III trial
comparing weekly DP with tri-weekly DTX in
MO09.06 RANDOMIZED PHASE elderly patients with advanced NSCLC.
III TRIAL COMPARING WEEKLY Methods: Eligibility criteria in this trial were as
DOCETAXEL (DTX) AND CISPLATIN followed: chemotherapy-naive; unÀt for bolus P
(CDDP) COMBINATION (DP) WITH TRI- administration; stage III/IV or relapsed NSCLC
WEEKLY DTX ALONE IN ELDERLY after completely surgical resection; age70 years
PATIENTS WITH ADVANCED NON- old; PS (ECOG) 0-1. Patients were randomized to
SMALL CELL LUNG CANCER (NSCLC): receive either weekly DP or tri-weekly DTX by the
RESULTS OF AN INTERGROUP TRIAL minimization method, balancing for study site, age
OF JCOG0803/WJOG4307L (<75/75), and stage (III/IV). Weekly DP comprised
Koji Takeda1, Tetsuya Abe2, Akira Yokoyama2, administration of DTX (20 mg/m2) and CDDP (25
Yuichiro Ohe3, Shinzoh Kudoh4, Yukito Ichinose5, mg/m2) intravenously on days 1, 8, and 15 every 4
Masao Harada6, Koichiro Kudoh7, Funihiro Oshita8, weeks. In tri-weekly DTX alone, DTX (60 mg/m2)
Yuka Fujita9, Terufumi Kato10, Nobuyuki Katakami11, was administered intravenously on day 1 every 3
Isao Goto12, Junki Mizusawa13, Taro Shibata13, weeks. The primary endpoint was overall survival
Shinichiro Nakamura14, Masahiko Ando15, Kazuhiko (OS). The planned sample size was 190 pts in each
Nakagawa16, Nagahiro Saijo16, Tomohide Tamura17 arm, to provide an 80% power to detect a 0.752
1
Department Of Clinical Oncology, Osaka City hazard ratio for weekly DP to tri-weekly DTX in
General Hospital/Japan, 2Department Of Internal regard to the OS, and a 5% one-sided alpha.
Medicine, Niigata Cancer Center Hospital/ Results: Between October 2008 and September
Japan, 3Division Of Thoracic Oncology, National 2010, 276 patients were randomized (DTX/DP:
Cancer Center Hospital East/Japan, 4Department 137/139). The Àrst planned interim analysis was
Of Respiratory Medicine, Osaka City University performed on 221 assessable patients (DTX/DP:
Garaduate School Of Medcine/Japan, 5Department 108/113, <75/75: 22/78%, male/female: 70/30%,
Of Thoracic Oncology, National Kyushu Cancer PS 0/1: 35/65%, III/IV or relapse: 32/68%).
Center/Japan, 6Hokkaido Cancer Center/Japan, Information time, deÀned as the proportion of
7
National Center For Grobal Health And Medicine/ interim events to planned events, was 24% (73/304).
Japan, 8Thoracic Oncology, Kanagawa Cancer The median survival times (MST) of the weekly
Center/Japan, 9Asahikawa Medical Center/Japan, DP and tri-weekly DTX groups were 13.3 and 17.3
10
Kanagawa Cardiovascuiar And Respiratory months, respectively (hazard ratio [95% C.I.]: 1.557
Center/Japan, 11Institute Of Biomedical Research [0.976-2.485]). The predictive probability that
weekly DP would be superior to tri-weekly DTX Hia Percy/France, 15Medical Oncology, Centre
at the time of the Ànal analysis was 0.996%, which René Gauducheau/France, 16Pneumologie, Ap-hp
led to early termination of the trial. In subgroup St-louis/France, 17Chest Medicine Department,
of 75 years, the MST of the weekly DP and tri- Grenoble University Hospital/France, 18Intergroupe
weekly DTX groups were 13.3 and 17.3 months, Francophone De Cancérologie Thoracique (IFCT)/
respectively. In this trial, there was no interaction France
like to the results of JCOG0207. The major grade 3-4
toxicities were (%DTX/DP): neutropenia 88/11%, Background: The 2004 ASCO guidelines
anemia 3/16%, anorexia 1/10%, febrile neutropenia recommended a platinum-based doublet
17/0%, pneumonitis 3/2%. Treatment-related death chemotherapy for the treatment of Àt patients with
occurred in 3 patients of the weekly DP arm. The advanced non-small cell lung cancer (NSCLC) and a
proportion of patients with an improved symptom monotherapy for elderly patients. Subgroup analyses
score (FACT-L lung symptom subscale) after 3 of elderly patients within randomized controlled
courses of treatment was higher in the tri-weekly trials suggested that a platinum-based doublet might
DTX arm. increase survival in elderly. Therefore, we conducted
Conclusion: This trial failed to demonstrate any a phase III trial comparing the carboplatin -weekly
advantage of the addition of CDDP to single-agent paclitaxel doublet to monotherapy in elderly patients
DTX in Àrst-line chemotherapy for elderly patients with advanced NSCLC.
with advanced NSCLC. Methods: Patients aged 70 to 89 years, PS 0-2,
Keywords: Elderly, NSCLC, Cisplatin, Docetaxel with locally advanced or metastatic NSCLC were
randomized between carboplatin-weekly paclitaxel
(4 cycles, total duration 16 weeks) and vinorelbine
Medical Oncology I Tuesday, 5 July 2011 10:30-12:00 or gemcitabine monotherapy (5 cycles, total duration
15 weeks). Primary endpoint was overall survival.
MO09.07 CARBOPLATIN WITH Secondary endpoints included progression-free
WEEKLY PACLITAXEL DOUBLET survival, response, toxicity and quality of life.
VERSUS MONOTHERAPY IN ELDERLY QOL was assessed during treatment by European
PATIENTS WITH ADVANCED NON- Organisation for Research and Treatment of Cancer
SMALL CELL LUNG CANCER: QUALITY QLQ-C30 (inclusion, week 6, week 18)
OF LIFE ANALYSIS (QOL) OF IFCT-0501 Results: From April 2006 to December 2009, 451
TRIAL patients were included (median age: 77). Median
Elisabeth Quoix1, Jean-Philippe Oster2, Virginie overall survival was 10.3 months for the doublet and
Westeel3, Eric Pichon4, Gérard Zalcman5, Armelle 6.2 months for monotherapy (hazard ratio 0.64; 95%
Lavolé6, Jérôme Dauba7, Didier Debieuvre8, Pierre conÀdence interval, 0.52 to 0.78, p < 0.0001). One-
Jean Souquet9, Laurence Bigay-Gamé10, Olivier year survival was 44.5% versus 25.4%, respectively.
Molinier11, Eric Dansin12, Michel Poudenx13, Fabien Compliance with QOL was 94% at baseline, 62%
Vaylet14, Jaafar Bennouna15, Jean Trédaniel16, Denis at week 6 and 49% at week 18. Both regimens had
Moro-Sibilot17, Dominique Herman2, Laurence similar baseline QOL. At week 6, the global QOL is
Baudrin18, Franck Morin18, Bernard Milleron18 comparable between the two regimens (mean score
1
Pulmonary Medicine Department, Strasbourg 54.7 vs 56.9), but there was more pain (30.2 vs 18.7,
University Hospital/France, 2Pneumologie, Ch/ p=0.003) and dyspnea (47.4 vs 36.8, p=0.014) in
France, 3Chest Medicine Department, Besançon the monotherapy, and more diarrhea in the doublet
University Hospital/France, 4Pneumologie, Chu/ (8.8 vs 18.4, p=0.003). At week 18, the global QOL
France, 5Chu Cote De Nacre/France, 6Pneumologie, is similar between the two regimens (58.2 vs 61.8).
Hôpital Tenon/France, 7Oncologie, Ch/France, Regarding evolution between inclusion and week
8
Pulmonary Medicine Department, Haute 18, the global QOL was similar in the two regimens,
Saône Community Hospital/France, 9Service but there was an improvement in Role Functioning
De Pneumologie Dr Souquet, Hôpital Lyon Sud, (-1.9 versus -15.3, p=0.026) and an increasing of the
Hospices Civils De Lyon/France, 10Thoracic fatigue (-0.6 vs 12.4, p=0.039) in the doublet.
Oncology, Toulouse University Hospital/France, Conclusion: Despite increased toxicity, the
11
Le Mans Regional Hospital/France, 12Centre Oscar quality of life analysis of carboplatin-weekly
Lambret/France, 13Crlcc/France, 14Pneumologie, paclitaxel doublet was preserved over vinorelbine
or gemcitabine monotherapy in elderly patients geriatric assesment as a decision tool.

with NSCLC. According to the signiÀcant survival Methods: French multicentric randomized phase
beneÀt, this Ànding should modify the paradigm of III study in patients aged 70, PS 0-2 with stage
treatment in performance status 0-2 elderly patients IV NSCLC comparing a treatment algorithm based
with advanced NSCLC. on standard criteria (PS and age) in arm A with
Keywords: Quality of Life, Elderly, Non-small cell an experimental, optimized algorithm based on
lung cancer, doublet an abbreviated geriatric assessment (aGA) plus
or more a CGA in arm B. In arm B, if the aGA
results are normal, the patient is treated with 4
Medical Oncology I Tuesday, 5 July 2011 10:30-12:00 cycles of dual-agent therapy based on platinum
(carboplatin AUC 5 D1 + pemetrexed 500 mg/
MO09.08 STUDY ESOGIA-GFPC m2 D1 q21D if the histology is non epidermoid,
08-02 - PHASE III, RANDOMIZED, carboplatin AUC5 D1 + gemcitabin 1000 mg/m2
MULTICENTER TRIAL INVOLVING D1-D8 q21D if the histology is epidermoid), with no
SUBJECTS OVER 70 YEARS OF further geriatric assessment. When the aGA reveals
AGE WITH NON SMALL-CELL abnormalities, a comprehensive geriatric assesment
LUNG CANCER OF STAGE IV AND (CGA) is used to deÀne two subpopulations on
COMPARING A “CLASSICAL” Balducci’s fragility scale, who will receive either
STRATEGY OF TREATMENT monotherapy (docetaxel 38 mg/m2, D1-D8 q21D)
ALLOCATION (DUAL-AGENT THERAPY or best supportive care. In arm A, the same dual
BASED ON CARBOPLATIN OR agent therapy or monotherapy will be allocated but
MONOTHERAPY WITH DOCETAXEL according only to PS and age. The primary endpoint
ALONE), BASED ON PERFORMANCE is Time to treatment failure.The total number of
STATUS AND AGE, WITH AN subjects to enroll is 490 patients
“OPTIMIZED” STRATEGY ALLOCATING Results: From Jan 2010 to feb 2011 data-cut, 156
THE SAME TREATMENTS ACCORDING patients were randomized. Baseline characteristics
TO A SIMPLIFIED GERIATRIC (%): male 78, adenocarcinoma 61, PS 0/1/2
SCREENING SCALE, PLUS A MORE :27/56/16, median age 77yr (range 70-87), score
THOROUGH GERIATRIC EVALUATION ADL 0/1/2: 83/8/9, IADL 0/1/2:62/21/17, charlson
IF NECESSARY. number of co-morbidities 0/1/2:40/32/28. 49% of
Romain Corre1, Clarisse Audigier-Valette2, Henri the patients received docetaxel, 15% carboplatine-
Bérard3, Lionel Falchero4, Christophe Demattei5, gemcitabine, 26% carboplatine-pemetrexed, 14%
Herve Le Caer6 the best supportive care. 83 patients (53%) had an
1
Pneumology, Hôpital Pontchaillou/France, 2Service adverse event (AE) of any grade. % grade 1/2/3/4/5
De Pathologie Respiratoire, Chi/France, 3Service De AEs were 40/32/23/1.5/3.5 most commonly anemia
Pathologie Respiratoire, Hôpital D’Instruction Des (24%), asthenia (19%), nausea (8%). 53 patients
Armées Sainte Anne/France, 4Pneumologie, Centre (33%) had 69 serious AEs.
Hospitalier/France, 5Biostatistics, Ghu Carémeau/ Conclusion:
France, 6Oncology, Centre Hospitalier Dracenie/ This is the Àrst phase III trial that tries to validate
France the use of a CGA as a screening tool in treatment of
patients70 years old with stage IV NSCLC. The
Background: Incidence of advanced NSCLC in the use of the CGA is feasible in practise. The different
elderly is increasing. Current recommendations are chemotherapies used (carboplatin-gemcitabine,
monotherapies. Study IFCT 05-01 communicated carboplatine-pemetrexed, or docetaxel) are generally
in 2010 has demonstrated the superiority of weekly well tolerated, most AEs are of mild-moderate
paclitaxel plus carboplatin to monotherapies but with intensity. The study is ongoing
a high rate of toxic deaths. The use of comprehensive Keywords: geriatric assesment, NSCLC, Elderly,
geriatric assessment (CGA) is recommended to treatment
detect the patient’s vulnerability and to predict the
treatment tolerance but its integration in treatment A revised/updated abstract may be included in
decision making does not remain clearly deÀned. the Late Breaking Abstract Supplement, available
The aim of this study is to validate the use of a at the 14th World Conference on Lung Cancer.
Medical Oncology I Tuesday, 5 July 2011 10:30-12:00 PFS with V (p=0.03) but no difference in DCR
nor OS. There was no difference between the age
MO09.09 ELDERLY CHEMO- groups in grade 3-4 heme AE. However, women >
REFRACTORY NSCLC PATIENTS 65 yrs had a higher rate of grade 3-4 non-heme AE
DERIVE BENEFIT FROM SALVAGE (p=0.05) that was primarily seen with S (p=0.04).
TARGETED THERAPY - SUBGROUP Older pts were more likely to report diarrhea and GI
ANALYSIS OF CLINICAL OUTCOME symptoms. Women age > 65 and age > 70 were more
AND TOXICITY FROM THE BATTLE likely to require dose reductions but this was not
TRIAL treatment speciÀc. Additional biomarker information
Anne Tsao1, Suyu Liu2, J.J. Lee2, Christine Alden1, and differences between age groups and gender will
Edward Kim1, George Blumenschein1, Roy Herbst1, be evaluated.
Scott Lippman1, Ignacio Wistuba3, Waun K. Hong1 Conclusion: Fit elderly NSCLC patients should be
1
Thoracic And Head & Neck Medical Oncology, considered for salvage targeted therapy as there is
University Of Texas M.D. Anderson Cancer Center/ no adverse impact on survival; in fact, older men >
United States Of America, 2Biostatistics, University 65 yrs derive signiÀcant clinical beneÀt to certain
Of Texas M.D. Anderson Cancer Center/United agents. Gender differences in tolerance were seen in
States Of America, 3Pathology-research, University older women.
Of Texas M.D. Anderson Cancer Center/United Keywords: Elderly, vandetanib, erlotinib, sorafenib
States Of America
Background: BATTLE was a phase II trial that Medical Oncology I Tuesday, 5 July 2011 10:30-12:00
randomized 255 patients (pts) into 4 separate trials:
erlotinib (E), erlotinib-bexarotene (E-B), vandetanib MO09.11 ETHNIC DIFFERENCES IN
(V), and sorafenib (S). Treating elderly chemo- SURVIVAL OUTCOME IN PATIENTS
refractory NSCLC pts is often challenging; we WITH ADVANCED STAGE NON-SMALL
sought to determine if older pts on the BATTLE trial CELL LUNG CANCER- RESULTS OF
had worse outcomes or more adverse events (AE). A META-ANALYSIS OF RANDOMISED
Methods: Chemorefractory NSCLC pts with PS CONTROLLED TRIALS
0-2 and any line of prior therapy were enrolled. Marie Loh1, Tony Mok2, Sai-Hong I. Ou3, Byoung-
Following tumor biomarker evaluation, pts were Chu Cho4, Wee-Lee Yeo5, Dan G. Tenen1, Richie
randomized to oral therapy with E (150 mg daily), Soong1, Ross A. Soo5
1
E + B (400 mg/m2 daily), V (300 mg daily), or Cancer Science Institute Of Singapore, National
S (400 mg twice daily) with Q8 wk radiographic University Of Singapore/Singapore, 2Department
assessment. AE were assessed by NCI-CTC v. 3.0. Of Clinical Oncology, The Chinese University Of
Subgroup analysis was conducted via Fisher’s exact Hong Kong/Hong Kong, 3Department Of Internal
test for age groups (> 65 v > 65 years; > 70 v 70 Medicine, Chao Family, Comprehensive Cancer
years; > 75 v > 75 years), treatments, and gender. Center/United States Of America, 4Division Of
Kaplan-Meier method, log-rank tests, and Cox Medical Oncology, Yonsei Cancer Center/Korea,
5
proportional hazards models were also used. Department Of Haematology-oncology, National
Results: In the ITT population, median age 62 University Cancer Institute/Singapore
(range 26-84); 16% age < 50, 29% age 51-60,
34% age 61-70, 22% > 70 yrs; 46% F, 9% PS 0, Background: Although inter-ethnic differences
77% PS 1, 14% PS 2. No differences in RR or OS in survival to cytotoxic chemotherapy in patients
were seen between any age groups. However DCR with NSCLC exist, an analysis of survival
at 8 wks was better in older women > age 70 yrs outcomes based on ethnicity has not yet been fully
(p=0.06) and men > 65 yrs (p=0.008); also, men > evaluated systematically using large patient cohorts.
65 yrs (p=0.0068) and men > 70 yrs (p=0.09) had Furthermore, recent trial results may be confounded
better PFS. Treatment-speciÀc analyses showed by the use of the epidermal growth factor receptor
that older men > 65 yrs treated with V had a better (EGFR) tyrosine kinase inhibitor (EGFR TKI).
PFS (p=0.03). Male pts > 70 yrs had an improved Methods: A meta-analysis was performed using
DCR with E (p=0.05) and an improved OS with S trials identiÀed through MEDLINE. Summary data
(p=0.04). However, women age > 70 yrs had a worse on median overall survival (OS), time to progression,
progression free survival and overall response rate Medical Oncology I Tuesday, 5 July 2011 10:30-12:00
(ORR) were collected from randomized controlled
trials. Outcomes were compared between Asian and MO09.12 EFFICACY, TOLERABILITY
Caucasian studies. AND BIOMARKER ANALYSES
Results: Of the 1182 citations identiÀed, 391 FROM A PHASE III, RANDOMIZED,
treatment arms (Asian 90, Caucasian 301) were PLACEBO CONTROLLED, PARALLEL
analysed. The median OS and ORR in Asian and GROUP STUDY OF GEFITINIB AS
Caucasian studies for all chemotherapy regimens was MAINTENANCE THERAPY IN PATIENTS
10.1 months and 8.0 months (p<0.001), and 32.2% WITH LOCALLY ADVANCED OR
and 25.9% (p<0.001), respectively. The median OS METASTATIC NON-SMALL-CELL LUNG
in Asian and Caucasian studies for monotherapy, two CANCER (NSCLC) IN CHINA (INFORM)
drugs, and three drug or more combination was 9.9 (C-TONG 0804)
and 6.8 months, 10.3 and 8.6 months, and 9.4 and Li Zhang1, Shen L. Ma2, Xiang Q. Song3, Bao H.
8.0 months, respectively (all p<0.001). In studies Han4, Ying Cheng5, Cheng Huang6, Shu J. Yang7,
published pre-EGFR TKI, the median OS and ORR Xiaoqing Liu8, Yun P. Liu9, Meng Z. Wang10, X.
in Asian and Caucasian studies for all chemotherapy Zhang11
1
regimens was 9.1 months vs 7.3 months (p<0.001), Medical Oncology, Sun Yat-sen University Cancer
respectively and 29.0% and 23.0% (p<0.006), Center/China, 2Zhejiang Cancer Hospital/China,
3
respectively. The median OS in Asian and Caucasian Medical Oncology, AfÀliated Tumor Hospital
studies for monotherapy, two drugs, and three drug Of Guangxi Medical University/China, 4Internal
or more combination pre EGFR TKI was 8.9 and 6.5 Medicine, Shanghai Jiaotong University AfÀliated
months (p<0.005), 9.1 and 7.3 months (p<0.001), Shanghai Chest Hospital/China, 5Jilin Cancer
and 9.3 and 7.6 months (p<0.003), respectively. In Hospital, Jilin Cancer Hospital/China, 6Medical
3rd generation platinum doublets, the median OS in Department, The Cancer Hospital Of Fujian/China,
7
Asian and Caucasian studies was 11.3 months and Henan Cancer Hospital/China, 8Tumor Medical,
9.5 months (p<0.001), respectively and ORR was 307 Hospital Of The Academy Of Military Medical
35.0% and 29.8% (p<0.001), respectively. Sciences/China, 9First Hospital Of China Medical
Univ,/China, 10Peking Union Medical Hospital/
China, 11Astrazeneca, Shang Hai, China/China
Background: The phase III, randomized,

multicenter, parallel group INFORM study
investigated the efÀcacy, safety and tolerability
of geÀtinib v placebo as maintenance therapy
in patients with locally advanced or metastatic
NSCLC following standard 1st line platinum based
chemotherapy.
Methods: Patients (>18years, recruited at 27 centers
from 26 September 2008-10 August 2009) had
stage IIIB/IV NSCLC, performance status (PS) 0-2,
and had completed 4 cycles of 1st line platinum
based doublet chemotherapy without progression or
unacceptable toxicity. Patients were randomized 1:1
Conclusion: Ethnic differences in survival and to geÀtinib 250mg/day or placebo on discontinuation
response rate to chemotherapy exist and of 1st line therapy. The primary endpoint was
should be considered in clinical trial designs progression-free survival (PFS). Secondary
especially in the global context. endpoints include overall survival (OS), objective
Keywords: Chemotherapy, ethnicity, meta-analysis, response rate (ORR), disease control rate (DCR),
Non-small cell lung cancer symptom improvement (Lung Cancer Subscale
[LCS]) and tolerability. Assuming a geÀtinib:placebo
hazard ratio of 0.7, 265 PFS events are required to
demonstrate superiority of geÀtinib (2-sided 5%
signiÀcance level, 80% power). Assessing efÀcacy free survival (PFS) beneÀts compared to placebo,
according to tumor biomarker status (EGFR and irrespective of EGFR status (SATURN,Capuzzo
K-Ras mutations) were pre-planned exploratory 2010).In patients with mNSCLC and stable
objectives. disease (SD) after 1L standard platinum-based
Results: By 20 January 2011, 265 PFS events chemotherapy,the overall survival beneÀts observed
had occurred. PFS and OS in the intent-to-treat were largest and it is for this group that Erlotinib is
population (n=296) and in clinical and biomarker indicated as a maintenance treatment in the European
subgroups will be analyzed (Cox proportional Union (EMA 2010).1LM Erlotinib in SD mNSCLC
hazards model adjusted for WHO PS [0,1 v 2], has been demonstrated to be cost-effective in a recent
histology [adenocarcinoma v non-adenocarcima], analysis (Vergnenègre 2010); the cost-effectiveness
smoking status [never-smoker v smoker], and best of 1LM Erlotinib speciÀcally in EGFR wildtype
response to Àrst-line chemotherapy [complete (WT) mNSCLC has not yet been assessed.
response/partial response v stable disease]). ORR, Methods: The incremental cost per life year gained
DCR and LCS improvement rates will be analyzed of 1LM Erlotinib in patients with EGFR WT
using logistic regression adjusted for the same mNSCLC and SD after 1L chemotherapy compared
covariates as PFS. Tolerability will be assessed. to BSC was assessed in a cost-effectiveness analysis
Exploratory biomarker analyses will be performed for 5 European countries (the UK, Germany, France,
according to tumor biomarker status (positive, Spain, Italy). An Area-under-the-Curve model
negative, unknown), where appropriate. consisting of three health states (PFS, progressive
Conclusion: Final, event driven PFS data will be disease (PD) and death) was used, where patients
available in April 2011. We will submit the Ànal enter the model in PFS and after each month, can
abstract in 13 May, 2011, which will include PFS, stay in PFS or move to PD or death. The model is
OS,ORR , safety and biomarker analysis. based on OS and PFS data from the SATURN SD
Keywords: maintenance therapy, NSCLC, geÀtinib EGFR wildtype mNSCLC subgroup, which were
Àtted with log-logistic survival functions to model
A revised/updated abstract may be included in the proportion of patients in PFS and death over
the Late Breaking Abstract Supplement, available patients’ lifetime. The proportion of patients in PD
at the 14th World Conference on Lung Cancer. was modeled as PD=OS-PFS. Country-speciÀc
costs considered were the 1LM Erlotinib therapy
cost (modelled as the time to complete treatment
Medical Oncology I Tuesday, 5 July 2011 10:30-12:00 cessation,using ex-factory prices) and Erlotinib
adverse event costs (most common Grade 3/4
MO09.13 MAINTENANCE ERLOTINIB events), and 2L treatment cost (90 days of Docetaxel
IN STABLE DISEASE EGFR WILDTYPE assumed for both treatment groups, for proportion
ADVANCED NON-SMALL-CELL LUNG of patients). Costs and effects were discounted at a
CANCER: A COST-EFFECTIVENESS rate of 3% per annum; deterministic and probabilistic
ANALYSIS FOR 5 EUROPEAN sensitivity analyses (PSA) using Monte Carlo
COUNTRIES Simulation (1’000 iterations) were undertaken to
Silke Walleser1, Joshua A. Ray2, Helge Bischoff3, assess uncertainty in the base case assumptions.
Alain Vergnenegre4, Hubertus Rosery5, Stefan Results: 1LM Erlotinib compared to BSC in SD
Walzer2 EGFR WT mNSCLC resulted in 4.57 months of
1
Independent Consultant/Switzerland, 2F. Hoffmann- life gained (Erlotinib:17.82 vs BSC:13.24); and
la Roche Pharmaceuticals Ag/Switzerland, 3Thoracic 1.14 months of life without progression gained
Oncology, Thoraxklinik/university Of Heidelberg/ (Erlotinib:4.29 vs BSC:3.15). The analyses showed
Germany, 4Hôpital Du Cluzeau/France, 5Aim Gmbh total costs of Tarceva ranging from 10’542€ (Italy)
- Assessment In Medicine Research And Consulting/ to 13’203€ (Germany) and total costs of BSC from
Germany 2’393€ (Italy) to 3’623€ (Germany), resulting in
incremental total costs ranging from 7’897€ (the
Background: Erlotinib maintenance therapy in UK) to 9’580€ (Germany). The mean incremental
patients with locally advanced or metastatic non- costs per life year gained of Erlotinib 1LM compared
small cell lung cancer (mNSCLC) has demonstrated to BSC in SD EGFR WT mNSCLC were between
signiÀcant overall survival (OS) and progression- 20’711€ (the UK) and 25’124€ (Germany), and
thus well within a range usually considered as demonstrated noninferiority in terms of overall
cost-effective. Results were not largely variable survival (OS) compared to carboplatin/paclitaxel.
to changes in variables tested in deterministic Here, we present the Ànal analysis of survival data.
sensitivity analyses. The most sensitive variable was Methods: A total of 564 Patients (pts) with stage
the discount rate for effects, which at 6% resulted in IIIB or IV NSCLC were randomly assigned to
the highest ICER observed (26’429 €, Germany). receive either carboplatin/S-1, carboplatin AUC 5
PSA conÀrmed Àndings from deterministic analyses. mg/ml/min on day 1 plus oral S-1 80 mg/m2/day
Conclusion: Erlotinib 1L maintenance treatment (40 mg/m2 b.i.d.) on days 1 to 14, or carboplatin/
is value for money compared to BSC in SD EGFR paclitaxel, carboplatin AUC 6 mg/ml/min plus
wildtype mNSCLC independent of country setting. paclitaxel (200 mg/m2) on day 1, every 21 days. The
Keywords: EGFR wildtype, erlotinib, NSCLC study included patients with ECOG PS of 0-1, aged
Advanced Stage, Maintenance treatment 20-74, and preserved organ functions. The analysis
was updated using 2 year follow-up data. The
planned subgroup (stage, PS, histology, gender and
Medical Oncology I Tuesday, 5 July 2011 10:30-12:00 smoking status) analysis was assessed using the Cox
regression model. This study expected 442 events.
MO09.14 PHASE III TRIAL COMPARING Results: At the Ànal analysis, total of 446 death
CARBOPLATIN/S-1 TO CARBOPLATIN/ events were observed. The overall median OS
PACLITAXEL IN TREATMENT-NAïVE was 15.2 months (95%CI, 12.3–17.8) for the
PATIENTS WITH ADVANCED NON- carboplatin/S-1 arm and 13.1 months (95%CI,
SMALL CELL LUNG CANCER (NSCLC): 11.7–14.9) for carboplatin/paclitaxel arm. The
SUBGROUP ANALYSIS AND UPDATED adjusted 95% CI of the hazard ratio (HR) for the OS
RESULTS OF THE LETS STUDY of 0.956 was 0.793–1.151. In subgroup analysis,
(WJTOG3605). the HRs (95% CI) in each subgroup were 1.004
Miyako Satouchi1, Isamu Okamoto2, Satoshi Morita3, (0.689–1.463) / 0.973 (0.786–1.205) for stage IIIB/
Hiroshige Yoshioka4, Koji Takeda5, Takashi Seto6, IV, 1.132 (0.805–1.594) / 0.920 (0.737–1.149) for
Nobuyuki Yamamoto7, Masahiro Fukuoka8, Toyoaki PS 0/1, 0.713 (0.476-1.068)/ 1.060 (0.859–1.308)
Hida9, Nobuyuki Katakami10, Hiroshi Saito11, Hiroshi for squamous (sq)/non-squamous (non-sq), 0.953
Senba12, Kenji Tamura8, Soichiro Yokota13, Takashi (0.774–1.174) /0.971 (0.640–1.473) for male/female
Nakano14, Yoshiro Tanio15, Kazuhiko Nakagawa2 and 0.961 (0.785–1.176) / 1.055 (0.654–1.700) for
1
Thoracic Oncology, Hyogo Cancer Center/Japan, smoker /non-smoker. The 95% CI for the HR in each
2
Kinki Univercity Faculty Of Medicine/Japan, subgroup included 1.00. The median PFS was 4.1
3
Yokohama City University Medical Center/Japan, months in the carboplatin/S-1 arm and 4.8 months in
4
Department Of Respiratory Medicine, Kurashiki the carboplatin/paclitaxel arm in the ITT population,
Central Hospital/Japan, 5Clinical Oncology, Osaka with a corresponding HR of 1.035 and 95% CI of
City General Hospital/Japan, 6National Kyusyu 0.875 to 1.224.
Cancer Center/Japan, 7Division Of Thoracic Conclusion: Consistent with the results of interim
Oncology, Shizuoka Cancer Center/Japan, 8Kinki analysis, this updated analysis demonstrated
University School Of Medicine, Nara Hospital/ improved noninferiority for OS by carboplatin/S-1.
Japan, 9Aichi Cancer Center/Japan, 10Institute Of Subgroup analysis of OS according to stage, PS,
Biomedical Research And Innovation Hospital/ gender and smoking status were consistent with the
Japan, 11Department Of Respiratory Medicine, Aichi primary analysis. Conversely, these Àndings suggest
Cancer Center Aichi Hospital/Japan, 12Kumamoto that carboplatin/S-1 may be more beneÀcial for sq
Regional General Hospital/Japan, 13Toneyama carcinoma pts.
National Hospital/Japan, 14Division Of Respiratory Keywords: S-1, Carboplatin, phase III, Subgroup
Medicine, Department Of Internal Medicine, Hyogo analysis
College Of Medicine/Japan, 15Osaka General
Medical Center/Japan
Background: We have previously reported the

results of interim analysis of the LETS study
[Okamoto et al. JCO 2010] in which carboplatin/S-1
Session MO10: Classical Pathology for pT2a/p2 (n=67). As a result of model A, VPI
(P=0.006) were identiÀed as independent predictors
Tuesday, 5 July 2011 of a poor prognosis. But As a result of model B, VPI
(P=0.091) were not identiÀed.
Conclusion: From the viewpoint of prognosis
Classical Pathology Tuesday, 5 July 2011 10:30-12:00 in tumors with a diameter of 3 cm or less, elastic
layer invasion is a border of VPI, and p1 and p2
MO10.01 ELASTIC LAYER INVASION pleural involvement should be combined as a single
INFLUENCED OVERALL SURVIVAL IN category. So the 7th TNM classiÀcation of UICC and
RESECTED NON–SMALL CELL LUNG JLCS is appropriate.
CANCER WITH A DIAMETER OF 3 CM Keywords: Lung cancer, Visceral Pleural Invasion,
OR LESS. Elastic layer invasion, TNM classiÀcation
Hirofuimi Uehara1, Yukinori Sakao1, Mingyon Mun1,
Ken Nakagawa1, Yuichi Ishikawa2, Makoto Nishio3, A revised/updated abstract may be included in
Sakae Okumura1 the Late Breaking Abstract Supplement, available
1
Thoracic Surgical Oncology, Cancer Institute at the 14th World Conference on Lung Cancer.
Hospital/Japan, 2Pathology, Cancer Institute
Hospital/Japan, 3Thoracic Oncology Center, Cancer
Institute Hospital, Japanese Foundation For Cancer Classical Pathology Tuesday, 5 July 2011 10:30-12:00
Research/Japan
MO10.02 SIGNIFICANCE OF EXTENT OF
Background: Visceral Pleural Invasion (VPI) by VASCULAR INVASION AND LYMPHATIC
lung tumor was recognized to be a factor of poor PERMEATION: PROGNOSTIC
prognosis in lung cancer. In 2009, the deÀnition of IMPLICATION IN COMPLETELY
VPI was changed from P2 (visceral pleural surface RESECTED NON-SMALL CELL LUNG
invasion) to P1 (elastic layer invasion) in 7th UICC CANCER
TNM classiÀcation. And in 2010, The Japan Lung Yoshihisa Shimada1, Genichiro Ishii2, Junji Yoshida1,
Cancer Society (JLCS) adopted that deÀnition in Keiju Aokage1, Tomoyuki Hishida1, Mitsuyo
the new version. Thus, if a tumor invades the elastic Nishimura1, Norihiko Ikeda3, Kanji Nagai1
1
layer and it is 3 cm or less in size, it will be classiÀed Division Of Thoracic Surgery, National Cancer
as T2a. Center Hospital East/Japan, 2Pathology Division,
Methods: We reviewed the records of 669 patients Research Center For Innovative Oncology, National
with non–small cell lung cancer with a diameter of Cancer Center Hospital East/Japan, 3Department Of
3 cm or less. Histologically, VPI was evaluated by Surgery, Tokyo Medical University/Japan
elastic Àber staining and subdivided into four pleural
invasion grades according to the JLCS criteria, as Background: The presence of vascular invasion
follows: p0, tumor with no pleural involvement (V) and lymphatic permeation (Ly) has been
beyond its elastic layer; p1, tumor extension beyond reported to be a strong predictor of prognosis, but
the elastic layer of the visceral pleura but with no the signiÀcance of the extent of V and Ly has yet to
exposure on the pleural surface; p2, tumor exposure be clearly demonstrated. The aim of this study was
on the pleural surface but no involvement of adjacent to classify V and Ly according to their extent and to
anatomic structures; and p3, tumor that involves assess their prognostic signiÀcance in patients with
adjacent anatomic structures. We distributed P factor non-small cell lung cancer (NSCLC).
in a model of A (P1-2 vs P0) and B (P2 vs P0-1) and Methods: We reviewed 1155 consecutive patients
performed analysis. with NSCLC underwent complete resection for their
Results: It was only model A that has correlation clinicopathological characteristics and prognoses.
with lymph node involvement. The 5-year survival
rates and the number of patients in each p factor
were 83% for P0 (n=525), 61% for P1 (n=70), 57%
for P2 (n=61), and 61% for P3 (n=13). In each
pT factor were 89% for pT1a (n=247), 81% for
pT1b (n=231), 69% for pT2a/p1 (n=54), and 67%
prognostic factors. (a) Patients with T2 tumors of Ly2

and those with T3 tumors, and (b) patients with T1
tumors of V+ (V1-2) and those with T2 tumors showed
essentially identical survival curves (Figure 2).
Conclusion: According to the extent of vessel
invasion, OS rates were signiÀcantly different
between each extent group for both V and Ly. Ly2
and V+ (V1-2) were independently signiÀcant
prognostic predictors. T2 tumors of Ly2 should be
upgraded to T3, and T1 tumors of V+ (V1-2) should
be upgraded to T2 in the future TNM ClassiÀcation.
Keywords: NSCLC, vascular invasion, lymphatic
permeation

Classical Pathology Tuesday, 5 July 2011 10:30-12:00
MO10.03 PROGNOSTIC SIGNIFICANCE

OF INTRATUMORAL VASUCULAR
INVASION IN NON-SMALL CELL
LUNG CANCER – A CANDIDATE
OF PATHOLOGICAL PROGNOSTIC
FACTORS IN THE NEXT TNM
CLASSIFICATION
Hisashi Saji1, Tatsuya Inoue1, Gaku Yamaguchi1,
Yujin Kudo1, Masaharu Nomura2, Jun Matsubayashi2,
Masatoshi Kakihana1, Jitsuo Usuda1, Naohiro
Kajiwara1, Tatsuo Ohira1, Norihiko Ikeda1
1
Thoracic Surgery, Tokyo Medical University/Japan,
2
Pathology, Tokyo Medical University/Japan
Background: Intratumoral vascular invasion (ITVI)

in patients with non-small cell lung cancer (NSCLC)
has been reported to be a strong prognostic predictor
of recurrence. However, it has not been incorporated
in the latest 7th TNM classiÀcation. The objective
Results: The numbers of the patients according to of this study is to evaluate its signiÀcance as a risk
vessel invasion status and its extent were as follows; factor for recurrence and survival.
no V (V0): 608 (52.6%), intratumoral V (V1): 512 Methods: A total of 1924 consecutive patients with
(44.3%), extratumoral V (V2): 35 (3.0%), no Ly (Ly0): pathological T1-4N0-2 non-small cell lung cancer
901 (78.0%), intratumoral Ly (Ly1): 155 (13.4%), and underwent complete resection at least lobectomy
extratumoral Ly (Ly2): 99 (8.6%). The overall survival with lymphadenectomy from January 1990 to
(OS) curves stratiÀed by the extent of (a) V or (b) Ly December 2007 at the Tokyo Medical University
were signiÀcantly different from each other (Figure 1). Hospital. Complete resection was deÀned as
Multivariate analysis showed that Ly2 status, presence cancer-free surgical margins both macroscopically
of V (V1-2), older age, larger tumor size, preoperative and microscopically. Among these patients, were
serum CEA (carcinoembryonic antigen) level, lymph excluded because of preoperative chemotherapy or
node metastasis, and pleural invasion were signiÀcant radiotherapy or both (n=94) or because of low-grade
malignant histologies (n=31) including carcinoids, poor prognostic factor. In the 7th edition of the TNM
mucoepidermoid carcinomas and adenoid cystic ClassiÀcation for Lung and Pleural Tumours, VPI
carcinomas. The remaining 1799 patients were is deÀned as comprising both PL1 and PL2. Tumors
enrolled in this study. The recurrence-free survival 3 cm or less (T1a and T1b) with VPI are upstaged
(RFS) and overall survival (OS) was estimated using as T2a, while tumors greater than 3 cm and 7cm or
the Kaplan-Meier method and differences were less (T2a and T2b) with VPI remain T2. However,
determined by the log rank test. Cox proportional it is still controversial whether PL1 and PL2 are
hazard ratios were used to identify independent risk equivalent and whether they can be combined to
factors for RFS and OS. deÀne VPI, or how tumors with VPI should be
Results: Patients characteristics as follows: classiÀed, especially T2 tumors.
Men 1158 (64.4%), Age 64.2 (17-87), Methods: We reviewed 2946 consecutive surgically
Adenocarcinoma 1242 (69.0%), Squamous resected NSCLC patients with T1a, T1b, T2a, T2b or
cell carcinoma 432 (23.5%), T1a/b/T2a/b/T3/ T3 tumors for their clinicopathologic characteristics
T4=501/405/555/112/153/73, N0/1/2=1306/253/260, and prognoses. Visceral pleural invasion was
Well differentiated 588 (32.7%), ITVI 980 (54.5%), classiÀed using the criteria of the 7th edition of the
Lymphatic permeation 970 (53.9%), Visceral TNM ClassiÀcation for Lung and Pleural Tumours.
pleural invasion 1274 (70.8%). The proportion of Results: There were no signiÀcant differences in
recurrence-free patients at 5 years was 68.4% for survival between PL1 and PL2 patients (Àg 1A).
patients with ITVI and 86.9% for those without ITVI We therefore decided to combine the PL1 and PL2
(p<0.0001). The 5 year survival rate was 58.7% patient groups into a single VPI+ group and to
for patients with ITVI and 81.2% for those without compare survival with a PL0 (VPI-) group to analyze
ITVI (p<0.0001). On the multivariate analyses, ITVI the impact of VPI on T classiÀcation. The best
proved to be an independently statistically signiÀcant survival was observed in patients with a T1a/VPI-
risk factor for RFS (HR=1.347, p=0.0357) and OS tumor, followed by those with a T1b/VPI- tumor.
(HR=1.422, p=0.0017) (Table 1). In comparison, survival was similarly worse among
Conclusion: In the Patients with resected T1-4N0-2 patients with a T1a/VPI+, T1b/VPI+, T2a/VPI-, T2b/
NSCLC, ITVI was an independently signiÀcant VPI-, or T2a/VPI+ tumor. The worst survival was
risk factor for RFS and OS. Our data suggested observed in patients with a T2b/VPI+ or T3 tumor
that ITVI may provide additional information (Àg 1B).
for the next TNM classiÀcation. Further large-
scale cohort studies, including global prospective
validation analyses and multi-institutional studies are
warranted.
Keywords: prognostic factor, intratumoral vascular
invasion
Conclusion: Otherwise T2a tumors with VPI may be

Classical Pathology Tuesday, 5 July 2011 10:30-12:00 classiÀed as T2b tumors, and T2b tumors with VPI
may be classiÀed as T3 tumors in the next edition
MO10.04 VISCERAL PLEURAL INVASION of the TNM ClassiÀcation for Lung and Pleural
CLASSIFICATION IN NON–SMALL CELL Tumours.
LUNG CANCER. Keywords: Visceral Pleural Invasion, Non-small cell
Akikazu Kawase1, Junji Yoshida1, Genichiro Ishii2, lung cancer, TNM classiÀcation
Yoichi Ohtaki1, Masayuki Nakao1, Keiju Aokage1,
Tomoyuki Hishida1, Mitsuyo Nishimura1, Kanji Nagai1 A revised/updated abstract may be included in
1
Division Of Thoracic Surgery, National Cancer the Late Breaking Abstract Supplement, available
Center Hospital East/Japan, 2Pathology Division, at the 14th World Conference on Lung Cancer.
Research Center For Innovative Oncology, National
Cancer Center Hospital East/Japan
Background: Visceral pleural invasion (VPI) by

non–small cell lung cancer (NSCLC) is known as a
Classical Pathology Tuesday, 5 July 2011 10:30-12:00 Keyword: adenocarcinoma, lung, small biopsy
specimen, grading system, histologic pattern,
MO10.06 THE 3-TIER HISTOLOGY prognosis
GRADING SYSTEM OF LUNG
ADENOCARCINOMA FOR SMALL A revised/updated abstract may be included in
BIOPSY SPECIMENS PREDICTS the Late Breaking Abstract Supplement, available
DISEASE RECURRENCE AND OVERALL at the 14th World Conference on Lung Cancer.
SURVIVAL
Hua-Ling Kao1, Yi-Chen Yeh1, Fu-Pang Chang1, Yu-
Chung Wu2, Chun-Ming Tsai3, Teh-Ying Chou4 Classical Pathology Tuesday, 5 July 2011 10:30-12:00
1
Department Of Pathology And Laboratory
Medicine, Taipei Veterans General Hospital/ MO10.07 MICROPAPILLARY
Taiwan, 2Department Of Surgery, Taipei Veterans MORPHOLOGY IS AN INDEPENDENT
General Hospital/Taiwan, 3Division Of Thoracic PREDICTOR OF RECURRENCE
Oncology/department Of Chest Medicine, Taipei IN PATIENTS UNDERGOING
Veterans General Hospital/Taiwan, 4Pathology LIMITED RESECTION FOR LUNG
And Laboratory Medicine, Taipei Veterans General ADENOCARCINOMA (LAC) 2CM
Hospital/Taiwan Junichi Nitadori1, Adam J. Bograd1, Kyuichi
Kadota1, Camelia S. Sima2, Eduardo Morales1, Kei
Background: Recently several studies have Suzuki1, Nabil P. Rizk1, Valerie W. Rusch1, William
established different objective grading systems D. Travis3, Prasad S. Adusumilli1
1
which provide prognostic information for lung Department Of Surgery, Thoracic Service, Memorial
adenocarcinoma in surgical specimen. The Sloan-kettering Cancer Center/United States Of
prognostic information provided by small lung America, 2Epidemiology And Biostatistics, Memorial
biopsy specimen has not been studied. Sloan-kettering Cancer Center/United States Of
Methods: In our study, the prognostic utility of three America, 3Pathology, Memorial Sloan-kettering
scoring systems including total scores, worst score Cancer Center/United States Of America
and predominant score based on a 3-tier grading
system was applied in 93 lung biopsy specimen. The Background: Among patients who undergo limited
grade 1 tumor has bronchioloalveolar pattern, grade resections for stage I lung cancer, prognostic factors
2 has acinar and/or papillary patterns, and grade 3 to stratify patients at increased risk of recurrence
has micropapillary and/or solid patterns. have not been identiÀed. Comprehensive histological
Results: The total scoring system ( P = 0.016 ) subtyping (IASLC/ATS/ERS) has been proposed to
counted by the sum of 2 most predominant grades predict prognosis in stage I LAC. Micropapillary
and worst scoring system ( P = 0.01 ) counted by (MIP) morphology is associated with high risk of
highest grade present in specimen both provide recurrence. The aim of this study is to investigate the
prediction for patient’s risk of disease recurrence. prognostic role of MIP morphology in LAC 2cm
Furthermore, we subdivided patients into low (total following limited resections.
scores = 2, 3, or 4 or worst score = 1 or 2) and high Methods: Retrospective review of patients who
(total scores = 5 or 6 or worst score = 3) risk groups underwent limited resection for lung cancer (n=489,
based on the scoring systems. In high risk group 01/2004-12/2007) was performed. Inclusion
patients, the 5-year disease-free survival rate was criteria: LAC 2cm with available H&E slides for
0.36 and overall survival rate was 0.47, compared to pathological review; exclusion criteria: clinical
0.71 and 0.65 in the low risk group. Patients in high / pathologic stage II and above, multicentric
risk group had higher stage (II, III and IV) and more disease, lung cancer surgery within preceding
lymph nodes metastasis compared to the low risk 2 years, and patients who received induction
group (P=0.007). therapy. Comprehensive histological subtyping was
Conclusion: These two scoring systems based on performed as per the newly proposed IASLC/ATS/
simpliÀed, objective 3-tier grading system could ERS LAC classiÀcation (MIP component percentage
provide valuable outcome prediction information recorded in 5% increments). Recurrence free
for lung adenocarcinoma patients with small biopsy probability (RFP) was assessed via Kaplan-Meier
specimens. survival analysis.
Results: 121 patients met inclusion criteria Classical Pathology Tuesday, 5 July 2011 10:30-12:00
(64% women, median age 70yr (47-88 yrs), 14%
never-smokers; 107 Stage IA, 14 stage IB; 86 MO10.08 PROGNOSTIC SIGNIFICANCE
and 35 patients underwent wedge resection and OF SOLID COMPONENT IN
segmentectomy, respectively). Micropapillary PULMONARY ADENOCARCINOMA
component 5% was associated with increased risk Yoichi Ohtaki1, Junji Yoshida1, Genichiro Ishii2,
of recurrence (n=42, 56% 3-year RFP) as compared Keiju Aokage1, Tomoyuki Hishida1, Mitsuyo
to <5% (n=79, 93% 3-year RFP) micropapillary Nishimura1, Kanji Nagai1
1
component (p<0.001). Following adjustment Division Of Thoracic Surgery, National Cancer
for both vascular and lymphatic invasion, which Center Hospital East/Japan, 2Pathology Division,
were signiÀcant on univariate analysis (p<0.001), Research Center For Innovative Oncology, National
micropapillary component 5% remained an Cancer Center Hospital East/Japan
independent predictor of recurrence. Tumor to
surgical margin is not a predictor of recurrence in our Background: Histologically, solid adenocarcinoma
cohort. is the lesser differentiated adenocarcinoma
subtype, but only a few studies have evaluated its
invasiveness and prognostic impact independently
of the other subtypes. We retrospectively analyzed
pulmonary adenocarcinoma patient survival in our
single institution database to evaluate the impact of
the amount of solid adenocarcinoma components
(SAC) on survival, and to propose a method of
incorporating SAC into the T classiÀcation in future
staging systems.
Methods: We reviewed 504 consecutive patients
with surgically resected pulmonary adenocarcinoma
for their clinicopathologic characteristics and
prognoses, stratifying patients according to
predominant adenocarcinoma subtype. In the tumors
containing SAC, we categorized the ratio of SAC
Conclusion: The presence of 5% micropapillary into the following 3 groups; pure, moderate (1/10
component is a strong predictor of recurrence in or more, but not pure), and slight (less than 1/10).
patients undergoing limited resection for LAC We deÀned solid adenocarcinoma components
2cm. With the potential increase in the number of (SAC) as cancer nests without any other subtype
small LAC patients detected by screening CT scans of structures (lepidic, acinar, or papillary growth),
who may subsequently undergo limited resection, regardless of mucin production. In pure SAC
predictors of recurrence are needed. As one in two tumors, we conÀrmed mucin production by the
patients with 5% micropapillary morphology may alcian blue-periodic acid Schiff method. To evaluate
recur within 3 years, either aggressive surveillance the invasiveness and the prognostic signiÀcance
or further intervention may be indicated for these of SAC, we examined the correlations between
patients. presence or absence of SAC and the following
Keywords: NSCLC - Early stage, Limited clinicopathological features by univariate and
Resection, IASLC/ATS/ERS classiÀcation, multivariate analyses: age, gender, smoking history,
micropapillary preoperative serum carcinoembryonic antigen level,
T status, nodal involvement, lymphatic permeation,
A revised/updated abstract may be included in vascular invasion, and pleural invasion.
the Late Breaking Abstract Supplement, available Results: Although patients with SAC (SAC+)
at the 14th World Conference on Lung Cancer. had signiÀcantly poorer prognoses than patients
without any SAC (SAC-), there were no statistically
signiÀcant differences in survival among the 3
SAC ratio groups (5-year overall survival rate;
SAC-: 87.5%, SAC+: 60.3%). SAC signiÀcantly
1
correlated with the following pathological invasive Division Of Pathology, Japanese Foundation
features: T classiÀcation, nodal involvement, For Cancer Research/Japan, 2Thoracic Surgical
lymphatic permeation, vascular invasion, and Oncology, Cancer Institute Hospital/Japan
pleural invasion. Multivariate analysis showed
SAC was an independent prognostic factor both in Background: The number of small-sized lung
the entire cohort (p=0.020) and in stage I patients cancer is increasing in number. Small sized tumors
(p=0.024). Patient groups stratiÀed by pathological can include adenocarcinoma (AD) with 100%-
T classiÀcation up to T2b, could be divided into 4 5 year survival which should be synonymous of
categories according to SAC status in decreasing histologically adenocarcinoma, in situ (AIS) or
order of survival: I) T1a/SAC-; II) T1b/SAC-; III) minimally invasive adenocarcinoma (MIA) of a
T1a/SAC+, T1b/SAC+, and T2a/SAC-; and IV) T2a/ proposed new IASLC/ATS/ERS classiÀcation in
SAC+ and T2b/SAC-. 2011. Intra-operative frozen diagnosis (IOFD)
Conclusion: Pulmonary adenocarcinoma patients could help surgeons to decide the area of resection,
with any amount of SAC had worse prognoses especially for limited operation of small sized AD.
than those without any SAC. The presence of The purpose of this study is to clarify the utility
SAC signiÀcantly correlated with the pathological and limitation of IOFD of pulmonary lesions and
invasive features, and it was an independent to evaluate whether IOFD can predict the Ànal
unfavorable prognostic factor. SAC was an upstaging pathologic diagnosis and invasion degree or not.
factor in T classiÀcation for T1 and T2a pulmonary Methods: Surgically resected 124 lung specimens
adenocarcinomas. If SAC is present, we propose T1 were reviewed on pathologic factors of IOFD and
and T2a tumors should be classiÀed as T2a and T2b, Ànal diagnosis (FD), and calculated concordance
respectively. rate between them. IOFD was performed on HE
stained slides of a small part of tumor. FD was done
based on the HE and elastic stained slides of FFPE
specimen of whole tumor. The examined pathologic
factors were as following; pathologic diagnosis
(PDx), presence or absence of invasion/minimally
invasion area, histologic predominant subtype
of proposed IASLC-ATS-ERS revision of AD
classiÀcation and tumor differentiation. In discordant
cases, the reasons were examined in detail.
Results: Among 124 specimens, 88 were primary
lung cancers (75 AD, 12 Squamous cell carcinoma
(SQ), 1 large cell carcinoma), 17 metastatic tumors,
and 19 were benign or mesenchymal tumors.
Concordance rate for each factor of all specimens was
as following; 82.3% for overall PDx factors, 98.4 %
Keywords: mixed subtype, Adenocarcinoma, for judgment of benign or malignant, 92.8% for tumor
Surgery, solid adenocarcinoma type, 99.0% for tumor differentiation, 98.6% for
predominant subtype of AD, respectively. Among 124
specimens, Àfty lesions were small sized lung cancer
Classical Pathology Tuesday, 5 July 2011 10:30-12:00 (2cm or less in diameter), including 36 primary lung
cancer (34 AD, 2 SQ), 9 metastatic tumor and 5 other
MO10.09 EVALUATION OF HISTOLOGIC lesions. Concordance rate for each factor of small
ACCURACY ON DIAGNOSIS AND sized lesions is as following; 78.0% for overall PDx
INVASION OF SMALL-SIZED LUNG factors, 96.0% for judgment of benign or malignant,
CANCER USING INTRA-OPERATIVE 94.0% for tumor type, 98.0% for tumor differentiation,
FROZEN SECTION 100% for predominant subtype of AD, respectively.
Noriko Motoi1, Wakako Hamanaka1, Takehiko Oba1, Concordance rate for invasiveness of small sized AD
Shin Karita1, Hiroshi Ono1, Yuichi Saito1, Seijiro was 82.4%. The reasons of discrepancy were based
Sato1, Kentaro Inamura1, Mingyon Mun2, Yukinori on tumor heterogeneity, sampling error, frozen section
Sakao2, Sakae Okumura2, Yuichi Ishikawa1 artifact, or some difÀcult rare cases.
Conclusion: IOFD can predict the Ànal diagnosis EGFR and compared it to an ED-speciÀc EGFR
of lung cancer in most cases (82.3%), even in antibody. Compared to a presentation at the Chicago
small-sized tumors (78.0%) and invasion degree of Multidisciplinary Thoracic Oncology Meeting 2010,
AD (82.4%). To prevent disagreement about PDx, the patient numbers increased by 40% and the clinical
pathologist should pay attention to tumor processing data are updated.
(sampling, sectioning and staining). A careful Methods: Ninety-eight surgically-treated NSCLC
macroscopic observation is strongly recommended, Japanese patients who received geÀtinib upon
especially for small sized tumors. recurrence were evaluated using IHC, scoring either
Keywords: Invasion, adenocarcinoma, in situ (AIS), membrane (MEM) alone or in combination with the
minimally invasive adenocarcinoma (MIA), lung cytoplasm (MEMC), on a 0-400 H-score scale, with
adenocarcinoma either an EGFR ID- (5B7, Ventana Medical Systems,
Inc, Tucson, AZ) or ED-speciÀc antibody (3C6, VMSI).
GeÀtinib monotherapy was received in 1st-, 2nd, or 3rd-
Classical Pathology Tuesday, 5 July 2011 10:30-12:00 line in 10%, 44%, and 46% of the patients, respectively.
Results: EGFR protein expression scores were
MO10.11 IMMUNOHISTOCHEMISTRY universally higher when using the ID-speciÀc
USING AN EGFR INTERNAL DOMAIN- antibody with a mean of 170 and 183 for MEM and
SPECIFIC ANTIBODY PREDICTS MEMC, respectively, compared to 37 and 50 for the
RESPONSE AND OUTCOME TO AN ED antibody. EGFR protein expression, as determined
EGFR TYROSINE KINASE INHIBITOR. by the ID speciÀc antibody, was signiÀcantly higher
Murry W. Wynes1, Yasufumi Kato1, Céline in responders (n=21) vs non-responders (n=73)
Mascaux1, Bernadette G. Reyna Asuncion1, with mean values of 213 vs 156 (p=0.021) and
Stephanie A. Sanchez2, Jun Matsubayashi3, Koichi 231 vs 168 (p=0.001), when considering MEM or
Yoshida4, Toshitaka Nagao3, Kinya Furukawa5, MEMC. EGFR protein expression wasn’t different
Norihiko Ikeda4, Fred R. Hirsch6 between responders and non-responders using the ID
1
Medical Oncology, University Of Colorado/United antibody. ROC curve analysis using the ID antibody
States Of America, 2Biostatistics, Ventana Medical and MEMC scores showed 217.5 as the best cutoff
Systems, Inc/United States Of America, 3Division (AUC=0.73, p=0.002) to predict response with a
Of Anatomic Pathology, Tokyo Medical University/ sensitivity, speciÀcity, accuracy, and likelihood ratio
Japan, 4Division Of Thoracic Surgery, Tokyo of 66.6%, 74.0%, 72.3% and 2.56. Evaluation with
Medical University/Japan, 5Division Of Thoracic MEM alone was marginally signiÀcant at predicting
Surgery, Tokyo Medical University, Ibaraki Medical response, while ED antibody evaluation of MEM or
Center/Japan, 6Medical Oncology And Pathology, MEMC was not predictive. Activating EGFR exon 19
University Of Colorado/United States Of America or 21 mutations (n=43) predicted response (p=0.005)
with sensitivity, speciÀcity, accuracy and likelihood
Background: Assessment of speciÀc predictive ratio of 76.2%, 60.3%, 64.0% and 1.92. Increased
biomarkers for response and outcome to targeted EGFR expression determined with the ID antibody
therapies is today a part of standard management for and MEMC evaluation associated with increased
patients with advanced non-small cell lung cancer median PFS (11.7 months vs 5.0, Log-rank p=0.034)
(NSCLC). Several biomarkers are being evaluated and OS (38.6 vs 14.9, p=0.040), both from geÀtinib.
for response or resistance to epidermal growth factor Conclusion: We conÀrmed in an expanded cohort
receptor (EGFR) tyrosine kinase inhibitors (TKIs). that EGFR protein expression, evaluated by IHC
Mutations in the TK domain of EGFR are the best using an internal domain-speciÀc antibody and by
predictor of response to EGFR TKIs to date. However, scoring membrane and cytoplasmic expression,
~30% of patients with mutations don’t initially better predicts response and outcome to geÀtinib in
respond and all relapse. Results from clinical studies NSCLC patients than the more often used external
with EGFR TKIs using EGFR protein expression by domain-speciÀc antibody. These data emphasize the
immunohistochemistry (IHC) with external domain importance of method choice (e.g. antibody speciÀcity
(ED) speciÀc detection antibodies are conÁicting. and compartment assessed) to assess the expression of
In this study we determined the predictive value of EGFR.
EGFR protein expression using an antibody that Keywords: immunohistochemistry, EGFR,
speciÀcally detects the internal domain (ID) of biomarker, Prediction of response
Classical Pathology Tuesday, 5 July 2011 10:30-12:00 metastasises samples (p=0.009) and with samples
from centres other than university hospital (p=0.018).
MO10.12 ROUTINE DIAGNOSIS OF By contrast, frozen and cytological samples were not
EGFR MUTATIONS IN NON SMALL a signiÀcant cause of incomplete results. A binary
CELL LUNG CANCER IN FRANCE: logistic regression model was used to evaluate
RETROSPECTIVE RESULTS OF RHôNE predictive factors for incomplete results. Odds Ratio
MOLECULAR GENETIC PLATFORM for bone samples is 2.343 (1.005-5.460; p = 0.049).
AFTER ONE YEAR OF EXERCISE. EGFR mutations were more common in female than
Myriam Locatelli Sanchez1, Sebastien Couraud1, male (63% vs 37%, p < 0.0001) and more common
Pierre Paul Bringuier2, Jean Yves Scoazec2, Pierre in adenocarcinomas than in other histologic subtypes
Jean Souquet1 (p<0.0001). No signiÀcant difference was observed
1
Service De Pneumologie Dr Souquet, Hôpital Lyon according to age, sample type or health centre. Using
Sud, Hospices Civils De Lyon/France, 2Service adjusted model, Odds Ratio for mutation in case of
D’anatomie Et Cytologie Pathologiques, Hôpital adenocarcinoma is 0.5552 [0.431-0.708] for male
Edouard Herrriot, Hospices Civils De Lyon/France and 1.868 [1.538-2.270] for female (p<0.001). 133
EGFR mutations were found in 121 patients (11
Background: The French National Institute of patients had at least 2 mutations): 51.9% in exon
Cancer developed several platforms for routine 19 (89.9% are activating deletions), 27.1% in exon
molecular diagnosis of cancer. Platforms perform 21 (86.1% L858R activating mutation), 13.5% in
detection of epidermal growth factor receptor exon 20 (38.9% of resistance mutations and many
(EGFR) mutations in stage IV non-squamous unknown mutations) and 7.5% of detected mutations
lung cancer because their presence is correlated to were in exon 18 (70% of sensitizing mutation).
response to tyrosine kinase inhibitors. The aim of Finally, 20 new mutations are described, mainly in
this retrospective study was to describe results of exon 18 and 20.
routine EGFR mutations diagnosis, to determine risk Conclusion: This retrospective study shows that
factors for failure or incomplete results, and to assess EGFR mutations detection is feasible in routine
main clinical and molecular features of mutated practice. The rate of mutations in this study is 15.7%.
patients. As expected, mutations mainly occur in female with
Methods: This study was performed on samples adenocarcinoma. Moreover, bone metastasis samples
sent to the Rhône platform between 09/09 and 09/10. are associated with an incomplete result whereas
Genomic DNA was extracted from tissue after frozen or cytological samples don’t seem to be a risk
microdissection. Exons 18 to 21 were PCR ampliÀed factor of failure.
and sequenced. Data were collected from application Keywords: molecular genetic plaform, EGFR
forms sent to the lab. Results were categorized in mutations, Non small cell lung cancer
mutation, wild type, “indeterminate” (failure on
more than 2 exons) or “partial” (failure on exon 18
or 20). The latter two categories were considered as Classical Pathology Tuesday, 5 July 2011 10:30-12:00
“incomplete results”.
Results: 792 tumor samples were analysed. The MO10.13 WHICH TYPES OF
mean patient age was 65 years (42-88), 62% patients DIAGNOSTIC TISSUE SAMPLES ARE
were male and 79.8% had an adenocarcinoma. ADEQUATE FOR EGFR TESTING OF
Samples were sent by university hospital (30.4%), NON-SMALL CELL LUNG CANCER?
secondary hospitals (36.4%) or private clinics Paul Cane, Sioban Fraser, Khalid Tobal, George
(33.2%; p=0.131). Samples concerned primitive Santis
tumor in 70% of cases. EGFR mutations (all kinds) Histopathology, Guy’s And St Thomas’ Hospital/
were found in 15.7% samples, EGFR wild type in United Kingdom
65.2%, “partial wild type” results in 10.4% and
indeterminate results in 8.8%. Main reasons of Background: It is becoming increasingly necessary
indeterminate results were: poor DNA quality (n=40) to perform molecular testing of diagnostic samples
and not enough tumour cells in analysed sample of non-small cell lung cancers (NSCLC) in order
(n=30). The rate of incomplete results was 19.2%. to determine suitability for targeted therapies.
Incomplete results were more frequent with bone There has been concern whether the tissue samples
currently used for routine diagnosis of NSCLC are showed no obvious trend. Unguided FNA, EBUS-
of sufÀcient size and quality to enable molecular TBNA, bronchoscopic biopsy and core biopsies
testing. all provided sufÀcient cells for mutation analysis
Methods: We retrieved 126 consecutive NSCLC in the vast majority of cases using cold PCR and
samples from the pathology archives at our direct sequencing. There is no signiÀcant difference
institution from 2008-10 that had been tested for in sample size between EBUS-TBNA samples and
epidermal growth factor receptor (EGFR) and bronchoscopic or core biopsy samples.
kRAS gene mutations by “cold” polymerase chain Keywords: Non-small cell lung cancer, EGFR,
reaction (cold-PCR) sequencing. Cold-PCR uses Adequacy, Sample size
a lower denaturation temperature resulting in
preferential ampliÀcation of mutant DNA, increasing
the sensitivity of mutation detection. The series Classical Pathology Tuesday, 5 July 2011 10:30-12:00
included a range of routine specimen types including
unguided Àne-needle aspirate (FNA), endobronchial MO10.14 SAMPLE QUALITY CRITERIA
ultrasound-guided transbronchial needle aspiration FOR ROUTINE EGFR MUTATION
(EBUS-TBNA), bronchoscopic biopsy, core biopsy, SCREENING – PATHOLOGICAL
surgical biopsy and surgical resection. Cell block FEATURES MAY BE MORE USEFUL
preparations were used to assess cytological samples. THAN CLINICAL PHENOTYPE IN A UK
For each sample, the total number of viable tumour POPULATION
cells present in a single histological section and Alexandra Leary1, David Gonzalez2, Andrew
the proportion of the section that was tumour was G. Nicholson3, Andrew Wotherspoon1, Franklin
calculated by two authors (PC and SF) using light Olansunkanmi4, Mary O’Brien1, Sanjay Popat1
1
microscopy. Department Of Medicine, Royal Marsden Hospital/
Results: United Kingdom, 2Department Of Molecular
Sample type Number Median Median tumour cell Number Number Diagnostics, Institute Of Cancer Research/United
of cases tumour % count (range) Failed DNA with EGFR
(range) extraction or kRAS Kingdom, 3Histopathology, Royal Brompton
(%) mutation (%)
Hospital/United Kingdom, 4Medical Oncology, Royal
Unguided FNA 9 45 (10-100) 450 (46-550) 1 (11%) 4 (44%)
EBUS-TBNA 44 70 (10-95) 2525 (65-39800) 1 (2.3%) 14 (31.8%)
Marsden Hospital/United Kingdom
Bronchial 12 45 (10-90) 3000 (295-40000) 1 (8.3%) 9 (75%)
biopsy
Background: There is now a clinical need for
Core biopsy 13 55 (5-75) 3000 (260-15000) 0 (0%) 8 (61.5%)
(lung or pleura) routine EGFR mutation testing in NSCLC. EGFR
Surgical biopsy 16 35 (5-95) 35100 (45-600000) 0 (0%) 5 (31.2%) screening requires good quality tissue, high
Surgical
resection
30 70 (30-95) 268000 (4160-
600000)
0 (0%) 10 (33.3%) sensitivity, and acceptable turn-around time (TAT).
The Royal Marsden Hospital started routine EGFR
Only three of the 126 samples could not be tested screening in January 2009. Here, we report our
for mutations because they did not provide sufÀcient prospective experience, describing sample type/
quality DNA for analysis. Two of these were very source, histological subtype, TAT, specimen quality,
small, containing only 100 and 105 tumour cells and screening outcome.
each per section. The third contained 5900 tumour Methods: NSCLC sections received over 24 months
cells and was 50% tumour but still failed, possibly were screened for EGFR mutations in exons 18 to 21
due to degraded DNA. The smallest sample in which using ARMS alone or in combination with fragment
we were able to detect a mutation was also the analysis and sequencing. A total of 907 samples were
smallest sample in the series, composed of 45 cells, screened from January 2009. We focused this study
5% tumour. The overall detection rate of mutations on Year 1 samples, collecting data on cellularity,
was 14.6% (18/123) for EGFR and 26.0% (32/123) TAT, demographics and clinical outcome. A subset
for kRAS. There was no signiÀcant difference in of samples (N=96) from a single institution also
tumour cell count between the EBUS-TBNA group underwent detailed histological subtyping.
and combined bronchoscopic and core biopsy groups Results: Overall, EGFR mutation(M+) prevalence
using a t-test (p=0.45). was 12.7%. Numbers tested increased markedly from
Conclusion: The number of cells available for 33 in the Àrst 6 months to 473 in the last 6 months to
mutation analysis increases with the size of the January 2011 (Fig1). In Year 1, most samples were
sample. The percentage of tumour in the samples diagnostic specimens (72% core, 4% FNA, 14%
surgical, 10% not speciÀed). TAT was 4.9 working Session MO11: Preclinical Models II
days (95%CI=4.5-5.5). EGFR mutations included
50% ex19del, 38% L858R, and 12% ex20ins. Tuesday, 5 July 2011
Mutation rate was higher (20%) among non-smoking
women with adenocarcinomas, but 30% of mutations
were identiÀed among current or ex-smoking Preclinical Models II Tuesday, 5 July 2011 10:30-12:00
men. Median survival in EGFR-M+ patients was
482d compared to 407d for EGFR-M- patients. Of MO11.01 SMAC MIMETIC (JP1201)
the 96 samples with detailed pathological review SENSITIZES WILD TYPE EGFR NON
all EGFR-M+ tumours (20/96, 21%) were non- SMALL CELL LUNG CANCERS (NSCLCS)
mucinous adenocarcinomas (ADCs) and 100% were TO MULTIPLE CHEMOTHERAPY
TTF1+ (versus 73% in EGFR-M-). No mutations AGENTS AND ERLOTINIB IN AN IAP
were detected in more poorly differentiated NSCLC- DEPENDENT FASHION
NOS or NSCLC-favouring ADC. Mutation testing Rachel M. Greer1, Michael Peyton1, Luc Girard2,
failure improved markedly from 18% (29/152) in Yang Xie3, Lai Wang4, Adi F. Gazdar1, Patrick
Year 1 to 5.4% (41/755) in Year 2. Factors associated Harran5, Rolf A. Brekken2, Xiaodong Wang6, John D.
with successful testing were better sample cellularity Minna7
1
and higher DNA concentrations. However 75% of Hamon Center For Therapeutic Oncology Research,
samples with poor cellularity but representative of Ut Southwestern Medical Center/United States Of
tumor were informative, and mutation prevalence America, 2Hamon Center For Therapeutic Oncology
was 9%. Although samples with low DNA Research, University Of Texas Southwestern
concentration (<2ng/ƫL) had a higher test failure rate Medical Center/United States Of America, 3Clinical
(30% vs. 3.9% for [DNA]>2ng/ƫL), the mutation Sciences, Ut Southwestern Medical Center/United
detection rate was 9.2%. States Of America, 4Research And Development,
Joyant Pharmaceuticals/United States Of America,
5
Department Of Chemistry And Biochemistry,
University Of Californa At Los Angeles/United
States Of America, 6Department Of Biochemistry,
University Of Texas Southwestern Medical Center/
United States Of America, 7Hamon Center For
Therapeutic Oncology Research, Internal Medicine,
Pharmacology, University Of Texas Southwestern
Medical Center/United States Of America
Background: The inhibitors of apoptosis proteins

(IAPs) are key regulators of apoptosis, and are in turn
Conclusion: Routine EGFR mutation screening inhibited by the second mitochondrial activator of
using diagnostic samples is feasible, fast and caspases (SMAC). In many cancers various IAPs are
informative in over 93% of cases. Although up regulated and are believed to be factors leading to
pathological review is critical, even small samples increased drug resistance, to combat this many small
with low cellularity and DNA content may be molecule mimetics of SMAC have been created,
successfully tested. Mutations tend to occur such as JP1201. Cytotoxicity due to SMAC mimetic
in better-differentiated non-mucinous TTF1+ treatment in a subset of cancer cells (including 18%
adenocarcinomas. Whether these histological criteria of 50 non-small cell lung cancer, NSCLC lines) has
may be more useful to select patients for EGFR been well documented, and is dependent on de novo
testing in a UK population than smoking status and synthesis of TNFƠ, and RIPK1 dependent TNFR1
gender merits further investigation. signaling. Clinical testing of NSCLC with SMAC
Keywords: EGFR, mutation testing mimetics as a single agent should thus focus on TNFƠ
producing lung cancers. However, we were interested
A revised/updated abstract may be included in in whether SMAC mimetics sensitize non TNFƠ
the Late Breaking Abstract Supplement, available producing NSCLCs to available chemotherapies and
at the 14th World Conference on Lung Cancer. targeted therapies for lung cancer.
Methods: Using multiple in vitro assays; And Molecular Medicine, Mcmaster University
proliferation assays, colony formation assays, - Juravinski Cancer Center/Canada, 3Pathology
annexin V staining, western blotting, we explored And Molecular Medicine, St. Joseph’s Hospital -
the ability of JP1201 to sensitize NSCLCs to McMaster University/Canada, 4Brock University/
conventional chemotherapies across a panel of 20 Canada
NSCLC lines. We then tested JP1201 alone and with
chemotherapy in tumor xenografts to conÀrm in vitro Background: Standard clinical doses of chest
sensitization. Finally we explore the mechanism of radiotherapy of 60 – 63 Gy cause signiÀcant normal
sensitization using siRNA knockdowns of individual lung tissue damage but fail to offer adequate local
IAPs in a drug response assay, and transiently control for NSCLC, despite concurrent use of
transfected reporter constructs for 10 signaling chemotherapy. For that, there is an urgent need to
pathways that are involved in stress and cytotoxicity. develop effective and well tolerated radiosensitizers
Results: We Ànd that JP1201 sensitize (10 t0 1000 in NSCLC. Recently, we have shown that ionizing
fold) NSCLCs that do not respond to JP1201 alone radiation (IR) activates the energy sensor and tumour
to doxorubicin, erlotinib, gemcitabine, paclitaxel, suppressor AMP-activated kinase (AMPK) which
vinorelbine, gemcitabine + cisplatin, paclitaxel + leads to expression of cell cycle inhibitors such as
carboplatin and that this sensitization does not depend p53 and p21cip1. Further we observed that metformin
on TNFa secretion. Importantly JP1201 sensitized (MET) also activates AMPK, enhances the activation
NSCLCs with wild type EGFR to erlotinib (10-100 of this kinase by IR and the ionizing radiation
fold) Furthermore, combinations of JP1201 with (IR)-induced cytotoxicity in human NSCLC cells
gemcitabine or vinorelbine can robustly induce in culture. In the present study we investigated, in
apoptosis and control in vivo tumor growth which human NSCLC xenografts, the radio-sensitizing
translates to extended survival in NSCLC xenograft properties of MET. We also examined, in the same
models. The siRNA knockdown mechanistic studies tumours, the effects of IR and MET on the activity
show that sensitization to chemotherapy is dependent of AMPK, of the radioresistance mediator Akt as
on inhibition of IAPs; however, of great importance well as their putative downstream effectors, tumour
we Ànd that TNFR1, TNFƠ, and RIPK1 are not suppressor p53 and mRNA translation repressor
required for sensitization to chemotherapy. Finally, 4EBP1.
we Ànd that activation of ER stress as measured by Methods: A549 cells (2x106) were grafted in the
CBF/NF-Y promoter activity and the JNK pathway as franks of Balb/c immunodeÀcient athymic nude mice
measured by AP1 promoter activity are both involved and tumours were left to grow to 100 mm³. MET
in the sensitization of vinorelbine by JP1201. supplementation was delivered in drinking water
Conclusion: We conclude that IAP targeted therapy at a dose of 250 mg/kg daily, and IR of 10 Gy was
using a SMAC mimetic provides a new therapeutic delivered as a single fraction 7 days after initiation of
strategy for sensitizing NSCLCs to standard metformin administration. Eight weeks later animals
chemotherapy agents, and that this occurs best when were euthanized and tumours where isolated. Half
multiple pro-apoptotic pathways are activated. of each tumour was snap frozen for preparation of
Keywords: synergy, combination chemotherapy, IAP whole tumor lysates and immunoblotting analysis
and the other half was Àxed and embedded for
immunohistochemistry analysis. Tumour growth
Preclinical Models II Tuesday, 5 July 2011 10:30-12:00 kinetics and levels of total AMPK, phosphor- (P)-
AMPK and P-Acetyl-CoA Carboxylase (ACC),
MO11.02 THE ANTI-DIABETIC DRUG P-Akt, p53 and P-4EBP1 were evaluated.
METFORMIN SENSITIZES HUMAN Results: MET and IR alone inhibited signiÀcantly
NON-SMALL CELL LUNG CANCER A549 LC xenograft tumour growth. However,
(NSCLC) XENOGRAFTS TO IONIZING the combined treatment of MET and IR produced
RADIATION. an additive effect and inhibited tumour growth
Theodoros Tsakiridis1, Yaryna Storozhuk1, Toran signiÀcantly more than each treatment alone. IR and
Sanli2, Sarah Hopmans2, J.C. Cutz3, Evangelia MET enhanced AMPK phosphorylation and activity,
Tsiani4, Jim Wright1, Gurmit Singh2 detected by ACC phosphorylation. Similar to tumour
1
Radiation Oncology - Oncology, Juravinski Cancer growth kinetics, the combined treatment of MET+IR
Center - McMaster University/Canada, 2Pathology enhanced AMPK activity and phosphorylation
above the levels of each treatment alone. However, assays for TNF-Ơ.
we also detected that MET and IR treatments Results: HCC193 was found to be more sensitive
increased signiÀcantly the total AMPK Ơ subunit than H460 to BV6-induced apoptosis in a
levels in tumour tissues and caused a consistent concentration-dependent and time-dependent
potentiation of this effect when the two treatments manner. BV6 signiÀcantly sensitized both cell lines
were combined. On the other hand, MET inhibited to radiation (HCC193—DER=1.38, p<0.05 at 1mM
basal and radiation-induced Akt phosphorylation in BV6; H460—DER=1.42, p<0.05 at 5mM BV6),
xenografts. IR and MET increased p53 expression but a higher concentration of and longer incubation
and reduced phosphorylation of 4EBP1 while the timewith BV6 was necessary for H460 cells. The
combined MET+IR treatment potentiated those BV6-induced radiosensitization of HCC193 favored
effects. Our immunoblotting results were veriÀed the extrinsic pathway of apoptosis, while that of
with immunohistochemistry experiments. H460 favored the intrinsic pathway.
Conclusion: The present studies suggest that oral Conclusion: BV6, an IAP antagonist, signiÀcantly
therapy with MET inhibits growth and enhances enhanced the radiosensitization of HCC193 and
IR-induce cytotoxicity in human NSCLC xenograft H460 cells in vitro. More research is warranted to
tumours. IR and MET enhance the activity of the test the mechanism of action of BV6,and to assess its
signalling pathway of the tumour suppressor AMPK potential in vivo and in the clinical setting.
and inhibit that of the radioresistance mediator Akt. Keyword: BV6
These results demonstrate the potential of MET
to function as a useful adjunct to IR in-vivo and A revised/updated abstract may be included in
support evaluation of this drug in clinical trials in the Late Breaking Abstract Supplement, available
combination with radiotherapy. at the 14th World Conference on Lung Cancer.
Keywords: AMP-activated kinase, radiosensitizer,
metformin, Lung cancer
Preclinical Models II Tuesday, 5 July 2011 10:30-12:00
Preclinical Models II Tuesday, 5 July 2011 10:30-12:00 MO11.04 Y-BOX-BINDING PROTEIN

1: A POTENTIAL SUBTYPE-SPECIFIC
MO11.03 BV6, AN IAP ANTAGONIST, THERAPEUTIC TARGET IN
ACTIVATES APOPTOSIS AND MALIGNANT MESOTHELIOMA
ENHANCES RADIOSENSITIZATION OF Michaela B. Kirschner1, Lyn J. Schedlich1, Yuen
NON-SMALL CELL LUNG CARCINOMA Yee Cheng1, James J. Edelman2, Rayleen Bowman3,
IN VITRO Kwun M. Fong3, Nico Van Zandwijk1, Glen Reid1
1
Bo Lu Asbestos Diseases Research Institute,
Rad Onc, Thomas Jefferson Univ/United States Of Asbestos Diseases Research Institute/Australia,
2
America Cardiothoracic Surgical Unit, Royal Prince Alfred
Hospital; The Baird Institute; Faculty Of Medicine,
Background: Defects in the apoptosis pathway University Of Sydney/Australia, 3Department Of
limit the effectiveness of radiation in non-small cell Thoracic Medicine, The Prince Charles Hospital/
lung cancer (NSCLC) therapy. BV6 is an antagonist Australia
of cIAP1 and XIAP, members of the inhibitors of
apoptosis (IAP) family. We investigated the potential Background: The identiÀcation of novel therapeutic
of BV6 to sensitize NSCLC cell lines to radiation. targets for malignant mesothelioma (MM), an
Methods: HCC193 and H460 lung cancer cell lines asbestos-related malignancy with intrinsic drug
were treated with BV6 to investigate the effects of resistance, is an important unmet need. The Y-Box-
drug administration on cell proliferation, apoptosis, binding protein 1 (YBX-1), a DNA- and RNA-
inhibition of XIAP and cIAP1, and radiosensitivity. binding protein involved in transcriptional and
Subsequent immunoblotting and Hoescht staining translational regulation of many oncogenes and
were utilized to determine the role of apoptosis in tumour suppressor genes, could be one of those
radiosensitization. Finally, the pathway of apoptosis novel targets. Being overexpressed in various
was characterized by western blot analysis for cancers (e.g. NSCLC, breast) its nuclear expression
cleaved caspase-8 and cleaved caspase-9, and ELISA has been shown to be associated with late stages of
disease and a poor prognosis. Furthermore, YBX-1 is Preclinical Models II Tuesday, 5 July 2011 10:30-12:00
associated with the RNA-induced silencing complex
(RISC) which is important for the biogenesis of MO11.06 RNA APTAMER BLOCKADE OF
microRNAs (miRNAs). OSTEOPONTIN DECREASES INVASION
Methods: We used RNA interference to investigate AND EMT IN NON-SMALL CELL LUNG
the effects of gene silencing in established ATCC and CANCER
primary MM cell lines as well as the immortalized Jessica S. Donington1, Chandra M.V. Goparaju1,
normal mesothelial line Met-5A or primary Zhiyong Mi2, Ryan Harrington1, Nathalie Hirsch1,
mesothelial cells from pericardial Áuid. Growth Paul C. Kuo2, Harvey I. Pass1
1
inhibition was measured by SYBR Green staining of Cardiothoracic Surgery, Nyu School Of Medicine/
DNA, mRNA expression was quantiÀed by SYBR United States Of America, 2Loyola University
Green RT-qPCR and protein expression was assessed Medical Center/United States Of America
by western immunoblot. MiRNA expression after
YBX-1 knockdown was proÀled using NCode Background: Osteopontin (OPN) is a secreted
miRNA Microarrays and validation of array data was protein with a central role in the malignant
performed using miRNA speciÀc TaqMan RT-qPCR. phenotype of non-small cell lung cancer (NSCLC).
Results: Preliminary RNAi-based screening Epithelial-mesenchymal transition (EMT) is essential
identiÀed knockdown of a number of genes, for tumor invasion and metastatic spread. OPN
including YBX-1, to be growth inhibitory in MM expression in NSCLC is associated with activation
cells. Further investigations revealed that silencing of EMT. We hypothesize that OPN blockade by RNA
of YBX-1 is followed by profound subtype-speciÀc aptamer technology could decrease tumor invasion
growth inhibition in MM cell lines. Although in all by down regulation of EMT pathways.
cell lines transfection with YBX-1 siRNA led to a Methods: OPN RNA aptamer (OPN-R3) is a
reduction of YBX-1 mRNA and protein expression single stranded RNA that speciÀcally binds to OPN
of 80-90 %, the effect on cell growth was variable. by means of a complimentary three-dimensional
Four days after transfection the growth of the structure. We exposed three NSCLC cell lines, H358
biphasic cell lines MSTO-211H and MM05 was (low endogenous OPN), A549 and H460 (both with
reduced by 50-80 %, but only one of the epithelioid high endogenous OPN) to OPN-R3 and a control
cell lines used, H2452, showed similar effects, aptamer at concentration of 100nM/ml. We evaluated
while there was no growth inhibition in H28 and matrigel invasion at 48H and extracted RNA for RT-
H2052 (both epithelioid). Furthermore, silencing PCR evaluation of downstream targets associated
of YBX-1 does not affect the growth of either Met- with EMT.
5A or primary mesothelial cells from pericardial Results: OPN blockade by OPN-R3 resulted in
Áuid. Further experiments identiÀed a subset of 26 signiÀcant decreases in the number of invaded
miRNAs, including let-7f and miR-923, which are cells in the A549 (p=0.003) and H460 cell lines
differentially expressed only in those cells that show (p=0.039), but without effect in the H358 cell line.
inhibition of cell growth after YBX-1 knockdown. (Figure 1) RT PCR analysis demonstrated a decrease
In addition, these arrays showed that silencing of in expression of Snail-2, TGFb-1R, vimentin
YBX-1 alters the expression of miRNAs such as and N-cadherin with an associated increase in
miR-16 and miR-21, two miRNAs well known to be the expression of e-cadherin, cytokeratin-20, and
involved in oncogenesis of various solid tumours. desmoplakin, all consistent with a decrease in EMT
Conclusion: We have shown that siRNA- pathway activation. (Figure 2)
mediated silencing of YBX-1 leads to signiÀcant
growth inhibition predominantly in biphasic cells,
suggesting subtype-speciÀcity. YBX-1-silencing
induced dysregulation of a subset of miRNAs might
be involved in this effect. A peptide inhibiting YBX-
1 function as used in breast cancer models could be
developed as a potential treatment for biphasic MM.
Keywords: YBX-1, Malignant mesothelioma
PKC isozyme, is an oncogene overexpressed in

NSCLC tumors and cell lines, particularly those
with squamous histology (SCC). The PRKCI gene is
ampliÀed in most SCC and drives PKCƨ expression.
Aurothiomalate (ATM) disrupts the interaction
between PKCƨ and Par6 and exhibits potent anti-
tumor activity in NSCLC with elevated PKCƨ. A
phase I trial established a safe dose of ATM for
patients with advanced NSCLC. We now report
synergistic activity against SCC when both PKCƨ and
mTOR are inhibited. These data form the foundation
of a clinical trial for patients with advanced SCC.
Methods: ATM sensitive and insensitive cells were
grown in soft agar and treated with ATM, rapamycin,
targeted and/or cytotoxic agents and assessed for
anchorage independent growth. Representative ACA
Conclusion: RNA aptamers are emerging as a and SCC cells were grown in nude mice treated with
viable alternative to small molecules and antibody- ATM, rapamycin, both, or diluent. PKCƨ expression
based therapy in oncology because of high stability, was assessed by QPCR in primary NSCLC and in
low immunogenicity and very high afÀnity for cell lines. ATM dependent changes in NSCLC and
protein targets. The OPN-R3 aptamer signiÀcantly peripheral blood leukocyte (PBL) gene expression
decreased in vitro invasion in NSCLC cell lines were assessed by genome-wide gene expression
with high native OPN expression and resulted in analysis using Affymetrix chips to identify potential
decreased expression of targets associated with EMT. biomarkers of ATM-mediated PKCƨ inhibition.
Validation of these effects in vivo is underway. Results: ATM induced inhibition of anchorage
Keywords: Non-small cell lung cancer (NSCLC), independent growth in all NSCLC cell lines tested.
osteopontin, Epithelial-mesenchymal transition SCC cells tended to be more sensitive to ATM than
(EMT), Invasion ACA. PRKCI ampliÀcation was present in the two
most sensitive cell lines tested, H1703 and A427,
A revised/updated abstract may be included in both SCC cells. PKCƨ mRNA abundance correlated
the Late Breaking Abstract Supplement, available highly with ATM sensitivity. In 96 primary NSCLC
at the 14th World Conference on Lung Cancer. tumors, 23/36 SCC and 18/60 non-SCC tumors
were high PKCƨ expressers. ATM sensitivity did
not correlate to chemosensitivity in general but
Preclinical Models II Tuesday, 5 July 2011 10:30-12:00 correlated well with PKCƨ expression. ATM was
relatively non-toxic in nude mice bearing A427
MO11.07 COMBINED PROTEIN KINASE and H460 cells and inhibited growth of established
C IOTA AND MTOR INHIBITION FOR tumors at clinically relevant concentrations
TREATMENT OF SQUAMOUS LUNG consistent with the in vitro IC50 for the cell lines
CANCER. tested. Comparison of gene expression proÀles of
Helen J. Ross1, Roderick Regala2, Suzanne Randle2, H1703 cells with and without PKCƨ-RNAi treatment
Alan P. Fields2 revealed genes whose expression was signiÀcantly
1
Hematology/oncology, Mayo Clinic/United States altered by knock down of PKCƨ. Comparison with
Of America, 2Cancer Biology, Mayo Clinic Florida/ genes expressed in H1703 and PBLs treated with
United States Of America ATM or diluent revealed 22 genes commonly
regulated > 2-fold by both ATM and PKCƨ RNAi
Background: Targeted and maintenance therapies in H1703 and by ATM in PBLs. These are potential
for NSCLC are directed largely at adenocarcinomas biomarkers for ATM response. Rapalogs have
(ACA). However, for the approximately 40% of been tested in NSCLC patients with at best modest
NSCLC patients with squamous histology, targeted success. One method of resistance to mTOR
and maintenance therapies have not been well inhibitors is phosphorylation and reactivation of Akt
deÀned. Protein kinase C iota (PKCƨ), an atypical signaling. ATM inhibited rapamycin-induced Akt
phosphorylation, suggesting a possible mechanism bone scan and X-rays in 28 days after inoculating
for overcoming resistance. ATM and rapamycin and nuclei bone scan examination again before the
were highly synergistic against SCC cell lines and in mouse death, bone lesions for pathologic evaluation,
mouse tumor models. weight loss and survival time until 6 weeks.
Conclusion: Taken together, these data suggest that Results: This study indicated the combination group
combined inhibition of PKCƨ and mTOR with ATM signiÀcantly increased the apoptosis of the three
and rapamycin may be effective against SCC. We lung cancer cells in different time(P=0.00), and
are beginning a clinical trial of the combination as the G1/G0 phase proportion was higher than other
maintenance therapy for patients with advanced SCC treatment group. Western blot conÀrmed that the
after initial chemotherapy with correlative studies to role of p-p70S6K was inhibited apparently in the
assess mechanisms of response and resistance. combination group. The zoledronic acid combined
Keywords: PKCiota, mTOR, Squamous lung cancer with everolimus was effective in delay NSCLC
bone metastatic in animal model. Bone nuclei
scan results revealed that there were more bone
Preclinical Models II Tuesday, 5 July 2011 10:30-12:00 metastatic lesions in the control group than that in
the combination group for the Àrst bone metastasis
MO11.08 EVEROLIMUS COMBINED examination. In the treatment groups, bone nuclei
WITH ZOLEDRONIC ACID TREATING scan and radiographic imagine indicated that the
LUNG ADENOCARCINOMA BONE combination therapy signiÀcantly reduced bone
METASTASIS IN VITRO AND VIVO metastasis (9 versus 2 in the control group and
Yongfeng Yu, Zhengbo Song, S. Yang, Shun Lu combination group, p=0.017). The median survival
Department Of Shanghai Lung Cancer Center, days were 29, 35, 41, 42 in control group, zoledronic
Shanghai Chest Hospital, Jiaotong University, acid group , everolimus group and combination
Shanghai/China group respectively(P=0.00).
Conclusion: The results indicated that zoledronic
Background: Bone metastases contribute to burden acid combined with everolimus had synergistic
of disease in patients with non-small cell lung interaction to delay NSCLC bone metastasis and
cancer (NSCLC). Zoledronic acid is now proposed prolonged survival time in vivo.
to have the cytostatic effects on anti-tumour
effects. Everolimus, an serine-threonine kinase
mammalian target of rapamycin (mTOR) inhibitor, Preclinical Models II Tuesday, 5 July 2011 10:30-12:00
has been proven effective as an anti-cancer agent
in a broad range. The purpose of this study is to MO11.09 PI3K INHIBITORS, PI-103, GDC-
detect the effect of different treatment in vitro and 0941, AND BEZ235, OVERCOME HGF-
vivo and to evaluate the efÀcacy of zoledronate MEDIATED RESISTANCE TO EGFR-TKIS
alone and combined with everolimus treating lung IN EGFR MUTANT LUNG CANCER
adenocarcinoma bone metastasis. Seiji Yano1, Ivan S. Donev1, Tadaaki Yamada1, Shinji
Methods: MTT assay was applied to analyze Takeuchi1, Kunio Matsumoto2
1
these different treatments (zoledronic acid group, Medical Oncology, Kanazawa University Cancer
everolimus group, zoledronic acid combined with Research Institute/Japan, 2Tumor Dynamics And
everolimus group , control group) on proliferation Regulation, Kanazawa University Cancer Research
of lung cancer cells(A549, H460, SPC-A1). Flow Institute/Japan
cytometry analysis was performed to assess the cell
cycle phase distribution and apoptosis. The human Background: The acquired resistance to epidermal
lung adenocarcinoma cancer high bone metastasis growth factor receptor (EGFR) tyrosine kinase
cells SPC-A-1BM were inoculated into the cardiac inhibitors (TKIs) is one of the most serious problems
ventricle of 40 BALB/c mice. They were randomized on the management of EGFR mutant lung cancer.
into 4 groups(zoledronic acid group, everolimus We recently reported the novel mechanism that
group, two drugs combination group, and control hepatocyte growth factor (HGF) induces EGFR-
group), and received treatments for 3 weeks after TKI resistance by activating Met which restores
4 days of tumor implantation. Bone metastases phosphorylation of downstream MAPK-ERK1/2 and
was assessed by measurement of total-body nuclei PI3K-Akt pathways.
Methods: We determined whether inhibition of States Of America, 6Department Of Pathology And

PI3K, a downstream molecule of both EGFR and Laboratory Medicine, University Of California
Met, could overcome HGF-mediated EGFR-TKI At Davis/United States Of America, 7Response
resistance in EGFR mutant lung cancer cells, PC-9 Genetics/United States Of America, 8Cancer Center,
and HCC827. Here, we explored therapeutic effect of University Of California At Davis/United States Of
inhibitor PI-103, GDC-0941 (a derivative of PI-103 America, 9The Jackson Laboratory/United States Of
with better pharmacokinesis), and BEZ235, on HGF- America
induced EGFR-TKI resistance in vitro and in vivo.
Results: Unlike geÀtinib or erlotinib, continuous Background: NOD-scid IL2Rgammanull (NSG)
exposure with PI-103, GDC-0941, and BEZ235 mice lack functional B and T cells and natural killer
inhibited proliferation of PC-9 and HCC827 cells, cell activity and are the most immunodeÀcient, yet
even in the presence of HGF. Moreover, transient physiologically durable, murine models available for
exposure of PI-103 combined with geÀtinib caused consistent xenoengraftment of human primary tumors
sustained inhibition of Akt phosphorylation, but not and for in vivo drug testing. The overarching goal of
ERK1/2 phosphorylation, resulting in induction of this project is to use NSG mice to propagate non-small
tumor cell apoptosis even in the presence of HGF. In cell lung cancer (NSCLC) tumor cells from individual
geÀtinib-resistant xenograft model using PC-9 cells patients and validate a novel “co-clinical trial” strategy
mixed with HGF high producing Àbroblasts, PI-103 (i.e., concurrent evaluations of patients and patient-
or GDC-0941 monotherapy did not inhibit tumor derived xenografts [PDXs] in immunodeÀcient NSG
growth. However, PI-103 or GDC-0941 combined mice) as a platform to directly address and overcome
with geÀtinib successfully regressed geÀtinib- bottle-necks in the clinical application of state-of-the-art
resistant tumor. cancer genomics and personalized therapy.
Conclusion: These results indicate that transient Methods: Utilizing a transdisciplinary research
blockade of PI3K-Akt pathway by PI3K inhibitors collaboration between the University of California
and geÀtinib could overcome HGF-mediated at Davis Cancer Center and The Jackson Laboratory,
resistance to EGFR-TKIs by inducing apoptosis in fresh tumor specimens are engrafted subcutaneously
EGFR mutant lung cancer. into the Áanks of NSG mice. First human-to-mouse
Keywords: drug resistance, PI3K inhibitors, EGFR (P0) tumors and serially-passaged PDX tumors have
mutant lung cancer, HGF been subjected to 1) histomorphological assessment by
H&E and immunohistochemical (IHC) stains, 2) RT-
PCR-based molecular analyses of EGFR and K-Ras
Preclinical Models II Tuesday, 5 July 2011 10:30-12:00 mutations, EML4-ALK fusion transcripts, 3) RNA
expression levels of ERCC1, RRM1 and TS genes,
MO11.11 CHARACTERIZATION OF and 4) comprehensive genomic analyses by Affymetrix
PATIENT-DERIVED NSCLC NSG Human SNP 6.0 and Human Gene 1.0 ST Arrays.
MOUSE MODELS FOR PERSONALIZED Passages of Àrst (P1) and second (P2) mouse-to-mouse
THERAPY tumors are being evaluated for response to in vivo drug
Tianhong Li1, Sonal Desai1, Royce F. Calhoun2, testing.
David T. Cooke2, Valerie Kuderer2, Clifford G. Results: Of more than 200 cancers engrafted in
Tepper3, Ryan R. Davis4, Laurel A. Beckett5, Phillip our consortium over the past year, 42 of these were
Mack1, Primo N. Lara1, Regina Gandour-Edwards6, NSCLC tumors; of these, 8 were discontinued due to
Kathleen Danenberg7, Ralph Devere White8, Neal non-progressive growth and 1 due to non-matching
Goodwin9, David R. Gandara1 histology. To date, 25 tumors (60%) remain within the
1
Internal Medicine, Div. Hematology/oncology, 9-month incubation period. Patients demographics
University Of California At Davis/United States and clinicopathologic characteristics corresponding
Of America, 2Division Of Cardiothoracic Surgery, to the Àrst 7 NSCLC PDX models are as follows:
University Of California At Davis/United States male:female, 6:1; active smokers:prior smokers,
Of America, 3Department Of Biochemistry And 2:5, cigarette use, median 58.6 pack/year; and
Molecular Medicine, University Of California At adenocarcinoma;squamous cell carcinoma, 2:5. The
Davis/United States Of America, 4Mind Institute, median time from engraftment to P0 passage was 70.0
University Of California At Davis/United States Of days (range: 59–106 days). Histomorphological and
America, 5University Of California At Davis/United IHC correlation between PDX tumors and original
patient NSCLC tumors is excellent. Most engrafted susceptible to mutation-based resistance creating
NSCLC tumors have poor prognostic features: poorly a medical need for second-generation agents. For
differentiated tumors (n=6), K-Ras mutation (n=3), EGFR inhibitors, the T790M gatekeeper mutation
and low median expression levels of chemotherapy accounts for ~50% of resistance. Potent irreversible
predictive biomarkers ERCC1, RRMI and TS RNA T790M inhibitors are in development but can exhibit
(1.00, 0.85, and 1.81, respectively). There was no toxicity due to co-inhibition of native (endogenous)
statistically signiÀcant difference between the original EGFR, suggesting that T790M-selective agents will
patient and P0 tumors with respect to RNA expression be required. For the ALK inhibitor crizotinib, clinical
levels of ERCC1 (p=0.52) and TS (p=0.83). Among resistance has been linked to the L1196M gatekeeper
these biomarkers, the best correlation between PDX mutation. Previously, we have identiÀed AP26113
and P0 tumors is seen for ERCC1 expression. Ongoing as a potent ALK inhibitor that overcomes this and
experiments are testing these NSCLC PDX models other mutations. A broad kinase screen revealed that
for correlation with patient response to platinum-based AP26113 also reversibly inhibits EGFR harboring
therapy. Further molecular and genomic analyses are activating and T790M mutations.
ongoing and will be presented. Methods: The activity of AP26113 against native,
Conclusion: To our knowledge, this is the largest activated (L858R or delE746_A750 [DEL]), and
cohort of NSCLC PDX models yet established. Our T790M mutant (L858R/T790M or DEL/T790M)
initial experience demonstrates close similarity between forms of EGFR was examined in NSCLC as well
PDX and original patient tumors with regards to as engineered Ba/F3 and 3T3 cell lines. EGFR
histomorphological features and molecular biomarker signaling was assessed by measuring levels of
expression. Further characterization is needed to deÀne phosphorylated EGFR (Y1068), in vitro proliferation
the role of these models as clinically relevant research measured by MTS assay, and in vivo tumor growth
platforms for selecting and validating personalized measured in mouse xenografts following daily oral
cancer therapy based on molecular biomarker proÀling dosing.
and in vivo drug testing. Results: AP26113 was essentially inactive against
Keywords: patient-derived xenografts, personalized native EGFR, inhibiting signaling with IC50s >1000
therapy, in vivo drug testing, NSCLC, NSG mice nM in a NSCLC cell line (H358) and native EGFR-
transduced Ba/F3 and 3T3 cells. In contrast, potent
A revised/updated abstract may be included in activity was demonstrated against activated forms
the Late Breaking Abstract Supplement, available of EGFR. EGFR signaling was inhibited with IC50s
at the 14th World Conference on Lung Cancer. of 10-50 nM in HCC827 (DEL), DEL Ba/F3 and
L858R 3T3 cells. In HCC827 cells, proliferation
was inhibited with an IC50 of 105 nM. In an
Preclinical Models II Tuesday, 5 July 2011 10:30-12:00 HCC827 xenograft model, doses of 25 mg/kg or
greater induced tumor regression (>33%) and >90%
MO11.12 AP26113, A POTENT ALK and >60% inhibition of EGFR signaling 10 and
INHIBITOR, IS ALSO ACTIVE AGAINST 24 hours after dosing. SigniÀcantly, AP26113 also
EGFR T790M IN MOUSE MODELS OF demonstrated potent activity against T790M mutant
NSCLC forms of EGFR. EGFR signaling was inhibited with
Juan J. Miret, Frank Wang, Rana Anjum, Sen Zhang, IC50s of 10-63 nM in H1975 (L858R/T790M),
Jeffrey Keats, Michelle Cookson, Yaoyu Ning, and DEL/T790M and L858R/T790M Ba/F3 and
Scott Wardwell, Lauren Moran, Qurish Mohemmad, 3T3 cells. In H1975 and DEL/T790M Ba/F3 cells
Yihan Wang, Jiwei Qi, Rachel Squillace, Narayana proliferation was inhibited with IC50s of 85-350
Narasimhan, David Dalgarno, Tim Clackson, nM. In an H1975 xenograft model, doses of 50 and
William Shakespeare, Victor Rivera 75 mg/kg led to signiÀcant tumor growth inhibition
Biology, Ariad Pharmaceuticals/United States Of (45%). In a DEL/T790M Ba/F3 xenograft model,
America doses of 50 and 75 mg/kg led to tumor stasis and
50% tumor regression. In both models, substantial
Background: Activating mutations in EGFR and prolonged inhibition of EGFR signaling was
anaplastic lymphoma kinase (ALK) are drivers in observed.
~20% of all NSCLCs. First generation EGFR and Conclusion: AP26113 is a novel reversible inhibitor
ALK inhibitors are clinically efÀcacious, but are of activated and resistant mutants of EGFR, and
does not inhibit the native enzyme. Importantly, oral cancer are independent of KRAS status. To test
doses that are efÀcacious in mice against activated this hypothesis we evaluated antitumor activity of
and T790M mutant EGFR are similar to those linifanib, as monotherapy or in combination with
active against native- and crizotinib-resistant ALK carboplatin/paclitaxel (CP), in NSCLC xenograft
variants, suggesting that AP26113 is a dual ALK/ models utilizing cell lines harboring either wild type
mutant EGFR inhibitor. These data support clinical or mutated KRAS.
evaluation of AP26113 in patients with resistant Methods: Tumor growth inhibition (TGI) was
EGFR-driven tumors. assessed in H1299 (KRAS wt) and Calu-6FP (KRAS
Keywords: EGFR T790M, reversible kinase mut) Áank xenograft models using tumor volumes
inhibitor, AP26113, ALK measured when the control groups were terminated
(day 43 and 32 respectively). Linifanib was
evaluated as monotheray (6.25 – 25 mg/kg/day BID,
Preclinical Models II Tuesday, 5 July 2011 10:30-12:00 PO) and in combination with CP.
Results: As monotherapy linifanib was active
MO11.13 EFFICACY OF LINIFANIB IN (TGI > 50%) in both NSCL tumor models at all
PRECLINICAL MODELS OF NSCLC doses tested. When dosed in combination with
WITH WILD-TYPE AND MUTATED KRAS CP the response was generally greater than either
Daniel H. Albert1, David Reuter1, Paul A. Ellis1, Gail therapy alone. The highest level of inhibition with
Bukofzer1, Cherrie K. Donawho1, Mark D. Mckee2, combination therapy was in the KRAS-mutant
Justin L. Ricker2, Dawn M. Carlson2, Steve K. model where maximal TGI (85%) was achieved
Davidsen3 with a dose (6.25 mg/kg/day) 4-fold lower than the
1
Dept R4n2, Abbott Laboratories/United States Of optimal efÀcacious dose (25 mg/kg/day). Drug-
America, 2R48k, Abbott Laboratories/United States related toxicity was not observed in any dose group.
Of America, 3R460, Abbott Laboratories/United
States Of America
Background: KRAS is an oncogene encoding a

GTP-binding protein that regulates cell growth,
differentiation and apoptosis via multiple interactions
including MAPK, STAT and PI3K. KRAS mutations
have been reported in 22% of lung adenocarcinomas
and are associated with poor overall outcome in
cancer. Patients with NSCLC undergoing therapy
with erlotinib have poorer disease control if a KRAS
mutation is present (14% vs. 37% for wild-type,
Kim et al. AACR 2010;#1981). A similar trend
linking KRAS mutations to resistance to EGFR
inhibitors has been observed in colorectal carcinoma Conclusion: Linifanib is active in RAS-wild
(Dempke WC, Heinemann V. Anticancer Res. 2010 type and in RAS-mutant models of NSCLC as
Nov;30(11):4673-7). EGFR-related resistance is monotherapy and in combination with carboplatin/
not fully understood, but these clinical outcomes paclitaxel. These results support the potential
suggest the need for additional therapy to overcome therapeutic utility for linifanib in KRAS-mutant
resistance linked to KRAS mutations. Linifanib NSCLC. The mechanism for the enhanced activity
(ABT-869) is a potent VEGF/PDGF RTK inhibitor with chemotherapy in the KRAS-mutant model is
that is active in lung cancer models and has exhibited being investigated.
clinical signals of activity in a phase 2 NSCLC Keywords: angiogenesis, VEGFR2 inhibitor, Kras,
trial (ESMO 2010, abstract 41). The primary mode combination therapy
of action of linifanib is thought to be on tumor
vasculature through inhibition of the VEGF and
PDGF signaling pathways with limited direct effects
on tumor proliferation. Therefore we hypothesized
that antitumor effects of linifanib observed in lung
Preclinical Models II Tuesday, 5 July 2011 10:30-12:00 growth inhibition. Similar results were obtained
in the HCC827TR3 xenograft model. However, in
MO11.14 CONTINUOUS INHIBITION the H1975 xenograft model, combination therapy
OF THE EPIDERMAL GROWTH of erlotinib (75 mg/kg) with docetaxel (5 mg/kg)
FACTOR RECEPTOR (EGFR) WITH showed no synergistic antitumor effect compared
ERLOTINIB ENHANCED ANTITUMOR with docetaxel (5 mg/kg) monotherapy. In in
ACTIVITY OF CHEMOTHERAPY vitro tests, EGFR phosphorylation was inhibited
AGAINST ERLOTINIB-RESISTANT NON by erlotinib in EBC-1 and HCC827TR3, but not
SMALL CELL LUNG CANCER (NSCLC) in H1975 cells. In the HPAC xenograft model,
XENOGRAFTS. combination therapy of erlotinib (75 mg/kg) with
Toshiki Iwai, Masatoshi Shirane, Yoichiro Moriya, docetaxel (30 mg/kg) showed signiÀcantly superior
Kaori Fujimoto-Ouchi antitumor effect compared with docetaxel (30 mg/
Product Research, Chugai Pharmaceutical/Japan kg) monotherapy (TGI: 89% and 60%; p<0.01). In
this model, EGFR phosphorylation of HPAC cells
Background: Erlotinib, an effective EGFR was inhibited by erlotinib in vivo.
tyrosine kinase inhibitor, has been shown to Conclusion: The combination therapy of erlotinib
provide signiÀcant clinical beneÀt for patients with docetaxel was considered to be a superior
with metastatic NSCLC (BR.21, SATURN) and treatment modality compared to docetaxel
pancreatic cancer. But signiÀcant numbers of patients monotherapy after disease progression on erlotinib
proceed to progressive disease (PD) during erlotinib monotherapy in NSCLC.
monotherapy due to the occurrence of erlotinib Keywords: EGFR, erlotinib, resistant,
resistance caused by a secondary mutation (T790M) Chemotherapy
in EGFR or by MET ampliÀcation though tumor
maintains the expression of EGFR. Standard therapy
for the patients with PD has not been established. In Session MO12: End Of Life Care
the present study, we investigated the combination
therapy of erlotinib with docetaxel in erlotinib- Tuesday, 5 July 2011
resistant xenograft models.
Methods: Three erlotinib-resistant NSCLC cell-lines
(EBC-1, H1975, HCC827TR3) were subcutaneously End Of Life Care Tuesday, 5 July 2011 10:30-12:00
inoculated into BALB/c nude mice. Drug
administration started when tumor volume reached MO12.01 AN INTER-PROFESSIONAL
100-300 mm3. Erlotinib was orally administered once DYSPNEA MANAGEMENT CLINIC:
a day and docetaxel was intravenously administered COLLABORATING TO MANAGE
once every 3 weeks. Antitumor effect was evaluated SHORTNESS OF BREATH
by tumor growth inhibition (TGI) on day 22. As Lynn Kachuik1, Kayvan Amjadi2
1
an in vivo erlotinib-resistant tumor model, HPAC Palliative Care, The Ottawa Hospital/Canada,
2
pancreatic cancer cells were subcutaneously Respirology: Interventional Pulmonology, The
inoculated and erlotinib administration started when Ottawa Hospital / University Of Ottawa/Canada
tumor volume reached approximately 100-300 mm3,
and was continued until tumor growth inhibition Background: Our cancer centre provides lung
was not observed. The mice were rerandomized and cancer care for 1.2 million residents. The centre
treated with erlotinib in combination with docetaxel. has seen 728 new lung cancer patients per calendar
Antitumor effect was evaluated on day 22. EGFR year from 2007- 2009 and has treated 1103 cases
and downstream signal transduction molecules were with either systemic or radiation therapy. In addition
analyzed by western blotting. lung cancer patients accounted for an average of
Results: In the EBC-1 xenograft model, combination 8338 patient visits per calendar year or 695 visits
therapy of erlotinib (75 mg/kg) with docetaxel (5 per month. Dyspnea is one of the most distressing
mg/kg) showed signiÀcantly superior antitumor symptoms experienced by lung cancer patients
effect compared with docetaxel (5 mg/kg) at any point in the disease trajectory. A three day
monotherapy (TGI: 84% and 55%; p<0.01), whereas prevalence study conducted at our centre in 2007
erlotinib (75 mg/kg) monotherapy showed no tumor using the Edmonton Symptom Assessment System
(ESAS) indicated that shortness of breath of > 4/10 End Of Life Care Tuesday, 5 July 2011 10:30-12:00
was an issue in 51% of 54 lung patients included
in the study. Since dyspnea was such an issue for MO12.02 ASSESSMENT OF PALLIATIVES
our patients, we piloted a ½ day inter-professional CARE (PC) IN ADVANCED NON SMALL
clinic for patients experiencing distressing dyspnea CELL LUNG CANCER PATIENTS
(ESAS score > 4/10). It included assessment of the (NSCLC): AN OBSERVATIONAL STUDY
patient by various clinicians (physician, nurse, social FROM GFPC. BASELINE DATA AT
worker, occupational therapist, respiratory therapist) INCLUSION
with oncology and palliative care expertise. The goal Alain Vergnenegre1, Stéphane Hominal2, Isabelle
of the clinic was to identify any underlying clinical Monnet3, Gérard Oliviero4, Nathalie Baize5,
causes of the dyspnea and apply best evidence Clarisse Audigier-Valette3, Henri Bérard6, Gislaine
in individualizing interventions, education and Fraboulet7, Herve Le Caer8, Christos Chouaid9
1
counseling to help patients manage their shortness Pathologie Respiratoire, Hôpital Du Cluzeau/
of breath. Validated tools were used in the initial and France, 2Ch, Service De Pathologie Respiratoire/
follow up assessments to measure the effectiveness France, 3Service De Pathologie Respiratoire, Chi/
of interventions as well as patient outcomes. France, 4Service De Pathologie Respiratoire, Chr/
Methods: The patients were assessed at initial and France, 5Département De Pneumologie, Centre
follow up visits using a series of validated tools Hospitalaire Universitaire Angers/France, 6Service
relevant to dyspnea. These included: the Edmonton De Pathologie Respiratoire, Hôpital D’instruction
Symptom Assessement System, the Baseline Des Armées Sainte Anne/France, 7Service De
Dyspnea Index, the Transitional Dyspnea Index, Pathologie Respiratoire, Ch/France, 8Oncology,
the six minute walk test, incentive spirometry, Centre Hospitalier Dracenie/France, 9Service De
oxygen saturation levels, respiratory rate, pulse, Pathologie Respiratoire, Chu Saint Antoine/France
blood pressure, the Palliative Performance Scale, the
Eastern Cooperative Oncology Group scale and the Background: Palliatives cares (PC) appears as
European Organization for Research and Treatment an important modality of advanced non small cell
of Cancer Quality of Life Questionnaire 30. In lung cancer patients (NSCLC) management (1).
addition, patients were asked about their satisfaction Little is known in France about the time of their
with the care received. All results were entered into a initiation, their contents, the quality of life (QoL) and
protected data base. economical impact.
Results: In analyzing our data we wanted to know Methods: ETOBSUP was an observational study,
if patients attending the Dyspnea Management performed in 39 centres of the GFPC, a national
Clinic beneÀted from the inter-professional team’s network of lung cancer management specialized
involvement and collective knowledge related to centres. All the consecutives patients, with PC
managing shortness of breath. We will report on the initiated, were included between July 1st 2009 and
results of our data analysis including parameters June 30th 2010. Information about management,
such as dyspnea scores, clinical outcomes, functional type of PC and QoL assessment (EQ5-D) were
status, and quality of life. prospectively collected every 3 months, with one
Conclusion: Dyspnea is a very distressing year follow-up. Uni and multivariate analyses
symptom for lung cancer patients. Data related researched factors associated to PC.
to targeted management via a focused clinic with Results: The study included 444 patients, median
a knowledgeable inter-professional team, use of age was 63 y [37-90], 72.5% males, 59.9% PS 0-1,
appropriate tools and individualized strategies will 19.2% PS2, 8.3% PS>2; median weight loss was
be presented. 5.1% [0-38.9]. Histology was: adenocarcinoma in
Keyword: interprofessional dyspnea management 61.2% of patients, squamous cell 18.9%, others
19.9%. Metastases were preferentially in bones
(25%), lung (21%), brain 15%, adrenal glands
(12.7%). An organized announcement of cancer
was performed in 71% of cases, with the help of a
psychologist in 17.6%. The mean delay between
diagnosis and announcement was 9 days ± 15.
Before PC, NSCLC management was surgery
(10.3%), chemotherapy (36%), radiotherapy chemotherapy. Toxicity was manageable and 36 pts
(14.9%), symptomatic treatments (43.4%). (37%) presented G3+ toxicities (NCI-CTC v.3.0).
Conclusion: ETOBSUP was an observational study, Partial tumor response was seen in 17 pts (18%),
which could provide characteristics and follow-up complete response in 1 pt (1%) and stable disease
of NSCLC patients with palliative cares. Complete in 35 pts (36%). In a mean follow-up of 13 mo, 47
data’s, including type of PC and factors signiÀcantly deaths were observed. The median OS was 15.4 mo.
associated with PC will be presented at the meeting. No difference in 1-year OS was observed between
Keywords: palliative care, Lung cancer, pts with CCI < 7 vs. 7 (56% vs. 71%, HR 1.51,
observational study p=0.174). Estimated 1-year OS was signiÀcantly
better for pts with ECOG-PS 0-1 vs. 2+ (65% vs.
55%, HR 0.46, p=0,017), BMI > 21 vs. 21 kg/m2
End Of Life Care Tuesday, 5 July 2011 10:30-12:00 (70% vs. 48%, HR 0.58, p=0.059), HB 12 vs. < 12
g/dL (70% vs. 46%, HR 0.43, p=0.003), low CRP (<
MO12.03 CHEMOTHERAPY IN ELDERLY 66 mg/L, ROC analysis) vs. elevated CRP (75% vs.
PATIENTS WITH ADVANCED NSCLC: 53%, HR 0.39, p=0.045). ECOG-PS 0-1 and BMI >
A RETROSPECTIVE ANALYSIS OF THE 21 kg/m2 before chemotherapy remained signiÀcant
IMPACT OF PERFORMANCE STATUS, as favorable prognostic factors in terms of OS in a
CHARLSON COMORBIDITY INDEX, multivariate analysis.
BODY MASS INDEX AND HEMOGLOBIN Conclusion: Our results suggest that chemotherapy
AND C-REACTIVE PROTEIN LEVELS can be delivered safely and good outcomes can be
ON OVERALL SURVIVAL observed in selected NSCLC patients aged 65 y.
Tiago K. Takahashi, Caroline C.L. Barbosa, Paulo Those pts with ECOG-PS 0-1 and BMI >21 kg/m2
M. Hoff, Gilberto Castro Jr presented better OS rates and, if conÀrmed in other
Clinical Oncology, Instituto Do Cancer Do Estado studies, these prognostic factors must be taken into
De Sao Paulo/Brazil account in treatment selection.
Keywords: elderly patients, Chemotherapy,
Background: Elderly patients (pts) diagnosed prognostic factors, Non-small cell lung cancer
with advanced NSCLC can be safely treated with
platinum-based chemotherapy, but pt selection is
a critical issue. We aimed to study the outcomes End Of Life Care Tuesday, 5 July 2011 10:30-12:00
of pts aged 65 y and diagnosed with advanced
NSCLC treated with chemotherapy, and the impact MO12.04 INCIDENCE OF PAIN IN
of performance status (PS), Charlson comorbidity CA.LUNG PATIENTS REFERRED TO
index (CCI), body mass index (BMI), hemoglobin PALLIATIVE CARE
(HB) and C-reactive protein (CRP) levels on overall Lingegowda K. Boregowda
survival (OS). Palliative Medicine, Kidwai Memorial Institute Of
Methods: It is a retrospective study on pts aged Oncology/India
65 y diagnosed with advanced NSCLC and
consecutively treated with chemotherapy from Background: Lung cancer being the major cancer
Jul/2007 to Jun/2010. Pre-treatment ECOG-PS, in men in the world, in developing country like India
CCI, BMI, HB and CRP levels were analyzed as Ca.Lung constitutes 7.1% in men and 2%in women.
prognostic factors. OS was estimated by the Kaplan- Still majority of our patients present to hospital in an
Meier method and curves were compared with advanced stage. More than 80% will be having pain
log-rank. A multivariable Cox proportional hazards in this stage and they need only palliative care as
model was used to control for prognostic factors. there is no role for curative treatment.
Results: 97 pts were identiÀed: median age 70 y (65- Methods: 446 patients were screened who were
89 y), 68% male, 75% ECOG-PS 0-1, 72% smokers; rererred to palliative care department over a perios
61% adenocarcinoma; median of 1 metastatic site. of 3 months from all the departments. Total 38
Chemotherapy regimens included carboplatin- patients with diagnsis of Ca.Lung were rererred from
paclitaxel (47%), cisplatin-gemcitabine (33%) and Surgical and Medical oncology.
gemcitabine alone (9%), delivered in a median Results: 90% of patients had pain at the time of
of 4 cycles. 37 pts were treated with second line reporting to palliative care centre.
Conclusion: Routine referral to palliative care centre the 6 months, with the highest uncertainty in the 6
from the day of diagnosis solve many problems month of diagnosis (T4) (M= 64.7, SD= 9.4).
in Ca.Lung patients. Early referral will improve Conclusion: The relatively low scores in role
patients comfort from pain. and social functions and high uncertainty in these
Keywords: palliative care, Ca.Lung, pain patients have suggested the major impact of lung
cancer on patients’ daily life. Future intervention
studies to integrate these concerns and disease related
End Of Life Care Tuesday, 5 July 2011 10:30-12:00 psychological/ physical care would be strongly
suggested to improve lung cancer patients’ QOL.
MO12.06 CHANGES OF QUALITY OF Keywords: Quality of Life, uncertainty, social function,
LIFE AND UNCERTAINTY IN NEWLY role function
DIAGNOSED ADVANCED LUNG
CANCER PATIENTS – A 6 MONTHS
LONGITUDINAL STUDY End Of Life Care Tuesday, 5 July 2011 10:30-12:00
Yeur-Hur Lai1, Yu-Chio Liao2, Yun-Hsing Lee1,
Chong-Jen Yu3, Pan Chyr Yang4 MO12.07 HEALTH-RELATED QUALITY
1
School Of Nursing, National Taiwan University/ OF LIFE IN PATIENTS WITH LUNG
Taiwan, 2Yuanpei University/Taiwan, 3Pulmonary CANCER: VALIDATION OF THE
And Critical Care Medicine, National Taiwan MEXICAN-SPANISH VERSION OF THE
University Hospital/Taiwan, 4National Taiwan EORTC QLQ-LC13 QUESTIONNAIRE
University College Of Medicine/Taiwan Carolina Nuñez-Valencia1, Luis Fernando Oñate
Ocaña2, Leonardo Reynoso-Erazo3, Pablo Espinoza-
Background: Lung cancer is one of the most Mireles-de-Villafranca2, Patricia Angulo Camarena4,
threatening diseases due to its limited survival time. Diana Flores Estrada4, Oscar Arrieta4
1
However, limited information has reported about Unidad De Postgrado, Facultad De Psicología,
patients’ quality of life and uncertainty during the Universidad Nacional Autónoma De México/Mexico,
2
Àrst 6 months of being diagnosed as lung cancer. The División De Investigación, Instituto Nacional De
purposes of this study were to (1) examine the changes Cancerología/Mexico, 3Unidad De Postgrado,
of quality of life (QOL; global & multi-dimensions); Universidad Nacional Autónoma De México/Mexico,
4
and (2) examine the changes of uncertainty in advanced Clínica De Cáncer De Pulmón, Instituto Nacional
lung cancer patients during the Àrst 6 months of De Cancerología/Mexico
diagnosis.
Methods: A prospective longitudinal study was Background: Lung cancer (LC) is the main cause
conducted to recruit 83 newly diagnosed non-operable of cancer-related mortality worldwide and health-
non-small cell lung cancer (NSCLC) patients from related quality of life (HRQL) is fundamental
a medical center in Northern Taiwan. Patients to evaluate treatment results. Our objective is
were assessed of their QOL changes (measured by to validate the Mexican-Spanish versions of the
EORTC-QLQ) and uncertainty (measured by Mishel’s European Organization for Research and Treatment
’Uncertainty of Illness Scale; MUIS) at four time of Cancer (EORTC) Quality-of-Life Questionnaire
points (pretreatment and 1, 3, 6 months from receiving QLQ-C30 and QLQ-LC13 disease-speciÀc
treatments, T1- T4, respectively). questionnaire module in Mexican patients with LC.
Results: The results showed that patients had a Methods: Translation procedures followed EORTC
moderate level of global QOL across the Àrst 6 guidelines. Both instruments were completed by
months of diagnosis. Among the Àve QOL related patients with LC, before, during and after treatments.
dimensions, patients reported to have relatively lower Tests for reliability and validity were performed.
scores in social function and role function related QOL Test-retest was performed on a subset of patients.
dimensions. Patients reported to have lowest social Results: One hundred and Àfty-three patients
function (SF) related QOL before treatment (T1) and completed both questionnaires. Compliance rates
relatively highest SF in the 6 months of diagnosis. were high, and questionnaires were well accepted.
Patients had relatively better physical and emotion Patients with better Karnofsky or ECOG
functions related QOL across the 6 months. However, performance status reported better functional HRQL
patients also reported to have high uncertainty across scores. Different scales in the QLQ-C30 and QLQ-
LC13 were accurately related to the of patients Conclusion: The Mexican-Spanish versions of
clinical characteristics. The scale of global health EORTC QLQ-C30 and QLQ-LC13 questionnaires
status and the Àve functional scales correlated with are reliable and valid for HRQL measurement
KPS and ECOG. Some of the symptom scales from in Mexican patients with LC and therefore are
both QLQ-C30 and the QLQ-LC13 questionnaires recommended to be used in clinical trials.
correlated with some indicators; e.g. the fatigue scale Keyword: cancer, quality of life, EORTC, validation
correlated with KPS, ECOG, lymphocyte levels and studies, questionnaires, Mexico.
body mass index (BMI); both the scales of dyspnea
and cough correlated with smoking history. Nine A revised/updated abstract may be included in
out of ten multi-item scales of both questionnaires the Late Breaking Abstract Supplement, available
presented Cronbach’s alpha coefÀcients >0.7. at the 14th World Conference on Lung Cancer.
Multitrait scaling analysis demonstrated good
convergent and discriminant validity. The test-
retest differences were expected; functional scales End Of Life Care Tuesday, 5 July 2011 10:30-12:00
improved after chemotherapy as well as disease
symptom scales. Treatment side-effects scales MO12.08 RELIABILITY AND VALIDITY
worsened. Additionally, patients with better scores OF THE THAI TRANSLATED VERSION
on the (>66) had a median survival of 16.6 months, (THAI PPS ADULT SUANDOK) OF THE
compared to 8.3 months for those with lower scores PALLIATIVE PERFORMANCE SCALE
(P=0.009). (PPSV2)
Busyamas Chewaskulyong1, Ladarat Sapinun2,
Michael Downing3
1
Department Of Medicine, Chiangmai University/
Thailand, 2Maharajnakornchiangmai Hospital,
Chgiangmai University/Thailand, 3Of Palliative
Care, Victoria Hospice/Canada
Background: The Palliative Performance Scale

(PPS) was Àrst introduced by Anderson and
Downing in 1996 as a new tool for measurement of
performance status in palliative care and has been
used for communication, analysis of home nursing
care workload, proÀling admissions and discharges
to the hospice unit and prognostication. PPS has been
translated into other languages including French,
Japanese, German, Portuguese, Spanish, Arabic and
Thai. The Thai version is known as Thai PPS Adult
Suandok where the word Suandok is representative
of a university hospital in Chiang Mai, Thailand
and meaning ‘Àeld of Áowers’ The Thai PPS Adult
Suandok tool was translated from the Palliative
Performance Scale (PPSv2) and tested for reliability
and validity.
Methods: A set of 22 simulated palliative care
patients’ cases were based on real patient scenarios
but modiÀed for anonymity and contain brief
descriptions of each case’s demographics, primary
diagnosis, medical, social and family history, signs
and symptoms, medications and care plan. The set
was used by 70 nurses and physicians to determine
a PPS score on time-1, and then repeated two weeks
later as time-2. A survey questionnaire was also
completed for qualitative analysis. Sample size End Of Life Care Tuesday, 5 July 2011 10:30-12:00
calculations are based on the Ho study with a
minimum required of 44 raters. Data was analyzed MO12.09 INTERNATIONAL
for inter- and intra-rater reliability using the single PRACTICE SURVEY ON PALLIATIVE
rating intraclass correlation coefÀcient (ICC) for LUNG RADIOTHERAPY: THIRD
absolute agreement and for consistency using INTERNATIONAL CONSENSUS
two-way random-effects models. Participant WORKSHOP ON PALLIATIVE
reliability was evaluated using Cohen’s kappa, RADIOTHERAPY AND SYMPTOM
which is a chance-corrected measure of agreement CONTROL
between two participants. Rater reliability was George Rodrigues1, Fergus Macbeth2, Bryan
also evaluated using a randomized block ANOVA Burmeister3, Karie-Lynn Kelly4, Andrea Bezjak5,
incorporating rater as a random effect. This Corey J. Langer6, Carol Hahn7, Anushree Vichare8,
analysis accommodates the dependent nature Benjamin Movsas9
1
of the data, where the same rater is providing Radiation Oncology, London Regional Cancer
observations for both time points. It allows Program/Canada, 2National Institute For Health
evaluation of the effects over time and possible And Clinical Excellence/United Kingdom, 3Princess
interactions of time with the cases. . The study was Alexandra Hospital/Australia, 4Kootenai Cancer
reviewed and received ethics approvals by both the Center/United States Of America, 5Princess
Chiang Mai University and University of Victoria Margaret Hospital/Canada, 6University Of
Research Ethics Boards. Pennsylvania/United States Of America, 7Duke
Results: 70 raters consisting of 51 nurses and Radiation Oncology/United States Of America,
8
19 physicians completed both time periods. The American Society For Radiation Oncology (astro)/
Time-1 ICC for absolute agreement is 0.911 (95% United States Of America, 9Henry Ford Hospital/
CI 0.86-0.96) and for consistency is 0.92 (95% United States Of America
CI 0.87-0.96). The Time-2 ICC for agreement is
0.905 (95% CI 0.85-0.95) and for consistency Background: The purpose of this work is to
is 0.912 (95% CI 0.86-0.96). These Àndings disseminate international practice survey results
indicate good agreement among participants and and consensus statement on palliative therapy
also were somewhat higher in the Time-2 re-test of lung cancer created in conjunction with the
phase. Cohen’s kappa score is 0.55 demonstrated Third International Lung Cancer (LC) Consensus
a moderate agreement. Thematic analysis from the Workshop.
surveys showed that 91% felt PPS to be a valuable Methods: In conjunction with an ASTRO practice
clinical tool overall, with it being “very useful” or guideline, an online international practice survey and
“useful” in several areas including care planning of international consensus statements was conducted
78% and 20%, disease monitoring 69% and 27% during the summer of 2010. The palliative lung
and prognostication 61% and 31% respectively. RT workshop committee agreed on Àve questions
Some respondents noted difÀculty in determining relating to (1) patient selection, (2) thoracic external
appropriate scores in paraplegic patient or those beam (XRT) fractionation, (3) endobronchial
with feeding tubes, while others found the brachytherapy (EBB), (4) concurrent chemotherapy
instructions long or difÀcult. (CC), and (5) palliative endpoint deÀnitions. A
Conclusion: The Thai PPS Adult Suandok PubMed search for primary/cross-referenced practice
translated tool has good inter- and intra-rater guidelines, consensus statements, meta-analyses,
reliability and can be used regularly for clinical and/or systematic reviews was conducted. Final
care. consensus statements were created after review
and discussion of the available evidence. The
practice survey consisted of 3 sections focusing
on respondent demographics, factors for use and
dose fractionation of radiotherapy, and 5 cases
exploring the role of external beam radiotherapy,
endobronchial brachytherapy, and concurrent
chemoradiation in the setting of metastatic lung
cancer.
Results: A total of 279 individuals responded to the End Of Life Care Tuesday, 5 July 2011 10:30-12:00
survey over a 3 month period. Most respondents were
hospital-based academic or government radiation MO12.11 PROSPECTIVE STUDY ON THE
oncologists. A wide distribution of practice location IMPACT OF ANXIETY AND DEPRESSION
and experience was observed. Factors consistently IN SURVIVAL AND QUALITY OF LIFE OF
related to use and choice of external beam dose CANCER PATIENTS WITH NON-SMALL
fractionation included: expected treatment effect to CELL LUNG CANCER WITH ADVANCED
patient, symptom severity, patient choice, performance DISEASE AND GOOD PERFORMANCE
status, and previous radiation to site. Factors STATUS
consistently not related to use and dose fractionation Laura P. Angulo Camarena1, Yuzmiren Dorantes
included: requirement for future radiation therapy, Gallareta2, Carolina Nuñez-Valencia1, Oscar Arrieta2
1
department policy, and wait lists. A signiÀcant range Clinica De Cancer De Pulmon, Instituto Nacional
of dose fractionation schedules existed for external De Cancerologia/Mexico, 2Subunidad De
beam (n=35) and endobronchial brachytherapy Investigación, Instituto Nacional De Cancerologia/
treatment (n=10). The integration of concurrent Mexico
chemotherapy was recorded by a signiÀcant minority
of respondents despite lack of level I evidence Background: Lung cancer is a very often disease, with
to support its use. Geographical differences in a high mortality rate, often accompanied with anxiety
usage of external beam dose fractionation, and of and depression, and are not recognized as capable of
concurrent chemotherapy were seen in the survey. The been corrected, and can affect the quality of life and
following summary statements reÁect the consensus survival in this patients
of the international working group. 1. Key factors Methods: In a prospective manner, we studied 82
involved in the decision to deliver palliative RT patients with NSCLC in IIIB-IV stage Immediately
include performance status, tumor stage, pulmonary after the diagnosis, before to receive treatment. We
function, XRT volume, symptomatology, weight measure depression and anxiety with 2 scales HADS
loss, and patient preference. 2. Palliative thoracic and MINI, and quality of life with (EORTC QoL 30
XRT is generally indicated for stage IV patients with LC11) in three times.
current/impending symptoms and stage III patients Results: We found depression in 32.9%, anxiety
treated for palliative intent. 3. There is no evidence in 34.1% in the Àrst evaluation, with a signiÀcant
to routinely recommend EBB alone or in conjunction difference in women (RR 3.23; CI 95%, 1.1-9.4; p=
with other palliative maneuvers in the initial palliative 0.035) and people with poor performance status (RR
management of endobronchial obstruction due to 2.7; CI95%, 1.01-7.6; p= 0.045). Depression and
LC 4. There is currently a no evidence to routinely anxiety patients showed signiÀcant differences in
recommend CC with palliative-intent RT. 5. Standard quality of life in all the functional subscales of the QoL.
assessment of symptoms and health-related quality-of- GHS, RF, FF, FE, FS, FC (p= 0.05). Survival rates
life using validated questionnaires should be utilized were markedly different in depressed patients (6.8±2.2
in palliative RT LC trials. months), comparing with non depressed (14±1.8
Conclusion: Various patient, tumor, treatment, and months) on anxiety patients (11.6±2.3) (p=0.05).
logistical factors are associated with the variable use
and external beam dose fractionation of palliative lung
treatments. Despite an expanding literature, continued
prospective randomized investigations to better
deÀne the role of external-beam RT, endobronchial
brachytherapy, and concurrent chemotherapy in the
context of thoracic palliation of LC patients is needed.
Keywords: Lung cancer, External-beam Radiation
Therapy, Consensus Statement, Practice Survey

of end of life options, CPR, ICU care, palliative

chemotherapy and site of death. Details of discussion
were analyzed in terms of feasibility and effect on
understanding of end of life care option and patients
–health care agents relationship.
Results: Early intervention of end-of life care
discussions were feasible in 21 of 23 patients with
newly diagnosed advanced stage non-small cell lung
cancer. Only 2 patients were refused to discuss further
regarding end-of- life care options due to emotional
disturbance. Two months follow-up discussion
revealed that all 21 patients who completed the Àrst
end-of life care discussions were still maintainng their
hope of getting well and satisÀed with their choices
as well. Although the patients choices on various
Conclusion: Depression strongly inÁuences the end-of-life options were varied, they also reported
evolution of the lung cancer patient, resulting in a better understanding of end-of-life care options and
lower quality of life, and survival. Depression is an increased conÀdence in their health care agents.
independent prognostic factor, so can receive attention. Conclusion: Early intervention of this sensitive and
Keywords: depression, Anxiety difÀcult end of life care discussion between patients
and health care agent might be feasible without
A revised/updated abstract may be included in losing the hope of getting well in most of the patients
the Late Breaking Abstract Supplement, available with newly diagnosed non-small cell lung cancer.
at the 14th World Conference on Lung Cancer. Furthermore, early end-of-life discussion might have
some beneÀcial effect on improving patients-health
care agent relationship.
End Of Life Care Tuesday, 5 July 2011 10:30-12:00 Keywords: end of life discussion, palliative care,
hospice care
MO12.12 EARLY INTERVENTION OF
END-OF-LIFE CARE DISCUSSION IN A revised/updated abstract may be included in
PATIENTS WITH ADVANCED NON- the Late Breaking Abstract Supplement, available
SMALL CELL LUNG CANCER: A PILOT at the 14th World Conference on Lung Cancer.
STUDY
Sang Won Shin, Sun Goo Kim, Yeul Hong Kim
Oncology Hematology Dept, Korea University/Korea End Of Life Care Tuesday, 5 July 2011 10:30-12:00
Background: Frank and early discussion of end-of- MO12.13 PALLIATIVE CARE FOR
life options with patients diagnosed with incurable PATIENTS WITH ADVANCED LUNG
cancer should be an essential part of medical CANCER
practice. However, these conversations occur most Marianna Koczywas1, Betty R. Ferrell2, Karen L.
often during a patient’s Ànal days or weeks of life. A Reckamp1, Mihaela C. Cristea3, Brian Tiep4, Dana
recent study suggests health care agents may put off Tarcatu5, Jay Thomas5, Fred Grannis6, Gwen Uman7
1
holding end-of -life discussion that involve subjects Medical Oncology And Therapeutic Research,
like advance directives, hospice or site of death. City Of Hope/United States Of America, 2Nursing
Methods: We conducted a pilot study to assess the Resreach & Education, Dept. Of Population
feasibility of early end-of- life discussion, less than Sciences, City Of Hope/United States Of America,
3
1 month of diagnosis, in patients with advanced Dept Of Medical Oncology, City Of Hope/United
non-small cell lung cancer. Early intervention with States Of America, 4Pulmonary, City Of Hope/
facilitated and detailed questionnaire followed by United States Of America, 5Palliative Care, City Of
frank discussions between the physician/nurse and Hope/United States Of America, 6Thoracic Surgical
the patients/family members regarding the beneÀt Oncology, City Of Hope/United States Of America,
7
and burdens of life sustaining treatment, choices Vital Research/United States Of America
Background: This National Cancer Institute End Of Life Care Tuesday, 5 July 2011 10:30-12:00
funded Program Project (P01) is an interdisciplinary
research project focused on palliative care, quality MO12.14 EVALUATION OF NON-
of life (QOL), and symptom control in lung cancer SMALL CELL LUNG CANCER (NSCLC)
which is diagnosed in 213,000 Americans each year. PATIENT’S QUALITY OF LIFE
The purpose of this study is to test usual care versus DURING 2ND LINE CHEMOTHERAPY
integration of palliative care encompassing four TREATMENT
dimensions of QOL. Bárbara Parente1, Encarnação Teixeira2, Henrique
Methods: Our two previous pilot projects in a NCI Queiroga3, João Cunha4, Ana Fernandes5, António
Comprehensive Cancer Center demonstrated the Meleiro6, Ulisses Brito7, Maria P. Ferreira8, Maria
unmet needs in lung cancer across QOL domains J. Melo9, António Araújo10, Cristina Matos11, Teresa
and the limited use of supportive care services by Cardoso12, Ana C. Duarte13, Maria L.S. Valente14,
those with lung cancer. Project 2 of this Program Marco Liebermann15, José Duarte16, Fernando
focuses on late stage lung cancer, and uses a two Barata17
1
group, prospective, tandem enrollment comparing Pneumology, Centro Hospitalar De Vila Nova De
usual care to a structured palliative care intervention. Gaia/Portugal, 2Hospital De Santa Maria/Portugal,
3
Patients are followed for 6 months and measures Hospital De São João/Portugal, 4Hospital De São
include the FACT-L, FACIT- Spiritual, MSAS, Marcos/Portugal, 5Centro Hospitalar De Trás-os-
Social Support tool and a Chart Audit capturing montes E Alto Douro/Portugal, 6Centro Hospitalar
medical care and health system resources used. A De Setúbal/Portugal, 7Hospital Central De Faro/
Geriatric Oncology Core also supports this project Portugal, 8Instituto Português De Oncologia,
addressing concerns in elderly patients with lung Lisboa/Portugal, 9Hospital Pulido Valente/Portugal,
10
cancer, including function, social support and Instituto Português De Oncologia, Porto/Portugal,
11
comorbidities. Hospital Egas Moniz/Portugal, 12Hospital Espírito
Results: This usual care phase sample of Stage IV Santo/Portugal, 13Hospital Distrital De Beja/
lung cancer (N=80) included 70% female, 43% Portugal, 14Centro Hospitalar Cova Da Beira/
minority patients. Seventy one percent had at least Portugal, 15Hospital Distrital De Santarém/Portugal,
16
1 other chronic illness and 20% had a prior cancer Hospital Garcia De Orta/Portugal, 17Centro
diagnosis. MSAS scores revealed key symptoms Hospitalar De Coimbra/Portugal
to include lack of energy, difÀculty sleeping,
worrying, dyspnea and pain and MSAS distress of Background: With recent evolutions on 1st line
x=3.3 on scale of 0-4. FACT-L data indicated key treatment better response rates and lower toxicities,
QOL concerns related to sexuality (x=2.83), fear 2nd line therapy had a major. For most advanced non-
of worsening disease (x=3.18), sleep disruption small cell lung cancer (NSCLC) patients therapeutic
(x=3.2), overall poor QOL (x=3.24) and lack of goals for this stage includes not only to live longer
energy (x=3.3). Greatest spiritual concerns from the but also to have better Quality of Life. For these
FACIT-Spiritual tool included lack of meaning, lack patients, 2nd line chemotherapy provides an important
of purpose and trouble feeling at peace. Chart audit impact in improving symptoms and Quality of
data documented limited use of advanced directives Life. To evaluate the impact of 2nd line treatment on
or palliative care consultation. NSCLC patients’ Quality of Life measured by the
Conclusion: Findings identify signiÀcant gaps in scales EORTC-C30 and EORTC-LC13.
supportive care in lung cancer and provide direction Methods: Prospective, observational and multicenter
for the intervention phase of a comprehensive study. Data from NSCLC patients who have initiated
educational intervention and enhanced resources for 2nd line chemotherapy were collected. Quality of life
lung cancer patients. These Àndings lead to creation assessments were performed at 5 different moments:
of a four part, QOL education program speciÀc to at baseline, and 6, 12, 18 weeks and one year after
lung cancer and a interdisciplinary care planning entering the study or in case of disease progression
process involving multiple disciplines. or death.
Results: A total of 219 patients with a median age
of 62 years were included. Included patients were
mostly men (74.4%) and had a history of smoking
habits (former smokers 41.6%; smokers 31.5%). Most
commonly used 2nd line treatment was pemetrexed Nick K. Hayward3, Belinda E. Clarke4, Edwina E.
(58.4%), followed by erlotinib (21.2%), docetaxel Duhig4, Rayleen Bowman2, Kwun M. Fong2
1
(17.8%) and other (2.7%). Quality of life assessed by School Of Medicine, University Of Queensland/
EORTC-C30 scale presented signiÀcant differences Australia, 2Department Of Thoracic Medicine, The
for global health status and functional evaluation Prince Charles Hospital/Australia, 3Oncogenomics
scores between baseline and Ànal evaluation (p=0.001; Laboratory, Queensland Institute Of Medical
p<0.001, respectively). The various functioning scales Research/Australia, 4Department Of Anatomical
presented signiÀcant differences: physical (p<0.001), Pathology, The Prince Charles Hospital/Australia
role (p<0.001), emotional (p=0.049), cognitive
(p=0.002) and social (p<0.001). Concerning symptoms’ Background: MicroRNAs (miRNAs) are a family
scores, signiÀcant differences were found only for of small, non-coding RNA species that negatively
symptoms such as fatigue (p<0.001), pain (p<0.001), regulate expression of numerous target genes,
and dyspnea (p=0.012). No signiÀcant differences were including oncogenes and TSGs. Aberrant miRNA
found for these three global scores between the patients expression has been documented in multiple
treated with different drugs (pemetrexed, erlotinib and tumour types and has been linked to development
docetaxel). Using the EORTC-LC13 scale, signiÀcant and progression of cancer. The aim of this study
differences were found only for symptoms such as was to identify miRNAs that may be important
dyspnea (p=0.047), cough (p=0.042) and chest pain in the pathogenesis of non-small cell lung cancer
(p=0.024).Between patients treated with different drugs (NSCLC).
only alopecia was increasedfor patients treated with Methods: Global miRNA expression was measured
docetaxel (Mean: pemetrexed -1.0 vs. erlotinib -1.4 vs. in 175 fresh-frozen primary NSCLCs and 90 normal
docetaxel 2.9; p=0.003). lung samples selected from TPCH Lung Tumour
Conclusion: Patients’ Quality of Life improved Bank using the Agilent miRNA array (G4470A).
signiÀcantly between baseline and the last visit in Differentially expressed miRNAs were identiÀed
all evaluated global scores (global health status and using class comparison analysis (univariate t-test and
overall functioning). However, between patients treated random permutation) in BRB-ArrayTools (Version
with different drugs only docetaxel seemed to have a 6.3.0-Beta_3) and considered statistically signiÀcant
negative impact on alopecia. Despite, in general, no if p <0.05. Differentially expressed (DE) miRNAs
signiÀcant differences were registered for patients’ were identiÀed within the following cohorts: i)
symptoms or for the EORTC-LC13 scale, it is worth Primary NSCLCs and paired normal lung (n=126);
noting that all functional scales, such as physical, role, ii) Non-recurrent (clinically disease-free for 36
emotional, cognitive and social functioning presented months post-resection) compared to recurrent
signiÀcant differences between baseline and the Ànal cases (recurrence within 3-18 months) (n=93); iii)
evaluation. Adenocarcinomas with EGFR mutation (Exon 19/21)
Keywords: non-small cel lung cancer, Quality of and/or ampliÀcation compared to EGFR negative
Life, Chemotherapy controls (n=59); iv) Never smokers compared to ever
smokers adenocarcinomas (n=77); and v) Asbestos
exposed (>20 asbestos bodies per gram wet weight)
Session MO13: Novel Cancer Genes and compared to non-exposed (0 AB/gww; n= 60)
Pathways NSCLCs (n=120).
Results: Class comparison analysis identiÀed DE
miRNAs unique to each lung cancer phenotype and
these results are summarised in Table 1. Biological
validation of candidate miRNA expression will be
Novel Cancer Genes and Pathways Wednesday, 6 July 2011 14:30- performed using TaqMan qRT-PCR and this data will
16:00 be presented at the meeting.
Conclusion: Genome-wide proÀling of miRNA
MO13.01 IDENTIFICATION OF expression has yielded putative candidate miRNAs
ABERRANT MICRORNAS IN LUNG that may contribute to the biology of important lung
CANCER cancer phenotypes including recurrence, EGFR
Morgan R. Davidson1, Santiyagu M.F. Savarimuthu1, mutations and asbestos-related lung malignancies.
Ian A. Yang2, Casey M. Wright1, Krishna B. Sriram1, Further validation of these candidate miRNAs
is required to explore potential role in lung sequencing was performed to characterise the
tumourigenesis. Once conÀrmed, these miRNAs mutation spectrum in non-small cell lung cancer
represent a basis from which to design novel (NSCLC) samples and to assess the contribution of
diagnostic, prognostic and therapeutic tools and genomic variants to disease outcome.
focus individualised treatments. Supported by: Methods: 16 NSCLC samples were selected for
National Health and Medical Research Council, sequencing on the SOLiD platform. The tumour
Cancer Council Queensland, Australian Lung samples were partitioned based on post-surgery
Foundation, The Prince Charles Hospital Research disease outcome (Progressive disease – PD;
Foundation Table 1. Summary of candidate miRNAs Disease Free - DF) and were pairwise matched
identiÀed in each clinical phenotype from global on epidemiological and cytological parameters.
miRNA expression proÀling. Abbreviations: AC – Microarray analysis was used to select speciÀc genes
Adenocarcinoma; SCC – Squamous Cell Carcinoma for targeted exon sequencing using the SureSelect
system. Bioinformatics pipelines were developed for
Analysis Group miRNA Fold Change variant detection and characterisation. Nucleotide
Lung Cancer (p=0.00001) AC (n=72) 3B 2.0 – 3.4 variants were scored using SNVMix and compared
8? 2.4 – 8.0 with known variant/polymorphism datasets
SCC (n=54) 2B 2.9 – 27.0 (dbSNP/1000 genomes).
11 ? 2.3 – 4.9
Results: Within the targeted areas of the genome, high
Recurrence (p=0.05) AC (n=50) 8? 1.6 - 2.2
sequence coverage was achieved (~40x). A number
1B 1.3
SCC (n=43) 1? 2.0
of single nucleotide variants (SNVs) were identiÀed
EGFR (p=0.05) AC (n=59) 3B 2.1 - 2.6
within the targeted genes in lung tumour samples from
Never Smoking (p=0.05) AC (n=77) 3B 2.1 - 2.8 both PD and DF categories. In the initial analysis, the
Asbestos Exposure (p<0.05) NSCLC (n=120) 2 ? 1.3-1.4 SNVs contained some novel variants, some previously
AC (n=60) 1? 1.5 known polymorphisms and some variants previously
shown to associate with cancer. For example, in the
Keywords: NSCLC, MicroRNAs latter category we were able to identify KRAS codon
12/13 mutations within a subset of the PD samples,
but not within the DF samples.
Novel Cancer Genes and Pathways Wednesday, 6 July 2011 14:30- Conclusion: Second-generation sequencing has
16:00 been used to identify coding mutations in 361 genes
within lung cancer samples. The methods developed
MO13.02 SECOND-GENERATION may have future prognostic utility in determining
SEQUENCING OF NON-SMALL CELL disease outcome amongst lung cancer patients.
LUNG CANCER: IDENTIFICATION
OF MUTATIONS ASSOCIATED WITH
PROGRESSIVE DISEASE Novel Cancer Genes and Pathways Wednesday, 6 July 2011 14:30-
Russell Hyde1, Olaide Y. Raji1, Lisa Olohan2, Olga 16:00
Vasieva2, Kevin Ashelford2, Andy Brass3, Richard D.
Page4, Neil Hall2, John K. Field1 MO13.03 CLINICAL RELEVANCE OF
1
Molecular And Clinical Cancer Medicine, GENOMIC COPY NUMBER VARIATIONS
University Of Liverpool/United Kingdom, 2Institute IN SPIRAL-COMPUTED TOMOGRAPHY
Of Integrative Biology, University Of Liverpool/ (CT) DETECTED LUNG TUMORS
United Kingdom, 3School Of Computer Science, Carla Verri1, Patrizia Gasparini1, Mattia Boeri1,
University Of Manchester/United Kingdom, Federica Facchinetti1, Giovanna Chiorino2, Paola
4
Liverpool Heart And Chest Hopital/United Kingdom Ostano2, Maurizia Mello Grand2, Ugo Pastorino3,
Gabriella Sozzi1
1
Background: Genetic mutations are a hallmark Dep.of Experimental Oncology And Molecular
of lung cancer progression. Recent advances in Medicine, Fondazione Irccs Istituto Nazionale Dei
sequencing technology provide a window into the Tumori/Italy, 2Cancer Genomics Lab, Fondazione
genomic variability within individual tumours, and Edo Ed Elvo Tempia/Italy, 3Unit Of Thoracic
may ultimately have prognostic and/or predictive Surgery, Fondazione Irccs Istituto Nazionale Dei
value. A study involving second-generation Tumori/Italy
Background: Lung cancer is the leading cause of relevance in spiral-CT detected tumors. The common
cancer deaths worldwide. Early detection studies deÀned regions could identify a class of tumors
using spiral-CT in heavy smokers have reported a with elevate grade of malignancy. Gene expression
major increase in lung cancer diagnosis and reduction analysis and microRNA expression proÀling,
of mortality. These observations indicate the need both obtained with microarray platforms, will be
for biomarkers of indolent or aggressive disease. correlated with CNV data to identify target genes
Chromosomal alterations play a critical role in tumor involved in tumorigenesis.
initiation and progression and particularly in lung Keywords: spiral CT-detected lung cancer, Genomic
cancer where multiple chromosome alterations were unbalances, clinico-pathological association, Array-
commonly reported in cytogenetic analysis, indicative CGH
of a marked genomic instability. The purpose of
the study is to characterize genomic unbalances in A revised/updated abstract may be included in
lung tumor cases identiÀed in a completed spiral-CT the Late Breaking Abstract Supplement, available
screening trial with an extensive follow-up and to at the 14th World Conference on Lung Cancer.
identify the clinical relevance of recurrent chromosome
changes investigating the association with clinico-
pathological characteristics of patients. Novel Cancer Genes and Pathways Wednesday, 6 July 2011 14:30-
Methods: Array-CGH proÀling (Agilent platform) was 16:00
performed in a selected series of 20 CT-detected lung
tumor samples (17 NSCLC, 1 SCLC, 2 carcinoids) MO13.04 PROGNOSTIC VALUE OF
and the regions with signiÀcant copy number variation HSA-MIR-210 OVEREXPRESSION IN
(CNV) were identiÀed using ADM-2 algorithm. NON-SMALL CELL LUNG CANCER BY
Results: A different level of genomic complexity QUANTITATIVE REAL-TIME RT-PCR
(number and size of unbalances) was observed: 6 cases Jun Ohsugi, Yuka Kimura, Yuzuru Watanabe, Takumi
with high level changes, 7 cases with an intermediate Yamaura, Naoyuki Okabe, Hiroshi Yaginuma, Takeo
level and 7 cases with limited unbalances. In NSCLC Hasegawa, Yoko Mera, Athushi Yonechi, Mika
extensive regions with CNV were observed in 1q, Hoshino, Mithunori Higuchi, Yutaka Shio, Hiroyuki
2q, 3q, 5p, 7p, 8q (gains) and 3p, 7q, 8p, 10q, 13q, Suzuki, Akio Ohishi, Mitukazu Goto, Thoracic
16, 17p, 19p, 22q (losses), in SCLC cases CN gains Surgery, Fukushima Medical University/Japan
in 2q, 5p and CN losses in 1p, 2p, 3p, 5q, 6q, 16q,
17p, 21p and in carcinoid tumors ampliÀcation of the Background: Hypoxic conditions in solid
entire chromosome 5 and CN losses in 1p, 6q, 10, 11, malignances are thought to be involved to the
18q were observed. Smaller regions were delimited resistance to cytotoxic chemotheraphy and also be
and were observed to be recurrently altered in several associated with a poorer prognosis. Recently, several
samples as reported in Table 1. Preliminary statistical studies have been reported that hsa-miR-210 is
analysis demonstrated that CNV of speciÀc genomic one of the highly up-regulated miRNAs in hypoxic
regions was signiÀcantly correlated with high tumor cells. In this study, we examined the expression of
stage (2q37.3 ; 8p11.23), histotype (14q13.1-13.2 hsa-miR-210 to identify a prognostic signiÀcance in
gain in ADC and loss in other histotype), FEV1% patients with non-small cell lung cancer (NSCLC).
<90% (19p13.3-12), tumor growth rate (6p21.32). Methods: The subjects of this study consistes of
Interestingly, CNV of 4q13.2 was associated with 80 patients with NASLC who underwent complete
patients’ outcome. Table 1. Recurrent regions of copy resection since 2004 to 2007. No patients had
number alterations in 20 CT-detected tumors. received any prior anticancer treatment. They
included 61 adenocarcinomas and 19 squamous cell
Gains Losses Gains or Losses carcinomas, and 54 stage1, 11 stage2, 13 stage3, 1
1q21.1-21.3 5p15.33 2p21 2q37.3 3p25.3 3q26.1 3q26.32 4q13.2 stage4 cases. Hsa-miR-210 expression, determined
7q11.21-q11 1q11.23 3p26.3-26.1 5q13.1- 6p21.32 8p11.23
by real time RT-PCR, was deÀned by ƋƋ Ct
17p25.3 22q 13.2 7p11.2-p11.1 12p13.31 14q13.1-13.2
8p23.1 15q11.2 16q21-q23.1 method. The level of hsa-miR-210 expressions in
17p13.1 19p13.3-12 cancer tissues were assessed after comparison with
corresponding noncancerous tissues and with respect
Conclusion: We demonstrated that chromosome to RNU6B expression. The relationship between
unbalances could be of clinical and pathological the hsa-miR-210 expression and clinic pathological
factors was statistically analyzed. Novel Cancer Genes and Pathways Wednesday, 6 July 2011 14:30-
Results: To analyze impacts of the expression 16:00
of hsa-miR-210 on clinic pathological variables
and survaival, the patients were divided into two MO13.06 AN EFFECTIVE DNA DAMAGE/
subgroups by median value (high expression REPAIR SIGNALING PATHWAY-
group and low expression group). Then, we TARGETED THERAPY FOR LUNG
examined for correlations between the hsa-miR-210 CANCER COMBINING A NOVEL DUAL-
expression and clinic pathological variables.The FUNCTIONAL DNA-ALKYLATING/HDAC
high expression group had an association with INHIBITOR WITH TUMOR SUPPRESSOR
recurrent disease (p=0.04), whereas hsa-miR-210 GENE NANOPARTICLES
expression was not correlated with age, gender, Lin Ji1, Jing Lin1, Kai Xu1, Shaoyu Yan1, Yi Chen2,
tumor size, histology, lymph metastasis, pathological Jack A. Roth1
1
stage, ly factor and v factor. In terms of survival Thoracic & Cardiovascular Surgery, The University
analysis, there was the weak correlation between Of Texas M.D. Anderson Cancer Center/United
the expression of hsa-miR-210 and overall survival States Of America, 2Northlake Biosciences/United
(p=0.090, 5y-survaval rate of high epression group States Of America
and low expression group are 66.6% and 77.4%
respectively). Futhermore, high expression group Background: DNA alkylating agents such as
showed signiÀcant short disease free survival as platinum and nitrogen mustard are effective cancer
compared with low expression group (5y-desase chemotherapeutics. They kill proliferating tumor
free survaival in high expression group and low cells by inducing high levels of DNA damage
expression group were 35% and 59.1% respectively, leading to cell-cycle arrest and cell death. However,
p=0.001). More importantly, hsa-miR-210 their highly toxic side effects and the common drug
expression was an independent prognostic factor in resistance exhibited in tumors limit their anticancer
disease free survaival analyzed by Cox multivariate efÀcacy and clinical beneÀts. Here we describe
analysis(HR: 1.24, 95%Cl 1.046-12.173, p=0.042). a novel strategy using a new class of rationally
designed DNA alkylating agents combined with gene
therapy targeting the DNA damage/repair pathway.
Methods: We evaluated the therapeutic effects of
a novel alkylating agent NL101, a bendamustine
derivative that has a dual function of DNA alkylation
and pan-HDAC inhibition, in a panel of more than
50 human NSCLC and SCLC cell lines. We also
explored treatment strategies of combining NL101
with novel tumor suppressor genes NPRL2, a
regulator of the DNA damage checkpoint pathway,
and p53, a regulator of apoptosis and drug resistance
in the DNA damage/repair pathway, in lung cancer.
Conclusion: According to our resluts, the expresson Results: We detected a high potency of tumor cell
of hsa-miR 210, one of the major miRNA associates proliferation inhibition by NL101 treatment across
hypoxic state of cancer tissues, could be an important lung cancer cell lines, with IC50 doses ranging from
prognostic factor in patients with NSCLS. nanomolar to lower micromolar levels. A 20 to
Keyword: hsa-miR-210 lung cancer RT-PCR 100-fold higher level of cytotoxicity was observed
across these lung cancer cell lines, particularly in
SCLC cell lines, treated by NL101 than in cell lines
treated by bendamustine, a nitrogen mustard agent
that is currently in Phase II and III clinical trials in
SCLC patients. We analyzed the NL101-induced
DNA damage in NSCLC H1299 cells by Comet
assay and found that NL101 induced a signiÀcantly
higher degree of DNA damage than that induced
by either bendamustine or cisplatin at the same IC20
dose level for each individual agent. A combination proÀles of AIS with those of eIA showing lymph
of NL101 with either DOTAP:Cholesterol (DC)- node metastasis or a fatal outcome, and used cDNA
complexed NPRL2 or p53 expressing plasmid DNA microarray to screen for differentially expressed
nanoparticles showed no signiÀcant effect on drug- genes that were related to tumor progression. (Aya
induced DNA damage. We analyzed DNA-damage- Shiba-Ishii, Int J Cancer. 2011)
induced apoptosis using an anti-ssDNA antibody- Methods: Among genes showing signiÀcantly
based apoptosis assay by FACS and detected a higher expression in eIA than in AIS, we
signiÀcantly enhanced induction of apoptosis in Ànally focused on stratiÀn (SFN, 14-3-3
both combination treatments with NL101+DC- sigma), and performed real-time RT-PCR
NPRL2 and NL101+DC-p53. We also found that and immunohistochemistry (IHC) using lung
combination treatment with NL101 and DC-NPRL2 adenocarcinoma specimens. For functional analysis,
nanoparticles promoted a synergistic inhibitory we carried out siRNA transfection and subsequent
effect on growth of SCLC H69 and GLC16 cells at cell proliferation assay with a lung adenocarcinoma
effective dose levels of NL101 from IC10 to IC75. cell line (A549). Furthermore, the methylation status
Conclusion: Our results suggest that a combination in the promoter region of SFN was examined by
treatment using a novel dual targeting DNA real-time MSP.
alkylating agent/HDAC inhibitor with pro-apoptotic Results: IHC revealed that more than 95% of eIAs
tumor suppressor genes in the DNA damage/repair were immunopositive for SFN, in comparison to
signaling pathway will enhance chemotherapeutic only 13% of AISs (P <0.05). Functionally, after
sensitivity, promote anti-cancer therapeutic suppression of SFN expression by siRNA, A549
synergism, and overcome drug resistance. This showed lower cell proliferation than untreated
implies a translational application of this novel controls. Real-time MSP showed that normal lung
combination therapy for a more effective lung cancer tissue and AIS bore a completely methylated SFN
treatment strategy. (Supported by NIH/NCI SPORE promoter, and that the promoter regions of most
P50CA70907 and RO1CA116322). invasive adenocarcinomas were at least partially
Keywords: DNA damge and repair pathway, DNA methylated (Figure). The expression of SFN was
Alkylating Agents, Tumor Suppressor Genes, strongly correlated with its methylation level.
combination therapy for lung cancer Furthermore, statistical analysis revealed that the
methylation level became lower with increased
A revised/updated abstract may be included in pathological stage, but no clear relationship with p53
the Late Breaking Abstract Supplement, available abnormality was found.
Novel Cancer Genes and Pathways Wednesday, 6 July 2011 14:30-

16:00
MO13.07 DEMETHYLATION-INDUCED
OVEREXPRESSION OF STRATIFIN
IS A UNIVERSAL ABNORMALITY SFN was originally identiÀed as a p53-inducible gene
DURING THE PROGRESSION OF LUNG causing G2 arrest and allowing the repair of damaged
ADENOCARCINOMA DNA. Functional inactivation of SFN, mostly by
Aya Shiba-Ishii, Junko Kano, Masayuki Noguchi epigenetic hypermethylation, has been observed in
Department Of Pathology, Graduate School Of various human malignancies. On the other hand,
Comprehensive Human Sciences, University Of many reports have indicated up-regulation of SFN in
Tsukuba/Japan various types of Here we also demonstrated that the
expression of SFN was signiÀcantly higher in eIA
Background: Adenocarcinoma in situ (AIS) of than in AIS, and enhanced the proliferative capacity
the lung has a very favorable prognosis, with a of lung adenocarcinoma cells. Therefore, SFN might
5-year survival rate of 100%. However, early but be a context-dependent gene that acts as an oncogene
invasive adenocarcinoma (eIA) sometimes has a in lung adenocarcinoma. Methylation analysis
fatal outcome. Here we compared the expression suggests that methylation-related silencing of SFN
usually occurs in normal lung tissue and AIS, and months). Array CGH log 2 data was analyzed using the
that promoter demethylation triggers aberrant SFN Genomic IdentiÀcation of SigniÀcant Targets in Cancer
overexpression in invasive adenocarcinoma in p53- (GISTIC) algorithm. Thresholds for ampliÀcation and
independent manner. deletions were set at log2 values of 0.848 and -0.737.
Conclusion: Demethylation-induced SFN Validation of the DNA copy number of candidate genes
overexpression occurs during progression of early was performed using quantitative PCR (q-PCR), using
lung adenocarcinoma, and this accelerates malignant QuantiTect primers (Qiagen, Hilden, Germany).
progression by enhancing the proliferation capacity Results: In the 62 SCC samples, GISTIC identiÀed
of tumor cells. frequent and high amplitude ampliÀcations in six regions
Keywords: stratiÀn, demethylation-induced and deletions in 14 regions. Loss of 18q22.3 occurred
overexpression, lung adenocarcinoma signiÀcantly more frequently in recurrent versus non-
recurrent SCCs (54% vs. 24%, p=0.033) and contained
7 genes, SOCS6, DOK6, RTTN, CYB5A, C18orf55,
Novel Cancer Genes and Pathways Wednesday, 6 July 2011 14:30- NETO1 and CCDC102B with signÀcantly lower DNA
16:00 copy number in the recurrent tumors (p<0.05 for all
7 genes). Technical validation using an independent
MO13.08 SOCS6 DELETION IS method, q-PCR, conÀrmed lower DNA copy number
ASSOCIATED WITH RECURRENCE in recurrent versus non-recurrent SCCs for SOCS6
IN SURGICALLY RESECTED LUNG (p=0.003). Biological validation using q-PCR in an
SQUAMOUS CELL CARCINOMA independent cohort of 85 SCCs provided further
Krishna B. Sriram1, Jill E. Larsen2, Santiyagu M.F. conÀrmation that SOCS6 deletion was more common in
Savarimuthu1, Casey M. Wright1, Belinda E. Clarke3, recurrent vs. non-recurrent tumors (p=0.006).
Edwina E. Duhig3, Nick K. Hayward4, Rayleen Conclusion In this study, we have used array CGH to
Bowman1, Ian A. Yang1, Kwun M. Fong1 identify genomic regions associated with recurrence in
1
Department Of Thoracic Medicine, The Prince primary lung SCC. Loss of 18q22.3 occurs at greater
Charles Hospital/Australia, 2Hamon Center For frequency in recurrent SCCs and contains SOCS6. The
Therapeutic Oncology Research, University Of biological role of SOCS6 in promoting recurrence in
Texas Southwestern Medical Center/United States Of SCC requires further investigation using in-vitro and in-
America, 3Department Of Anatomical Pathology, The vivo models.
Prince Charles Hospital/Australia, 4Oncogenomics Keywords: recurrence after surgical resection,
Laboratory, Queensland Institute Of Medical squamous cell carcinoma, Array comparative genomic
Research/Australia hybridization
Background: Despite undergoing surgical resection,

recurrence of the primary lung squamous cell Novel Cancer Genes and Pathways Wednesday, 6 July 2011 14:30-
carcinoma (SCC) occurs in 50% of subjects within 16:00
5 years. DNA copy number aberrations may be an
important mechanism of regulation for putative MO13.09 ACTIVATION OF PI3K/AKT/
oncogenes and tumor suppressor genes involved in MTOR/S6RP AND MEK/ERK SIGNALING
promoting recurrence of lung SCC. Array comparative PATHWAYS IN NSCLC DEPENDING ON
genomic hybridization (array CGH) is a high- EGFR AND KRAS MUTATIONS STATUS.
resolution platform that can identify DNA copy number Nathalie Prim1, Michele Legrain2, Anne-Claire
aberrations of genes and has recently been used for the Voegeli2, Eric Guerin2, Agnès Neuville3, Gilbert
identiÀcation of novel cancer genes in several solid Massard4, Mircea Vasilescu4, Nicola Santelmo4,
organ malignancies. To date, it has not been used to Jean-Marie Wihlm4, Marie Pierre Gaub2, Bertrand
study the genes involved in recurrence of lung SCC. Mennecier1, Elisabeth Quoix1, Marie Pierre
Methods: Array CGH was performed using Chenard3, Michele Beau-Faller2
1
Agilent G4410B aCGH 4 (Agilent Technologies Service De Pneumologie, Chu De Strasbourg/
Inc) microarrays on DNA from fresh frozen France, 2Chu De Strasbourg, Molecular Laboratory/
tumour tissue obtained from 62 SCCs; 28 recurrent France, 3Service De Pathologie, Chu De Strasbourg/
(recurrence of disease within 18 months) and 34 France, 4Service De Chirurgie Thoracique, Chu De
non-recurrent subjects (no disease recurrence at 36 Strasbourg/France
Background: Among the different signaling pathways among mutational status. These results of weak
controlled by epidermal growth factor receptor expression of phospho-ERK could be explained
(EGFR) and involved in progression of non small by negative feedback of phosphatase MKP-3/
cell lung carcinomas (NSCLC), phosphatidylinositol DUPS6 which is expressed in 59/61 (97%) of all
3-kinase (PI3K)/Akt/ mTOR and the RAS/RAF/ the tumors. In the wild-type tumors, expression of
MAPK pathways seems to play a critical role in the phospho-mTOR is correlated with expression of
cell survival or metabolism and in the cell growth both phospho-S6RP Ser235/236 (p = 0.009) and
respectively. The activated status of these two phospho-S6RP Ser240/244 (p = 0.02), but only
pathways, according to the presence/absence of with expression of phospho-S6RP Ser235/236 (p
EGFR or KRAS mutations could be of interest in the = 0.04) in EGFR mutated tumors and not expected
perspective of multi-targeted therapies. Therefore, we with KRAS mutated tumors. Median progression
searched for the activation of several proteins of these free survival was 30 months, and no signiÀcant
two signalling pathways and analyzed their relationship prognostic value was found for phospho-mTOR,
with clinicopathologic features. phospho-S6RP Ser235/236 and phospho-S6RP
Methods: 74 primary lung tumors and matched Ser240/244 in all the group as well as in the EGFR
non-malignant lung tissues provided by the tumor or KRAS mutated sub-groups.
bank of the HÃ´pitaux Universitaires of Strasbourg, Conclusion: Different types of phosphorylation of
were obtained from NSCLC patients who underwent S6RP, phospho-S6RP Ser235/236 and phospho-S6RP
resection with curative intend,. All tumors contained Ser240/244 could be differently activated depending on
more than 50% of tumor cells and have been EGFR and KRAS mutation status, suggesting interest
selected according to the EGFR/KRAS mutation of inhibiting the both pathways in wild-type tumors.
status previously determined by direct sequencing: Keywords: MEK/ERK, PI3K/AKT/mTOR, EGFR,
19 mutated EGFR (16 adenocarcinomas, 11 Kras
females, 10 never-smokers), 22 mutated KRAS (17
adenocarcinoma, 8 females, 2 never-smokers) and 33
wild-type tumors (11 adenocarcinoma, 23 females, 4 Novel Cancer Genes and Pathways Wednesday, 6 July 2011 14:30-
never-smokers). Tissue microarray containing three 16:00
samples of each tumor and matched normal tissue
was constructed. Immunohistochemistry analysis MO13.11 MOLECULAR MECHANISMS
was realized for ERK (phospho-ERK Thr202/ AND MODULATION OF KEY KINASE
Tyr204), mTOR (phospho-mTOR Ser2448), two PATHWAYS UNDERLYING THE
phosphorylated forms of S6RP (phospho-S6RP SYNERGISTIC INTERACTION OF
Ser235/236 , phospho-S6RP Ser240/244) targeted by SORAFENIB WITH ERLOTINIB IN NON-
RAS pathway or PI3K pathway respectively, PTEN SMALL-LUNG CANCER (NSCLC) CELLS
and MKP-3/DUSP6. Elisa Giovannetti1, Henk Dekker1, Rocco Sciarrillo1,
Results: Phospho-mTOR is expressed in 46 (70%) Joline S. Lind2, Richard Honeywell1, Egbert F. Smit2,
tumors among them by 32 (72%) adenocarcinoma Henk M. Verheul1, Godefridus J. Peters1
1
and 13 (45%) squamous cell carcinomas, and highly Medical Oncology, VU University Medical Center/
expressed in the mutated EGFR/KRAS (29, 78%) Netherlands, 2Department Of Pulmonary Diseases,
tumors rather wild-type cases (17, 58%, p= 0.05). VU University Medical Center/Netherlands
Phospho-S6RP Ser235/236 is expressed in 28 (63%)
adenocarcinoma and 12 (41%) of squamous cell Background: Combination of drugs with different
carcinoma, and associated to KRAS mutated tumors targets is a logical approach in order to overcome
(16, 84%, p = 0.02). Phospho-S6RP Ser240/244 multilevel cross-stimulation among key pathways
is expressed in 21 (48%) adenocarcinoma and 17 in NSCLC progression such as EGFR, K-Ras and
(58%) squamous cell carcinoma, and half of the VEGFR. Sorafenib-erlotinib combination showed
EGFR/KRAS mutated cases and in 18 (54%) of clinical activity and an acceptable safety proÀle
wild-type cases, with no statistically difference was in two phase-II studies in chemo-naive stage IIIB/
observed among mutational status. Phospho-ERK is IV NSCLC patients (Lind et al., 2010; Gridelli
expressed in only 14 (20.9%) tumors mostly in by 11 et al., 2011), suggesting its role as potential
(25%) adenocarcinoma and 4 (14%) squamous cell salvage therapy in EGFR mutation-negative or
carcinoma with no statistically signiÀcant difference elderly patients. Therefore, this study was aimed
at evaluating mechanisms underlying sorafenib- that can be studied to identify NSCLC patients who
erlotinib interaction and novel possible determinants are likely to respond to this treatment.
to predict outcome to this therapy. Conclusion: Erlotinib-sorafenib combination is
Methods: Eight NSCLC cell lines were selected an attractive approach to block different signalling
on the basis of their heterogeneous pattern of pathways as well as the same pathways at different
EGFR and Raf-kinase-inhibitor protein (RKIP) levels, overcoming erlotinib-resistance. Several
expression, as well as by differential EGFR and mechanisms including apoptosis-induction,
K-Ras mutations. Pharmacologic interaction modulation of expression/phosphorylation of RKIP
was studied using the MTT/SRB assays and data and crucial kinases contribute to this synergistic
were evaluated with the combination index (CI) interaction and should be evaluated in future trials
method, while effects on EGFR, Erk1/2 and Akt for the rational development of erlotinib-sorafenib
phosphorylation, cell cycle and apoptosis were combination in NSCLC.
studied with western blot, ELISA, Áow cytometry Keywords: synergistic interaction, sorafenib,
and Áuorescence microscopy, respectively. Finally, erlotinib, Kinase modulation
drug measurements in medium and cells were
performed using a previously validated LC-MS/ A revised/updated abstract may be included in
MS method (Honeywell et al., 2010), while kinase the Late Breaking Abstract Supplement, available
activity proÀles of cell lysates in the presence and at the 14th World Conference on Lung Cancer.
absence of erlotinib, sorafenib and their combination
were generated on PamChip arrays comprising 144
tyrosine containing peptides derived from known Novel Cancer Genes and Pathways Wednesday, 6 July 2011 14:30-
human protein phosphorylation sites. 16:00
Results: MTT demonstrated the key role of EGFR
and K-Ras mutations for erlotinib activity, with MO13.12 AN RNAI SCREEN IDENTIFIES
IC50s ranging from 0.05 uM in H3255 (carrying NEW MOLECULAR TARGETS IN
EGFR-L858R activating mutation) to 2.88 uM in MALIGNANT MESOTHELIOMA
A549 (G12S-K-Ras mutated) and 20.2 uM in H1975 Glen Reid1, Lyn J. Schedlich1, Sumedha Gattani1,
(carrying EGFR-T790M resistant mutation) cells, Michaela B. Kirschner1, Rayleen Bowman2, Kwun
while a reverse relationship was found between M. Fong2, Nico Van Zandwijk1
1
sorafenib cytotoxicity and RKIP expression. Asbestos Diseases Research Institute, University
Synergism was detected in all cell lines, with CI Of Sydney/Australia, 2Department Of Thoracic
mean values ranging from 0.4, in H460 (G61H- Medicine, The Prince Charles Hospital/Australia
K-Ras mutated), to 0.9, in H292 (K-Ras/EGFR
wild-type cells), in the simultaneous 72h exposure. Background: Treatment options in malignant
Erlotinib produced a slight G1 blockade, while mesothelioma (MM) are limited. Despite some
sorafenib slowed cell cycle progression and induced improvement in chemotherapy and combined
apoptosis, which was signiÀcantly increased in the modality approaches of MM, new therapeutic targets
combination, i.e. 20.0 and 19.3% in H1975 and are urgently needed. RNAi screening provides a
A549 cells, respectively. Sorafenib alone and in means of identifying potential new targets for further
combination reduced Akt and ERK phosphorylation pre-clinical assessment.
in both erlotinib-sensitive and resistant cells, e.g. in Methods: Data from previous gene expression
A549 cells the pERK/totalERK ratio decreased by proÀling studies in MM were used to select targets
-75%, associated with signiÀcant RKIP modulation. for a rational RNAi screen. Two siRNAs per target
No direct drug interaction in medium from exposed gene were used to screen established and primary
cells was detected by LC-MS/MS measurement. mesothelioma cell lines using optimised transfection
Finally, studies in lysates from A549 and H1975 cells conditions. Proliferation was used as the primary
exposed to erlotinib+sorafenib, after appropriate readout for effects of gene knockdown. Hits from
statistical analysis with multiple corrections, showed the primary screen were followed up by analysing
a signiÀcant inhibition of the phosphorylation of 13 time and dose dependency of growth inhibition and
overlapping peptides in both cell lines, including knockdown at the mRNA level. Effects of silencing
sites from VEGFR, RAF and PDGF-beta, but also were further assessed using small molecule drugs
CDK2 and SRC, suggesting possible new pathways speciÀc for targets.
Results: The gene expression data from previous involved in malignant growth in several tumor types
studies was used to select 40 gene targets that were including NSCLC and esophageal cancer. The aim of
upregulated in MM. The knockdown of a number of the present study was to investigate activin signals in
these genes was growth inhibitory in MM cell lines. MPM cell models and their contribution to malignant
These included genes involved in DNA synthesis growth and spreading.
(RRM1 and RRM2), control of cell cycle and cell Methods: The expression of the activin ơA, ơB, ơC
division (PLK1, NDC80, CHK1 and CDK1), and and ơE subunits (INHBA, INHBB, INHBC, INHBE),
apoptosis (BIRC5). The extent of growth inhibition activin receptors (ACVR2, ACVR2B, ALK4 and
was greatest with RRM1, RRM2 and PLK1, with 7) and activin antagonizing factors was analyzed in
less growth inhibition seen with CDK1 and NDC80, a panel of 10 MPM cell lines by RT- and qRT-PCR
and the least inhibition seen following knockdown and activin ơA expression was also analyzed by
of CHK1 and BIRC5. All targets were signiÀcantly immunohistochemistry in parafÀn embedded tissue.
silenced (>90 % reduction in mRNA). Small For functional analysis of activin signals, MPM cell
molecule drugs were also growth inhibitory in the lines were treated with exogenous activin A, activin
cell lines tested. The PLK1 inhibitor BI2536 was receptor inhibitors or activin A-targeting siRNA. Cell
very potent, with IC50 values in the range of 5-10 growth was assessed by MTT and clonogenic growth
nM. AZD, a CHK1/2 inhibitor was slightly less assays and cell migration by scratch and transwell
potent, with ranges of 30-60 nM. Roscovitine, a assays. Phosphorylation of Smad2 was analyzed
pan-CDK inhibitor, and the NDC80 inhibitor INH1 by Western blotting as readout for activation of the
were least effective, with IC50 values in the high canonical activin/TGFbeta signaling pathway.
nanomolar range. Results: Expression data in mesothelioma cell
Conclusion: RNAi screening identiÀed a number of models obtained by real-time PCR revealed high
genes involved in the proliferation of MM cells, a expression of activin ơA and activin receptors in most
number of which have not been previously linked to cell lines compared to non-malignant mesothelial
MM biology. Small molecules speciÀc or selective cells. Likewise, immunohistochemistry in parafÀn
for these targets were also growth inhibitory and embedded tissue sections of MPM patients showed
further testing in pre-clinical models is warranted. intense cytoplasmic staining for activin A in the tumor
An expanded RNAi-based screen may increase the cells of a subset of the cases analyzed. Treatment with
number of candidate therapeutic targets. exogenous activin A induced Smad2 phosphorylation
Keywords: Malignant mesothelioma, RNAi in all cell lines tested, thus demonstrating functionality
of the activin signaling axis in mesothelioma cells
models. In contrast to the human hepatoma cell line
Novel Cancer Genes and Pathways Wednesday, 6 July 2011 14:30- HepG2, which in agreement with previous reports
16:00 was inhibited, proliferation of mesothelioma cell
models was stimulated by activin A as observed by
MO13.13 DEREGULATION OF MTT assays and clonogenic assays. Treatment with
ACTIVIN SIGNALS CONTRIBUTES TO two different kinase inhibitors of activin receptors
AGGRESSIVENESS OF MALIGNANT (SB43154, A8301) in contrast, inhibited mesothelioma
PLEURAL MESOTHELIOMA CELLS cell proliferation and clonogenicity as well as
Julia Muenzker1, Mir Alireza Hoda2, Karin Schelch1, migration. As kinase inhibitors are not absolutely
Bahil Ghanim2, Martin Filipits1, Balazs Hegedus2, speciÀc for activin receptors and also co-target
Balazs Dome2, Walter Berger1, Walter Klepetko2, TGFbeta receptors, we also silenced activin ơA with
Michael Grusch1 siRNA oligonucleotides. As expected, transfection
1
Institute Of Cancer Research, Department Of with activin ơA siRNA but not scrambled control
Internal Medicine I, Medical University Vienna/ siRNA decreased activin ơA expression level and
Austria, 2Division Of Thoracic Surgery, Medical impaired cell proliferation.
University Vienna/Austria Conclusion: The data generated during this
investigation clearly suggest that deregulated activin
Background: Malignant pleural mesothelioma A signaling contributes to the malignant phenotype
(MPM) is an asbestos-related malignancy of mesothelioma cells and might therefore represent a
characterized by frequent resistance to chemo- and valuable candidate for therapeutic interference.
radiotherapy. Growth factors of the activin family are Keywords: pleural mesothelioma, activin signaling
Novel Cancer Genes and Pathways Wednesday, 6 July 2011 14:30- Session MO14: Surgery - VATS/Staging
16:00
MO13.14 MOLECULAR
CLASSIFICATION OF LUNG
ADENOCARCINOMA Surgery - VATS/Staging Wednesday, 6 July 2011 14:30-16:00
Jun Yokota1, Reika Iwakawa1, Hirokazu Okayama1,
Kouya Shiraishi1, Takashi Kohno2 MO14.01 AN ACADEMIC CENTER CAN
1
Division Of Multistage Carcinogenesis, National MOVE FROM OPEN LOBECTOMY
Cancer Center Research Institute/Japan, 2Division TO VATS LOBECTOMY AS UP FRONT
Of Genome Biology, National Cancer Center THERAPY FOR EARLY STAGE LUNG
Research Institute/Japan CANCER AND MAINTAIN A QUALITY
RESIDENT OPERATIVE EDUCATION
Background: Lung Adenocarcinoma has a David T. Cooke, Minghui Liu, Walid O. Mari, A P.
heterogeneous feature in molecular pathways for its Mahfoozi, Valerie Kuderer, J. N. Young, Royce F.
development. Up to present, three distinct pathways Calhoun
with alterations of EGFR, KRAS or ALK have been Division Of Cardiothoracic Surgery, University Of
elucidated. However, a considerable fraction of lung California, Davis Medical Center/United States Of
ADC cases do not carry these alterations. Therefore, America
we attempted to elucidate the clinicopathological and
molecular characteristics of ADCs without mutations of Background: Video-assisted thoracic surgery
the EGFR/KRAS/ALK genes (Triple-negative ADCs). lobectomy (VATSL) for early stage non-small cell
Methods: Two hundred and twenty six cases of lung cancer (NSCLC) has been shown to improve
primary lung ADCs were subjected to mutation analysis peri- and postoperative outcomes and patient quality
of the EGFR/KRAS/ALK genes and genome-wide of life compared to open lobectomy (OL). VATSL
expression proÀling. has also proved to be an oncologic equivalent
Results: EGFR, KRAS and ALK were mutually operation to OL for early stage NSCLC. VATSL
exclusively mutated in 127 (56%), 20 (9%) and 11 requires a high level thoracoscopic skill set with a
(4.9%) cases. Therefore, the remaining 68 cases steep learning curve. Completion of an attending
(30%) were deÀned as triple-negative ADCs. These 68 level VATSL learning curve might diminish the
cases were divided into two subclasses, groups A (36 operative experience of cardiothoracic (CT) surgery
cases) and B (32 cases), by an unsupervised clustering residents. Through this study we sought to compare
analysis according to the expression of 174 genes. VATSL vs. OL, during the period of moving from
Relapse free survival as well as overall survival of OL to VATSL with respect to patient outcomes, as
group A patients were signiÀcantly worse than those of well as measure the evolution of the CT surgery
group B patients and EGFR (+) patients. Although the resident operative experience.
number of KRAS (+) and ALK (+) patients were small, Methods: This is a single institution retrospective
similar trends were also observed. review of a prospective thoracic surgery database.
Conclusion: A subclass of triple-negative ADCs with The period of transition from OL to VATSL for early
unfavorable outcome was identiÀed by combination stage NSCLC was 2006-2007. The initial 65 VATSL
of mutation and expression proÀling analyses. Further were compared to 70 OL during this time period,
characterization of this subclass will be useful for matched by clinical variables. The CT resident Ànal
selection of patients who will beneÀt from adjuvant American Board of Thoracic Surgery (ABTS) case
chemotherapy after surgery. logs for the categories Pneumonectomy, Lobectomy,
Keywords: biomarker, pathway, Adenocarcinoma, Segmentectomy (PLS) and VATS were examined.
Prognosis Four chief residents from 2002-2005 (before
initiation of the VATSL program) were compared
A revised/updated abstract may be included in to four chief residents from 2006-2009 (after
the Late Breaking Abstract Supplement, available initiation of the VATSL program). Case numbers are
at the 14th World Conference on Lung Cancer. presented as percentages of the ABTS CT Pathway
requirements for categories PLS (30 required cases)
and VATS (15). Thoracic surgery residents after
2005 are provided with VATSL operative technique following lobectomy on a national scale.
literature and instructional videos. Residents were Furthermore, inaccurate procedure codes may have
taken through stepwise milestone sequences of been used in the identiÀcation of patient cohorts in
operative VATSL techniques before supervised recent analyses comparing perioperative outcomes
completion of an entire VATSL. Results were following VATS vs. open lobectomy (OPEN).
considered signiÀcant if p0.05. Methods: The 2008 Healthcare Utilization Project-
Results: There were no operative deaths in either Nationwide Inpatient Sample (HCUP-NIS) database
the VATSL or OL groups. Two patients in the was culled using the ICD-9-CM procedure codes
VATSL group were converted to open secondary distinguishing VATS vs. OPEN lobectomies (32.41
to intraoperative bleeding. Compared to OL the and 32.49, respectively) that were only available
VATSL group had reduced mean days on mechanical after October 2007. Prior to that date, only a non-
ventilation (0.00 vs. 0.30, p = 0.03), ICU length of speciÀc procedure code for lobectomy existed
stay (0.20 vs. 3.70, p=0.004) and hospital length of (32.4). Patient and provider demographic and
stay (4.30 vs. 8.80, p=0.001). Examining resident clinical characteristics, including hospital VATS
education, both the 2002-2005 and 2006-2009 volume (deÀned as 95th percentile, or 21 VATS/
cohorts had similar mean case numbers for PLS year), were recorded. Bivariate and multivariate
(44.8 vs. 51.3, p=0.63; % of requirement 149% vs. analyses were used to identify independent
171%) and the 2006-2009 group performed a greater predictors of outcome measures (30-day in-hospital
number of VATS cases (71.8 vs. 16.3, p=0.13; 478% total complications, length-of-hospital-stay [LOS],
vs. 108%). inpatient hospital costs, and in-hospital mortality).
Conclusion: These results illustrate that a Results: In the 2008 HCUP-NIS database, there
teaching institution can effectively move were 6,292 lobectomies identiÀed for patients with
from an OL approach to VATSL and, through primary lung cancer, including 1,523 with VATS
carefully planned and structured instruction of (24%). Compared with OPEN, patients undergoing
the residents, maintain patient safety and reduce VATS had fewer total complications (38% vs. 44%,
postoperative complications. At the same time, the p<0.001) and shorter median LOS (5 vs. 7 days,
resident operative experience is enriched. Further p<0.001). There were no signiÀcant differences in
enhancement of resident VATSL education in the median costs or mortality. Adjusting for patient/
future may involve surgical simulation. provider characteristics in multivariate analysis,
Keywords: VATS lobectomy, Lung cancer, Medical VATS was an independent predictor of fewer total
Education, Early Stage complications (OR=0.83, p=0.004) and shorter LOS
(2.3±0.3 day difference, p<0.001) compared with
OPEN. Patients undergoing VATS at high-volume
Surgery - VATS/Staging Wednesday, 6 July 2011 14:30-16:00 VATS hospitals had shorter median LOS (4 vs. 6
days, p=0.001) than those at low-volume VATS
MO14.02 IMPACT OF HOSPITAL hospitals. There were no signiÀcant differences
OPERATIVE VOLUME OF VIDEO- in total complications, median costs, or mortality.
ASSISTED THORACOSCOPIC Adjusting for patient/provider characteristics in
LOBECTOMY ON PERIOPERATIVE multivariate analysis, high hospital VATS volume
OUTCOMES FOR PRIMARY LUNG was an independent predictor of shorter LOS
CANCER (1.2±0.4 day difference, p=0.001) compared to low
Henry S. Park, Frank C. Detterbeck, Daniel J. Boffa, hospital VATS volume.
Anthony W. Kim Conclusion: On a national scale, VATS lobectomy
Department Of Surgery (thoracic), Yale University is independently associated with fewer total
School Of Medicine/United States Of America complications and shorter LOS for patients with
primary lung cancer, compared with OPEN
Background: Video-assisted thoracoscopic surgery lobectomy. For patients undergoing VATS
(VATS) is an increasingly utilized approach for lobectomy, high hospital volume is also associated
pulmonary lobectomy throughout the United States. with shorter LOS. The Àndings of this study may
Hospital operative volume of VATS lobectomy warrant further investigation as the national VATS
in primary lung cancer has not previously been experience and the collection of VATS lobectomy-
evaluated as a predictor of short-term outcomes speciÀc data continue to increase.
Results: There are no signiÀcant differences in sex,

age, or histopathological Àndings among three groups.
There are no operative death but one hospital death in
C-Gp., of interstitial pneumonia. There are no signiÀcant
differences in operating time, blood loss and transfusion
rate among the groups. The mean observation period
after the operation was 38.7 months ( range, 0.6 to
122 ms ). The overall 5-year survivals was 95.3 % for
C-Gr., 75 % for S- Gr., respectively. Major postoperative
Keywords: hospital volume, VATS lobectomy, complication in C-Gr. was signiÀcantly less than other
perioperative outcomes Grps. CPK ratio (CPKmax / preCPK) as a marker
indicating surgical damage to the muscles In C-Gr.is
signiÀcantly less than S-Gr. And mean maximum CRP
Surgery - VATS/Staging Wednesday, 6 July 2011 14:30-16:00 degree postoperatively in C-Gr. is signiÀcantly less than
the two other Grps. We used analogue pain scale and
MO14.03 MINIMUM INVASIVE record the self-estimation of the patients on the day 1,
COMPLETE VATS LOBECTOMY FOR 2, and 3 after operation.Post surgical pain which patient
C-IA LUNG CANCER WITH SUBXIPHOID felt is tended to reduce in C-Gr.
ROUTE Conclusion: The results of major pulmonary
Yoshinori Doki1, Kazutaka Senda1, Takahiro resection for C-IA lung cancer by c-VATS with
Homma1, Masayoshi Tohge1, Naoki Yoshimura1, subxiphoid route is feasible and acceptable by a
Tatsuhiko Kashii2, Shigeki Sugiyama3 patients’ view of point over operative phase.
1
Thoracic And Cardiovascular Surgery, Toyama Keywords: Complete VATS Lobectomy, Subxiphoid
University Hospital/Japan, 2Division Of Clinical route, Minimally invasive
Oncology, Toyama Uniersity Hospital/Japan,
3
Pulmonology, Tohmei-Atsugi Hospital/Japan A revised/updated abstract may be included in
Background: Pulmonary lobectomy by Complete at the 14th World Conference on Lung Cancer.
Video-assisted thoracic surgery (c-VATS) for early-
staged lung cancer patients has gained wide spread
acceptance in recent years. Its advantages are less Surgery - VATS/Staging Wednesday, 6 July 2011 14:30-16:00
invasiveness, better cosmesis and that contributes to
patients’ quality of life after the operation. So as to MO14.05 EXPERIENCE WITH
prevent all neuromuscle damages of the chest wall CT-GUIDED HOOK WIRE FOR
structures from rib spreading or cutting by electric LOCALIZATION OF SMALL
devices as possible, we have performed c-VATS PULMONARY NODULES PRIOR TO
lobectomy with subxiphoid route when the resected VIDEOTHORACOSCOPIC RESECTION.
specimen is extracted from chest cavity.In this Laureano Molins1, Eduard Mauri2, Marcelo
congress, we introduce our technical procedures, Sanchez3, Juan J. Fibla4, Jose M. Gimferrer5, Pedro
perioerative data and survival. Arguis3, Jose M. Mier4, Abel Gomez-Caro5, Miguel
Methods: From January 2003 to December Catalan5, Jose M. Sancho6, Jose Ramirez7
1
2010, there are 39 patients we have treated major Thoracic Surgery, Hospital Clinic/Spain,
2
lung resection followed by ipsilateral hilum and Diagnostic Imaging (CRC Sagrat Cor), Hospital
mediastinal radical dissection for c-IA lung cancer Universitari Sagrat Cor/Spain, 3Radiology, Hospital
patients by c-VATS with subxiphoid route. Our ordinal Clínic, Barcelona, Spain/Spain, 4Thoracic Surgery,
procedure is performed by 3 or 4 ports, and resected Hospital Universitari Sagrat Cor/Spain, 5Thoracic
specimen is over-wrapped in a pouch and extracted Surgery, Hospital Clínic/Spain, 6Pathology, Hospital
through subxiphoid route. We studied and investigated Universitari Sagrat Cor/Spain, 7Pathology, Hospital
clinical data of the patients by this procedure(C- Clínic/Spain
groupe) and compared to that by mini-thoracotmy
VATS(M-groupe) or by standard thoracotomy(S- Background: Resection of peripheral pulmonary
groupe) performed on the same period. nodules by videothoracoscopy offers a speciÀcity
of 100% with low morbidity. It sometimes requires Conclusion: The perioperative identiÀcation of the
extension of one of the incisions or the practice of small-sized pulmonary nodules enables a resection
a mini thoracotomy and digital palpation in order through videothoracoscopic surgery without the need
to locate them, when they are not totally subpleural of having to extend the incision or the practice of a
and/or because of their small size. The objective is to mini thoracotomy for palpation of the nodule. The
assess the results of the introduction of a CT-guided introduction of a CT-guided hook wire is, in expert
hook wire prior to the videothoracoscopic resection hands, a very safe and effective procedure that can
as a perioperative localization method. be carried out in an outpatient surgery programme.
Methods: From November 2004 to January 2011 Keywords: Videothoracoscopy, CT-guided Hook
Àfty two patients were programmed for localization of wire, Resection of Pulmonary nodule, Localization
pulmonary nodules smaller than 20mm by introduction of Pulmonary Nodule
of a CT-guided harpoon. The patient was later taken to
the surgical theatre for a videothoracoscopic resection
using endostaplers with a protected extraction of the Surgery - VATS/Staging Wednesday, 6 July 2011 14:30-16:00
specimen for anatomo-pathological examination, and
proceed in consequence. MO14.06 IMAGE-GUIDED VIDEO-
Results: Fifty two patients – 31 men and 21 women ASSISTED THORACOSCOPIC (VATS)
– from 28 to 84 years old (mean of 62,2 years) with RESECTION FOR DIAGNOSIS OF SMALL
nodules of a diameter maximum of 20mm (mean PERIPHERAL PULMONARY NODULES
of 9,57 mm and 37 nodules <10 mm). Six patients (SPN)
had the nodule(s) detected during the staging of Richard J. Finley1, John Mayo2, Joanne C. Clifton3,
a recently-diagnosed neoplasm; 29 patients with John Yee1, Annette Mcwilliams4, Stephen Lam5,
nodules detected during the follow-up of a previous Kenneth Evans1, John C. English6
1
neoplasm, and 17 patients without previous oncologic Surgery/thoracic Surgery, Vancouver General
history. Nine nodules were deÀned as GGO. Fifty Hospital/Canada, 2Radiology, Vancouver General
Àve harpoons were placed – three patients had Hospital/Canada, 3Surgery/thoracic, University Of
two simultaneous harpoons placed. During the British Columbia/Canada, 4Medicine/respiratory,
videothoracoscopic exploration, 52 harpoons were University Of British Columbia/Canada, 5Integrative
found in place and three of them had detached Oncology, Bc Cancer Research Centre/Canada,
6
themselves –2 were a different type of hook wire from Pathology And Laboratory Medicine, Vancouver
the original ones. A videothoracoscopic resection General Hospital/Canada
was carried out in all but two cases without need of
extending the incisions of ports. No complications Background: Poor diagnostic accuracy of
like hemorrage or pneumothorax were observed. bronchoscopy, needle biopsy or PET scan of growing
Among the 35 patients with a previous oncologic SPN in patients at high risk for either primary or
history, the nodules were neoplasic in 26 cases (13 metastatic lung cancer leads to requests for VATS
lung carcinoma, 4 colon, 3 melanoma, 2 breast and resection for pathologic diagnosis .Failure to visualize
1 of each: tipical carcinoid, parotid, endometrium or palpate SPN at VATS results in thoracotomy for
and urothelial) and 9 turned out to be benign (2 resection in over 50% of cases .The purpose of this study
hamartomas, 1 adenomatous hyperplasia, 1 chronic is to determine if preoperative CT-guided microcoil
pneumonia, 1 sarcoidosis, 3 inÁammatory inÀltrates localization of SPN followed by Áuoroscopically guided
and 1 intraparenchymal lymph node). Among the VATS resection decreases the need for thoracotomy for
17 patients without previous oncologic history, the diagnosis of SPN.
nodules were as follows: 12 bronchogenic carcinomas Methods: Between April 2003 – January 2011, 113
(3 doubles) and 5 benign (3 hamartomas, 1 undiagnosed SPN (£15 mm) in 110 consecutive patients
tuberculous nodule and 1 Àbrous nodule). The average were preoperatively localized using percutaneously
stay ranged between 4 and 72h, with 19 patients placed CT-guided platinum microcoils. Coils were placed
included in an Outpatient surgical program (36,5%); with the distal end deep to nodule and the superÀcial end
15 patients were discharged after 24 hours (28.8%), coiled on the pleural surface. Nodule and microcoil were
1 after 72h due to air leak (1.9%) and 17 after 5 days removed using endostaplers by Áuoroscopically guided
because an additional resection was performed after VATS wedge excision. Intraoperative frozen section
the pathologic intraoperative diagnosis. histopathologic diagnosis was performed.
Results: On average, nodules were 10.8± is poppyseed oil used as a radio-opaque contrast
3mm in diameter and 14.3±11 mm deep to the agent such as lymphangiography. We herein show
visceral pleural surface. Using CT guidance the the preoperative multi-marking with lipiodol using
microcoil was placed within 5mm of the nodule real-time CT Áuoroscopy for several lung resections.
in 106/109 with 2/107 requiring a chest tube for Methods: One hundred and twenty-eight pulmonary
pneumothoraces. Complete resection was successful nodules in 47 patients (32 male and 15 female)
in all patients (111/113 by VATS and 2/113 by were enrolled in this study. A number of the marked
thoracotomy). Mean microcoil insertion, Áuoroscopy nodules were ranged from 2 to 5 in unilateral lung of
and wedge resection operative minutes were: each patient. Of these, 14 were nodules with ground-
31.4±10; 1.4±1; 32.0±24. Backward linear regression glass opacity, 12 were cystic nodules, and 102 were
for operating time was dependent on nodule depth solid nodules on CT images. Our indication for
(p<0.001), Áuoroscopy minutes (p=0.007), and lipiodol making was as follows: the nodules were 1)
location segment of nodule (p=0.017). Pathologic in the ipsilateral lung, 2) less than 10mm, 3) located
diagnosis was: 27 benign, 21 metastatic, 65 primary far from the surface of visceral pleura, or 4) they
(Adenocarcinoma 45, BAC 9, Squamous cell 8, showed non-solid (ground-glass opacity or cystic)
Large cell 1, Small cell 2) cancers. Completion images on CT. All nodules were marked with 0.1
lobectomy occurred in 32 patients. Median follow-up to 0.5 ml lipiodol under a real-time CT Áuoroscopy
is 13.8 months (min 0.2, max 86.5). There were no just before the surgery. At surgery, we grasped the
local tumor recurrences. In the 52 Stage I patients, marked nodules with ring-shaped forceps under a
there have been four new primaries and one death C-arm Áuoroscope and then performed thoracoscopic
(48 months). In the 72% (81/113) of patients with lung resection.
bronchoscopy, needle biopsy or PET investigations, Results: All 128 nodules were successfully in multi-
preoperative treatment plan was changed by marking with lipiodol, and completely resected
microcoil guided VATS excision biopsy in 44% under the intraoperative Áuoroscopy. The mean
(36/81). time required to marking for a nodule was 18.5
Conclusion: Pre-operative localization of small minutes. Complications of the multi-marking were
peripheral pulmonary nodules (<15mm) using pneumothorax required thoracic drainage in 19
percutaneous CT guided platinum microcoils (40%) patients, pulmonary hemorrhage in 4 (9%),
followed by Áuoroscopic guided VATS excision bloody sputum in 2 (4%), and hematoma in the chest
provided pathologic diagnosis in 98% and changed wall in 1 (2%). The high incidence of pneumothorax
management in 44% of cases. was caused by the frequency of needle puncture
Keyword: microcoil to the lung. No other complications such as aero-
embolism were observed. The mean size of the
nodules was 6.8 mm (in range from 2 to 23 mm),
Surgery - VATS/Staging Wednesday, 6 July 2011 14:30-16:00 and their mean depth from the visceral pleural
surface was 8.2 mm (in range from 0 to 39 mm).
MO14.07 PREOPERATIVE MULTI- The pathologic diagnosis was primary lung cancer
MARKING WITH LIPIODOL FOR in 6 lesions (including 3 of bronchioloalveolar
THORACOSCOPIC RESECTION OF carcinoma), metastatic lung tumor in 73, atypical
SEVERAL SMALL PULMONARY adenomatous hyperplasia in 4, and other benign
NODULES lesion in 45. The use of lipiodol did not affect the
Kunihiko Terauchi, Junichi Shimada, Daishiro Kato, pathological Àndings.
Masanori Shimomura, Hiroaki Tsunezuka, Kaori Conclusion: Preoperative multi-marking with
Ichise lipiodol is a useful and precise procedure for
Department Of General Thoracic Surgery, Kyoto thoracoscopic resection of several small pulmonary
Prefectural University Of Medicine/Japan nodules. This method can be also recommended for
impalpable lung lesion such as ground-glass opacity
Background: As the development of the or cystic lesions.
computed tomography (CT) screening, several Keywords: Lipiodol marking, CT Áuoroscopy,
small pulmonary nodules are often detected on CT thoracoscopic resection, VATS
scanning. Several techniques have been reported for
their localization in thoracoscopic resection. Lipiodol
Surgery - VATS/Staging Wednesday, 6 July 2011 14:30-16:00 Conclusion: In this pilot study CT-guided
transbronchial metallic coil marking with an ultrathin
MO14.08 FLUOROSCOPY-ASSISTED bronchoscope with a coin on a patient’s chest wall
THORACOSCOPIC RESECTION OF after CT-assisted stimulation was found to be feasible
PULMONARY NODULES AFTER and safe. In our previous report, CT had been needed
COMPUTED TOMOGRAPHY–ASSISTED at least three times, but this method needed only twice
BRONCHOSCOPIC METALLIC COIL CT scan. It might be a useful method not only for
MARKING making a diagnosis but also for therapeutic wedge
Takanori Miyoshi, Hisashi Matsuoka, Masami resection in selected early lung cancers.
Morimoto, Naoki Hino, Masaru Tsuyuguchi Keywords: coil marking, VATS, CT assisted
Surgery, Tokushima Municipal Hospital/Japan bronchoscopy
Background: With advances in computed

tomography (CT), small pulmonary lesions Surgery - VATS/Staging Wednesday, 6 July 2011 14:30-16:00
previously unseen on chest radiographs are being
increasingly detected. Among lesions less than 10 MO14.10 MEDIASTINAL LYMPH
mm in size, a considerable number of malignancies NODE DISSECTION IN EARLY STAGE
have been reported. To localize small and deeply NON-SMALL CELL LUNG CANCER:
situated pulmonary nodules during thoracoscopy TOTALLY THORACOSCOPIC VERSUS
with roentgenographic Áuoroscopy, we developed a THORACOTOMY
marking procedure that uses a metallic coil and a coin. Dominique Gossot1, Ricard Ramos1, Philippe
Methods: Eleven patients underwent video-assisted Girard1, Pierre Validire2
1
thoracoscopic surgery for removal of 11 pulmonary Thoracic, Imm/France, 2Pathology, Imm/France
lesions. Fluoroscopy-assisted thoracoscopic
surgery after CT-assisted bronchoscopic metallic Background: Although major pulmonary resections
coil marking was performed using an ultrathin for early stage non-small cell lung cancer (NSCLC)
bronchoscope under Áuoroscopy viewing a coin are more and more frequently performed through
on a patient’s chest wall. The coin was simulated a thoracoscopy, the adequacy of lymphadenectomy
pulmonary lesion by the CT Àndings, and it was put achieved via this approach is still questioned. The
on the patient’s chest wall. During thoracoscopy, a aim of this study was to evaluate the results of lymph
C-arm-shaped roentgenographic Áuoroscope was node dissection during totally thoracoscopic major
used to detect the radiopaque nodules. The nodule pulmonary resections.
with coil markings was grasped with forceps and Methods: Clinical and pathologic data of
resected with endostaplers under Áuoroscopic and consecutive patients who underwent lobectomy or
thoracoscopic guidance. segmentectomy for clinical-N0 NSCLC between
Results: The marking procedure took 10 to 30 minutes January 1st, 2007 and December 31st , 2009 were
from insertion to removal of the bronchoscope. reviewed .The main evaluation criterion was the
There were no complications from the marking, and number of mediastinal lymph nodes and mediastinal
all 11 nodules were easily localized by means of stations dissected through a totally thoracoscopic
thoracoscopy. The metallic coil showed the nodules (TT) approach as compared with the classical
on the Áuoroscopic monitor, which aided in nodule posterolateral thoracotomy (PLT) approach.
manipulation. Nodules were completely resected under Results: : A total of 296 major pulmonary resections
thoracoscopic guidance, in partial resection in 10 cases (278 lobectomies and 18 anatomic segmentectomies)
and in segmentectomy in one case. The pathologic for clinical stage I-II NSCLC were performed, 96
diagnosis was primary adenocarcinoma in 6 patients, via a TT approach and 200 through PLT. Patients’
primary lung cancer except adenocarcinoma in 2 clinical characteristics were similar in both groups.
patients, a pulmonary metastasis from colon cancer The overall numbers of dissected mediastinal lymph
in 1 patient, an atypical adenomatous hyperplasia nodes and of dissected mediastinal stations were
in 1 patient and a nontuberculous mycobacteriosis similar in both groups (TT: mean±SD=17.7±8.2;
in 1 patient. One case of a bronchiolo-alveolar PLT: 18.2±9.3, p: 0.937, and 3.2±0.9 vs 3.4±0.9,
adenocarcinoma with an extensive two segments was respectively). The overall numbers of stations (TT:
performed a curative segmentectomy. mean ±SD 5.1±1.1; PLT: 4.5±1.2) and lymph nodes
(TT: 22.6±9.4, PLT: 25.4±10.8) were slightly but operating time was 215 min (range, 190–280 min).
signiÀcantly different between the 2 groups (p<0.001 Ten lobectomies and two wedge resections were
and p=0.033, respectively); There was no difference performed with en bloc chest-wall resection and
in terms of postoperative complications, although mediastinal lymphadenectomy. In one patient, a
patients from the TT group had signiÀcantly fewer combined transmanubrial and posterior thoracotomy
chest tube days (mean±SD=4.0±1.8 vs 5.7±3.9, p< was required to remove the tumor. In another, a
0.001) and shorter hospital length of stay (7.0±2.5 liquoral Àstula was treated intra-operatively. R0
days vs 10.3±7.4, p< 0.001). resection was achieved in all 12 patients. The
Conclusion: For patients undergoing thoracoscopic average blood loss was 415 mL (range, 250–1200
lobectomy or segmentectomy for clinical early mL). There was no postoperative mortality; four
stage NSCLC, the quality of mediastinal lymph patients developed postoperative pneumonia. The
node dissection is equivalent to that performed by median length of hospitalization was 9,5 days
thoracotomy. (range, 8–30 d). The mean operative follow-up to
Keywords: lymph node dissection, Surgery, VATS date is 25,4 months (range, 6-46 months). No repeat
surgical procedure has been required. Seven patients
remain well with no clinical or radiological evidence
Surgery - VATS/Staging Wednesday, 6 July 2011 14:30-16:00 of recurrence. One patient developed a controlateral
lung nodule and is under chemiotherapic treatment.
MO14.11 THE VIDEO-ASSISTED Four patients died; two developed metastatic disease,
MODIFIED SHAW-PAULSON APPROACH one developed acute myeloid leukemia and the last
FOR PANCOAST TUMORS died of a cardiopulmonary insufÀciency.
Francesco P. Caronia1, Enrico RufÀni2, Attilio Conclusion: This technique is technically
Ignazio Lo Monte3 demanding. A high-quality video system and the
1
Thoracic Surgery, Policlinico Morgagni/Italy, ability to combine the use of thoracoscopic and
2
Chirurgia Toracica, Ospedale San Giovanni standard instruments are essential for success, but no
Battista/Italy, 3Surgery, University Of Palermo/Italy new instruments are required other than those used in
standard procedures. Additionally, all team members
Background: We describe the initial use of video can follow the surgical steps in detail, which is a
assisted thoracic surgery (VATS) with the Shaw- useful teaching tool. The short-term results have
Paulson approach in 12 patients with Pancoast tumors, been encouraging, but it would be interesting to
in order to minimize chest wall trauma. conduct this technique in a randomized study with
Methods: Between March 2004 and September a larger series against the use of thoracotomy alone.
2010, 12 patients with Pancoast tumors underwent a This is an effective and safe approach to assess
modiÀed VATS Shaw-Paulson approach, lung resection resectability and minimize postoperative trauma in
with an en bloc chest-wall resection and mediastinal complex surgery for superior sulcus tumors, and it is
lymphadenectomy. All patients underwent neoadjuvant now in routine use in our department.
chemoradiotherapy. The procedure began with the Keywords: Lung cancer, video-assisted thoracic
exploration of the pleural cavity using a 30-degree surgery, superior sulcus tumors
videothoracoscopic camera. Surgery was performed
using standard techniques and combining the use of
a high posterior thoracotomy parallel to the vertebral Surgery - VATS/Staging Wednesday, 6 July 2011 14:30-16:00
border of the scapula, and thoracoscopic ports. After the
involved chest wall attached to the lung was resected MO14.12 POSITIVE PLEURAL LAVAGE
through the posterior thoracotomy, either lobectomy or CYTOLOGY IS A PREDICTOR OF POOR
wedge-resection could be performed with VATS. PROGNOSIS IN RESECTED NSCLC
This posterior thoracotomy preserves the latissimus Federico Mazza1, Paola Maineri2, Enrico Ferrari3,
dorsi, and avoids extension of the thoracotomy through Antonella Alloisio3, Maria Teresa Piras3, Giovanni
the fourth or Àfth intercostal space. No prosthesis was Battista Ratto3
1
necessary to cover the Ànal chest wall defect. Thoracic Surgery, Istituto Nazionale Per La Ricerca
Results: There were 9 men and 3 women with Sul Cancro/Italy, 2Ospedale Santa Corona - Asl2
a mean age of 61 yrs (range, 39-73 yr). Patients Savona/Italy, 3Istituto Nazionale Per La Ricerca Sul
were either IIB (n=5) or IIIA (n=7). The average Cancro/Italy
Background: TNM is the best prognostic descriptor Surgery - VATS/Staging Wednesday, 6 July 2011 14:30-16:00
about Lung Cancer. Nevertheless there are some
clinicopathological characteristics not included in MO14.13 PARATRACHEAL
TNM, but potentially related to NSCLC prognosis: LYMPHADENECTOMY DURING A LEFT
one of them is Pleural Lavage Cytology (PLC). SIDED THORACOTOMY FOR LUNG
Methods: From January 2003 to December 2008, CANCER RESECTION. WHAT CHANGES
PLC has been performed in 397 consecutive NSCLC WHEN COMBINED WITH SYSTEMATIC
patients who underwent surgical resection. Follow-up DISSECTION ?
was available in 376 patients. PLC was obtained from Alper Toker1, Serhan Tanju1, Erkan Kaba1, Serkan
100ml of saline solution instilled in the pleural cavity Kaya1, Dilek Yilmazbayhan2
1
soon after thoracotomy, before any lung manipulation Thoracic Surgery, Istanbul University Istanbul
and in absence of pleural effusion. Medical School/Turkey, 2Pathology, Istanbul
Results: There were 280 male and 96 female, with University Istanbul Medical School/Turkey
a median age of 69 (ranging from 36 to 86). PLC
was positive in 13 patient (3,5%). Positive cytologic Background: Theoretical reasons which are often
Àndings were observed only in adenocarcinoma cited to support systematic nodal sampling or
patients (13 of 193 resected adenocarcinomas: 6,7%). complete mediastinal lymphadenectomy during
Positive PLC was signiÀcantly related to pT category lung cancer resection, are skip metastasis and occult
(1,6% in pT1; 2,4% in pT2; 12,2% in pT3-4; p = lymph node metastasis. The goal of this study was to
0,001) and pN2 with more than one mediastinal determine effects of paratracheal lymphadenectomy.
lymph node station involved (38,5% versus 2,3% of Methods: Sixty-six patients who had left sided hilar
single-pN2, p = 0,003); no correlations were found primary lung cancer with a negative mediastinal
between PLC and age, extent of surgery, R0 resection, uptake in PET-CT and negative mediastinoscopy,
p-stage, presence of lymph node skip metastasis or underwent left thoracotomy. Dissection of the nodes
extranodal inÀltration. The overall 5-year survival (2R, 4R, 2L, 4L) were accomplished without ductus
rates were 27,7%% in PLC positive cases and 54,9% arteriosus division and arcus aorta mobilization.
in PLC negative cases (p = 0,001) (Àgure 1); this Patients’ demographics, histology, total number
difference was also signiÀcant when the analysis of lymph nodes dissected, number of nodes from
was limited to p-stage I NSCLC (50% vs 68%; p each station, number of metastatic lymph nodes,
= 0,005). Despite the longer median follow-up for morbidity and mortality were recorded. The
PLC negative patients (2,87 years versus 2,1 years), number of dissected paratracheal lymph nodes were
recurrences were observed more frequently in PLC compared to the number of standart systematic
positive patients: 69,2% versus 34,5% (p = 0,034). lymph nodes dissected from the left lung.
Among PLC positive cases there was no difference in Results: The mean number of resected nodes in the
the patterns of recurrence (55,6% local versus 44,4% superior mediastinum was 8.7 (range 2 – 20 nodes),
distant metastasis, p = 0,729). Multivariate analysis 3.4 from 4R, 2.5 from 4L, 0.5 from 2L and 2.1 from
showed Àve independent prognostic factors (age, R0 2R. Six patients (9.0 %) were diagnosed with occult
resection, pT, pN, bulky-pN2), not including PLC. N2 disease, and two (3.0%) of these patients also had
concomitant N3 disease. Complications related to
the operation and this technique were observed in 18
patients (27.2%) patients. A total of 567 nodes were
dissected from paratracheal area with a total of 10
nodes positivity in six patients. Systematic dissection
of the stations 5 to 9 nodes recruted 509 nodes with
10 nodes positivity in 10 patients. There were 3
Conclusion: This study showed that PLC positive common patients in both positive groups.
NSCLC patients have a worse overall survival and Conclusion: Paratracheal lymp node dissection
an higher recurrence rate, even in early stage disease. through left thoracotomy increases the number
We suggest to consider PLC positive patients as of nodes dissected twice as much. In this study,
an high risk category, eligible for adjuvant therapy this technique provided 3 more N2 patients when
regardless of the p-stage. combined with standard systematic dissection. This
Keywords: Prognosis, NSCLC, pleural lavage, cytology technique could be considered prior to a decision
for a major resection if intraoperative N1 and N2 Methods: Advanced NSCLC patients who
positivity was diagnosed. Also, when an exploratory experienced disease progression following 1 or 2
thoracotomy for an undiagnosed mass turns out to prior chemotherapy regimens, ECOG PS 0-2, and
be a NSCLC, dissection of the mediastinum may be measurable disease were included. Study treatment
considered prior to resection. was randomly assigned to include erlotinib (150
Keywords: Lung cancer, Mediastinal staging, mg PO QD) in combination with either placebo,
Mediastinal lymph node dissection, Left R1507 at 9mg/kg/week or R1507 at 16 mg/kg/Q 3
thoracotomy weeks, i.v. Treatment cycles were repeated every
3 weeks. The primary endpoint was comparison of
the 12-weeks PFS rate and the secondary endpoints
Session MO15: Medical Oncology II included response rate, PFS, OS, safety assessment
and exploratory correlative studies.
Wednesday, 6 July 2011 Results: 171 patients were enrolled, with the
following characteristics: median age 61 years, 33 %
female, 12% never-smokers, 86% stage IV, 88% PS
Medical Oncology II Wednesday, 6 July 2011 14:30-16:00 0/1, 25% squamous histology, 51% adenocarcinoma,
and 74% with 1 prior regimen. The median number
MO15.01 R1507, A MONOCLONAL of doses of R1507 was 6 and 3.5 for the weekly
ANTIBODY TO INSULIN-LIKE GROWTH and Q3 weeks arms respectively. Grade 3/4 adverse
FACTOR RECEPTOR-1 (IGF-1R), IN events were noted in 37%, 44%, and 48% of patients
COMBINATION WITH ERLOTINIB FOR with placebo, weekly, and Q 3 weeks R1507 therapy
ADVANCED STAGE NON-SMALL CELL respectively.
LUNG CANCER (NSCLC): A PLACEBO-
CONTROLLED, RANDOMIZED PHASE II Parameter E + Placebo E + R1507 E+R1507
STUDY. (weekly) (Q 3 wks)
Suresh Ramalingam1, David Spigel2, Martin Steins3, N 57 pts 57 pts 57 pts
Jeffrey Engelman4, Silvia Novello5, Wilfried Response rate 8.8% 8.8% 7%
Eberhardt6, Claus Schneider7, Lucio Crino8, 12-weeks PFS rate 39% 37% 44% (NS)
Pasi A. Janne9, Lian Liu10, David Chen11, Carrie Median PFS 1.5 m 1.6 m 2.7 m (P= NS)
Brownstein11, Martin Reck12 Median OS 8.1 m 8.1 m 12.1 m (P=0.04)
1
Hematology And Medical Oncology, Winship Gr 3/4 skin rash 8% 7% 10%
Cancer Institute Of Emory University/United Gr 3/4 fatigue 6% 10% 7%
States Of America, 2Sarah Cannon Research Hyperglycemia (any) 0 3% 9%
Institute/United States Of America, 3Thorax Klinik/
Germany, 4Massachusetts General Hospital/ Candidate biomarkers including IGF-1R, free IGF1,
United States Of America, 5Clinical And Biological total IGF, IGFBP-3, pAKT, PTEN, EGFR and Kras
Sciences, University Of Turin, Aou San Luigi/Italy, were evaluated in tissue specimens (n=165). The
6
Internal Medicine [Cancer Research], University 12-weeks PFS rate was higher with R1507 Q3 weeks
Duisburg-Essen/Germany, 7Zentral Klinik/Germany, in patients with high free IGF-1 levels, compared to
8
University Of Perugia/Italy, 9Lowe Center For placebo (46% vs. 18%). The 12-weeks PFS rate in
Thoracic Oncology, Dana Farber Cancer Institute/ patients with K-ras mutation was 22% with R1507
United States Of America, 10Roche Pharmaceuticals/ compared to 0 with placebo.
China, 11Roche Pharmaceuticals/United States Of Conclusion: The addition of R1507 to erlotinib did
America, 12Krankenhaus Großhansdorf, Zentrum Für not result in a signiÀcant improvement in PFS for
Pneumologie Und Thoraxchirurgie/Germany an unselected group of advanced NSCLC patients in
the 2nd/ 3rd line therapy setting. K-ras status and free
Background: R1507 (Hoffman LaRoche) is a IGF-1 bioactivity in serum demonstrated predictive
selective, fully human, recombinant monoclonal potential in an exploratory analysis.
antibody (IgG1 subclass) against IGF-1R. Activation of Keywords: NSCLC, IGF-1R, R1507, erlotinib
IGF-1R pathway contributes to resistance to geÀtinib
and erlotinib therapy. Therefore, we conducted a
randomized study of R1507 with erlotinib (E).
Medical Oncology II Wednesday, 6 July 2011 14:30-16:00 dose intensity of IMC-A12 88%, erlotinib 78%. 2
patients at 15 mg/kg q21 experienced DLTs (1 x grade
MO15.02 A PHASE I/II STUDY OF 3 fatigue, 1 x grade 3 rash and mucositis requiring
ERLOTINIB IN COMBINATION WITH dose reduction), 2 required dose modiÀcation or
THE ANTI-INSULIN-LIKE GROWTH cessation in cycle 1, and mean dose intensity of
FACTOR-1 RECEPTOR (IGF-1R) IMC-A12 95%, and erlotinib 75%. 14 patients were
MONOCLONAL ANTIBODY IMC-A12 evaluable for response. 3 patients had stable disease as
(CIXUTUMUMAB) IN PATIENTS WITH best response and 11 patients had progressive disease.
ADVANCED NON-SMALL CELL LUNG 13/18 patients had EGFR mutation testing performed.
CANCER (NSCLC). 3 patients had EGFR mutant tumors (1 x 6mg/kg, 2
Andrew J. Weickhardt1, Robert C. Doebele1, Anna x 5mg/kg), with median Progression Free Survival
B. Oton1, Grace Dy2, Jannice Lettieri1, Delee A. (PFS) 217 days (range 91 - 245). 10 patients had
Maxson1, Michelle Reynolds1, Mary K. Jackson1, EGFR wild type tumors: median PFS was 31 days.
Amy Brown1, Araba Adjei2, Gerald J. Fetterly2, Alex Tissue and serum have been collected from patients
A. Adjei2, David R. Camidge1 and will be analyzed for other biomarkers of toxicity
1
Thoracic Oncology, University Of Colorado and response.
Cancer Center/United States Of America, 2Medical Conclusion: The combination of IMC-A12 at 6mg/
Oncology, Roswell Park Cancer Institute/United kg q7 and 15mg/kg q21 and full dose erlotinib is not
States Of America tolerable in unselected NSCLC patients as measured
by both DLTs and achievable dose intensity. IMC-A12
Background: Crosstalk between the IGF-1R and at 5mg/kg q7 was tolerable per DLT but also required
the Epidermal Growth Factor Receptor (EGFR) is a dose reductions in a signiÀcant proportion of patients.
potential mechanism of resistance to EGFR Tyrosine Progression to the planned randomized phase II
Kinase Inhibitors (TKIs). This study evaluated study in unselected patients has been cancelled. The
the combination of erlotinib with an anti-IGF-1R combination may be beneÀcial to EGFR mutant
recombinant fully humanized IgG1 monoclonal patients but randomized data in a mutant speciÀc
antibody (IMC-A12) to assess safety and efÀcacy. population would be required to conÀrm this.
Methods: Eligibility included: PS 0-2, metastatic Keywords: EGFR, IGFR, NSCLC
NSCLC, age >18, adequate organ function. Initial
safety-lead and drop-down cohorts used erlotinib
150mg QD with IMC-A12 6 or 5mg/kg days 1, Medical Oncology II Wednesday, 6 July 2011 14:30-16:00
8, 15, 22 in q28 day cycles (Cohorts 1 and 2).
Tolerability required completion of 1 cycle in 8 of MO15.03 EXPLORATORY BIOMARKER
10 patients without dose limiting toxicity (DLT). ANALYSES FROM A PLACEBO-
Emerging PK data led to a third cohort (3+3 design) CONTROLLED PHASE II STUDY
at IMC-A12 at 15mg/kg day 1 in q21 day cycles. (OAM4558G) OF METMAB IN
Dose limiting toxicity (DLT; CTC v. 3.0) was any COMBINATION WITH ERLOTINIB IN
non-hematological toxicity => grade 3 within cycle PATIENTS WITH ADVANCED NON-
1, excluding rash, diarrhea, nausea or hyperglycemia SMALL-CELL LUNG CANCER (NSCLC)
if controllable within 7 days of holding drug and no Wei Yu1, Ajay Pandita1, Elicia Penuel1, Rajiv Raja1,
dose reductions occurred, or treatment delay of => 7 Jiping Zha1, Sankar Mohan1, Rupal Desai1, Rajesh
days due to drug-related toxicity. D. Patel1, Ling Fu1, An Do1, Jason Mango1, Vaishali
Results: 18 patients entered the study (6 at 6mg/ Parab1, Marina Lipkind1, Jenny Huang1, Mirella
kg, 8 at 5mg/kg, 4 at 15mg/kg at 6mg/kg), with Lazarov1, Vanitha Ramakrishnan1, Lukas Amler2,
median age 65. PS 0/1 = 5/13. 4 patients at 6mg/kg Premal Patel1, Amy Peterson1, Robert Yauch3
1
q7 experienced DLTs (3 x grade 3 fatigue, 1 x grade Genentech/United States Of America, 2Genentech,
3 rash not resolving within 7 days), 5 requiring dose Genentech/United States Of America, 3Oncology,
modiÀcation or cessation in cycle 1, with mean dose Genentech/United States Of America
intensity across all cycles of IMC-A12 60%, erlotinib
58%. At 5mg/kg, 1 patient experienced DLT (1 x Background: Met is associated with a poor outcome
grade 3 rash not resolving within 7 days), 3 requiring in many cancers, including NSCLC. MetMAb is a
dose modiÀcation or cessation in cycle 1, with mean monovalent anti-cMet receptor antibody that inhibits
HGF-mediated activation of c-Met. In a Phase II Medical Oncology II Wednesday, 6 July 2011 14:30-16:00
study of MetMAb in combination with erlotinib
in patients with advanced NSCLC (n=128), an OS MO15.04 BIOMARKER ANALYSIS OF
beneÀt was demonstrated in Met Dx + patients A RANDOMIZED, DOUBLE-BLIND,
(n=65, deÀned as ³50% of tumor cells staining 2+ or PLACEBO-CONTROLLED PHASE 2
3+ intensity for c-Met by IHC), HR=0.37, p=0.002. STUDY OF ERLOTINIB WITH AND
Methods: Archival tumor tissue specimens were WITHOUT ENTINOSTAT, A CLASS
analyzed using FISH, qRT-PCR or various mutation 1 ISOFORM SELECTIVE HISTONE
detection techniques to explore tumor biomarkers DEACETYLASE INHIBITOR (HDAC)
related to c-Met and/or EGFR signalling. Analyses IN PATIENTS WITH ADVANCED NON-
with outcome were carried out independently of Met SMALL CELL LUNG CANCER (NSCLC;
Dx status. ENCORE-401)
Results: In general, baseline characteristics were Robert Jotte1, Samir Witta2, Marcus Neubauer3,
comparable for patients with evaluable tumor or Alexander Spira4, Robert Ruxer5, Kartik Konduri6,
plasma specimens. MET median mean copy number Fred R. Hirsch7
1
was 3.44 copies/cell (range 1.6–25.0 [96 evaluable Lung Cancer, Lung Cancer Clinic Of The Rockies/
specimens]; true gene ampliÀcation was detected United States Of America, 2Mountain Blue Cancer
in 8%. There was a non-signiÀcant trend toward Center/United States Of America, 3Kansas City
improved OS when MET FISH-positivity was Cancer Center/United States Of America, 4Fairfax
deÀned as 5 copies/cell (HR=0.47, p=0.19), but Northern Va/United States Of America, 5Texas
not at lower thresholds (ie. 4 copies; HR=0.89, Oncology/United States Of America, 6Texas
p=0.82). An OS HR of 1.37 (95% CI: 0.43–4.36) Oncology Pa/United States Of America, 7Cancer
was observed in 23 patients with both MET and Center, University Of Colorado/United States Of
EGFR FISH copy number gains (high polysomy or America
ampliÀcation). EGFR mutations were detected in
13 of 112 evaluable specimens (12%); mutations Background: Epigenetic processes have been shown
were detected in 6 of 7 patients with objective to contribute to de novo and reversible acquired
responses. KRAS mutations were detected in 26 drug resistance to EGFR-TKI. We have previously
of 112 evaluable specimens (23%); status did not presented that exploratory biomarker analysis of
affect OS on MetMAb. High expression levels patient samples from ENCORE-401, a randomized,
(median) of MET, HGF, EGFR, AREG or EREG placebo controlled phase 2 clinical trial with the
mRNA were not an independent predictor of OS class 1 selective HDACi, entinostat in combination
beneÀt. However, the OS beneÀt in Met Dx+ patients with the EGFR-TKI erlotinib (ENCORE-401)
(n=32) was not as robust (HR=0.69, p=0.48) in the identiÀed a subset of patients expressing high
patient population for whom qRT-PCR data was e-cadherin levels who derived greater clinical beneÀt
available (n=67). In addition, a non-signiÀcant with the entinostat combination vs erlotinib alone;
trend for improved OS with MetMAb was observed PFS (3.7 mos vs 1.9 mos; HR 0.55 (95% CI 0.22-
in patients with low baseline plasma HGF levels 1.37 p=0.19))and OS (9.4 mos vs 5.4 mos; HR 0.36
(HR=0.46, p=0.11). (95% CI 0.14-0.94 p=0.03))1. Completed biomarker
Conclusion: This study provides further support characterization of this study will be presented.
for c-Met IHC as the most robust, sensitive and Methods: 132 patients with previously treated
independent predictor of OS beneÀt from MetMAb. stage IIIB/IV NSCLC, no-prior erlotinib, PS < 2,
Analysis of biomarkers is warranted in future clinical and tissue available for biomarker assessment, were
studies. randomized (1:1) to erlotinib 150 mg PO QD days
Keywords: NSCLC, cMet, MetMAb, erlotinib 1-28 plus entinostat 10mg PO or placebo days 1 and
15 Q 28 days [ = 1 cycle] for a maximum of 6 cycles.
Biomarker analysis completed to date includes
E-cadherin IHC, EGFR FISH, EGFR sequencing,
KRAS sequencing, and Veristrat serum proteomic
proÀling.
Results: Updated biomarker results are as follows:
University/United States Of America, 3Oncologie

Médicale, Institut Gustave Roussy/France, 4Medical
Division, Ospedale Santa Maria Della Misericordia/
Italy, 5Medical Oncology, University Of Colorado
Anschutz Medical Campus/United States Of America,
6
Instituto Nacional De Enfermedades Neoplasicas/
Peru, 7Medical Oncology, Yale University School
Of Medicine/United States Of America, 8University
Medical Center, Ulm/Germany, 9Merck & Co., Inc/
United States Of America, 10Medical Oncology,
Catalan Institute Of Oncology/Spain
For e-cadherin, previously stained slides were re-
scored using a semi-quantitative hybrid scoring Background: Mutations in KRAS are present in
algorithm with a strong association between scoring ~25% of patients with advanced NSCLC. Preclinical
methods (p<0.0001). Patients classiÀed as e-cadherinHI data support the role of mammalian target of
by either scoring system derived greater clinical rapamycin (mTOR) in KRAS mediated oncogenesis.
beneÀt from entinostat plus erlotinib vs erlotinib Ridaforolimus is an inhibitor of mTOR which has
alone. A full characterization of the e-cadherin high been shown to have efÀcacy in advanced endometrial
and low subsets by EGFR mutation, EGFR copy cancer and soft tissue sarcoma. Everolimus, another
number, KRAS status, and Veristrat will be presented. mTOR inhibitor was previously evaluated in
Conclusion: E-cadherin may deÀne a subset of unselected patients with advanced NSCLC and found
patients for whom epigenetic modulation with an to have a response rate <5%. We hypothesized that
HDACi can provide clinical beneÀt with EGFR- by enrichment for patients with NSCLC and KRAS
TKI. Follow-up studies should be carried out mutations, treatment with ridaforolimus would be
to conÀrm these promising Àndings in selected associated with higher response rates and prolonged
patient populations deÀned by sensitivity to stable disease relative to available standard
EGFRi. In addition, recently completed biomarker treatments for NSCLC.
characterization of samples from these patients Methods: Patients with stage IIIB/IV non-small cell
indicates that EGFR copy number and EGFR lung cancer who had received prior chemotherapy
mutation status be evaluated in follow on studies for NSCLC were eligible. All patients initiated
along with e-cadherin levels to conÀrm the role of treatment with oral ridaforolimus 40 mg once
epithelial mesenchymal tumor phenotype as the daily on a 5 day per week schedule. After 8 weeks,
determinant of clinical beneÀt to the entinostat – patients had response assessment. Patients with
erlotinib combination. >30% tumor shrinkage remained on ridaforolimus,
Keywords: EGFR-TKI, histone deacetylase, patients with >20% tumor growth came off study.
Biomarkers, epigenetics Patients with stable disease were randomized 1:1 to
placebo or ridaforolimus. The primary endpoint of
the study was progression-free survival (PFS) during
Medical Oncology II Wednesday, 6 July 2011 14:30-16:00 the randomization. Here, we report the results of a
planned interim analysis of 8 week progression-free
MO15.06 A RANDOMIZED survival and radiographic response after initial 8
DISCONTINUATION PHASE II TRIAL OF weeks of treatment.
RIDAFOROLIMUS IN NON-SMALL CELL Results: 72 patients were enrolled at the time of
LUNG CANCER (NSCLC) PATIENTS the interim analysis (36 women, median age 58
WITH KRAS MUTATIONS [range 28-85]). All patients had KRAS mutations.
Gregory J. Riely1, Julie Brahmer2, David Planchard3, Data from 61 patients was available for efÀcacy
Lucio Crino4, Robert C. Doebele5, Luis Maz analysis. 29/61 (44%, 95% CI 36-60%) patients were
Lopez6, Scott N. Gettinger7, Christian Schumann8, progression-free at 8 weeks. The overall response
Shanghong Guan9, B Atkins9, S Ebbinghaus9, Rafael rate (CR+PR) at 8 weeks was 1/61 (2%, 95% CI
Rosell10 0-10%). 14/61 patients discontinued study treatment
1
Medicine, Memorial Sloan-Kettering Cancer prior to 8 weeks. Median progression-free survival
Center/United States Of America, 2Johns Hopkins was < 2 months. The most common grade 3 adverse
events were fatigue (10%), diarrhea (5%), and (11.1%). The majority of histological diagnoses
mucositis (8%). were adenocarcinomas (14 cases; 77.8%) and
Conclusion: Due to lack of efÀcacy meeting pre- squamous cell carcinomas were followed (3 cases;
deÀned thresholds, this study was discontinued. 16.7%). However, there was no signiÀcant difference
Ridaforolimus at this dose and schedule does not according to KRAS mutation status because of small
have sufÀcient activity in KRAS mutant NSCLC to population of mutation group. The median PFS time
warrant further study. Multicenter studies enrolling of total 10 patients with KRAS mutation treated
only patients with KRAS mutant NSCLC are with EGFR-TKIs were 2.1 months. Interestingly,
feasible. 3 patients had both mutations of EGFR and KRAS
Keywords: Kras, ras, mammalian target of unlike previous studies, 2 patients who treated with
rapamycin, Non-small cell lung cancer EGFR-TKIs showed favorable response.
Conclusion: The data indicate that KRAS mutation
is less frequent in Asian than Caucasian patients.
Medical Oncology II Wednesday, 6 July 2011 14:30-16:00 Although it is suggested that EGFR and KRAS
mutations occur in mutually exclusive, very few of
MO15.07 CLINICAL FEATURES OF the patients with KRAS mutation showed also EGFR
PATIENTS WITH NON SMALL CELL mutation and relatively favorable response to EGFR-
LUNG CANCER WHO HARBOR KRAS TKIs. Additional large scale prospective studies are
MUTATION: A SINGLE CENTER needed in order to validate the clinical signiÀcance
EXPERIENCE IN KOREA of KRAS mutation.
Hee Joung Kim1, Sun Jong Kim1, Gwang Ha Yoo1, Keywords: KRAS mutation, Non small cell lung
Won Dong Kim1, Seo Young Oh2, Wan Seop Kim2, cancer
Kye Young Lee1
1
Internal Medicine, Konkuk University Hospital/
Korea, Democratic People’s Republic Of, Medical Oncology II Wednesday, 6 July 2011 14:30-16:00
2
Pathology, Konkuk University School Of Medicine/
Korea, Democratic People’s Republic Of MO15.08 PHASE II STUDY OF
REOVIRUS WITH PACLITAXEL (P) AND
Background: It is currently known that KRAS CARBOPLATIN (C) IN PATIENTS WITH
mutation is a poor predictive biomarker to METASTATIC NON-SMALL CELL LUNG
chemotherapy and epidermal growth factor receptor CANCER (NSCLC) WHO HAVE KRAS OR
(EGFR) kinase inhibitors (geÀtinib and erlotinib) in EGFR-ACTIVATED TUMORS.
patients with non–small cell lung cancer (NSCLC). Miguel A. Villalona-Calero1, Elaine Lam1, Gregory
This study aims to deÀne the incidence of KRAS Otterson1, Weiqiang Zhao2, Kavitha Donthireddy1,
mutations and evaluate clinical features and Jennifer Thurmond1, Erin Hade3, Justin Pennington1,
outcome of patients with NSCLC who harbor KRAS Karl Mettinger4, Matt Coffey4
1
mutation. Medical Oncology, The Ohio State University/
Methods: Two hundred and twenty-seven patients United States Of America, 2Pathology, The Ohio
with NSCLC who performed KRAS mutation State University/United States Of America, 3Center
analysis by pyrosequencing were included in this For Statistics, The Ohio State University/United
retrospective study and their clinical characteristics States Of America, 4Oncolytics/Canada
were analyzed according to KRAS mutation status of
their tumors. Background: Reovirus is a naturally occurring virus
Results: KRAS mutation was found in 18 (7.9%) which preferentially infects and causes oncolysis in
of 227 patients and which was less prevalent than tumor cells with a Ras-activated pathway. Cells that
in western countries. Ten mutations (55.6%) were express high levels of EGFR are also susceptible to
point mutation at codon 12 (GGT), 6 mutations reovirus infection. In preclinical studies, reovirus
(33.3%) were point mutation at codon 61 (CAA), induces host immunity and cell cycle arrest, acting
and 2 mutations (11.1%) were found at codon 13 synergistically with standard cytotoxic agents.
(GGC) in exon 2. Median age of 18 patients with Its adverse effects are mild to moderate Áu-like
KRAS mutation was 66.5 years (range 43-85 years). symptoms. We have hypothesized those patients with
There were 15 males (88.3%) and 2 never-smokers EGFR-mutated, EGFR-ampliÀed, or Kras-mutated
NSCLC should all have a common downstream And Oncology, Medical College Of Wisconsin/United
activated Ras pathway and should be susceptible to States Of America, 3Radiation Oncology, Medical
treatment with reovirus College Of Wisconsin/United States Of America
Methods: We designed a Fleming, single-arm, phase
II study to evaluate the objective response rate and Background: In the era of PET scan, the incidence
6-month progression-free survival of reovirus in of oligometastatic non-small cell lung cancer
combination with P and C as Àrst-line therapy in patients (NSCLC) has increased. Even though, chemotherapy
with metastatic NSCLC. Eligible patients had ECOG remains the mainstay of therapy for metastatic
PS 0-2, adequate organ function, no prior systemic NSCLC, the pattern-of-failure after Àrst-line
chemotherapy for metastatic disease, and tumors with chemotherapy needs to be deÀned to determine if
the speciÀed genotype, as per CLIA certiÀed testing. local ablative therapy can be pursued to a limited
Adjuvant chemotherapy, or erlotinib/geÀtinib for pts number of metastatic sites.
with EGFR mutant tumors was permitted. Methods: We performed a retrospective review on
Results: 17 patients have received Reovirus (3 x consecutive patients with advanced NCSLC treated
1010 TCID50) intravenously daily on days 1-5, in at the Medical College of Wisconsin, Milwaukee
combination with C and P. Initial doses used were between 2007 and 2010. All sites of disease at
C AUC 6 on day 1, and P 200 mg/m2,on day 1 of presentation and at subsequent follow-ups after Àrst-
each 21-day cycle. Due to exacerbation of prior line chemotherapy were abstracted, including the
gastrointestinal conditions and febrile neutropenia number of organs involved and individual metastatic
(1 each) in Àrst two pts, doses were reduced to P 175 sites. Patients were classiÀed as oligometastatic
mg/m m2 and C AUC 5. Overall, 73 cycles (per pt if they had 3 metastatic sites (not including the
median 4, range 1-8) have been administered. Grade primary lung tumor).
3-4 adverse events included grade 4 neutropenia Results: A total of 116 patients were analyzed:
(4 pts), anemia,fatigue, electrolyte abnormalites, median age 61.9 years (28-88 years) and males 66
diarrhea, (2 pts), and single cases of nausea, (57%). Tumor histology: 63% adenocarcinoma, 18%
vomiting, and sepsis. Molecular tumor demographics squamous cell carcinoma, 14% poorly differentiated
included: 8 Kras mutant, 2 EGFR mutant, 7 EGFR carcinoma, 3% bronchoalveolar carcinoma and 2%
ampliÀed. Response evaluation to date in 16 pts adenosquamous carcinoma. First-line chemotherapy:
showed 5 PR, 9 SD, 2 PD. 68% platinum-doublet, 28% platinum-doublet
Conclusion: Reovirus can be administered safely with bevacizumab, 2% single-agent non-platinum
in combination with C/P and patient selection is chemotherapy and 2% erlotinib. At presentation,
feasible in the clinical setting. Clinical efÀcacy and 48 patients (41%) had oligometastatic NSCLC. At
best setting for subsequent randomized evaluation last follow-up, 87 (75%) had tumor progression
will be assessed at the completion of the trial. after Àrst-line chemotherapy, of which 84 had
well documented sites of progression. Tumor
A revised/updated abstract may be included in progression occurred only in existing disease sites
the Late Breaking Abstract Supplement, available (primary tumor and existing metastatic sites) without
at the 14th World Conference on Lung Cancer. development of new metastatic lesions in 46%.
Medical Oncology II Wednesday, 6 July 2011 14:30-16:00
MO15.10 PREVALENCE OF
OLIGOMETASTATIC NON-SMALL CELL
LUNG CANCER AND PATTERN-OF-
FAILURE ANALYSIS AFTER FIRST-LINE
CHEMOTHERAPY: A POTENTIAL ROLE
FOR CONSOLIDATIVE RADIOTHERAPY.
Ghazaleh Bahrami1, Patrick Foy2, Kiran Devisetty3,
Nicholas Choong2
1
Hematology/oncology, Medical College Of
Wisconisin/United States Of America, 2Hematology
Conclusion: In metastatic NSCLC, we identiÀed Secondary endpoints: Progression-Free survival

that progression after Àrst-line chemotherapy (PFS), dyspnoea (CTCAE3.0), dysphagia, patterns
occurred commonly in the primary tumor or existing of recurrence. The trial was approved by the required
metastatic sites. This supports the concept that there authorities and all patients gave informed consent.
is a subset of patients with limited metastatic disease The study is listed in clinicaltrials.gov number
that may beneÀt from local ablative therapy. NCT01282450.
Keywords: Non-small cell lung cancer, Metastasis, Results: 39 patients (23 males and 16 females,
Sites of disease mean age 62.9 ± 9.7 years, range 44-82) were
included from 27-07-2006 till 14-11-2010.
Performance status: 0: 3 patients, 1: 33, 2: 3.
Medical Oncology II Wednesday, 6 July 2011 14:30-16:00 Histologies: Squamous cell carcinoma: 10 patients,
adenocarcinoma: 13, large cell: 10, NSCLC not
MO15.11 RADICAL TREATMENT speciÀed: 6. T-stage: T0: 1 patient, T1: 7, T2:11,
OF NON-SMALL CELL LUNG T3: 8, T4:12. N-stage: N0: 12 patients, N1: 2, N2:
CANCER (NSCLC) PATIENTS WITH 17, N3: 8. “Local stage”: I: 1 patient, II: 9, IIIA: 10,
SYNCHRONOUS OLIGOMETASTASES: IIIB: 19. 33 patients had a single distant metastasis,
RESULTS OF A PROSPECTIVE PHASE II 2 patients 2, 3 patients 3 and 1 patient 4 metastases.
TRIAL (NCT01282450) Location metastases: Brain: 15, bone: 10, pleura:
Dirk De Ruysscher1, Bart Reymen2, Angela Van 3, adrenal gland: 4, extra-thoracic lymph nodes:
Baardwijk2, Rinus Wanders2, Jacques Borger2, Anne- 3, ovary: 1, muscle: 2, contra-lateral lung: 1. 35
Marie Dingemans3, Gerben Bootsma4, Cordula patients received chemotherapy; 11 sequential
Pitz5, R Lunde5, Wiel Geraedts6, Brigitta Baumert7, chemo-radiation (cisplatin-gemcitabine), 24
Philippe Lambin1 concurrent chemo-radiation (cisplatin-etoposide or
1
Department Of Radiation Oncology (MAASTRO), cisplatin-vinorelbine). All patients received 3 cycles
Grow, Maastricht University Medical Centre/ of chemotherapy. Mean radiation dose to the primary
Netherlands, 2Radiation Oncology, MAASTRO tumour and hilar or mediastinal lymph nodes: 65.6
Clinic/Netherlands, 3Pulmonology, Maastricht ± 6.5 Gy/ 33 ± 12.3 days; radiation dose to brain
University Medical Center/Netherlands, metastases: 20 Gy/ 1 fraction (stereotactic), mean
4
Pulmonology, Atrium Mc Parkstad/Netherlands, dose to other than brain metastases: 63.7 ± 6.9 Gy.
5
Pulmonology, Laurentius Ziekenhuis/Netherlands, Surgery: adrenal metastasis: 3/3 patients, ovary 1/1,
6
Pulmonology, Orbis Mc/Netherlands, 7Department contralateral lung: 1/1. Median OS: 13 months (95
Of Radiation Oncology (MAASTRO Clinic), Grow - % CI: 5.7-20.3), 1-year OS: 53 %, 2-year OS: 17
School For Oncology And Developmental Biology, %. Median PFS: 10 months (95 % CI: 6.8-13.4),
Maastricht University Medical Centre/Netherlands 1-year PFS: 45 %, 2-year PFS: 10 %. Location of
Àrst tumour progression: in radiation or surgical
Background: Mainly retrospective series suggest Àeld: none; brain: 52 %, bone: 33 %, skin: 5 %,
that a subgroup of patients with NSCLC with less mediastinal lymph nodes: 5 %, liver: 5 %, Toxicity:
than 5 metastatic lesions may experience long-term Oesophagus: G3: 15 %, no G4-5; dyspnoea: G2: 5
survival when all macroscopic tumour sites are %, no G3 or more.
treated radically. We therefore started a prospective Conclusion: In this prospective series, exclusively
single-arm phase II trial to investigate the outcome consisting of NSCLC patients with oligometastatic
of patients with synchronous oligometastatic disease disease at presentation and with 75 % of them having
when treated radically. “local stage III” disease, radical treatment may
Methods: Main inclusion criteria: Pathological improve PFS but long-term survival remains very
proven NSCLC; UICC 6th edition stage IV; low, mostly due to brain (52 %) and bone (33 %)
oligometastases (< 5) at primary diagnosis, which metastases. Improved systemic control is needed and
are amendable for radical local treatment (i.e. PCI may be worth investigating.
surgery or radiotherapy to a biological equivalent Keywords: Non-small cell lung cancer,
of at least 60 Gy/ 30 fractions), performance status Oligometastases, combined modality treatment,
0-2. Main exclusion criteria: stage I-III, except advanced disease
for T4 because of pleural metastases without
effusion. Primary endpoint: Overall survival (OS).
Medical Oncology II Wednesday, 6 July 2011 14:30-16:00 radiotherapy (CT then CTRT) to residual thoracic
disease; 13 underwent concurrent chemoradiation
MO15.12 DEFINITIVE DOSE (CTRT) followed by systemic chemotherapy; and 11
THORACIC RADIOTHERAPY IN had multiple chemotherapeutic regimens followed by
OLIGOMETASTATIC STAGE IV NON- radiotherapy (CT then RT) at time of progression of
SMALL CELL LUNG intrathoracic disease. The table summarizes median
Eric P. Xanthopoulos1, Annemarie T. Fernandes1, survival from diagnosis in these patients both by site
Sandra GrifÀth2, Smith Apisarnthanarax1, John of metastases at diagnosis and treatment approach.
P. Christodouleas1, Beth Eaby-Sandy3, Corey J. Univariate analyses identiÀed no signiÀcant
Langer3, Tracey Evans3, James Stevenson3, Stephen predictors of survival across race, sex, N-stage at
Hahn1, Ramesh Rengan1 diagnosis, site of metastatic disease at diagnosis,
1
Radiation Oncology, Abramson Cancer Center, tumor histology, treatment dose and treatment type.
University Of Pennsylvania/United States
Of America, 2Department Of Biostatistics & Survival from Diagnosis by Metastases Survival from Diagnosis by Treatment
Epidemiology, University Of Pennsylvania/United Metastases N Median

Survival
95% CI Treatment N Median 95% CI
Survival
States Of America, 3Hematology/oncology, Abramson M1 nodes only 4 38 m >10 m CT then CTRT 4 44 m >17 m
Cancer Center, University Of Pennsylvania/United Contralateral 2 Last seen at CTRT 13 19 m 12 – 40 m
lung only 28 & 32 m
States Of America
Brain only 8 17 m >11 m CT then RT 11 13 m >10 m
Bone only 10 14 m 5 – 44 m
Background: Stage IV NSCLC patients have less Multi-organ 4 12 m >6 m
than a one year median survival from diagnosis,
usually due to distant progression. Currently, the Conclusion: Median survival of these select patients
role of deÀnitive thoracic radiotherapy in these with metastatic NSCLC at diagnosis treated with
patients is controversial. This study reports treatment deÀnitive thoracic radiation compares favorably
parameters and associated survival outcomes to those with more advanced stage IV disease at
in patients receiving deÀnitive dose thoracic diagnosis. Prospective trials are needed to determine
radiotherapy for stage IV disease. if these outcomes are result of an aggressive
Methods: An institutional database was reviewed treatment approach or selection bias.
to identify patients that (1) presented with Stage Keywords: oligometastatic, deÀnitive dose
IV NSCLC at initial tumor diagnosis, who were radiotherapy, stage IV, Non-small cell lung cancer
(2) subsequently prescribed at least 50 Gy for their
thoracic disease. The Kaplan-Meier method was
used to estimate survival outcomes. The relationship Medical Oncology II Wednesday, 6 July 2011 14:30-16:00
between parameters and survival were assessed using
log rank tests and Cox models. MO15.13 OLIGOMETASTASES IN NSCLC
Results: Between January 2003 and July 2010, the PATIENTS: IS SURGERY JUSTIFIED?
University of Pennsylvania treated 28 oligometastic Oleg Pikin, Konstantin Kolbanov, Vladimir Glushko,
stage 4 NSCLC patients with thoracic radiotherapy Ali Amiraliev, Dmitriy Vursol, Artem Kartoveshenko
to 50+ Gy. 11 patients were male and 13 non- Thoracic Surgery, P.a.hertsen Moscow Research
caucasian. They had a median age of 57.5 y and Institute Of Oncology/Russian Federation
treatment dose of 66 Gy. Of 25 with known nodal
status, 3 had N1, 9 N2 and 9 N3 disease. All patients Background: The prognosis in patients with distant
had a Karnofsky Performance Status of 80+ at metastases of NSCLC is generally poor. Surgical
diagnosis. And they each had fewer than Àve sites resection of isolated distant metastases in NSCLC
of extrathoracic or contralateral lung metastases. patients is not widely accepted and chemotherapy
Across all patients, the median survival time was 19 is usually administered. The study was aimed to
months (95% CI 13 – 40 months) from diagnosis evaluate the long-term results and prognosis after
and 15 months (95% CI 7 – 37 months) from start surgical resection of oligometastases in NSCLC
of deÀnitive dose radiotherapy. The median lag patients.
between diagnosis and start of radiotherapy was 5 Methods: 63 patients with isolated distant
months. Patients were treated as follows: 4 received metastases of NSCLC were operated on in our
systemic chemotherapy followed by consolidative clinic from 1998 to 2009. Solitary brain metastasis
was diagnosed in 32, pleural metastases – in 15, Session MO16: Biomarkers VII
adrenal metastases – in 11, renal metastases – in
2, chest wall – in 2 and mesentery sigmoid colon Wednesday, 6 July 2011
metastasis – in one patient. Synchronous metastases
were detected in 42 (66,7%) (brain – 18, pleura
- 15, adrenal – 7, others – 2), metachronous – in Biomarkers VII Wednesday, 6 July 2011 14:30-16:00
21 (33,3%) patients. The primary lung cancer was
completely resected in all cases. Surgery included MO16.01 EVALUATION OF NSCLC
pneumonectomy – in 12 (19,0%), lobectomy – in 48 DIAGNOSTIC EFFICIENCY OF DNA
(76,2%) and wedge resection – in 3 (4,8%) patients. METHYLATION BIOMARKERS IN
Simultaneous lung resection and metastatic lesion BRONCHIAL WASHINGS
removal was performed in 24 (38,1%) patients Georgios Nikolaidis1, Olaide Y. Raji1, Julie Bryan1,
(brain – 1, pleura – 15, adrenal – 7, chest wall – Jennie Goggin1, Stephanie Unsworth1, Tom Giles2,
2). In patients with pleural spread lung resection John K. Field1, TriantaÀllos Liloglou1
1
and pleuroectomy was followed by intraoperative Molecular & Clinical Cancer Medicine, University
photodynamic therapy. Of Liverpool/United Kingdom, 2Royal Liverpool
Results: Postoperative complications were Broadgreen University Hospital Trust/United
registered in 10 (15,9%) patients, mortality rate was Kingdom
4,7%. Median survival after pulmonary resection
and removal of brain metastasis was 16,8 months, Background: Lung cancer is the most lethal
after lung resection with pleuroectomy – 14,2 malignancy worldwide and late diagnosis is a
months, adrenalectomy – 10,6 months. Patients signiÀcant reason for this. The Liverpool Lung
after nephrectomy (2), chest wall resection (2) Project (LLP) encompasses retrospective and
and sigmoid colon resection survived 14, 18, 6, prospective studies aiming to the reduction of lung
14 and 36 months respectively. One and 3-year cancer mortality through the development of a
survival after removal of brain, pleural and adrenal molecular-epidemiological risk assessment model
metastases was 58,0%, 52,0%, 32,6% and 21,8%, which will facilitate early detection of lung cancer
20,0%, 0% respectively. Two patients (6,2%) with and thus early intervention. DNA methylation is
solitary brain metastasis and T1N0 primary lung an epigenetic modiÀcation with key role in gene
cancer survived more than 5 years without evidence transcriptional control, embryonic development,
of recurrence. One patient after pleuroectomy imprinting and cancer. A large number of studies
and PDT is alive 62 months with recurrence. in lung cancer have revealed abnormal DNA
Synchronous or metachronous detection of distant methylation patterns involving a variety of genes.
lung cancer metastases does not inÁuence the The aim of this study is to evaluate a number of
survival. DNA-methylation biomarkers in bronchial washings
Conclusion: Aggressive surgery in patients with for their efÀciency in assisting diagnosis of new lung
oligometastatic NSCLC is justiÀed in selected cancer cases.
patients especially with solitary brain metastasis Methods: Targets from previous high throughput
and limited pleural dissemination. Surgical approaches were validated in an independent set of
resection permits to improve long-term results and 48 non-small cell lung cancer samples and paired
quality of life in patients with isolated distant lung normal tissues using Pyrosequencing. Quantitative
cancer metastases. methylation-speciÀc PCR (qMSP) assays were
subsequently for the successful 11 candidates. These
were evaluated in a training set of 408 bronchial
washing (BW) samples (194 Cases and 214 Controls).
Multifactor Dimensionality Reduction (MDR) was
used to select the best subset of the markers with
good discrimination. The diagnostic efÀciency of this
panel was evaluated in an independent validation set
of 248 BW samples (139 cases and 109 controls). A
logit method was used to obtain the sensitivity and
speciÀcity of the six markers
Results: Pyrosequencing methylation analysis was thought to make little difference in terms of
conÀrmed signiÀcant hypermethylation in the patient response to therapy. However, increasing
NSCLC tissue for the following promoters: RASSF1, efforts toward developing new molecularly targeted
p16, WT1, CYGB, RARơ, CDH13, DAPK, p73, agents, which tend to have signiÀcant activity in
TMEFF2, TERT and MGMT. Analysis in the certain groups of patients but not others, has driven
training BW set demonstrated signiÀcant differences a need to identify biomarkers that can distinguish
in the detected hypermethylation frequency in cases clinically relevant biological subsets of NSCLC. We
over controls for RASSF1, p16, WT1, CYGB, have shown that NSCLC can be differentiated into
RARơ and TERT. This panel of six markers was epithelial-like (EL) and mesenchmyal-like (ML)
used to screen independent BW samples in a tumors based on gene expression and biomarkers
validation set. The overall performance analysis of of this epithelial vs. mesenchymal state have been
the six biomarkers in addition to cytology revealed associated with erlotinib activity in vitro and in the
that there was no detection bias in different groups clinic. Increasing evidence suggests that changes in
of gender, age or smoking status. LogicF analysis DNA methylation may accompany the phenotypic
demonstrated that the top Àve predictors were WT1, transition from an epithelial to a mesenchymal
cytology, RASSF1, TERT and p16. While cytology state in lung cancer cells. It follows that speciÀc
alone provides a 49.5% sensitivity, 99.5% speciÀcity, methylation patterns may reÁect the underlying
the use of Àve classiÀers provided 76.2% sensitivity, biology and pathogenesis of a given tumor. Thus
92.3% speciÀcity (AUC=0.89). knowledge of the methylation proÀle of tumors
Conclusion: DNA methylation can be detected may enable clinical decision-making. To further
in bronchial washings with high speciÀcity. It is explore the question of whether phenotypic subsets
estimated that a panel of 10-12 markers would be of NSCLC can be deÀned by their DNA methylation
sufÀcient to increase diagnostic sensitivity to >90% patterns, we developed an integrated genomics
at >95% speciÀcity. approach combining gene expression proÀling and
Keywords: molecular diagnostics, epigenetic methylated DNA immunoprecipitation (meDIP).
biomarkers, bronchial washings Methods: Microarray expression proÀling, treatment
with 5-aza-2’-deoxycytidine, microtiter assays for
in vitro response to erlotinib, meDIP-chip, QPCR,
Biomarkers VII Wednesday, 6 July 2011 14:30-16:00 QMSP, bisulÀte sequencing, pyrosequencing.
Results: Using a supervised analysis strategy based
MO16.02 DNA METHYLATION on in vitro drug response to erlotinib and EL/ML
PROFILING DEFINES CLINICALLY status for both gene expression and meDIP-chip,
RELEVANT BIOLOGICAL SUBSETS OF we identiÀed >200 candidate markers that show
NSCLC potential phenotypic speciÀcity – i.e. induced or
Kim Walter1, Tom Januario1, Thomas Holcomb1, enriched. 62 of these markers were further analyzed
Richard Bourgon2, Srinka Ghosh2, Zemin Zhang2, by sodium bisulÀte sequencing with 25-75%
Robert Soriano3, Jeremy Stinson3, Leo Iniguez4, showing phenotype speciÀc methylation patterns,
Howard Stern5, Zora Modrusan3, Somasekar depending on the discovery strategy. We developed
Seshagiri3, Garret Hampton1, Lukas Amler1, Robert quantitative methylation speciÀc PCR (QMSP)
Yauch1, David S. Shames1 assays on 14 markers and pyrosequencing assays for
1
Oncology Diagnostics, Genentech/United States another Àve. All of these markers were tested in a
Of America, 2Bioinformatics And Computational panel of NSCLC lines (N=90) with deÀned response
Biology, Genentech Inc/United States Of America, phenotypes to erlotinib. Both classes of methylation
3
Molecular Biology, Genentech Inc/United States Of biomarkers (methylated in either sensitive or
America, 4Advanced Research, Roche Nimblegen/ resistant subsets, but not both) showed a good
United States Of America, 5Pathology, Genentech correlation with erlotinib activity or EL/ML status.
Inc/United States Of America We further examined these markers in matched
NSCLC tumors, and all showed signiÀcant tumor
Background: Non-small cell lung cancer (NSCLC) speciÀcity. We are in the process of retrospectively
has multiple histological subtypes including testing these novel methylation biomarkers in
adenocarcinoma, squamous cell carcinoma, large clinical samples to determine their prognostic or
cell carcinoma, and others. Until recently, histology predictive signiÀcance.
Conclusion: These results validate our integrated represented samples collected at diagnosis, mid-way
genomics approach to identifying methylation through treatment, and at six months follow-up.
biomarkers that reÁect an underlying clinically NMR data was analyzed using the Chenomx NMR
relevant biology in lung cancer cells. This work Suite to ascertain metabolite identiÀcation and
provides proof-of-principle that DNA methylation concentrations. The Wiley-NIST database (2005)
proÀles could be used to inform clinical decision- was used be used for metabolite identiÀcation of
making in the context of early-phase targeted therapy GC-MS data. Multivariate statistical analysis was
trials. conducted using either in-house tools developed in R
Keywords: erlotinib, Predictive biomarkers, DNA or Umetrics software for analysis using unsupervised
methylation, EMT principal component analysis (PCA) or orthogonal
partial least squares discriminant analysis (OPLS-
DA). Model signiÀcance was assessed using a cross-
Biomarkers VII Wednesday, 6 July 2011 14:30-16:00 validated ANOVA.
Results: Median patient age=64 years (range 42-77),
MO16.03 A PILOT STUDY 60% were male, 29% were current smokers, 7 had
CHARACTERIZING PRE- AND POST- limited SCLC and 18 had NSCLC (stage I=1, II=3,
TREATMENT METABOLOMIC III=18). The median disease free survival=17 months
PROFILES OF LUNG CANCER PATIENTS (range 8-25) and 2 year overall survival=53%.
Desiree Hao1, M O. Safaraz2, Dafydd G. Bebb3, The metabolite proÀles were highly reÁective of
Camelia Lee4, Cynthia M. Card3, Marilyn David5, the binary survival (p<0.001 by NMR & GCMS),
Anthony M. Magliocco6, Aalim Weljie2 disease progression (NMR, p<0.001; GCMS,
1
Medical Oncology, Tom Baker Cancer Centre/ p=0.007) and stage (NMR, p=0.001). The NMR
Canada, 2Department Of Biologic Sciences, data was also reÁective of disease pathophysiology
University Of Calgary/Canada, 3Department Of (NSCLC vs SCLC) across all time points (p=0.003),
Medical Oncology, Tom Baker Cancer Centre/ and survival from the baseline samples alone
Canada, 4Department Of Nursing, Tom Baker (p=0.004). The NMR metabolomics data was weakly
Cancer Centre/Canada, 5Clinical Research Unit, reÁective of the difference between the various
Tom Baker Cancer Centre/Canada, 6Department Of time points (p=0.103), however a signiÀcant model
Pathology, Tom Baker Cancer Centre/Canada could be built distinguishing baseline from post-
treatment samples (p=0.0005), suggesting that the
Background: The metabolic proÀle of various samples during treatment represent an intermediate
cancerous /non-cancerous tissues can be correlated state. Multivariate regression of cotinine levels to
with cell growth and death, tumour type and stage. metabolite proÀles indicate that smoking status can
Changes in the serum metabolome not only reÁect be predicted in baseline samples, during treatment
the changes that are caused directly by the disease, and post-treatment.
but may also register host response to treatment. Conclusion: This exploratory study suggests that
Analysis of the metabolome in bioÁuids by nuclear there may be differences in the metabolomic proÀle
magnetic resonance (NMR) spectroscopy or gas between NSCLC vs. SCLC, smokers vs. non-
chromatograph mass spectrometry (GC-MS) can smokers and pre- and post-treatment. Intriguingly, it
simultaneously quantify hundreds of metabolites appears as though there remains a metabolic imprint
resulting in patterns that may deÀne tumour types, in the serum from baseline, through treatment and
stage, differences in physiologic state (smokers vs post-treatment which can predict survival, disease
non-smokers) and in turn, may correlate with clinical progression, and pathophysiology. Larger cohorts
outcomes. In this pilot study, we sought to evaluate will be needed to corroborate these Àndings and
the pre- and post-treatment metabolomic proÀles of determine whether metabolomic patterns could be
25 non-metastatic lung cancer patients undergoing useful as predictive or prognostic markers.
chemotherapy ± radiation. Keyword: metabolomics
Methods: Serum specimens were prospectively
collected prior to treatment, 5 times during treatment,
and in follow-up at 30 days, 3, 6 and 12 months post-
treatment. A subset of samples were characterized
using NMR spectroscopy and GC-MS. These
Biomarkers VII Wednesday, 6 July 2011 14:30-16:00 early stages and homogeneous treatments. We
realize during this side-biological project BIO-
MO16.04 PROGNOSTIC AND IFCT-00-02 II, high resolution micro-arrays with
PREDICTIVE VALUES OF HIGH- Agilent Technologies (44K) on 100 snap-frozen
RESOLUTION MOLECULAR DNA tumors. An univariate analysis (Fisher exact test)
MARKERS IN NON-SMALL CELL following by a multivariate analysis of biological
LUNG CANCERS (NSCLC) OF IFCT- markers and clinical data (age, gender, performans
00-02 TRIAL (PHASE III STUDY status, histological type, TNM classiÀcation, and
COMPARING A PREOPERATIVE AND modalities of surgery) could be helpful to deÀne
A PERIOPERATIVE CHEMOTHERAPY different prognosis/predictive sub-groups of
WITH TWO DIFFERENT NSCLC patients.
CHEMOTHERAPY REGIMENS IN Results: The population of the 100 selected frozen
RESECTABLE NSCLC). tumors appeared comparable to the whole group
Michele Beau-Faller1, Marc Guennegues2, Eric of patients (n= 528), excepted for histological
Guerin1, Wolfgang Raffelsberger3, Olivier Poch3, criteria with more adenocarcinomas in the CGH
Frédéric Le Prêtre4, Martin Figeac4, Laurence array group (p = 0.002) and for response rate with
Baudrin5, Florence De Fraipont6, Pierre Oudet1, an objective response rate at 38% in the CGH array
Gérard Zalcman7 group versus 56% in the other patients (p<0.001).
1
Chu De Strasbourg, Molecular Laboratory/France, Survival analysis is comparable between patients
2
Canceropole Grand-est/France, 3Bio-informatique included in the CGH array analysis and the others
Igbmc/France, 4Institut De Génomique/France, (Log Rank test at 0.6 for overall survival and at
5
Intergroupe Francophone De Cancérologie 0.8 for progression-free survival). Most frequent
Thoracique/France, 6Uf Cancérologie Biologique ampliÀcations are observed for chromosome arms
Et Biothérapie/France, 7Laboratoire De Génétique 5p, 1q, 8q, 7p, 3q, 14q and 20q and most frequent
Moléculaire/France deletions for chromosome arms 9p, 8p, 3p, 13q,
17p, 18q. No signiÀcantly different CGH array
Background: Early stages of non small-cell features were found when considering sex, tumor
lung cancer (NSCLC) could beneÀt of complete stage or chemotherapy treatment group. Squamous
resection, but Àve-years survival appeared less cell carcinoma displays a higher penetrance of
than 50%. Completely resected NSCLC patients gains of 3p arm (SOX2, FXR1, PI3KCA) and losses
frequently experience local or systemic relapse of 6p, with the strongest difference at the end of
of their disease. In order to decrease the risk of the chromosome 3q. Comparison of responders and
relapse, combination of surgery and chemotherapy non-responders points at the end of chromosome
could be proposed. The aim of the clinical trial 10q (MGMT, GLRX3, FGFR2) being deleted
IFCT-00-02 is to determine optimal treatment more frequently in responders. AmpliÀcation
schedules of stage I and II NSCLC patients. It is of chromosome 1q (RRM2B) and 7p (EGFR) is
a an open-labeled randomized phase III national associated with a lower PFS (14.7 vs 48.6 months,
multicentric trail in which two doublets of p< 0.005 and 15 vs 49 months respectively). When
chemotherapy are administrated, one with cisplatin- combining 7p and 11q alterations, the altered group
gemcitabine and the other one with carboplatin- diplays a mean OS of25.5 months versus 56 months
paclitaxel. At present, apart from clinical stage, for patients not displaying these alterations.
there are no established cancer - speciÀc clinical Conclusion: CGH array could be useful to select
variables or biomarkers that reliably identify candidates genes to be study at a genomic level in
individuals at increased risk of death after surgical order to select NSCLC for adjuvant chemotherapy.
resection – individuals who could be candidates Keywords: NSCLC, prognostic marker, Predictive
for adjuvant therapy or alternative management marker, CGH array
strategies. It is also no predictive molecular DNA of
chemosensitivity.
Methods: This national clinical trial had included
528 consecutive patients, and lung tumor
tissues were systematically collected to realize a
unique tumor bank of NSCLC patients all with
Biomarkers VII Wednesday, 6 July 2011 14:30-16:00 There was no signiÀcant prognostic value of EGFR
mutation: HR=1.26 [0.81-1.96] p=0.31 for OS and
MO16.06 A POOLED ANALYSIS TO HR=1.25 [0.84-1.85] p=0.26 for DFS. There was no
EVALUATE THE PROGNOSIS AND statistically signiÀcant heterogeneity between trials
PREDICTIVE VALUE OF EGFR (p=0.77 and 0.56 for OS and DFS). Patients with
MUTATION ON SURVIVAL IN PATIENTS both WT and mutated EGFR derived OS beneÀt
WITH KRAS WILD-TYPE LUNG from ACT (HR WT: 0.60 [0.39-0.92] p=0.02; HR
ADENOCARCINOMA mutated: 0.67 [0.30-1.50] p=0.33). There was no
Jean-Charles Soria1, Elisabeth Brambilla2, Gwénaël signiÀcant interaction between EGFR status and
Le Teuff3, Ming S. Tsao4, Pasi A. Janne5, Pierre treatment arm for OS (p=0.80). No heterogeneity
Hainaut6, Miquel Taron7, Robert A. Kratzke8, Frances was observed between trials (p=0.59). Similar results
A. Shepherd9, Jean-Pierre Pignon On Behalf Of The were observed for DFS (WT HR: 0.67 [0.46-0.97]
Lace-Bio Group3 p=0.03; mutated HR: 0.66 [0.33-1.33] p=0.24;
1
Department Of Medicine, Institut Gustave Roussy/ interaction p=0.97). No heterogeneity was observed
France, 2Institut Albert Bonniot, Inserm U823/ between trials (p=0.62). Among the patients with
France, 3Institut Gustave Roussy/France, 4Princess ADC and KRAS mutation, the rates of EGFR
Margaret Hospital/Canada, 5Lowe Center For mutation were 0% (0/27), 4% (3/78) and 2% (1/58)
Thoracic Oncology, Dana Farber Cancer Institute/ in IALT, JBR.10 and CALGB, respectively.
United States Of America, 6International Agency For Conclusion: In this pooled analysis, EGFR
Research On Cancer/France, 7Suny Upstate Medical mutations status was neither signiÀcantly prognosis
University/United States Of America, 8University nor predictive for OS and DFS in patients with KRAS
Of Minnesota/United States Of America, 9Medical wild-type lung adenocarcinoma in three adjuvant
Oncology, Princess Margaret Hospital/Canada chemotherapy trials. This work was supported by
LNCC, SanoÀ-Aventis.
Background: EGFR mutation occurs in 10-15% in Keyword: EGFR mutation, meta-analysis, predictive
lung cancer, mainly in tumors of adenocarcinoma value, lung adenocarcinoma
(ADC) histology. This mutation is rare in patients
with KRAS mutation. Because the prognostic and
adjuvant chemotherapy (ACT) predictive roles of Biomarkers VII Wednesday, 6 July 2011 14:30-16:00
EGFR mutation status remain unclear, the LACE-
Bio group undertook this pooled analysis of EGFR MO16.07 INSULIN-LIKE GROWTH
mutation status in 295 patients with ADC and KRAS FACTOR-1 RECEPTOR INHIBITION
wild-type (WT) who participated in 3 randomized OVERCOMES GEFITINIB
trials of platinum-based ACT or observation. RESISTANCE IN MUCINOUS LUNG
Methods: Pooled analysis included IALT, JBR10 ADENOCARCINOMA
and CALGB-9633 trials. EGFR exon 19 and 21 Amandine Hurbin1, Marie Wislez2, Benoit Busser1,
mutations were assessed by polymerase chain Martine Antoine2, Corine Tenaud1, Nathalie Rabbe2,
reaction / bidirectional sequencing in cases with Sandrine Dufort1, Florence De Fraipont1, Denis
DNA quality allowing KRAS mutation search. Main Moro-Sibilot1, Jacques Cadranel2, Jean-Luc Coll1,
endpoint was overall survival (OS). The hazard ratio Elisabeth Brambilla1
1
(HR) and its 95% conÀdence interval were estimated Institut Albert Bonniot, Inserm U823/France, 2AP-
using the multivariable Cox model stratiÀed by trial HP Hopital Tenon/France
and adjusted for clinical and pathological variables.
Results: Among 295 lung ADC KRAS WT patients Background: An appropriate selection of patients is
with a 5.6-years median follow-up, 55 (19%) had an a major challenge for the treatment of non-small cell
EGFR mutation: 21% (n=19), 20% (n=24) and 15% lung cancer (NSCLC) with epidermal growth factor
(n=12) in IALT (n=91), JBR10 (n=123) and CALGB receptor-tyrosine kinase inhibitors (EGFR-TKI). In
(n=81), respectively (p=0.56). More females individuals with tumors harboring EGFR mutation,
had EGFR mutations than males (26% vs. 14%, EGFR-TKI is an option as initial therapy and have
p=0.01). There were 128 and 159 events for OS demonstrated signiÀcant clinical efÀcacy against the
and disease-free survival (DFS), respectively from disease. However, de novo or acquired resistance to
290 analysed patients due to missing covariates. EGFR-TKI invariably develops. Prospective trials
in lung adenocarcinoma with bronchioloalveolar Acknowledgements: this work was supported by

carcinoma (BAC) features demonstrated that the Roche Diagnostics GmbH and grants and research
mucinous subtype presents a poorer outcome fellowships from “La Ligue contre le Cancer, comité
under EGFR-TKI treatment than the non-mucinous de l’Isère” and “projet libre” INCa.
subtype. Our aim was to determine the molecular Keywords: EGFR-TKI, apoptosis, IGF1R,
characteristics associated with resistance to Adenocarcinoma
EGFR-TKI in mucinous and non-mucinous
adenocarcinoma.
Methods: Eighty adenocarcinoma-BAC samples, Biomarkers VII Wednesday, 6 July 2011 14:30-16:00
including 34 tumors from patients treated with
geÀtinib in a phase II clinical trial from Intergroupe MO16.08 INFLUENCE OF BRCA1 AND
Francophone de Cancérologie Thoracique ASTROCYTE ELEVATED GENE-1 AS
(IFCT0401), were classiÀed as mucinous (n=32) IDENTIFIED BY MULTIPLEX TARGET
or non-mucinous (n=48) adenocarcinoma. PROFILING OF GENE EXPRESSION
EGFR, insulin-like growth factor-type 1 receptor ON OUTCOME IN ERLOTINIB-
(IGF1R), amphiregulin and thyroid-transcription TREATED NON-SMALL-CELL LUNG
factor-1 (TTF-1) expressions were studied by CANCER PATIENTS HARBORING EGFR
immunohistochemistry and EGFR and KRAS MUTATIONS
mutations status were evaluated in these samples. Miquel Taron1, Susana Benlloch2, Rafael Rosell1,
EGFR and IGF1R pathways and treatments were Jose Javier Sanchez3, Carlota Costa2, Ana Jimenez-
further analyzed on relevant cell lines. Capitan2, Clara Mayo2, Jordi Bertran-Alamillo2,
Results: We demonstrated that four biological Miguel Angel Molina2, Bartomeu Massuti4,
markers were differentially expressed between the Carlos Camps5, Margarita Majem6, Dolores Isla7,
two subtypes: mucinous tumors that overexpressed Mariacarmela Santarpia8, Santiago Viteri2, Amaya
IGF1R (p <0.0001) and amphiregulin (p=0.004) with Gasco2, Teresa Moran1, Enric Carcereny1, Cristina
a tendency for more frequent KRAS mutations, in Queralt1, Itziar De Aguirre1
1
contrast to non-mucinous tumors that overexpressed Oncology, Catalan Institute Of Oncology, Hospital
EGFR (p <0.0001) and TTF-1 (p <0.0001) with more Germans Trias I Pujol/Spain, 2Pangaea Biotech,
frequent EGFR mutations (p=0.037). Higher IGF1R Dexeus University Institute/Spain, 3Statistics,
(p=0.02) and lower TTF-1 (p=0.02) expression was Autonomous University Of Madrid/Spain, 4Hospital
associated with disease progression under geÀtinib General De Alicante/Spain, 5Hospital General De
treatment. We observed in vitro cross talk between Valencia/Spain, 6Oncology, Hospital De Sant Pau/
EGFR and IGF1R signaling pathways in geÀtinib- Spain, 7Hospital Lozano Blesa/Spain, 8University
resistant H358 mucinous cells. Anti-amphiregulin Hospital Policlinico G Martino/Italy
siRNAs and anti-IGF1R treatments sensitized the
H358 cells to geÀtinib-induced apoptosis with Background: Non-small-cell lung cancer (NSCLC)
additive effects. patients bearing epidermal growth factor receptor
Conclusion: Anti-amphiregulin and anti-IGF1R (EGFR) mutations treated with erlotinib attain
treatments could overcome the resistance of a median progression-free survival (PFS) of 14
mucinous tumors to EGFR-TKI, including those with months. However, the duration of PFS is variable
KRAS mutation. Our results highlight that mucinous and there is a need to identify genetic cofactors that
and non-mucinous adenocarcinoma subtypes are allow predictive accuracy to be improved. We had
different entities with different therapeutic responses previously determined that low BRCA1 mRNA
to EGFR-TKI. Characterizing adenocarcinoma expression correlates with a signiÀcantly prolonged
subtype and status of IGF1R and amphiregulin PFS of 27 months. We hypothesize that the detection
might allow identifying patients that could beneÀt of aberrant expression of other components in
new combinational therapy with EGFR-TKI and multiple parallel signalling pathways involved in
anti-IGF1R molecules, especially for mucinous DNA repair could further deÀne the predictive model
subtype. These data will foster the development of based only on BRCA1 expression and the pre-
therapeutic strategies for treating adenocarcinoma treatment T790M EGFR mutation.
with mucinous component. Methods: We used the NanoString nCounter gene
expression system, which captures and counts
individual mRNA transcripts, to analyze the expression Dexeus University Institute/Spain, 3Statistics,
of 48 selected genes, most of which are involved in Autonomous University Of Madrid/Spain, 4Hospital
homologous recombination repair. CodeSets (Reporter General De Alicante/Spain, 5Hospital General De
and Capture probe sets) were custom designed by Valencia/Spain, 6Oncology, Hospital De Sant Pau/
NanoString Technologies. Gene expression levels were Spain, 7Catalan Institute Of Oncology, Hospital
correlated with clinical outcomes. Duran I Reynals/Spain, 8Clínica Rotger/Spain,
9
Results: Fifty-Àve erlotinib-treated NSCLC patients Hospital Teresa Herrera/Spain
were examined. PFS for patients with low BRCA1
and low-intermediate astrocyte elevated gene-1 Background: NSCLC p with EGFR mutations respond
(AEG-1) was not reached, while it was 4 months to the oral EGFR tyrosine kinase inhibitors erlotinib
for those with intermediate-high BRCA1 and high and geÀtinib, although the duration of response in
AEG-1 levels and 18 months for those with other individual p is unpredictable. In our previous study,
combinations (P=0.004). Median survival for we found that erlotinib-treated p with low BRCA1
patients with low BRCA1 and intermediate AEG- mRNA levels had a progression-free survival (PFS) of
1 levels was not reached, while it was 21 months 27 months (m) vs 10 m for p with high levels (P=0.02).
for those with intermediate-high BRCA1 and high AEG-1 is a multifunctional oncogene that plays a role
AEG-1 levels and 29 months for those with other in several carcinogenic processes. Through PI3K/Akt,
combinations. Based on these Àndings we generated AEG-1 activates IKK, leading to phosphorylation and
a BRCA1/AEG-1 combined risk group model, destabilization of the NF-kB inhibitor NFKBIA, which
classifying patients into low-, intermediate-, and is a gatekeeper for EGFR signaling.
high-risk groups. Complete response was attained in Methods: Tumor mRNA expression levels of BRCA1
42.9% of patients in the low-risk group, compared and AEG-1 were assessed by quantitative PCR in 77
to 3% in the intermediate-risk group and 0% in the erlotinib-treated p with EGFR mutations. Expression
high-risk group (P=0.02). The hazard ratio for the levels were dichotomized at the median.
high-risk group was 7.29 (P=0.007). Results: PFS was longer in p with low AEG-1
Conclusion: The BRCA1/AEG-1 gene expression expression (27 vs 12 m; P=0.003). Median survival
model could be an essential tool for therapeutic (MS) was not reached for p with low AEG-1 levels
decision making and could provide robust predictive and was 24 m for p with high levels (P=0.08). Based
information for physicians, patients and families.The on these results, we generated an AEG-1/BRCA1
early identiÀcation of a high-risk group can be useful risk model: p with high levels of both genes were
in the development of new therapeutic strategies. considered high-risk, p with low levels of both genes
Keywords: Non-Small-Cell Lung Cancer, BRCA1, were low-risk, and p with high levels of one and low
AEG-1, NanoString levels of the other gene were intermediate-risk. PFS
was not reached in the low-risk group, while it was
18 m for the intermediate-risk group and 8 m for the
Biomarkers VII Wednesday, 6 July 2011 14:30-16:00 high-risk group (P=0.00006) (HR for high- vs low-risk
groups, 6.6; 95%CI, 2-4-18; P<0.00001). MS was not
MO16.09 ASTROCYTE ELEVATED GENE reached in the low-risk group, while it was 31 m for
1 (AEG-1) MRNA EXPRESSION IN NON- the intermediate-risk group and 18 m for the high-risk
SMALL-CELL LUNG CANCER (NSCLC) group (P=0.05). In the multivariate analysis for PFS,
PATIENTS (P) WITH EPIDERMAL the only independent prognostic variables were bone
GROWTH FACTOR RECEPTOR (EGFR) metastases (HR, 2.7; 95%CI, 1.1-6.5; P=0.03) and the
MUTATIONS AEG-1/BRCA1 risk groups (HR for high-risk group,
Rafael Rosell1, Carlota Costa2, Miquel Taron1, Jose 7.7 (95%CI, 2.8-21.3; P<0.00001).
Javier Sanchez3, Susana Benlloch2, Teresa Moran1, Conclusion: The two-gene risk model based on
Bartomeu Massuti4, Carlos Camps5, Margarita Majem6, AEG-1 and BRCA1 mRNA expression was strongly
Enric Carcereny1, Felipe Cardenal7, Amaya Gasco2, associated with clinical outcome, with signiÀcantly
Nuria Mederos2, Ignacio Magri2, Santiago Viteri2, shorter PFS and MS in the high-risk group. This
Christian Rolfo8, Rosario Garcia-Campelo9, Ana model can be useful for the proper individualized
Jimenez-Capitan2, Itziar De Aguirre1, Cristina Queralt1 management of p with EGFR mutations.
1
Oncology, Catalan Institute Of Oncology, Hospital Keywords: AEG-1, EGFR mutations, Non-Small-
Germans Trias I Pujol/Spain, 2Pangaea Biotech, Cell Lung Cancer
Biomarkers VII Wednesday, 6 July 2011 14:30-16:00 Biomarkers VII Wednesday, 6 July 2011 14:30-16:00
MO16.11 CLONALITY STATUS MO16.12 ONCOGENE STATUS PREDICTS

OF MULTIFOCAL LUNG PATTERNS OF METASTATIC SPREAD IN
ADENOCARCINOMAS BASED ON THE TREATMENT-NAïVE LUNG CANCER
MUTATION PATTERNS OF EGFR AND Robert C. Doebele1, Christopher J. Sumey2, Delee A.
K-RAS Maxson3, Xian Lu4, Anna E. Barón4, Ana B. Oton1,
Kazuya Takamochi, Shiaki Oh, Kenji Suzuki Paul A. Bunn1, Marileila Varella-Garcia1, Dara L.
Division Of Thoracic Surgery, Juntendo University Aisner5, Wilbur Franklin5, David R. Camidge1
1
School Of Medicine/Japan Medical Oncology, University Of Colorado
Anschutz Medical Campus/United States Of
Background: The purpose of this study is to clarify America, 2Department Of Medicine, University
the clonality status of multifocal lung adenocarcinomas Of Colorado Anschutz Medical Campus/United
based on the mutation patterns of the epidermal growth States Of America, 3University Of Colorado Cancer
factor receptor (EGFR) and K-ras. Center, University Of Colorado Anschutz Medical
Methods: We analyzed 82 multifocal lung Campus/United States Of America, 4Biostatistics
adenocarcinomas from 36 patients who underwent And Informatics, University Of Colorado Anschutz
surgical resection. Genomic DNA was extracted from Medical Campus/United States Of America,
5
formalin-Àxed, parafÀn-embedded tissue and analyzed Department Of Pathology, University Of Colorado
for EGFR and K-ras mutations. We determined the Anschutz Medical Campus/United States Of America
clonality status of multifocal lung adenocarcinomas
based on the mutation patterns of the EGFR and K-ras. Background: The discovery of distinct subsets
Actuarial survival time was estimated and risk factors of non-small cell lung cancer characterized by
inÁuencing survival were evaluated for 31 patients with molecular oncogenes has greatly impacted oncogene-
synchronous multifocal lung adenocarcinomas. directed therapy. We hypothesized that the unique
Results: EGFR and K-ras mutations were detected in signaling pathways engaged by different dominant
36 (44%) and 19 (23%) of the 82 tumors, respectively. oncogenes in lung cancer would be associated with
EGFR mutations had occurred randomly in 19 (92%) distinct patterns of metastatic spread.
of the 22 patients with at least one EGFR mutated Methods: 229 consecutive patients with stage
tumors. K-ras mutations had occurred randomly in IV non-small cell lung cancer (NSCLC) at the
14 (93%) of the 15 patients with at least one K-ras University of Colorado (all non-squamous histology)
mutated tumors. Combing the results for the EGFR and who were positive for EGFR mutation (N=46),
K-ras mutation patterns, the clonality status could be KRAS mutation (N=45), ALK gene rearrangement
determined in 30 (83%) of 36 patients with multifocal (N=39), or wild-type for all three (triple negative,
lung adenocarcinomas. The 5-year survival was 100% N=99) were included. SpeciÀc organ sites of
for patients with multifocal lung adenocarcinomas metastatic disease (intra- and extrathoracic lymph
harboring the same clonality and 76% for patients nodes, intrapulmonary nodules, pleura, pericardium,
with those harboring different clonality (p = 0.21). The brain, liver, bone, adrenal) at the time of diagnosis
Cox regression identiÀed the pathological diagnosis were collected from initial staging using PET/
based on Martini and Melamed’s criteria as the only CT or CT body imaging, MR or CT brain imaging
signiÀcant prognostic factor. and clinical notes. The percentage of patients with
Conclusion: Both EGFR and K-ras mutations metastatic disease at a given site was compared
frequently occur randomly in multifocal lung between each molecular cohort (EGFR, KRAS, or
adenocarcinomas. Patients with multifocal lung ALK) and the triple negative cohort.
adenocarcinomas are expected to beneÀt from Results: ALK gene rearrangement was signiÀcantly
surgery regardless of the tumor clonarity status associated with pleural effusion (OR=4.03, 95% CI
because there was no signiÀcant difference between 1.85, 8.80, p<0.001.), pericardial effusion (OR=5.82,
patients with tumors harboring the same clonality 95% CI 1.38, 24.59, p=0.0155) and intrapulmonary
and patients with those harboring different clonality. nodules (OR=2.97, 95% CI 1.36, 6.46, p=0.008)
Keywords: Clonality, EGFR, K-ras, Multifocal compared to triple negative patients. ALK gene
Lung Adenocarcinomas rearrangement was also signiÀcantly associated
with metastatic spread to intrathoracic lymph nodes
(OR=3.81, 95% CI 1.54-9.45, p=0.003), compared Toronto General Hospital/Canada, 5Department

to the triple negative cohort, and had a similar but Of Medical Oncology, University Health Network,
non-signiÀcant association with extrathoracic lymph Princess Margaret Hospital And Univeristy Of
nodes (OR=2.94, 95% CI 1.02, 8.48, p=0.07). Toronto/Canada
Patients with ALK gene rearrangements (OR=5.2,
95% CI 1.43, 18.91, p= 0.012) and patients with Background: Primary tumor xenografts (XG)
EGFR mutations (OR=5.0, 95% CI 1.42, 17.59, demonstrate greater representation of the spectrum
p= 0.019) were predisposed to liver metastasis of tumor histology and heterogeneity found in
compared to the triple negative cohort. KRAS clinical tumors than established cell lines. We have
mutation was not associated with increased risk of systematically attempted to establish XG from
any metastatic site compared to the triple negative surgically resected non-small cell lung cancer
cohort. No molecular cohort had a predisposition (NSCLC) by implanting the tumors into NOD-SCID
to adrenal, bone, or brain metastasis compared to mice. However, not all tumors engrafted to form
the triple negative cohort. The mean number of xenograft lines (Clin Cancer Res 2011;17:134-141).
metastatic disease sites in patients within the triple As the ability to form XG is correlated with poorer
negative cohort (mean=1.7 sites) was signiÀcantly disease-free survival of the patients, identiÀcation of
smaller than that of the ALK gene rearranged cohort molecular markers that are correlated with xenograft
(mean=3.0 sites, p<0.0001), but not within the EGFR establishment could indicate aberrations that are
(mean=1.8 sites, p=0.5624) or KRAS mutation drivers of aggressive biology in the primary tumor
cohorts (mean=1.6 sites, p=0.7031). and impact on clinical outcomes.
Conclusion: Untreated patients with ALK gene Methods: Tissue microarrays (TMAs) were
rearrangements displayed an increased likelihood constructed from the archival parafÀn blocks of the
of metastatic spread to several organ sites including primary patient tumors that formed XG or did not
pleura, pericardium, lung parenchyma, lymph formed XG (no-XG). DNA was isolated from tumor
nodes and liver at the time of diagnosis compared cores obtained from the same blocks. The gene copy
to patients without a known molecular driver (triple number of MYC and KRAS were evaluated by the
negative control group). EGFR mutation positive silver in situ hybridization (SISH) assay (Ventana
patients showed an increased likelihood of liver Medical Systems, Tucson, AZ) using gene speciÀc
metastases. The results support the hypothesis that probes (Ventana). For each tumor, 90 tumor cells
the dominant molecular oncogenes in NSCLC are were scored. The tumor was considered to have
associated with distinct patterns of metastatic spread. MYC or KRAS ampliÀcation if there was clear
Keywords: NSCLC, ALK, EGFR, Kras formation of probe clusters. For p53 and PTEN,
immunohistochemisty (IHC) was performed. Cases
were considered aberrant for p53 (P53+) if more
Biomarkers VII Wednesday, 6 July 2011 14:30-16:00 than 15% tumor cells were stained, and negative for
PTEN expression (PTEN-) if there was a complete
MO16.13 AMPLIFICATION OF MYC AND absence of tumor cell staining. In addition, the
ABERRANT EXPRESSION OF P53 AND DNA of patient primary tumors was analysed for
PTEN ARE PREDICTIVE OF ABILITY TO 19 oncogenes and 238 somatic mutations using the
FORM PRIMARY TUMOR XENOGRAFTS OncoCarta MassARRAY Chip (Sequenom®, San
IN RESECTED NON-SMALL CELL LUNG Diego, CA). All mutations were validated by direct
CANCER sequencing.
Naoki Yanagawa1, Mauro A. Saieg1, Derek Kohler1, Results: Primary tumor samples from 153 patients
Jenna Sykes2, Thomas John3, Gilda D.C. Santos4, (94 adenocarcinomas, 44 squamous cell carcinomas
Melania Pintilie2, Frances A. Shepherd5, Ming S. Tsao1 and 15 other types) were implanted. XG was
1
Department Of Pathology, University Health established in 64 (41.8%) cases. Of 153 total
Network, Princess Margaret Hospital And University cases, MYC ampliÀcation was seen in 49 (32.0%),
Of Toronto/Canada, 2Biostatistics, University Health KRAS ampliÀcation in 52 (34.0%), p53+ staining
Network, Princess Margaret Hospital And University in 68 (44.4%) and PTEN- staining in 63 (41.2%)
Of Toronto/Canada, 3Melbourne Centre For Clinical of the primary tumors. Tumors of XG patients
Sciences, Ludwig Institute For Cancer Research/ showed signiÀcantly greater proportion of MYC
Australia, 4Pathology, University Health Network, ampliÀcation (43.8% vs 23.6%, p=0.014), p53+
staining (57.8% vs 34.8%, p=0.005), and PTEN- mutations are of emerging clinical signiÀcance.
staining (56.3% vs 30.3%, p=0.002) than no-XG Unfortunately, resources for understanding this
patients. KRAS ampliÀcation was slightly, but not complex genetic information are limited.
signiÀcantly increased in XG tumors (42.2% vs Methods: We performed a literature review
28.4%, p=0.08). In multivariate analysis, MYC regarding the prevalence and clinical signiÀcance
ampliÀcation, p53+ and PTEN- were signiÀcantly of various treatments for ~40 mutations in 10 genes
associated with the ability to XG [Odds ratio and (EGFR, KRAS, BRAF, NRAS, PIK3CA, MEK1,
95% conÀdential interval (CI)]: MYC, 2.48 (1.02- AKT1, HER2, PTEN, and ALK) for NSCLC. Data
5.19, p=0.016); p53, 2.73 (1.35-5.53, p=0.005); from prospective and retrospective trials as well as
PTEN, 3.17 (1.56-6.44, p=0.002), but not KRAS preclinical studies were collected. We also conducted
ampliÀcation (1.59, 0.77-3.26, p=0.21). KRAS a retrospective review of the literature and identiÀed
mutations were seen in 34 (22.2%), and EGFR reports on over 1300 patients with EGFR mutations.
mutations in 23 (15.0%) primary tumor specimens, We collected data including gender, age, smoking
mostly adenocarcinomas (AC). In AC, MYC status, therapy and mutation status.
ampliÀcation was frequently seen in cases with wild- Results: Greater than 150 articles and abstracts were
type KRAS (p=0.061), but was not associated with reviewed and synthesized. Data was incorporated
EGFR mutation status (p=0.80). KRAS ampliÀcation into a website [www.mycancergenome.org] which
was not associated with the presence of KRAS health care providers and patients will be able to
mutation (p=0.18), EGFR mutation (p=0.79) or use within the clinic to improve their understanding
MYC ampliÀcation (p=0.80). of common and rare mutations and to aid in
Conclusion: MYC ampliÀcation by SISH, p53+ and their prioritization of therapies for patients with
PTEN- are predictive of the ability for early stage lung cancer. We provide direct links to available
NSCLC to form XG, and potentially are associated local and international clinical trials targeting
with poorer survival. speciÀc mutations. In our individual patient data
Keywords: Non-small cell lung cancer, MYC, review of EGFR mutations, we evaluated over
PTEN, primary tumor xenograft 2000 publications and identiÀed 115 papers
containing data on 1152 individual patients: 91%
adenocarcinoma, 62% never smokers, and 92% stage
Biomarkers VII Wednesday, 6 July 2011 14:30-16:00 IV. 154 different mutations identiÀed: 48% exon 19
deletion, 27% L858R, 3% G719X, 1% L861Q and
MO16.14 MYCANCERGENOME.ORG: 21% other. We are now developing a searchable
DEVELOPING A WEB-BASED TOOL TO database – DNA mutation Inventory to ReÀne
ENABLE A GENETICALLY INFORMED and Enhance Cancer Treatment [DIRECT] – for
APPROACH TO LUNG CANCER providers to access at the point of care.
TREATMENT Conclusion: Mycancergenome.org has been
Leora Horn1, Christine Lovly1, Heidi Chen2, Jenny launched and is being evaluated for functionality,
Andrews3, Paul Yeh3, Riyad Nasser3, Mia Levy3, ease of use and satisfaction. The DIRECT database
William Pao1 has started with patients with known EGFR
1
Hematology Oncology, Vanderbilt Ingram Cancer mutations, and will be expanded to incorporate all
Center/United States Of America, 2Biostatistics, known mutations with potential clinical signiÀcance.
Vanderbilt Ingram Cancer Center/United States Of We encourage other clinicians, investigators, and
America, 3Vanderbilt Ingram Cancer Center/United interested pharma/diagnostic companies to contribute
States Of America data as they emerge.
Keywords: Non-small cell lung cancer, Mutations,
Background: The treatment of patients with non- Metastatic Disease
small cell lung cancer (NSCLC) in the twenty
Àrst century has evolved into a complicated A revised/updated abstract may be included in
algorithm, requiring knowledge of an individual the Late Breaking Abstract Supplement, available
patient’s mutation status prior to initiating therapy. at the 14th World Conference on Lung Cancer.
Some mutations are associated with primary drug
sensitivity, some with primary drug resistance,
and some with secondary resistance. Other rarer
Session MO17: Epidemiology II Keywords: ground-glass opacity, nodule,

malignancy, computed tomography
Epidemiology II Wednesday, 6 July 2011 14:30-16:00
MO17.02 SUICIDE IN PATIENTS WITH
MO17.01 NATURAL COURSE OF THE CARCINOMA OF LUNG AND
GROUND-GLASS OPACITY LUNG BRONCHUS IN CALIFORNIA, 2000-2005
NODULE DETECTED BY LOW-DOSE Hamid R. Mirshahidi1, Kiumarss Nasseri2, Paul K.
COMPUTED TOMOGRAPHY IN Mills3
SUBJECTS WITHOUT HISTORY OF 1
Hematology/oncology, Loma Linda University
PREVIOUS MALIGNANCY Cancer Center/United States Of America,
Boksoon Chang1, Jung Hye Hwang2, Hojoong Kim1, 2
Epidemiology, University Of Liverpool/United
Sang-Won Um1 States Of America, 3Fresno Medical Education And
1
Medicine, Samsung Medical Center/Korea, 2Center Research Program, University Of California, San
For Health Promotion, Samsung Medical Center/ Francisco/United States Of America
Korea
Background: Compared to general population,
Background: Although focal ground-glass opacity patients with carcinoma of the lung and bronchus are
(GGO) nodule is generally reported to grow slowly, at higher risk of suicide, which is clustered in White
its natural course is still unclear. The purpose of this men diagnosed with cancers with poor prognosis.
study was to elucidate the natural course of screening- The objectives of this study were to determine the
detected focal GGO nodules without history of relative risk of suicide in lung cancer patients by
malignancy. detailed race/ethnicity and stage at diagnosis.
Methods: We retrospectively reviewed the records Methods: . Age adjusted suicide rates were
of patients who underwent screening low dose chest calculated for patients with cancers of the lung
computed tomography (CT) at the Samsung Medical and bronchus, based on cases registered with the
Center between June 1997 and September 2006. The California Cancer Registry for the years 2000-2005.
patients who underwent CT follow-up of more than Suicide rates in general population were based on the
2 years and had persistent focal GGO nodule(s) were California Death CertiÀcate Master Àles for the same
included in the study. The patients with a history of period and same race/ethnicity. Relative risks (RR)
previous malignancy or transient focal GGO nodule(s) for stage at diagnosis, marital and socioeconomic
were excluded from the study. status were also calculated.
Results: Ninety-four patients and 129 GGO nodules Results: . Of the 929,369 registered cases, 105,916
were included in the analysis. The median CT follow- were identiÀed as carcinoma of the lung and
up period was 59 (24–140) months. The median size bronchus and accounted for 134 of the 716 suicides
of nodule at the time of discovery was 6 (3-20) mm in this population. Although 0.2 percent of all death
in largest dimension. During follow-up, the size of among cancer patients was suicide, its RR in the
nodules were not changed in 81 patients (86.2%) and non-Hispanic White men and women, and Hispanic
increased in 13 patients (13.8%). Increase in nodule men were 5.87, 4.99, and 8.05, respectively. Suicide
size was associated with initial size (p<0.001) and in patients with lung cancer was only signiÀcantly
existence of solid part (p=0.003). Median volume higher only in non-Hispanic White men with a
doubling time of nodules with increase in size was relative risk of 5.85. It was also signiÀcantly higher
614 (330-4338) days. Twelve patients with increase in metastatic cases with a relative risk of 1.75.
in nodule size underwent surgical resection and 12 Conclusion: s. Considering the multifactorial nature
nodules were diagnosed as primary lung cancer. of suicide and its association with severity of the
Conclusion: Screening detected focal GGO nodules disease, and some of the patients demographics,
grows less than 20 percent in subjects without it is concluded that diagnosis of cancer, and the
history of malignancy. However, long-term follow- advanced stage of diagnosis that reduces the hope
up of more than 5 years are required for focal GGO for successful treatment, acts as precipitating factor
nodules due to slow growth rates. for suicide in patients who are already suicidal.
Oncologists who diagnose and manage patients with Methods: This analysis utilised genotyped data
cancers of the lung and bronchus should include on 2385 (Case=728, controls=1657) individuals
psychological evaluation in their routine to identify included in a candidate gene replication study.
patients with suicidal tendencies and prevent it from Potential epistasis among 20 replicated SNPs
happening. was explored using Multifactor Dimensionality
Keywords: Lung cancer, Suicide, Epidemiology Reduction (MDR) analysis to Àt all possible
n-loci SNPs combination models. The overall
A revised/updated abstract may be included in best combination was selected based on cross
the Late Breaking Abstract Supplement, available validation consistency (CVC) and model accuracy
at the 14th World Conference on Lung Cancer. in testing data (TA). Model coefÀcient for each
allelic combination of the best SNPs combination
was estimated from the model-based MDR(MB-
Epidemiology II Wednesday, 6 July 2011 14:30-16:00 MDR) and incorporated into the LLP risk model.
Predictive performance of extended model was
MO17.03 ADDED PREDICTIVE VALUE examined using measures of discrimination, risk
OF SNPS EPISTASIS IN THE LLP LUNG reclassiÀcation and clinical utility.
CANCER RISK PREDICTION MODEL Results: A 3-locus combination assuming additive
Olaide Y. Raji1, Stephen W. Duffy2, T. Liloglou1, genetic model provide the best discrimination
Robert P. Young3, John K. Field1 of subject’s status (CVC= 100%, TA=65%). The
1
Molecular And Clinical Cancer Medicine, MB-MDR also shows strongest associations for
University Of Liverpool/United Kingdom, 2Queens all 2- & 3-way interactions among SNPs is the
Mary University Of London/United Kingdom, ‘best’ combination. However, entropy analysis
3
University Of Auckland/New Zealand suggests redundancy for their pairwise interactions
(information loss range between -0.01 and -1.50%).
Background: Lung cancer risk models estimate Five allelic combinations were estimated to be of
individual‘s absolute risk of the disease within low risk, 11 each as uninformative and high risk
a speciÀed period. Such models are useful in with corresponding subject percentage of 5.4, 62.4
identifying and targeting high risk individuals and 32.2% respectively.
for early detection interventions. Smoking is a A statistically signiÀcant 8% increase in ROC-AUC
known causal factor for lung cancer, the majority was obtained with the addition of the SNP epistasis
of long term smokers would not develop the allelic effects into the prediction model with a net
disease whilst approximately 10-15% cases occur reclassiÀcation of 17.5% subjects. The decision
in non-smokers. This implies that lung cancer curve analysis revealed superior ‘net’ beneÀts for
risk models should include other important risk the extended model across a reasonable range of
factors including genetic and molecular variants for threshold probabilities (10-40%) at which patients
accurate risk. Relatively few genetic SNP variants may be indifferent to an intervention.
have been identiÀed for lung cancer through genetic Conclusion: The LLP risk model shows
association studies using Genome-Wide Association improvement with addition of a 3-locus epistasis
Study (GWAS) or Candidate gene approach. As effect. The expanded model provides improved
seen in other diseases, these markers only confer a stratiÀcation for a net 18% cases with no net
small effect leading to scepticism regarding their loss in controls. This expansion of the model
usefulness in risk prediction. Recent research trend allows reÁection on disease pathway mechanism
has suggested a role for gene-gene interactions unmeasured in non-genetic factors.
in disease aetiology. Addition of such interactive Keywords: risk prediction, Lung cancer, SNPs
effects may improved risk model predictions since Epistasis
many variants may exhibit strong interactions even
with weak or insigniÀcant marginal effect. We
explore potential epistasis (non-linear interactions)
amongst a panel of lung cancer susceptible SNPs
and assess their contributions to the predictive
ability of the Liverpool Lung Project (LLP) risk
model.
Epidemiology II Wednesday, 6 July 2011 14:30-16:00 106 (5%), other NSCLC variant in 129 (6%) and
not otherwise speciÀed in 668 (31%). 250 patients
MO17.04 STAGE III NON-SMALL CELL (12%) received surgery, 1681 received radiotherapy
LUNG CANCER (NSCLC): PATTERNS OF (78%) and 669 (31%) received chemotherapy. The
TREATMENT IN BRITISH COLUMBIA, optimal predicted radiotherapy utilisation in this
CANADA population was 77-87% and chemotherapy 78%.
Shalini K. Vinod1, Elaine Wai2, Cheryl Alexander2, 613 (29%) received curative treatment, 1314 (61%)
Jennifer Christie2 palliative treatment and 226 (10%) received best
1
Collaboration For Cancer Outcomes, Research supportive care alone. The use of curative treatment
& Evaluation, Liverpool Hospital/Australia, increased from 21% in 2000 to 35% in 2007. The
2
Vancouver Island Centre, British Columbia Cancer use of curative radiotherapy increased from 10.9%
Agency/Canada to 19.6% and chemoradiotherapy from 8% to 18.6%.
The use of surgery and best supportive care remained
Background: Stage III NSCLC comprises a similar over time. The median survival was 13
heterogeneous group of patients. Management months for Stage IIIA and 8 months for Stage IIIB
options range from any combination of surgery, NSCLC. Patients who had curative surgery had a
radiotherapy and chemotherapy to no treatment. Based median survival of 30 months, curative radiotherapy
on guidelines, estimates of optimal radiotherapy 21 months, palliative treatment 8 months and best
utilization at diagnosis range from 84%- 92% and supportive care 5 months (p<0.001). There was no
for chemotherapy 88%. However guideline-based change in survival over time.
treatment is not applicable in many patients due to Conclusion: A signiÀcant proportion of patients
age and comorbidities. The aims of this study were lacked pathological subtyping of their cancer which
to describe the patterns of treatment in a population- has become increasingly important in the era of
based cohort of patients with Stage III NSCLC targeted therapies. The utilisation of radiotherapy
and compare the utilization of chemotherapy and was similar to that predicted by models whereas
radiotherapy to that predicted by models. the utilisation of chemotherapy was signiÀcantly
Methods: All patients diagnosed with clinical or less. There was an increase in the use of curative
pathologic Stage III NSCLC between January 1st radiotherapy and chemoradiotherapy over time
2000-December 31st 2007 were identiÀed from suggesting translation of evidence into practice.
the prospective database of the British Columbia Keywords: Non-small cell lung cancer,
Cancer Agency (BCCA). Those who were cNX Radiotherapy, Chemotherapy, patterns of care
or cMX were excluded as were patients with
concomitant malignancies, a prior history of
malignancy and multifocal lung cancers. Details on Epidemiology II Wednesday, 6 July 2011 14:30-16:00
patient demographics, tumour characteristics, and
Àrst course of treatment were extracted. Survival MO17.06 IMPROVED PROGNOSTIC
data was derived from the British Columbia Vital STRATIFICATION OF STAGE I LUNG
Statistics Death Listings. All records were censored ADENOCARCINOMA (LAC) PATIENTS:
on 31st December 2008. Initial treatment was deÀned CLASSIFICATION AND REGRESSION
as that commenced within six months of diagnosis. TREE (CART) ANALYSIS BASED ON
Curative radiotherapy was deÀned as a minimum HISTOLOGICAL SUBTYPING
dose of 50Gy. Camelia S. Sima1, Kyuichi Kadota2, Akihiko
Results: 3429 patients with newly diagnosed Yoshizawa3, Emily C. Zabor1, Mithat Gonen1, Valerie
lung cancer were referred to BCCA. 1275 patients Rusch4, William D. Travis5, Prasad S. Adusumili2
1
were excluded leaving 2153 patients in the study Epidemiology And Biostatistics, Memorial Sloan-
population. The median age was 69 years and 55% Kettering Cancer Center/United States Of America,
2
were male. ECOG performance status was 0-2 Memorial Sloan-Kettering Cancer Center/United
in 1369 (64%), 3-4 in 392 (18%) and unknown States Of America, 3Pathology, Kyoto University/
in 392 (18%). Stage of disease was pIIIA in 160 Japan, 4Thoracic Surgery, Memorial Sloan-
(7%), cIIIA in 904 (42%), pIIIB in 54 (3%) and Kettering Cancer Center/United States Of America,
5
cIIIB in 1035 (48%). Pathology was SCC in 661 Pathology, Memorial Sloan-Kettering Cancer
(31%), adenocarcinoma 589 (27%), large cell in Center/United States Of America
Background: In patients with resected stage I

LAC, we hypothesized that a classiÀcation system
incorporating the distribution percentages of
multiple histological subtypes within the tumor
would efÀciently stratify patients and better predict
recurrence than the IASLC/ERS/ATS classiÀcation
system based on the most predominant histological
subtype (PredHist).
Methods: In 485 stage I LAC resected tumors
(training set, median follow-up=4 years), each
histological subtype (lepidic=LIP, acinar=ACI,
papillary=PAP, solid=SOL, micropapillary=MIP) Conclusion: A simple classiÀcation system based
was quantiÀed in 5% increments. CART on the mix percentage of histological subtypes
methodology was applied to generate a decision efÀciently stratiÀes patients with stage I LAC
algorithm that clustered patients with respect to with respect to their risk of recurrence and, in
their time to recurrence, based on the mix % of combination with clinic-pathological factors, can
histological subtypes. The resulting classiÀcation provide clinicians with an accurate instrument
system (%Mix) stratiÀed patients into groups whose for individual recurrence prediction in this very
risk of recurrence was calculated using Kaplan- homogeneous population.
Meier estimates. Results were compared to those of Keywords: Stage I lung adenocarcinoma, Individual
PredHist. A multivariate Cox proportional hazards risk prediction, Histological subtyping
model was built, and its ability to predict recurrence
was validated on an independent set of 487 stage I
LAC. Epidemiology II Wednesday, 6 July 2011 14:30-16:00
Results: CART decision algorithm (Figure) stratiÀed
patients into three groups with signiÀcantly different MO17.07 POLYMORPHISMS IN X-RAY
risk of recurrence (p<0.001). Compared to PredHist, REPAIR CROSS-COMPLEMENTING
%Mix reclassiÀed 29% (n=141) of patients, reducing GROUP 1 (XRCC1) BASE EXCISION
the proportion in the intermediate-risk category REPAIR GENE AND LUNG CANCER
from 76% to 59% (Table). Eighteen percent of all RISK IN INDUSTRIAL WORKERS WITH
patients had their risk classiÀcation improved (to CHROMATE EXPOSURE.
higher risk if recurred by 5 years, or to lower risk Yui Fujita1, Kazuya Kondo1, Abdellah H.K. Ali2,
otherwise). In a multivariate model adjusting for Toshiaki Namura1, Yoshitaka Senba1, Yukari Oiwa1,
gender, stage (IA vs. IB), necrosis and lymphatic Chikako Takai1, Hiromitsu Takizawa3, Yasushi
invasion, %Mix was independently associated with Nakagawa3, Hiroaki Toba3, Koichiro Kenzaki3, Shoji
recurrence (p=0.028). The multivariate model had Sakiyama3, Akira Tangoku3
1
a concordance probability of 0.72 (training dataset) Department Of Oncological Medical Services,
and 0.71 (independent validation dataset), indicating Institute Of Health Biosciences, The University Of
very promising prediction ability. Tokushima Graduate School/Japan, 2Respiratory
Medicine, Sohag University, Faculty Of Medicine/
Egypt, 3Department Of Thoracic, Endocrine
And Oncological Surgery, Institute Of Health
Biosciences, The University Of Tokushima Graduate
School/Japan
Background: Polymorphisms in DNA repair genes

have been associated to repair DNA lesions, and
might contribute to the individual susceptibility
to develop different types of cancer. The main
DNA repair pathways include nucleotide excision
repair (NER), base excision repair (BER), and
double-strand break repair (DSBR). It is known Epidemiology II Wednesday, 6 July 2011 14:30-16:00
that chromium is an important inhaled carcinogen
for lung cancer, and causes a variety of genetic MO17.08 THE EFFECT OF SEX AND
and related effects such as Cr-DNA adducts DNA HISTOLOGY ON OUTCOME IN
single-strand breaks, DNAdouble-strand breaks, A POPULATION OF NON-SMALL
DNA base damage and mutations. We investigated CELL LUNG CANCER PATIENTS IN
the relationship between 3 polymorphism sites MANITOBA, CANADA
(Arg194Trp, Arg280His, Arg399Gln) in the BER Marshall Pitz, Srisala Navaratnam
gene x-ray repair cross-complementing group 1 Internal Medicine - Section Of Medical Oncology
(XRCC1) and the risk of developing lung cancer in And Hematology, University Of Manitoba/Canada
industrial workers with chromate exposure.
Methods: We divided 75 workers with chromate Background: Non-small cell lung cancer (NSCLC)
exposure into 2 groups: workers with lung cancer is the leading cause of cancer-related mortality.
(LC+ group) and workers without lung cancer There is mounting evidence that cancer outcomes
(LC- group). Time of chromate exposure (years): are worse for males than for females. The effect of
23.1 vs 19.4, smoker rate: 85% vs 73%, Brinkman sex as an independent prognostic factor has not been
index: 510 vs 338. DNAs were extracted from completely described at the population level. We
specimens of sputum cytology or biopsy of sought to evaluate the effect of sex on mortality in a
bronchscopic examination for screening. Genotypes population of patients with NSCLC.
were determined by nested PCR-RFLP using each Methods: All patients with a diagnosis of NSCLC
speciÀc primer of 3 polymorphism sites (Arg194Trp, in Manitoba, Canada, from January 1, 1985, to
Arg280His, Arg399Gln). December 31, 2004, were identiÀed from the
Results: Variant genotypes of 399Gln (Arg/Gln and Manitoba Cancer Registry. Treatment data for
Gln/Gln) presented a statistically signiÀcant risk of these patients were extracted from the Manitoba
developing lung cancer in workers with chromate Health Physician Claims Database. The primary
exposure (OR = 3.76; 95%CI = 1.38-10.25). On outcome was survival of males compared to females,
the other hand, variant genotypes of 194 Trp (Arg/ calculated from date of diagnosis to date of death or
Trp and Trp/Trp) presented a statistically signiÀcant administrative censoring. Quantile regression with
reverse risk of developing lung cancer in workers generalized estimating equations and robust variance
with chromate exposure (OR = 0.22; 95%CI = 0.08- estimation, along with stratiÀed Cox proportional
0.61). Variant genotypes of 280 His (Arg/His and hazards regression were used to determine the
His/His) presented a not statistically signiÀcant risk independent effect of sex on survival and the
of developing lung cancer (OR = 1.89; 95%CI = interaction with histology, controlling for age, year
0.30-12.01). The frequency of Trp variant genotypes of diagnosis, and treatment group.
in Arg194Trp, His in Arg280His, Gln in Arg399Gln Results: A total of 10 908 patients with NSCLC
in this study is similar to that in Asian-populations were identiÀed from the Manitoba Cancer Registry.
studies (62.6% vs 39.3-63.2%, 6.7% vs 15.3-24.1%, Of these, 6665 were male and 4243 were female.
60% vs 37.6-58.7%, respectively) . Females had an overall median survival of 9.4
Conclusion: In conclusion, we found that XRCC1 months compared to 6.8 months for males (p
399Gln variant genotypes were associated with <0.001). Females treated with surgery had a
increased risk of lung cancer, and 194 Trp variant median survival of 53.3 months (95%CI 52.8-
genotypes showed a protective effect for lung cancer 53.9) compared to 33.4 months (95%CI 32.9-33.9)
in workers with chromate exposure. These results are for males. Females treated with chemotherapy,
compatible with the results of in vitro studies, which radiotherapy, and supportive care had median
demonstrated that the 399 Gln allele is associated survivals of 10.1 months (95%CI 9.2-11.0), 6.6
with higher mutagen sensitivity and higher levels of months (95%CI 6.0-7.1), and 2.2 months (95%CI
DNA adducts, and that 194Trp allele is associated 1.6-2.8), respectively. For males, median survivals
with lower mutagen sensitivity. were 8.5 months (95%CI 7.6-9.4), 6.0 months
Keywords: Lung cancer, chromium, polymorphism, (95%CI 5.5-6.5), and 1.9 months (95%CI 1.3-2.4),
base excision repair XRCC1 respectively. The adjusted hazard ratio (HR) for
death for males compared to females was 1.12
(95%CI 1.03-1.21, p = 0.01). Sex modiÀed the effect
of surgical treatment on survival with a HR of 1.26 patients and >75nmol/L in 2 patients. There was no
(1.13-1.40, p<0.001). Adenocarcinoma histology correlation between vitamin D levels, deprivation
signiÀcantly modiÀed the effect of sex on mortality score, stage of disease, timing or type of treatment
such that in those with adenocarcinoma, males had a or seasonal time of vitamin D measurement.
HR for death of 1.37 (1.24-1.51, p<0.001) compared Incidentally, 10 of the 38 patients with low vitamin
to females. This effect was consistent across all D levels had been diagnosed with bone metastases
treatment groups. on the basis of symptoms and bone scans.
Conclusion: In this large population-based cohort, Conclusion: In this study, 83% of patients had
females with NSCLC had a signiÀcantly better vitamin D deÀciency. This problem may be more
survival than males with the same disease. For widespread. Correction of vitamin D deÀciency may
patients with adenocarcinoma, this difference was reduce symptoms and improve quality of life. If
signiÀcantly stronger, and was seen in each treatment the sole site of progression is bone metastases, then
group. Sex and adenocarcinoma are independent replenishing vitamin D Àrst (unless there is evidence
prognostic factors for patients with NSCLC. of bone destruction) before switching systemic
Keywords: Non-small cell lung cancer, sex, therapies may be appropriate. Bone metastases could
Adenocarcinoma, population-based potentially be misdiagnosed2.
Keywords: Vitamin D DeÀciency, Lung cancer

MO17.09 VITAMIN D LEVELS IN
PATIENTS WITH LUNG CANCER: A MO17.11 IMPACT OF DIETARY HABITS
POTENTIAL CAUSE OF CONFUSION? ON EPIDERMAL GROWTH FACTOR
Janabel Said, Elaine M. Rankin, Colin S. Barrie RECEPTOR (EGFR) MUTATION STATUS
Oncology Department, Ninewells Hospital/United OF JAPANESE PATIENTS WITH LUNG
Kingdom ADENOCARCINOMAS
Yuki Yamane1, Motoki Iwasaki2, Akikazu Kawase1,
Background: Bone metastases are common in lung Katsuya Tsuchihara3, Sachiyo Mimaki3, Genichiro
cancer, affecting 40% of patients with non-small cell Ishii4, Horonobu Ohmatsu1, Seiji Niho1, Kiyotaka
and 70% with small-cell lung cancer1. Sievenpiper Yoh1, Kanji Nagai1, Yuichiro Ohe1, Shoichiro
et al2 noted that breast cancer patients with vitamin Tsugane2, Atsushi Ochiai4, Hiroyasu Esumi3, Koichi
D deÀciency may have similar symptoms to those Goto1
1
with bone metastases including bone pain and ‘hot Division Of Thoracic Oncology, National Cancer
spots’ on bone scans, indistinguishable from bone Center Hospital East/Japan, 2Epidemiology And
metastases. Thus, if bone pain and scan Àndings are Prevention Division, Research Center For Cancer
attributed incorrectly to metastatic disease rather Prevention And Screening, National Cancer Center/
than vitamin D deÀciency, anti-cancer therapy may Japan, 3Cancer Physiology Project, Research Center
be changed inappropriately. We were interested in For Innovative Oncology, National Cancer Center
the incidence of vitamin D deÀciency in our lung Hospital East/Japan, 4Pathology Division, Research
cancer population and report the results of our Center For Innovative Oncology, National Cancer
survey. Center Hospital East/Japan
Methods: Forty-six consecutive patients were
studied: age range 40–81, 31 female. Their diagnosis, Background: Epidermal growth factor receptor
stage of disease, treatment, month of vitamin D (EGFR) mutation plays a key role in the
measurement and Carstairs deprivation score3 were carcinogenesis of lung adenocarcinoma. However
noted. In Scotland, the lower limit of normal for little is known about the environmental and life
the active metabolite, 1,25-dihydroxyvitamin D3, is style factors, in particular dietary habits, inÁuencing
50nmol/L4. EGFR mutations.
Results: Only 8 of 46 patients had normal vitamin Methods: Between July 1999 and July 2004,
D levels; none were taking vitamin D supplements. 1995 consecutive patients with lung cancer were
Vitamin D levels were <25nmol/L in 16 patients, prospectively assessed on dietary habits using the
26-49nmol/L in 12 patients, 50-74nmol/L in 6 semiquantitative Food Frequency Questionnaire
(FFQ) which contains questions regarding 138 been 35 case series describing the occurrence of
foods in National Cancer Center Hospital East. LELC of the lung with Caucasians accounting
EGFR mutations (exon 19 deletion and exon 21 for only 20 cases of 155 cases. We present here a
L858R) were examined in 298 adenocarcinomas review of LELC of the lung in patients seen at the
of whom by direct sequence method. The intake Mayo Clinic, Minnesota from January 1, 1979 -
of nutrients was calculated with standard tables of December 31, 2010.
food composition in Japan, 5th revised and enlarged Methods: We searched Mayo Clinic Tumor
edition. The differences of consumption of 22 food Registry by using the words “lymphoepithelioma”
groups and 45 nutrients (energy-adjusted values and “lymphoepithelioma-like carcinoma”. In
using the residual method) between EGFR mutations addition, we searched the pathology SnoMed
positive (156 patients) and negative (142 patients) coding system using the codes ICD-8, and ICD-9.
were investigated by multivariate logistic regression Search was limited to the period of 1979 - 2010.
model adjusted for gender, age, smoking status and Results: There were 14 patients with a diagnosis
body mass index, regarding patients without EGFR of LELC of the lung (4 females, mean age=50.3
mutations as control cases. years and 10 males, mean age=64.9 years). Most
Results: The grain and carbohydrate consumption patients were either current or former smokers
of patients with EGFR mutations was signiÀcantly except one for never-smoker of Asian ethnicity.
lower than patients without EGFR mutations. Angiolymphatic or visceral pleura invasion
The multivariate-adjusted odds ratios and 95% was seen in 3 patients. Nine patients (64%)
conÀdence intervals for the third tertile of grain and presented with early stage disease (I, II), and 5
carbohydrate consumption of patients with EGFR patients (35%) presented with advanced stage
mutations in comparison with the Àrst tertile were disease (III, IV). Two patients (stage II and IV)
0.46 (0.24-0.87) (p for trend =0.021) and 0.44 (0.23- were Asian and positive for EBV by in-situ
0.85) (p for trend =0.016), respectively. hybridization. From the remaining 12 Caucasian
Conclusion: In the present study, it was patients, 2 (stage II and IV) were positive for
suggested that the lower consumption of grain and EBV by in-situ hybridization; 3 were negative;
carbohydrate correlated with EGFR mutations. and 1 had EBV Viral Capsid Antigen (VCA)
Further research to investigate the inÁuence of these IgG positive. Results were not available in the
dietary components and habits on carcinogenesis remaining 6 patients. Surgery was done in all
of lung adenocarcinoma with EGFR mutations is patients except for 2 stage IV patients. Only 2
warranted. patients received adjuvant chemotherapy, 5-FU/
Keywords: Epidermal growth factor receptor platinum in one patient and cisplatin/etoposide
(EGFR), EGFR mutation, lung adenocarcinoma, concurrent with radiation in another one. This
Dietary habits patient developed brain metastasis 5 months
after Ànishing chemoradiation. Locally recurrent
disease occurred in one patient. Three patients had
Epidemiology II Wednesday, 6 July 2011 14:30-16:00 distant metastatic disease on follow-up which with
one of them being positive for EBV. One stage IV
MO17.12 LYMPHOEPITHELIOMA- patient had complete remission after 2 cycles of
LIKE CARCINOMA OF THE LUNG: 31 5-FU/platinum then it progressed during period of
YEARS EXPERIENCE AT MAYO CLINIC, consolidate chemoradiation with weekly low dose
ROCHESTER, MINNESOTA carboplatin, but responded after re-initiation of
Thanyanan Reungwetwattana, Julian R. Molina 5-FU-based therapy. Patients Summary
Medical Oncology, Mayo Clinic/United States Of
America
Background: Lymphoepithelioma-like carcinoma

(LELC) of the lung, an Epstein-Barr virus
associated undifferentiated carcinoma, is the
very rare subtype of non-small cell lung cancer
(NSCLC). It has high incidence in young, non-
smoking, Asian patients. Currently, there have
Table estimated that less than 5% of adult cancer patients

ID Age Sex
Smoking
Race Staging EBV Surgery
Chemo-
Overall
RT Recurrence Survival
enroll to clinical trials. As a university hospital with
(Packyears) therapy
(months)
a dedicated thoracic oncology department, we aim to
Ex-smoker NA not
1 64 Male
(45)
White I T1N0M0
available
Wedge RUL No No Bone 44
identify barriers to patients enrollment in lung cancer
2 40 Female
Ex-smoker
(23)
White I T2N0M0 NA
Palliative
LUL lobectomy Taxol+ Yes
Local Left
hilar mass
47 clinical trials.
Carboplatin
Current-
Methods: We prospectively tracked factors that
3 72 Male White I T1N0M0 NA RUL lobectomy No No No 145
smoker (70) potentially affected patient accrual into lung cancer
Ex-smoker
4 67 Male
(30)
White I T1N0M0 NA Wedge LLL No No No 113
clinical trials at the Toulouse University Hospital.
5 69 Male
Ex-smoker
White I T1N0M0
negative
EBV in situ Wedge LUL No No No 7
Physicians were asked to complete questionnaires
(60)
hybridization
in the weekly oncology multidisciplinary staff from
Ex-smoker EBV VCA
6 57 Female
(30)
White I T1N0M0
IgG postive
wedge RUL No No No 30
1rst January 2010 to 28th June 2010. We collected
Current-
7 75 Male
smoker (45)
White II T1N1M0 NA RUL lobectomy No No No 16 data regarding patient characteristics, therapeutic
8 52 Female
Never
Asian II T1N1M0
positive Adjvant
EBV in situ LLL lobectomy 5-FU+ No NA NA
decision, protocol availability, clinical trial inclusion
smoker
hybridization Platinum
proposition and reasons of non participation.
negative
9 52 Male
Ex-smoker
(37)
White II T2N1M0 EBV in situ
hybridization
Right
pneumonectomy
No No NA 12 Results: We recruited three hundred and twenty one
10 68 Male
Ex-smoker
White IIIA T2N2M0 NA Wedge LUL No Yes Right lung 89
patients. Patients were mostly men (69%) with an
(50)
Adjuvant
average age of 62.7 years within a range of 40 to
positive
11 52 Female
Ex-smoker
(NA)
White IIIB T4N0M0 EBV in situ
RML, RLL
bilobectomy
CCRT
Cisplatin +
Yes Brain 12 89. Patients were proposed chemotherapy for 71%,
hybridization
Etoposide
radiotherapy for 17% and surgery for 12%. Two
negative
12 68 Male
Ex-smoker
(45)
White IIIA T2N2M0 EBV in situ
hybridization
Right
pneumonectomy
No No No Alive hundred Àfty seven were ineligible (80%); there was
Ex-smoker
positive Palliative no available clinical trial for 136 patients (42.3%)
13 61 Male White IV (colon) EBV in situ No 5-FU + No NA NA
(45)
hybridization Cisplatin and one hundred twenty one didn’t met eligibility
14 53 Male NA Asian
IV (cervical
positive
EBV in situ No
Palliative
5-FU +
Cervical
Yes lymph Alive
criteria (37.7%). The main reasons for ineligibility
lymph node)
hybridization Platinum node
were : presence of co-morbidities (6.5%), history of
a previous malignancy (6.9%), poor performance
Conclusion: The natural history of disease of LELC status (10.6%, advanced age (5.6%), residence far
of the lung in Caucasian might be different from from the hospital (10%) and tumor characteristics
Asian patients in term of patient’s age, smoking and (10.3%). Of the remaining sixty four patients,
EBV infection status. LELC of the lung is a very only twenty one (32%) agreed to enroll onto a
uncommon form of lung cancer in Western countries clinical trial. Eligible patients were younger with
that needs collaborative studies for achieving the a median age of 60.5 years. 43 patients have been
most beneÀt therapies. excluded due to patient-related criteria (poor PS,
Keyword: lymphoepithelioma of the lung abnormal blood tests results) and protocol-related
criteria (histology subtype, stage, therapeutics drugs
proscribed, prior treatment).
Epidemiology II Wednesday, 6 July 2011 14:30-16:00 Conclusion: Our results highlight the difÀculty
in accrual onto lung cancer clinical trials. Only
MO17.13 PATIENT PARTICIPATION a small proportion of patients were eligible for a
IN THORACIC CANCER CLINICAL clinical trial in our study due to a lack of clinical
TRIAL : PROSPECTIVE ANALYSIS IN A trials availability. IdentiÀcation of barriers to the
UNIVERSITARY HOSPITAL participation to clinical trials may help us to enhance
Stephanie Lozano1, Ludivine Leseux1, Elsa Peyrat- accrual and to develop tailored trials, particularly in
Detis1, Laurence Bigay-Gamé1, Laurent Brouchet2, orphan disease (small cell lung cancer, squamous
Alain Didier3, Julien Mazieres1 cell lung cancer, thymoma), and underrepresented
1
Thoracic Oncology, Toulouse University Hospital/ patients.
France, 2Thoracic Surgery, Toulouse University Keywords: participation, Lung cancer, Clinical trial,
Hospital/France, 3Pneumologie, Toulouse University eligibility criteria
Hospital/France
Background: Lung cancer is a worldwide concern,

with a low survival rate. Clinical trials are essential
for improving patient outcomes. Unfortunately, it is
Epidemiology II Wednesday, 6 July 2011 14:30-16:00 Session MO18: Clinical Cases and
Clinical Decisions II
MO17.14 LUNG CANCER RISK AT
LOW ASBESTOS EXPOSURE: META-
REGRESSION OF THE EXPOSURE-
RESPONSE RELATIONSHIP
Sjoukje Van Der Bij1, Hendrik KofÀjberg1, Virissa Clinical Cases and Clinical Decisions II Wednesday, 6 July 2011 14:30-
Lenters2, Lutzen Portengen2, Karel G.M. Moons1, 16:00
Dick Heederik2, Roel C.H. Vermeulen2
1
Julius Center For Health Sciences And Primary MO18.01 RECURRENT AND/OR
Care, University Medical Center Utrecht/ BILATERAL PNEUMOTHORAX
Netherlands, 2Division Of Environmental INDUCED BY BEVACIZUMAB
Epidemiology, Institute For Risk Assessment Pascal Dô1, Adrien Dixmier2, Radj Gervais3
1
Sciences/Netherlands Calvados, Centre Francois Baclesse/France,
2
Centre Hospitalier Régional/France, 3Centre
Background: Most previous lung cancer studies Francois Baclesse/France
focused on individuals heavily exposed to asbestos.
Therefore, the existing estimated lung cancer risks Background: Bevacizumab, a monoclonal antibody
per unit of exposure are mainly based on, and directed to vascular endothelial growth factor
applicable to, high exposures. However, increasing (Avastin; Genentech, Inc, South San Francisco,
interest lies in estimating risk at low exposures. CA), increases the efÀcacy of chemotherapy in
Methods: We Àtted linear and non-linear meta- many cancers. Bevacizumab’s principle side effects
regression models to 104 aggregated risk estimates are hypertension and proteinuria. Haemoptysis and
extracted from 19 asbestos lung cancer studies. gastro-intestinal perforation are other rare, yet life-
Associated relative risks (RRs) were calculated for threatening side effects.
several low cumulative asbestos exposure levels. The Methods: We report three cases of recurrent and/
sensitivity of these RRs to the inclusion or exclusion or bilateral life-threatening pneumothorax in three
of speciÀc studies was assessed. patients receiving bevacizumab.
Results: A natural spline model Àtted our data best. Results: Patient 1 was a non-smoking 42-year-old
With this model the relative lung cancer risk for man with a colorectal cancer and cavitary pulmonary
cumulative exposures levels of 0.1 f-y/ml, 4 f-y/ml, metastases. Bevacizumab and capecitabine achieved
and 40 f-y/ml was estimated to lie between 1.000- stabilisation. Five weeks later, left pneumothorax
1.001, 1.013-1.027, and 1.13-1.30, respectively. required chest tube insertion. At thoracoscopy,
After stratiÀcation by Àber type, a 3 to 4-fold multiple necrotic metastases were observed on
difference in RRs between chrysotile and amphibole the visceral pleura. Air leaks persisted despite
Àbers was found for exposures below 40 f-y/ml. surgical suture. The patient died eight weeks
Fiber type-speciÀc risk estimates were strongly after the occurrence of the pneumothorax. Patient
inÁuenced by a few studies 2 was a non-smoking 55-year-old woman with
Conclusion: The natural spline regression model pulmonary metastases of bronchial adenocarcinoma,
indicated that at lower asbestos exposure levels, presenting with right partial pneumothorax six
the increase in RR of lung cancer due to asbestos weeks after starting carboplatine, paclitaxel and
exposure may be larger than expected from previous bevacizumab. Chemotherapy was pursued without
meta-analyses. Heterogeneity in the results, however, bevacizumab. Three weeks later, chest CT revealed
limited accurate assessment of potency differences partial response but bilateral pneumothorax. Right
between different Àber types. Low exposed industry thoracoscopy achieved pneumothorax resolution.
or population-based cohorts with quantitative Left pneumothorax was stable until death one
estimates of asbestos exposure are required to year later. Patient 3 was a non-smoking 33-year-
substantiate the risk estimates at low exposure levels old woman with breast cancer and lymphangitic
from our new, Áexible meta-regression. spread to the left lung. Bevacizumab and paclitaxel
Keywords: Amphiboles, asbestos, Chrysotile, meta- achieved a partial response. Two months later, the
analysis patient presented with bilateral pneumothorax.
Despite chest tubes insertion and talc slurry, bilateral
pneumothoraces recurred. She declined thoracoscopy with NSCLC and spontaneous pneumothoraces
and died a further two months later. treated with Bevacizumab.
Conclusion: Pneumothorax in cancer patients Results: 1st case: A 41-year old never smoking asian
is a rare event. Smoking, chronic obstructive female was diagnosed with stage IV adenocarcinoma
pulmonary disease, proximal bronchial obstruction, of the lung with extensive intrapulmonary metastases
chemotherapy- or radiation-induced pulmonary in March 2006. She received Àfth line therapy
Àbrosis, rapid tumour lysis and necrosis of large with Bevacizumab, Gemcitabine and Vinorelbin
metastatic pulmonary lesions, enlargement of a from January 2008 until November 2008, when
rapidly necrotising tumour, are possible causes. None she presented with a pneumothorax on the right
of these mechanisms was present in our patients. As side. Besides, chest CT showed a regression
antiangiogenesis agents are responsible for tumour of the pulmonary nodules and the mediastinal
cavitation when administered for patients with lung lymph nodes. Bevacizumab was continued while
cancer, it is reasonable to assume that bevacizumab cytotoxic chemotherapy was stopped to decrease
may have favoured the disruption of pleural-based the risk for empyema. A few weeks later the
metastases into the pleural space. Recurrence may be patient presented with bilateral pneumothoraces.
due to healing defect secondary to antiangiogenetic A chest tube was placed on the left side when a
effect. We conclude that pneumothorax in these tension pneumothorax developed. While the right
patients was related to bevacizumab on the grounds pneumothorax had resolved completely, the left
that: 1.The pneumothorax occurred only a few pneumothorax persisted partially after the chest
weeks after initiating bevacizumab 2. Bilateral tube was accidentally removed. The patient was
involvement and/or recurrence despite chest tube discharged, and three weeks later she was admitted
insertion are unusual features 3. Usual causes were to hospital again with a pneumothorax on the
absent. Physicians using bevacizumab should be right side. Bevacizumab was stopped because of
aware of this rare, yet potentially life-threatening the poor performance status; best supportive care
complication consisting in bilateral and/or recurrent was started. At discharge, X-ray showed bilateral
pneumothorax. pneumothoraces again. The patient died three weeks
Keywords: bevacizumab, Pneumothorax later. 2nd case: A 61-year old former smoking male
with adenocarcinoma of the right upper lobe, stage
IV, with lymphangiosis carcinomatosa was treated
Clinical Cases and Clinical Decisions II Wednesday, 6 July 2011 14:30- with Bevacizumab and Docetaxel as third-line
16:00 therapy. He received two cycles of therapy and then
presented with worsening dyspnoea. Chest-X-ray
MO18.02 SPONTANEOUS revealed a small pneumothorax on the right side.
PNEUMOTHORAX IN NSCLC PATIENTS A chest tube was placed, but the patient died a few
TREATED WITH BEVACIZUMAB days later due to respiratory failure. 3rd case: A 73-
Lorena Koch, Ali Sensoy, Tamara Hernler, Friederike year old male had a left upper lobe resection due
Lins, Thomas Jenny, Simona Müller, Peter Cerkl to pulmonary adenocarcinoma in February 2010.
Pulmonology, Department For Pulmonology, He rejected adjuvant chemotherapy. Five months
Landeskrankenhaus Hohenems/Austria later, malignant pleural effusion on the left side,
diagnosed by cytology, developed. Chemotherapy
Background: Spontaneous pneumothorax in with Carboplatin, Vinorelbine and Bevacizumab
neoplasm of the lung is rare. There have been few was initiated. Pleural effusion regressed. After
reports on pneumothoraces in pulmonary metastases six cycles of therapy, the patient presented with
from different malignancies treated with effective an asymptomatic Áuidopneumothorax on the left.
cytotoxic chemotherapy. There is one recent report Clinically, there was no evidence for an insufÀciency
of a pneumothorax in a patient with lung metastases of the bronchus stump, so bronchoscopy was not
from colorectal cancer treated with Bevacizumab, performed. Bevacizumab was continued and six
and one report of a bilateral pneumothorax in a weeks later, X-ray revealed only pleural effusion.
patient with renal cell carcinoma treated with another Bevacizumab is still given as a maintenance therapy,
anti-VEGF drug, suggesting tumour shrinking from and the patient is still in a good state.
effective therapy as the cause for the pneumothorax. Conclusion: Bevacizumab is active in lung cancer
Methods: Here, we report three cases of patients and other solid tumours. To our knowledge, these
are the Àrst reports of Bevacizumab-associated Figure 1 illustrates 6 patients with tumor cavitation.
pneumothoraces in NSCLC. Physicians using The histological diagnosis in cavitated tumors
this agent should be aware of the occurence of was squamous cell carcinoma (SCC, n=14),
spontaneous pneumothorax, recognizing its toxicity adenocarcinoma (n=1) or undifferentiated large
may be closely related to its efÀcacy. cell carcinoma (n=1). In total, 8 patients with
Keywords: case report, Pneumothorax, a tumor cavitation (7 SCC) developed severe
bevacizumab, NSCLC pulmonary complications; tumor abscess (n=5), fatal
hemorrhage (n=2) and fatal embolism (n=1). Despite
intravenous antibiotics, 2 patients with a tumor
Clinical Cases and Clinical Decisions II Wednesday, 6 July 2011 14:30- abscess required open-window thoracostomy post-
16:00 CCRT. Overall survival for patients with or without
tumor cavitation was median 9.9 and 18.2 months,
MO18.03 TUMOR CAVITATION IN respectively (log-rank p=.208, ns).
PATIENTS WITH STAGE III NON-
SMALL-CELL LUNG CANCER
UNDERGOING CONCURRENT
CHEMORADIOTHERAPY: INCIDENCE
AND OUTCOMES
Erik C. Phernambucq1, Koen J. Hartemink2, Egbert
F. Smit3, M. A. Paul2, Pieter E. Postmus3, Suresh
Senan1
1
Netherlands, 2Department Of Thoracic Surgery, VU
University Medical Center/Netherlands, 3Pulmonary
Diseases, VU University Medical Center/
Netherlands Conclusion: During the course of CCRT, grade III
acute pulmonary complications developed in 50%
Background: Commonly reported complications of patients with stage III NSCLC who presented
following concurrent chemoradiotherapy (CCRT) with radiological features of a tumor cavitation.
in patients with stage III non-small-cell lung cancer The majority of patients had a SCC and the most
(NSCLC) include febrile neutropenia, radiation common complication was a tumor abscess.
esophagitis and pneumonitis. After observing cases Keywords: concurrent chemoradiotherapy, tumor
of infected tumor cavitation or ‘tumor abscess’ cavitation, stage III NSCLC
shortly after CCRT, we studied the incidence and
outcomes of tumor cavitation in a single institutional
cohort. Clinical Cases and Clinical Decisions II Wednesday, 6 July 2011 14:30-
Methods: Between 2003-2010, 87 patients with 16:00
a stage III non-small-cell lung cancer (NSCLC)
underwent platinum-based CCRT without subsequent MO18.04 RISK OF RIB FRACTURE
surgical resection. Diagnostic and radiotherapy AFTER STEREOTACTIC BODY
planning computed tomography (CT) scans were RADIATION THERAPY FOR PATIENTS
reviewed for tumor cavitation, which was deÀned as WITH PERIPHERAL LUNG TUMORS
a non-bronchial air-containing cavity located within Su Ssan Kim1, Eun Kyung Choi1, Si Yeol Song1,
the primary tumor. Pulmonary toxicities scored as Jungshin J. Lee2
1
Common Toxicity Criteria v3.0 grade III occurring Radiation Oncology, Asan Medical Center/Korea,
2
less than 90 days after end of radiotherapy, as well as Medical Oncology, Asan Medical Center/Korea
all follow-up data were obtained from a prospective
database. Background: The aim of this study is to evaluate the
Results: In the entire cohort, tumor cavitation risk of rib fracture after stereotactic body radiation
was observed on CT scans of 16 patients (18.4%), therapy (SBRT) for patients with primary or metastatic
and 20 patients (23%) experienced any grade III peripheral lung tumors . An analysis for risk factors
pulmonary toxicity other than radiation pneumonitis. correlated with the rib fracture was also performed.
Methods: From January 2006 to December 2009, 375 up. However, early regional or stump recurrence
lung tumors (296 patients) were treated with body- is easily missed on serial MDCT or FDG PET
frame-based hypofractionated radiation therapy at due to anatomic distortion, chronic granulation
Asan Medical Center. This study included 133 lesions tissue, combined complication, or surgical
(125 patients) which were adjacent to chestwall (less artifacts on image modalities even on dedicated
than 1cm) and followed up with chest CT for more chest radiologists. Learning objectives are 1) the
than 6 months. Fractional dose of 10-20 Gy was understanding of characteristics and spectrums
delivered to 85-90% of the planning target volume of early regional or stump recurrence, and 2) the
for consecutive for 4 days or twice a week. Total dose improvement early diagnosis of recurrence of
ranged from 36-60 Gy. The rib fracture was deÀned as NSCLC, using MDCT or FDG PET.
the appearance of the fracture line or the dislocation of Methods: We retrospectively reviewed the serial
the ribs on follow-up CT scans. Kaplan-Meier method MDCT images of 30 patients with regional or stump
and Log-rank test were used to get survival rate and recurrence without distant or obvious lung to lung
analyze the risk factors respectively. metastases. Among them, 25 patients had correlated
Results: Patients’ age ranged from 19-90 years FDG PET. Clinical symptoms were hemoptysis,
(median 70) and male gender was predominant cough or dyspnea. No signiÀcant clinical symptoms
(70.4%). Primary or recurrent lung cancer lesions were also frequent.
were 60% (80 lesions). With the median follow-up Results: We will illustrate growing endobronchial
period of 18 months (range: 7-54), total 47 cases of mass, daughter nodule, bulging out mass/ contour
the rib fracture were veriÀed. Median time to the rib change/voluminous at central portion, localized
fracture was 16 months (range: 4-40). The 18-month lymphangitic tumor spread, new enhancing foci
actuarial risk of the rib fracture was 31.7%. Female within granulation tissue, localized chest wall
gender and the higher prescribed dose were revealed invasion, adjacent radiotherapy or suture materials,
to be statistically signiÀcant risk factors. as regional or stump recurrence on MDCT. We will
Conclusion: The risk of the rib fracture was also demonstrate ipsilaterally located, localized
considerable especially for the peripheral lung tumors nodal mass with or without extra-nodal extension.
after stereotactic body radiation therapy, so clinical Conclusion: Familiarity with early regional or
attention should be given to the high-risk patients. The stump recurrence on follow-up MDCT and FDG
effort to decrease the dose to the chestwall should be PET may help the clinicians to establish adequate
made to reduce the risk of the rib fracture. treatment plan such as reoperation, chemotherapy,
Keywords: rib fracture, Lung tumor, stereotactic or radiotherapy. MDCT and FDG PET may augment
body radiation therapy diagnostic accuracy.

Clinical Cases and Clinical Decisions II Wednesday, 6 July 2011 14:30- the Late Breaking Abstract Supplement, available
16:00 at the 14th World Conference on Lung Cancer.
MO18.06 ILLUSTRATIVE REVIEW OF

VARIOUS EARLY DETECTION OF THE Clinical Cases and Clinical Decisions II Wednesday, 6 July 2011 14:30-
REGIONAL OR STUMP RECURRENCE 16:00
AFTER SURGERY AND/OR CCRT OF
THE NON SMALL CELL LUNG CANCER MO18.07 RETROSPECTIVE STUDY
USING MDCT AND FDG PET OF SIX PATIENTS WITH PRIMARY
Mi Young Kim TRACHEAL CARCINOMA
Department Of Radiology And Research Institute Of Yoshiro Nakahara1, Yukio Hosomi1, Yusuke Okuma2,
Radiology, Asan Medical Center/Korea Yusuke Takagi3, Mari Iguchi1, Tatsuru Okamura3,
Masahiko Shibuya1, Hirotoshi Horio4
1
Background: Early detection of intra-thoracic Department Of Respiratory Medicine, Tokyo
regional or stump recurrence after open thoracotomy Metropolitan Cancer And Infectious Disease Center
and/or concomitant (pre- or post operative) Komagome Hospital/Japan, 2Respiratory Medicine,
chemo-radiotherapy is very important for proper Tokyo Metropolitan Cancer And Infectious Disease
management for NSCLC patients during follow- Center Komagome Hospital/Japan, 3Department Of
Respiratory Medicine, Tokyo Metropolitan Cancer Background: Obesity is a risk factor for increased
And Infectious Diseases Center Komagome Hospital/ peri-operative morbidity and mortality in surgical
Japan, 4Department Of Thoracic Surgery, Tokyo patients. However, there have been limited studies
Metropolitan Cancer And Infectious Diseases Center to correlate morbidity of lung cancer resection with
Komagome Hospital/Japan obesity.
Methods: We performed a retrospective study
Background: Primary tracheal carcinomas are rare and of patients who underwent surgical resection for
little is known about the prognoses for such patients. Lung cancer at the Medical College of Wisconsin
Methods: We retrospectively analyzed data from six from 2008 to 2010. Data on patient demographics,
patients (male, n = 3; female, n = 3; median age, 59.5 weight, pathology Àndings and hospital course were
y; range, 34 - 75 y) with primary tracheal carcinoma abstracted after appropriate IRB approval.Peri-
treated at our hospital between 1980 and 2010. operative morbidity was deÀned as atrial Àbrillation,
Results: Four of the patients had adenoid cystic heart failure, respiratory failure, pulmonary
carcinoma and one each had squamous cell embolism or any medical complications arising
carcinoma and adenocarcinoma. Five patients had within 30 days after surgery.
been treated by surgical resection of the tumor and Results: Between 2008 and 2010,144 lung resections
one with advanced disease was treated only by were performed for lung cancer. Median age were
tracheal dilation using a stent. This patient died of 68(25-89) and 86(59.7%) were females. The body
disease progression 50 months after diagnosis. Four mass index (BMI) distribution were 32(22.2%)
of the Àve patients who had undergone resection in BMI 30, 60(41.6%) in BMI 25-29.9 group,
received postoperative adjuvant radiotherapy 46(31.9%) in 18.5-24.9 and 6(4.1%) were <18.5.
because of positive surgical margins. Brain In patients with BMI < 25, surgical procedures
metastasis that developed 27 months after resection consisted 31(59.6%) open lobectomy, 4(7.7%)
of the primary tracheal tumor in one patient was VATS lobectomy, 16(30.8%) wedge resection and
resected and intraoperative radiotherapy was 1(1.9%) pneumonectomy. In patients with BMI
delivered, but he died 2 months thereafter. Multiple 25, surgical procedures consisted: 54(58.7%) open
lung metastases that developed 43 months after lobectomy, 7(7.6%) VATS lobectomy, 27(29.3%)
resection of the primary tracheal tumor in one wedge resection and 4(4.3%) pneumonectomy.
patient were resected and she remained alive at 76 Tumor histology were: adenocarcinoma 64(44%),
months thereafter. One patient died of hepatocellular squamous cell cancer 48(33%), bronchoalveolar
carcinoma without tracheal carcinoma recurrence. 8(5%), large cell 5(3%) and mixed 19(13%). The
Two patients remained alive without recurrence 30 day mortality rate was 3.4% (5 patients), all of
for 53 and 78 months after resection. The median whom underwent open lobectomy and only 1 had
survival was 51.5 months (range, 30 - 119 months). BMI 25. Peri-operative morbidity occurred in
Conclusion: Although the prognosis of primary 7(13.5%) of normal BMI patients and 18(19.6%) of
tracheal carcinomas was relatively good, distant BMI 25 patients (p=0.3455). SpeciÀc morbidities
metastases tend to arise late after resection. encountered by patients with normal vs. BMI 25
Keyword: tracheal carcinoma were: atrial Àbrillation 5(9.6%) vs. 9(9.7%) (p=0.97),
Pulmonary embolism 0(0%) vs. 2(2.1%) (p=0.18),
congestive heart failure 0(0%) vs. 3(3.2%) (p=0.09),
Clinical Cases and Clinical Decisions II Wednesday, 6 July 2011 14:30- acute respiratory failure 0(0%) vs. 3(3.2%) (p=0.09)
16:00 and ARDS 2(3.8%) vs. 1(1.08%) (p=0.69).Median
hospital stay in both groups were 4.3 days.
MO18.08 SURGERY FOR LUNG CANCER Conclusion: Although there may be a slight trend
IN OBESE PATIENTS, RISKIER OR NOT? towards increased peri-operative congestive heart
Binod Dhakal1, Sunitha Sukumaran2, George Hassler3, failure and respiratory failure in overweight patients,
William Tisol3, Mario Gasparri3, Nicholas Choong2 overweight and normal weight patients do not differ
1
Internal Medicine, Medical College Of Wisconsin/ signiÀcantly in rates of peri-operative morbidities.
United States Of America, 2Hematology/oncology, Thus potentially curative resection of lung cancers
Medical College Of Wisconsin/United States Of can be offered to even signiÀcantly overweight
America, 3Cardiothoracic Surgery, Medical College patients, even if pneumonectomy might be required.
Of Wisconsin/United States Of America Keywords: Lung cancer, Surgery, Morbidity
Clinical Cases and Clinical Decisions II Wednesday, 6 July 2011 14:30- Conclusion: Pulmonary resection for patients with
16:00 severe coronary disease were feasible. Strategy
for preoperative anti-coagulant or platelet were
MO18.09 PULMONARY RESECTION FOR successful. Further investigation is warranted
PATIENTS WITH SEVERE CORONARY especially for patients with recent coronary stent
DISEASE: HOW TO MANAGE treatment, such as drug-eluting stent.
PREOPERATIVE ANTI-COAGULANT OR Keywords: pulmonary resection, Anti-coagulant
ANTI-PLATELET AGENT Agent, Anti-platelet Agent, Coronary Disease
Yoshitaka Kitamura, Nobumasa Takahashi,
Yoshikazu Miyasaka, Takamitsu Banno, Kohta A revised/updated abstract may be included in
Imashimizu, Kazuya Takamochi, Shiaki Oh, Kenji the Late Breaking Abstract Supplement, available
Suzuki at the 14th World Conference on Lung Cancer.
General Thoracic Surgery, Juntendo University/
Japan
Clinical Cases and Clinical Decisions II Wednesday, 6 July 2011 14:30-
Background: The number of lung cancer patients 16:00
with severe coronary disease is increasing.
According to the developed coronary intervention, MO18.11 A CASE OF PRIMARY
preoperative anti-coagulant or anti-platelet is SYNOVIAL SARCOMA OF THE LUNG
frequently necessary for those. However, feasibility DIAGNOSED BY GENE ANALYSIS
of pulmonary resection for such patients remains AFTER THE SURGICAL RESECTION OF
controversial and there are no guidelines at all. CHONDROSARCOMA ARISING FROM
Methods: Retrospective study was conducted on SCAPULA
754 patients who underwent pulmonary resection Yasuaki Kubouchi, Yuji Taniguchi, Yohei Yurugi,
at our institute between February 2008 and May Yuzo Takagi, Tomohiro Haruki, Shinji Fujioka, Ken
2010. Among them, 51 patients were complicated Miwa, Hiroshige Nakamura
with severe coronary disease. The reason for anti- Thoracic Surgery, Tottori University Hospital/Japan
coagulant or platelet medication was as follows;
percutaneous coronary intervention in 28 patients Background: Most synovial sarcomas arise around
(54.9%), atrial Àbrillation in 21 (41.2%), coronary joints, and primary synovial sarcoma of the lung is
artery bypass graft in 2 (3.9%). All those patients rare. We report a patient who was diagnosed with
were systemically heparinized and discontinued to be primary pulmonary synovial sarcoma based on gene
medicated with anti-coagulant or anti-platelet agents expression analysis.
for one week prior to surgery. Forty one patients Methods: The following is the case.
(80.4%) had primary lung cancer, 7 (13.7%) had Results: Case: A 63-year-old male has received
metastatic lung tumor, 2 (3.9%) had benign tumor regularly check up by orthopedic surgen in our
and pneumothorax was one (2.0%). Thirty four hospital for 12 years after curative resection of right
patients (66.7%) underwent lobectomy, 5 (9.8%) scapula chondrosarcoma. He was introduced to
segmentectomy and 12 (23.5%) wedge resection. our department because of an abnormal chest x-ray
Surgical outcome and feasibility of pulmonary shadow in the right upper lung without respiratory
resection of this strategy was investigated. symptoms. A chest CT revealed a 12×9mm tumor in
Results: There was no mortality, and surgical size that has relatively clear margin in the right upper
resections were completed for all patients without lobe. The patient was suspected of metastasis of
any lethal complications. There were no signiÀcantly chondrosarcoma to lung since tumor size increased
differences between hepariniaed patients and the to 13×11mm for 3 months, so we performed a wedge
other non-heparinized 703 patients in operation time, resection of the right lung by VATS (video assisted
intraoperative blood loss and the duration of chest thoracic surgery). Intraoperative histopathology
drain placement ( 146 vs 150 min; p=0.657, 49 vs 72 showed that the proliferation of fusiform cell
ml ; p=0.332, 3.3 vs 3.7 days; p=0.643, respectively). was observed and denied lung cancer. Final
No perioperative cardiovascular events were found histology revealed that the tumor was composed
at all. One patient developed hemosputum on the of densely proliferating uniform spindle-shaped
operation day, resulting in conservative cure. or oval cells in fascicles. The tumor cells were
immunohistochemically positive for vimentin, bcl-2 appears to arise a wide range at presentation and the
protein and CD99 and partially for cytokeratin, AE1/ most common anatomic setting for myopericytoma
AE3 and EMA. From these examinations, although it is the skin and superÀcial soft tissues of distal
was indicated synovial sarcoma or malignant solitary extremities.2 In the past few years, a wider
Àbrous tumor, we could not reach a deÀnitive distribution is described, including the oral or nasal
diagnosis. Reverse transcription polymerase chain region, the trunk, the intravascular location and even
reaction (RT-PCR) performed on frozen sections the intracalvarium.2,3 This unusual tumor had hitherto
demonstrated fusion gene transcripts of SYT-SSX not been reported in the lung.
(synaptotagmin- synovial sarcoma X). A deÀnitive Methods: Here, we introduce an unusual case of
diagnosis of synovial sarcoma of the lung was made. pulmonary myopericytoma presented as multiple
Reoperation was not performed, for the following nodules in a 26-year-old man. Clinical presentation,
reasons: (1) small tumor, (2) pleural lavage cytology radiological features and histopathologic Àndings of
during thoracotomy is negative (3) the metastases to the patient are reported.
hilar or mediastinal lymph node was not detected by Results: A 25-year-old man presented with dry
preoperative diagnostic imaging. At present 5 months cough for Àve months. CT and MRI of the chest
after surgery, there are no signs of recurrence. was notable for the bilateral, heterogeneously,
Conclusion: Few cases of pulmonary multiple nodules(Figure 1). Open lung biopsy was
carcinosarcoma after chondrosarcoma operation performed. The microscopic examination of the
have been reported. In patients with past history of mass showed that the lesions were composed of
malignant disease, it is important to be distinguished oval to spinal-shaped cells with a striking concentric
from metastatic lung cancer preoperatively. Since arrangement of cells around numerous variably
diagnosis of spindle cell tumors by cytological sized lesional blood vessels. Tumor cells were ill-
examination alone is difÀcult, immunohistochemistry deÀned cytoplasmic membranes with eosinophilic
and genetic studies are necessary. Primary synovial cytoplasm. Immunostaining demonstrated an
sarcoma easily develops local recurrence and distant accentuated vascular proliferative pattern with
metastasis, so the prognosis has been reported to CD31 and CD34 antibody which stained endothelial
be poor. We must be very careful with follow-up in cells. The cells surrounding vascular lumina
these cases. are strongly positive for vimentin and smooth
Keyword: synovial sarcoma muscle actin, but negative for desmin or S-100.
Correlating the histopathological features with
A revised/updated abstract may be included in the immunohistochemical Àndings, a diagnosis of
the Late Breaking Abstract Supplement, available myopericytoma was established (Figure2).
Clinical Cases and Clinical Decisions II Wednesday, 6 July 2011 14:30-

16:00
MO18.12 MYOPERICYTOMAS
PRESENTING AS MULTIPLE
PULMONARY NODULES
Xiaolian Song1, Changhui Wang1, Yongwei Yu2
1
Department Of Respiratory Medicine, Shanghai
Tenth People’s Hospital/China, 2Pathology
Department, Changhai Hospital, Second Military
Medical University/China
Background: Myopericytoma is a rare soft tissue

tumors with a hemangiopericytoma-like vascular
pattern. Histologically, it is characterized by a
concentric proliferation of oval to spindle-shaped
cells around vascular channels. Myopericytoma
was present in a conventional chest x-ray. CT

scan showed the mass (95x88x98mm) in anterior
mediastinum with invasion of the parietal pleura. No
distant metastases were found.
Results: The diagnosis was performed by
thoracoscopy. The pathology was mesenchymal
sarcoma. The case was inoperable, therefore
chemotheraphy was planned for the patient.
Conclusion: To the best of our knowledge, this is

the Àrst report of myopericytoma that involves the
pulmonary. The diagnosis of myopericytoma was
made on the basis of the prominent morphological
and immunoreactive Ànding. The differential
diagnosis includes a series lobus intermedius tumors
and other lung nodules, such as inÁammatory
pseudotumor, tuberculosis, sarcoidosis, lymphoma,
primarily lung cancer and metastatic tumor. Conclusion: Radiation–induced sarcoma is a
Keywords: Pulmonary, Histopathology, very rare complication of radiotherapy. It shows
Myopericytoma aggressive proliferation with a median survival of
about 12 months. Early diagnosis can be possible
because of tumor calciÀcation might be detectable
Clinical Cases and Clinical Decisions II Wednesday, 6 July 2011 14:30- even on the chest x-ray. Therefore calciÀcation seen
16:00 on chest x-ray after RT should be a reason for further
examination. In general, if the early diagnosis is
MO18.13 MALIGNANT done, surgical removal is often the only curative
MESENCHYMOMA OF THE CHEST treatment.
WALL FOLLOWING RADIOTHERAPY Keyword: mesenchymoma, radiotherapy, thorax
FOR BREAST CANCER
Tugce K. Hurkal1, Ozkan Demirhan2, Zuleyha
Bingol1, Ferah Ece1 Clinical Cases and Clinical Decisions II Wednesday, 6 July 2011 14:30-
1
Chest Diseases, Istanbul Bilim University Medical 16:00
School/Turkey, 2Thoracic Surgery, Istanbul Bilim
University Medical School/Turkey MO18.14 PRIMARY MEDIASTINAL
SARCOMAS: AN ANALYSIS OF
Background: The carcinogenic effect of ionizing TREATMENT AND OUTCOMES
irradiation has been well known. A long interval Matthew J. Bott1, Nicole Moraco2, Manjit Bains3,
(usually 10-20 years) between irradiation and Robert Downey3, Valerie W. Rusch3, Samuel Singer2,
development of cancer is characteristic of radiation – James Huang3
1
induced malignancy. Thoracic Surgery, Memorial Sloan-Kettering
Methods: Our Case: Fifty three year old woman Cancer Center/United States Of America, 2Surgery,
who had radiotherapy for breast cancer 13 years Memorial Sloan-Kettering Cancer Center/United
ago, developed a malignant mesenchymoma of States Of America, 3Thoracic Service, Department Of
the chest wall. The Àrst clinical symptom for this Surgery, Memorial Sloan-Kettering Cancer Center/
second malignancy was left sided chest pain which United States Of America
was progressively increasing and a regular opacity
Background: Primary sarcomas of the mediastinum well-differentiated liposarcoma associated with the
are rare tumors and limited data regarding their best prognosis. Surgical resection has remained the
natural history have been published. We analyzed mainstay of treatment and the beneÀt of adjuvant
the treatment and outcomes of these tumors in a therapies is unclear. Further progress in such rare
contemporary cohort of patients. diseases will likely require multi-institutional
Methods: Retrospective review of a single collaboration.
institution experience to assess presentation, Keywords: Sarcoma, mediastinum, survival,
treatment, and outcomes in patients with primary treatment patterns
mediastinal sarcomas. Data included demographics,
treatment details, pathologic Àndings, recurrence
patterns, and survival. Session MO19: SCLC II
Results: During the period 1983 to 2009, 48 patients
were seen at our institution for initial treatment Thursday, 7 July 2011
of primary mediastinal sarcomas. The median
age was 45 years (range 18-79 years) with a male
predominance (60%). The majority of tumors SCLC II Thursday, 7 July 2011 12:30-14:00
(46/48, 96%) were symptomatic with pain (29%),
dyspnea (25%), and cough (12.5%) as the most MO19.01 OMIT ELECTIVE NODAL
frequent chief complaint at presentation. The most IRRADIATION AND IRRADIATE
common histologic subtypes were: liposarcoma POST- VERSUS PRE-INDUCTION
(12, 25%), malignant Àbrous histiocytoma (7, CHEMOTHERAPY TUMOR EXTENT
15%), and synovial sarcoma (5, 10%). Surgery was FOR LIMITED-STAGE SMALL CELL
the primary treatment modality in 90% of cases LUNG CANCER: AN INTERIM ANALYSIS
(n=43) and half of these patients some received OF A PROSPECTIVE RANDOMIZED
adjuvant treatment post-operatively (chemotherapy NON-INFERIORITY TRIAL
12%, radiation 33%, both 5%). R0 resections were Ming Chen1, Xiao Hu1, Yong Bao1, Li Zhang2, Yuan
achieved in 51% of patients. Median follow-up for Y. Chen1, Ying Guo3, Kai X. Li4, Wei H. Wang5, Yuan
all surviving patients was 50.9 months (range 0.7 to Liu6, Han He7
1
244 months). Overall survival for the entire cohort Radiation Oncology, Sun Yat-sen University Cancer
was 35 months with 5- and 10- year survivals of 43% Center/China, 2Medical Oncology, Sun Yat-sen
and 30%, respectively. Patients who were unable to University Cancer Center/China, 3Good Clinical
undergo surgery or who were otherwise inoperable Practice, Sun Yat-sen University Cancer Center/
had signiÀcantly worse survival (p=0.0003). Low- China, 4Radiation Oncology, People’s Liberation
grade tumors were associated with a signiÀcantly Army 180 Hospital/China, 5Radiation Oncology,
better survival than high-grade tumors (p=0.004). Kiang Wu Hospital/China, 6Radiation Oncology,
Survival was signiÀcantly different amongst the AfÀliated Tumor Hospital Of Guangzhou Medical
different histologies (p=0.0006), with liposarcoma, College/China, 7Radiation Oncology, The First
desmoid tumors, and synovial sarcoma having the People’s Hospital Of Foshan City/China
longest median survivals (153 months, 85 months,
and 61 months, respectively). Although liposarcomas Background: Controversies exist with regard
had the longest median survival of the cohort, well- to thoracic radiotherapy (TRT) target volumes
differentiated tumors (median survival 153 months) for limited-stage small cell lung cancer (SCLC)
were associated with signiÀcantly better survival and few prospective studies specially designed
(p=0.006) compared with the de-differentiated to solve this issue were available in the past two
tumors (median survival 18 months). Tumor size, decades. This study compared the clinical outcomes
adjuvant treatment, and mediastinal location had no between limited-stage SCLC patients who received
signiÀcant impact on outcomes. TRT to different target volumes after induction
Conclusion: Mediastinal sarcomas are a chemotherapy.
heterogenous group of rare tumors with a poor Methods: Chemotherapy consisted of 6 cycles
prognosis in general. Among the histologies, of etoposide and cisplatin (EP) administered
liposarcoma, synovial sarcoma, and desmoid intravenously at 21-day intervals. After 2 cycles of
tumors have a more favorable prognosis, with EP, patients were randomly assigned to receive TRT
to either the post- or pre-chemotherapy tumor extent SCLC II Thursday, 7 July 2011 12:30-14:00
as study arm or control. Elective nodal irradiation
(ENI) was omitted for both arms. Forty-Àve MO19.02 PHASE II STUDY OF
Gy/30Fx/19d TRT was administered concurrently ACCELERATED HIGH-DOSE
with cycle 3 chemotherapy. Prophylactic cranial RADIATION THERAPY WITH
irradiation was administered to patients achieved CONCURRENT CHEMOTHERAPY FOR
complete remission. This study was designed as PATIENTS WITH LIMITED STAGE
a prospective randomized non-inferiority trial. SMALL-CELL LUNG CANCER: FINAL
An interim analysis was planned when the Àrst 80 RESULTS OF RTOG 0239
patients had been followed for at least 6 months, for Ritsuko Komaki1, Rebecca Paulua2, David S.
consideration of potentially inferiority in the study Ettinger3, Gregory M. Videtic4, Jeffery D. Bardley5,
arm. Bonnie S. Glisson6, Hak Choy7
1
Results: Forty-two and 43 patients were randomly Radiation Oncology, Unit 97, Ut MD Anderson
assigned to study arm and control respectively. Cancer Center/United States Of America, 2Statistics,
Thirty-one patients remained alive at the time of Rtog/United States Of America, 3Medical Oncology,
analysis, with a median follow-up of 29.5 months Johns Hopkins Hospital/United States Of America,
4
(6.4-97.9 months). Four patients of the study arm and Cleveland Clinic/United States Of America,
5
1 patient of the control developed distant metastasis Radiation Oncology, Washington University/United
after induction chemotherapy were not included in States Of America, 6Ut MD Anderson Cancer Center/
analysis for local control. The local recurrence rates United States Of America, 7Ut Southwest/United
were 31.6% (12/38) in the study arm and 28.6% States Of America
(12/42) in control respectively (P = .81). The isolated
nodal failure (INF) rates were 2.6% (1/38) and 2.4% Background: The purpose of this study was to
(1/42) respectively (P = 1.00). All INF sites were evaluate the effects of accelerated, high-dose
in the ipsilateral supraclavicular fossa. Mediastinal thoracic radiotherapy (TRT) given concurrently with
N3 was the only factor to predict INF (P = .004, etoposide and cisplatin on overall survival (OS), acute
OR = 29.33, 95% CI, 2.94-292.38). The median esophageal toxicity, and local control for patients with
survival time was 22.1 months in the study arm (95% limited-stage small cell lung cancer (LSCLC).
CI, 16.6-27.6 months) and 25.4 months (95% CI, Methods: Patients with LSCLC and good
20.4-30.4 months) in control, one to 3-year overall performance status received TRT to 61.2 Gy over 5
survival (OS) rates were 80.6%, 42.2%, 36.2% and weeks in once-daily 1.8-Gy fractions (fx) on days
78.9%, 52.2%, 36.4% respectively (P = .54). 1-22 followed by twice-daily 1.8-Gy /fx on days
23-33. Cisplatin (60 mg/m2 IV) and etoposide (120
mg/m2 IV) were given on days 1 and 22 of TRT
and etoposide (120 mg/m2 IV or 240 mg/m2 p.o.)
on days 2 & 3 and 23 & 24; 2 cycles of adjuvant
chemotherapy were given on days 43-45 and 64-66.
Patients achieving complete response were offered
prophylactic cranial irradiation (PCI). The primary
endpoint was OS at 2 years; secondary endpoints
were progression-free survival (PFS) and OS rates
at 1 year, median survival times, and rates of acute
esophagitis and treatment-related deaths (CTC v2.0),
Conclusion: The preliminary results indicated that response (RECIST1.0), and local and distant failure.
irradiate the post-chemotherapy tumor extent and Results: Seventy-two patients were accrued between
omit ENI did not decrease local-regional control, June 2003 and May 2006; 71 were eligible for
and the OS difference was not statistically signiÀcant analysis (median age 63, 52% female, 58% Zubrod
between the two arms. Further investigation is 0). Median follow-up time was 19.0 months for
warranted. all patients (54.6 months for living patients). The
Keywords: limited-stage, combined modality 2-year OS rate was 36.6% (95% conÀdence interval
treatment, Lung cancer, small cell, radiation target [CI] 25.6%-47.7%); 1-year OS, 77.5% (95% CI
volume 65.9%-85.5%); 1-year PFS, 42.3% (95% CI 30.7%-
53.4%); and median PFS time was 9.9 months Of Medicine/United States Of America, 11Lung
(95% CI 7.9-12.4 months). Thirteen patients (18%) Unit, Royal Marsden Hospital/United Kingdom,
12
experienced acute severe (grade 3+) esophagitis, University College London Hospital/United
and three patients (4%) died of treatment-related Kingdom
causes( One each : Neutropenic Sepsis, Neutropenic
Pneumonia & Pericardial Effusion). At 2 months Background: Small cell lung cancer (SCLC)
after chemoradiation, 41% had a complete response accounts for about 10-15% of all lung cancer cases,
and 39% a partial response. Fourteen patients (20%) with only one third presenting with limited stage
experienced local failure (LF), 31 (44%) distant (LS). Combination of chemotherapy (CT) and
metastasis (DM), and 5 (7%) both LF and DM. chest radiotherapy (RT) has improved survival at
Nine (12.7%) patients experienced brain metastases. 2 and 3 years but the optimal timing and duration
Forty-three patients received PCI, 22 of whom of RT remains controversial. The objective of this
received 25Gy in 10fx. There was no signiÀcant individual patient data meta-analysis was to assess
difference in OS between PCI vs. no PCI, although the timing of RT (early versus late) on the survival of
the number was small. patients in SCLC.
Conclusion: RTOG 0239 showed a 2-year OS of Methods: Trials of combined CT-RT for LS-SCLC,
36.6% which did not reach to the goal of 47%. with accrual between 1969 and 2006, comparing
The treatment was well tolerated with acceptable early (before days 49) versus later RT or short versus
toxicities. Main cause of failure was DM. This longer duration RT were eligible. Patients with good
protocol is now one of three arms of a prospective performance status (WHO 0-2) and who received
randomized trial of chemoradiation for LSCLC Àrst line therapy were included. Primary endpoint
(RTOG 0538/CALGB 30610). was overall survival (OS). Progression-free survival
Keyword: LSMCLC, Accelerated TRT with (PFS), and acute severe toxicities were also studied.
Chemotherapy CT compliance by arm was taken as the percentage
of the planned number of cycles that the patients
actually received. Pre-speciÀed trial classiÀcation
SCLC II Thursday, 7 July 2011 12:30-14:00 was performed to take into account the differences
of CT compliance between arms. Compliance was
MO19.03 A META-ANALYSIS OF considered different if the CT compliance rates
RANDOMISED TRIALS USING between the two arms were 10%, otherwise it was
INDIVIDUAL PATIENT DATA ON THE considered to be similar. Intent-to-treat analysis
TIMING OF CHEST RADIOTHERAPY based on Peto-Àxed effect model was used.
IN PATIENTS WITH LIMITED STAGE Results: There were nine trials including 2,304
SMALL CELL LUNG CANCER patients with a 10-years median follow-up. PFS
Dirk De Ruysscher1, Emmanuelle Paris2, Cécile data were not available for 2 trials (513 patients).
Le Péchoux3, Andrew T. Turrisi4, H. Pang5, Nevin No statistically signiÀcant effect on OS and PFS
Murray6, B. Lebeau7, M. Takada8, Dimosthenis- was seen between early and late RT (HR=1.00
Vassilios Skarlos9, Aw Blackstock10, Mary E.R. [0.91-1.09] for OS (p=0.92); heterogeneity test
O’Brien11, Stephen Spiro12, Jean-Pierre Pignon And between trials p=0.006; HR=0.93 [0.84-1.02] for
The Radiotherapy Timing In Small Cell Lung Cancer PFS (p=0.14); heterogeneity test p=0.07). For OS,
Collaborative Group2 a HR=0.79 [0.69-0.91] and 1.19 [1.05-1.34] were
1
Department Of Radiation Oncology (MAASTRO), estimated in trials with similar and different CT
Grow, Maastricht University Medical Centre/ compliance rates, as deÀned above (interaction
Netherlands, 2Institut Gustave Roussy/France, test p<0.0001). There was an absolute beneÀt at 3
3
Radiotherapy Unit, Institut Gustave Roussy/France, and 5-years (5.7% and 7.7%) in favour of early RT
4
Radiation Oncology Center, Sinai Grace Hospital/ in trials with similar CT compliance, but in those
United States Of America, 5Cancer And Leukemia trials were the two arms showed different rates of
Group B Statistical Center/United States Of America, compliance, survival was worse in early RT arm
6
Medical Oncology, British Columbia Cancer (- 3.8% and - 2.2% at 3 and 5 years). Similar results
Agency/Canada, 7Hôpital St Antoine/France, 8Osaka were observed for PFS (HR=0.81 vs. 1.12 p=0.0024)
Prefectural Habikino Hospital/Japan, 9Metropolitan and after exclusion of patients dying before 6 months
Hospital/Greece, 10Wakes Forest University School for both endpoints (test of interaction, OS, p=0.0002,
PFS, p=0.056). Trials giving hyperfractionated in the West Anglian region were retrospectively
RT (vs. standard RT), and trials with concomitant searched for patients with a histological diagnosis
platinum (vs. those without) showed higher effect of SCLC made between 2005 and 2009. Clinical
on survival (test of interaction, p=0.005 and information on staging, treatment, incidence and
p=0.01 respectively). We have observed more timing of brain metastases and date of death was
severe anaemia (337 events), HR=1.38 [1.07-1.79], gathered. Data was analysed using GraphPad Prism
oesophageal (226 events), HR=1.85 [1.39-2.45] and 4.0 and Instat 3.0 ().
cardiac (26 events), HR=2.79 [1.28-6.04] toxicity in Results: 425 patients with a histological diagnosis
early RT. of SCLC were identiÀed between 2005-2009. The
Conclusion: Differences in CT compliance between male to female ratio was 60:40 and median age
arms within trials mostly explains the heterogeneity was 68. 294 patients (69%) had extensive stage
of OS between the trials. This meta-analysis shows (ES) disease and 131 (31%) had limited stage (LS)
promising results for early RT in improving the disease. Overall survival was 14.9 months for LS
5-years survival in trials where CT compliance is versus 3.6 months for ES patients (p<0.0001).
similar in both arms. 67% of all patients received chemotherapy, 87%
Grants from PHRC and LNCC. (114/131) with LS compared to 58% (170/294) with
Keyword: Meta-analysis, Radiotherapy timing, ES disease. Median survival for LS disease receiving
Chemotherapy compliance, SCLC chemotherapy was 16.7 months versus 7.3 months
without. For ES disease, survival with chemotherapy
was 8.4 months versus 0.8 months without. PCI after
SCLC II Thursday, 7 July 2011 12:30-14:00 chemotherapy was given to 65% (74/114) patients
with LS disease and 27% (41/154) ES patients
MO19.04 MULTICENTRE STUDY OF without brain metastases at diagnosis. Regional
OVERALL SURVIVAL, INCIDENCE practice for delivery of PCI in ES patients changed
OF BRAIN METASTASES AND USE in June 2007 in line with the EORTC 08993-2293
OF PROPHYLACTIC CRANIAL trial data which showed a improved overall survival
IRRADIATION IN PATIENTS WITH with PCI; prior to this trial, only 11% (8/72)
SMALL CELL LUNG CANCER FROM ES patients were given PCI after chemotherapy
2005-2009. compared to 41% (33/80) subsequently (p<0.0001).
Niki Ainsworth1, David Saunders2, Lavinia Magee3, Overall survival for LS patients receiving PCI was
Ramesh Bulusu1, Kate Fife1, Yvonne Rimmer1, 19.9 months and 12.0 months without (p=0.009).
Kathryn Waite1, David Greenberg4, Susan V. Harden1 Overall survival was 12.6 months in patients with ES
1
Department Of Oncology, Cambridge University disease who received PCI and 7.0 months without
Hospitals NHS Foundation Trust/United Kingdom, (p=0.0007). In total 17% (73/425) patients developed
2
Cambridge University Medical School/United symptomatic brain metastases with 7% (30/425)
Kingdom, 3Papworth Hospital NHS Foundation presenting at diagnosis. The brain was not routinely
Trust/United Kingdom, 4Eastern Cancer Registration imaged in asymptomatic patients. Brain metastases
And Information Centre/United Kingdom developed after chemotherapy in 11% (13/115)
patients receiving PCI compared to 18% (28/153)
Background: Small cell lung cancer (SCLC) patients not receiving PCI (p=0.126).
commonly metastasises to the brain and is associated Conclusion: The outcome data from this multicentre
with a poor prognosis. Prophylactic cranial irradiation study compares well with published data on survival
(PCI) after chemotherapy was recently shown to for SCLC and incidence of brain metastases. This
improve overall survival in extensive as well as study supports the use of PCI in extensive as well
limited stage SCLC. This led to a change in practice as limited stage patients and shows how a change in
in 2007, to offer PCI to both extensive and limited regional practice can improve outcomes. However,
stage SCLC patients who responded to chemotherapy. for any individual, brain metastases can still occur
Survival data and the effect of PCI on clinical after PCI and conversely, may not develop even
outcomes for patients in the West Anglian region, if PCI is not given. We are now investigating
receiving radiotherapy in Cambridge, were assessed. whether a subgroup of SCLC patients most at risk
Methods: Eastern Cancer Registry and Information for developing brain metastases can be identiÀed in
Centre (ECRIC) data and multiple hospital databases advance, using novel magnetic resonance imaging
techniques within the UK National Cancer Research to treatment sequence & was found in pts who
Institute (NCRI) Lung Clinical Studies Group received concurrent TRT&PCI. Dose-fractionation
portfolio-approved CLUB-01 study. could only be compared for LSCLC pts &
Keywords: SCLC, PCI, brain metastases 25Gy/10 was associated with better survival than
30Gy/15(HR=0.72,p=0.05).
Conclusion: PCI was associated with a signiÀcant
SCLC II Thursday, 7 July 2011 12:30-14:00 survival beneÀt for both ESCLC&LSCLC pts
who had stable disease or a better response to
MO19.06 PROPHYLACTIC CRANIAL chemotherapy+/-TRT. Dose-fractionation appears
IRRADIATION(PCI) IN SMALL CELL important. PCI’s use was also associated with an
LUNG CANCER(SCLC): FINDINGS increase in overall & speciÀc grade 3+ AE rates.
FROM A NORTH CENTRAL CANCER Keywords: Small cell lung cancer, prophylactic
TREATMENT GROUP (NCCTG) META- cranial irradiation, toxicity, survival
ANALYSIS
Steven E. Schild1, Nathan Foster2, Jeffery P. Meyers2,
Helen J. Ross3, Phillip J. Stella4, Yolanda I. Garces5, SCLC II Thursday, 7 July 2011 12:30-14:00
Kenneth R. Olivier5, Julian R. Molina3, Larry R.
Past6, Alex A. Adjei7 MO19.07 A PHASE II STUDY OF
1
Radiation Oncology, Mayo Clinic/United States AMRUBICIN AND TOPOTECAN
Of America, 2Statistics, Mayo Clinic & Ncctg/ COMBINATION THERAPY IN PATIENTS
United States Of America, 3Medical Oncology, Mayo WITH RELAPSED OR EXTENSIVE-
Clinic & Ncctg/United States Of America, 4Medical DISEASE SMALL-CELL LUNG CANCER:
Oncology, St. Joseph Mercy Health System & Ncctg/ OKAYAMA LUNG CANCER STUDY
United States Of America, 5Radiation Oncology, GROUP TRIAL 0401
Mayo Clinic & NCCTG/United States Of America, Naoyuki Nogami1, Toshiyuki Kozuki1, Tetsu
6
Luther Hospital & NCCTG/United States Of Shinkai1, Yuka Katou1, Katsuyki Hotta2, Nagio
America, 7Medical Oncology, Roswell Park Cancer Takigawa2, Masahiro Tabata2, Katsuyuki Kiura2,
Institute/United States Of America Mitsune Tanimoto2
1
Thoracic Oncology, National Hospital Organization
Background: This meta-analysis was performed to Shikoku Cancer Center/Japan, 2Respiratory
evaluate the results of PCI in SCLC patients(pts). Medicine, Okayama University Hospital/Japan
739 pts with stable disease or better following
chemotherapy+/-thoracic RT(TRT) were included to Background: Chemotherapy is a mainstay in the
examine the potential advantage of PCI in a wider treatment of extensive-disease small-cell lung cancer
spectrum of pts than generally participate in PCI trials. (ED-SCLC), although the survival beneÀt remains
Methods: 318 pts with extensive SCLC(ESCLC) modest. We conducted a phase II trial of amrubicin
& 421 pts with limited SCLC(LSCLC) participated (a topoisomerase II inhibitor) and topotecan (a
in 4 NCCTG phase II trials. 459 pts received topoisomerase I inhibitor) in chemotherapy-naïve
PCI(30Gy/15 or 25Gy/10)& 280 did not. Survival and relapsed SCLC patients.
and Acute Events(AEs) were compared. Methods: Amrubicin (35mg/m2) and topotecan
Results: The 1 & 3-year survival rates were 73% (0.75mg/m2) were administered on days 3–5 and
& 20% for PCI pts vs 52% & 6% for no-PCI pts(p< 1–5, respectively. The objective response rate (ORR)
0.0001). This difference with PCI ((HR=0.61 (95% was set as the primary endpoint, which was assessed
CI: 0.52-0.72), p=0.0007)) was still signiÀcant separately in chemotherapy-naïve and relapsed cases.
in both ESCLC & LSCLC pts in multivariate Results: Fifty-nine patients were enrolled
analyses adjusting for age, performance status, (chemotherapy-naïve 31, relapsed 28). The ORRs
gender, stage, & number of metastatic sites. There were 74% and 43% in the chemotherapy-naïve
were signiÀcantly more grade 3+AE’s associated and relapsed cases, respectively. Survival data
with PCI(64%) compared to no PCI(50%) were also promising, with a median progression-
(p=0.0096). AE’s signiÀcantly associated with PCI free survival time and median survival time of 5.3
were: alopecia, anemia, esophagitis & lethargy. and 14.9 months and 4.7 and 10.2 months in the
The esophagitis Ànding appeared to be related chemotherapy-naïve and relapsed cases, respectively.
Even refractory-relapsed cases responded to the every 8 weeks and remained on therapy until disease
treatment favorably (27% ORR). The primary progression or unacceptable toxicity. The trial used
toxicity was myelosuppression with grades 3 or a two-stage design to assess the objective response
4 neutropenia in 97% of the patients, which led rate (ORR) in both SR (H1 30%, Ơ.10, ơ.20) and RR
to grades 3 or 4 febrile neutropenia in 41% of the cohorts (H1 20%, Ơ.05, ơ.20).
patients and two toxic deaths. Results: 40 pts with SR disease were enrolled over
Conclusion: This phase II study showed the 11 months. The RR arm is completing enrollment.
favorable efÀcacy and moderate safety proÀles of Pt characteristics of the SR pts: median age 62
a topotecan and amrubicin two-drug combination years, female 48%, ECOG 0-1 95%. Pts received
especially in relapsed patients with ED-SCLC. a median of 4 cycles (range 1-10) of NK012. The
Keywords: Small-cell lung cancer, SCLC, ORR assessed in 37 SR pts was 22% including
Topotacan, Amurubicin 2 complete responses; the disease control rate
(DCR=ORR+stable disease) was 68%. Fifteen SR
pts remained on treatment beyond 4 cycles. Survival
SCLC II Thursday, 7 July 2011 12:30-14:00 analyses are in progress. NK012 was well-tolerated
with the following grade 3/4 toxicities (> 5%):
MO19.08 NK012 (A NANODEVICE neutropenia (44%, 1 pt with febrile neutropenia),
FORMULATION OF SN-38) IN PATIENTS thrombocytopenia (13%), anemia (5%), diarrhea
WITH RELAPSED SMALL-CELL LUNG (8%), and no treatment-related deaths.
CANCER Conclusion: NK012 was active in pts with sensitive
David R. Spigel1, John Hainsworth1, Jeffrey R. relapsed SCLC with a 22% ORR and a 68% DCR.
Infante1, Johanna Bendell1, Suzanne Jones2, Andy Treatment was generally well tolerated with low
Lipman3, David Trent4, Eric Raefsky5, F.A. Greco1, rates of serious thrombocytopenia, anemia, and
Howard Burris1 diarrhea. Neutropenia was manageable and rarely
1
Oncology, Sarah Cannon Research Institute And associated with fever. A NK012 and platinum
Tennessee Oncology, Pllc/United States Of America, combination phase I study is in progress.
2
Sarah Cannon Research Institute/United States Keywords: Lung neoplasms, recurrence, Carcinoma,
Of America, 3Sarah Cannon Research Institute Small Cell, Topoisomerase I inhibitors
And Florida Cancer Specialists/United States Of
America, 4Sarah Cannon Research Institute And
Virginia Cancer Institute/United States Of America, SCLC II Thursday, 7 July 2011 12:30-14:00
5
Tennessee Oncology, Pllc/United States Of America
MO19.09 PATIENT OUTCOME AND
Background: NK012 is a polymeric micelle EXPLORATORY ANALYSIS FROM A
designed to release a slow and sustained PHASE 2A STUDY OF NAVITOCLAX
concentration of SN-38, the active metabolite of (ABT-263) IN PATIENTS WITH
irinotecan. Safety and antitumor activity have been ADVANCED/RELAPSED SMALL CELL
demonstrated in Phase I studies in patients (pts) with LUNG CANCER (SCLC)
refractory tumors including small-cell lung cancer Charles Rudin1, Edward B. Garon2, Moacyr Ribeiro
(SCLC). A phase II trial was performed to evaluate De Oliveira3, Philip Bonomi4, Ross D. Camidge5,
NK012 in pts with sensitive relapsed (SR) and Quincy Chu6, Giuseppe Giaccone7, Divis Khaira8,
refractory relapsed (RR) SCLC. Suresh Ramalingam9, Malcolm Ranson10, Christine
Methods: Pts with relapsed SCLC following one Hann11, Evelyn Mckeegan12, Brenda Chyla12, Barry
systemic regimen for extensive-stage SCLC or L. Dowell12, Arunava Chakravartty12, Catherine
chemoradiation for limited-stage SCLC were eligible. Nolan12, Todd Busman12, Mack Mabry12, Andrew
Pts had measurable disease, an ECOG performance Krivoshik12, Rod Humerickhouse12, Geoffrey
status (PS) of 0-2, and adequate organ function. Pts Shapiro13, Leena Gandhi13
1
with untreated brain metastases or prior irinotecan The Sidney Kimmel Comprehensive Cancer Center
were excluded. NK012 was given IV over 30 minutes At Johns Hopkins, Johns Hopkins University/United
once every 28 days at a dose based on pretreatment States Of America, 2Ucla’s Jonsson Comprehensive
UGT1A1 genotyping: 28 mg/m2 (wild-type (wt)/wt Cancer Center/United States Of America, 3Oncology,
and wt/*28) or 18 mg/m2 (*28/*28). Pts were restaged Northwest Medical Specialties, Pllc/United States Of
America, 4Rush University Medical Center/United (R=0.93) was conÀrmed. Exploratory analyses
States Of America, 5UC Davis Cancer Center/ using Cox Proportional Hazard Model for overall
United States Of America, 6Alberta Health Services/ survival demonstrated a positive relationship with
Canada, 7National Cancer Institute/United States the hazard of death for neuron-speciÀc enolase
Of America, 8Sunterra Oncology Associates/United NSE (p=0.0028), and circulating tumor cell (CTC)
States Of America, 9Emory University/United States number (p=0.016) at baseline. NSE, progastrin
Of America, 10The Christie NHS Foundation Trust/ releasing peptide (Pro-GRP) and CTC concentrations
United Kingdom, 11Johns Hopkins University/ after 14 days on therapy were lower in responders
United States Of America, 12Abbott/United States (deÀned as conÀrmed PR or SD > 4 cycles) vs
Of America, 13Dana-farber Cancer Institute/United non-responders (p=0.029, 0.0014, and 0.016
States Of America respectively), Pro-GRP concentrations after 35
days were lower in responders vs non-responders
Background: Small cell lung cancer (SCLC) is an (p=0.002), and correlated with lack of progression.
aggressive malignancy with few effective treatment Conclusion: Bcl-2 targeting by navitoclax is well
options after 1st-line therapy. Bcl-2 is a critical tolerated, but demonstrates modest single-agent
regulator of apoptosis that is overexpressed in the activity against advanced and recurrent SCLC.
majority of SCLC. Navitoclax is a potent and selective Correlative analyses suggest several putative
oral inhibitor of anti-apoptotic bcl-2 family members. biomarkers of clinical beneÀt. Based on preclinical
We conducted a phase 1/2a study of navitoclax, which synergy observed in multiple models, and the
in the phase I trial demonstrated antitumor activity and results of this single agent study, a phase 1 trial of
an acceptable safety proÀle in patients with SCLC and navitoclax with Àrst-line combination chemotherapy
other solid tumors. This report summarizes the clinical for SCLC has been initiated.
outcome and exploratory molecular correlative Keywords: Navitoclax, Phase 2 Trial, SCLC,
analyses from the completed phase 2 study. apoptosis
Methods: This was an open-label, multicenter phase
2a trial assessing safety and preliminary efÀcacy of
navitoclax in patients with advanced/relapsed SCLC. SCLC II Thursday, 7 July 2011 12:30-14:00
Enrolled patients received oral navitoclax at 325 mg
daily, following an initial lead-in of 150 mg daily for MO19.11 BENEFITS AND RISKS
7 days, on a 21-day cycle until progressive disease or OF USING ERYTHROPOIESIS-
intolerable toxicity. Key eligibility criteria included STIMULATING AGENTS (ESAS) IN NON-
measurable SCLC and ECOG status < 1. Endpoints SMALL CELL LUNG CANCER (NSCLC)
include tumor response by RECIST, progression- AND SMALL CELL LUNG CANCER
free survival, time to progression, overall survival, (SCLC) PATIENTS: RESULTS FROM
and ECOG performance status. Tumor assessments STUDY-LEVEL AND PATIENT-LEVEL
were performed at the end of every 2 cycles. Adverse META-ANALYSES OF CONTROLLED
events (AE) were graded by NCI CTCAE V3. ESA TRIALS IN LUNG CANCER
Results: 39 patients (median age, 64 yr [45-78]; Johan Vansteenkiste1, John Glaspy2, David Henry3,
54% female; ECOG status 1) were enrolled Heinz Ludwig4, Robert Pirker5, Dianne Tomita6,
in the phase 2 study; 5 had limited and 34 had Helen Collins6, Jeffrey Crawford7
1
extensive disease. 54% of patients received 2 prior Respiratory Oncology Unit, University Hospital
treatments (median 2 [1-8]). The most common Gasthuisberg/Belgium, 2University Of California At
treatment emergent toxicities at any grade were Los Angeles/United States Of America, 3University
thrombocytopenia (64%), nausea (59%), fatigue Of Pennsylvania/United States Of America,
4
(56%), diarrhea (54%) and vomiting (41%). Wilhelminenspital/Austria, 5Department Of
The most common grade 3 toxicities included Medicine I, Medical University Of Vienna/Austria,
6
thrombocytopenia (44%) and neutropenia (13%). Amgen Inc./United States Of America, 7Duke
Partial response was observed in one (2.7%) patient University Medical Center/United States Of America
and stable disease in 9 (24%). Median PFS was
46 days, and median OS was 96 days. A strong Background: The safety of ESAs in oncology
association between serum pro-gastrin-releasing patients is a topic of ongoing debate. We performed
hormone (GRP) and tumor Bcl-2 gene copy number study-level and patient-level meta-analyses of
controlled ESA trials in lung cancer to evaluate the

impact of ESA use on outcomes in patients with
NSCLC and SCLC.
Methods: Nine randomized, controlled studies
in lung cancer were identiÀed by literature search
for inclusion in the study-level analysis (2319
patients total; 1179 ESA-treated, 1140 control).
Eight studies were conducted in patients with
chemotherapy-induced anemia (CIA) and 1 in
NSCLC patients with anemia of cancer (AoC). Of
the 8 CIA trials, 5 had SCLC patients (581 ESA- Conclusion: An excess in the odds of mortality
treated, 545 control), 2 had NSCLC patients (409 was not observed for ESA-treated patients in the
ESA-treated, 400 control), and 1 trial had both study-level analyses of CIA studies; an increased
SCLC and NSCLC patients (156 ESA-treated, 158 risk of death or progression-related endpoints was
control). Because of differences in studies, random not observed when patient-level data for DA were
effects models were used to estimate overall effects; summarized across studies. ESA use was associated
data from the AoC study were not combined with fewer transfusions.
with CIA studies but are provided separately. Keywords: meta-analysis, SCLC, NSCLC, mortality
For patient-level meta-analysis, data from four
placebo-controlled darbepoetin alfa (DA) studies
of SCLC patients (n = 714) and NSCLC patients SCLC II Thursday, 7 July 2011 12:30-14:00
(n = 295) with CIA were analyzed. Mortality,
progression-related endpoints, and transfusions MO19.12 MEASUREMENT OF
were summarized in both analyses; the patient-level CIRCULATING TUMOR CELLS (CTCS)
meta-analysis also summarized adverse events IN PATIENTS WITH SMALL CELL LUNG
(AEs) and fatigue. CANCER (SCLC) DURING A PHASE II
Results: Study-level analysis: odds ratio CLINICAL TRIAL
(OR) for death in CIA studies was 0.87 (95% Maria Catherine Pietanza1, Lee M. Krug1, Camelia
conÀdence interval [CI], 0.68 to 1.12). The OR S. Sima2, Isabella Bergagnini1, Dyana K. Sumner1,
for progression-related endpoints in 5 CIA studies Mark G. Kris1, Martin Fleisher3
1
with progression data was 0.84 (0.65 to 1.09). Medicine/Thoracic Oncology Service, Memorial
The OR for transfusion incidence in CIA studies Sloan-Kettering Cancer Center/United States Of
was 0.34 (0.28 to 0.41). Patient-level analysis: America, 2Epidemiology And Biostatistics, Memorial
median survival was 41 weeks for the DA arms Sloan-Kettering Cancer Center/United States Of
and 38 weeks for placebo arms; the hazard ratio America, 3Clinical Laboratories, Memorial Sloan-
for death was 0.90 (0.78 to 1.03). Overall, 87% Kettering Cancer Center/United States Of America
of control and 84% of DA patients progressed
during treatment or follow-up. AEs summarized Background: The limited availability of tissue
included thromboembolic events (DA 11%, placebo in SCLC has been a barrier to research and care.
7%), cerebrovascular disorders (both groups New approaches are needed for this malignancy to
4%), pulmonary edema (both groups 1%), and aid in monitoring treatment response, assess risk,
pulmonary embolism (both groups 2%). From and serially interrogate tumor genotypes in a non-
week 5 to end-of-study, transfusions occurred in invasive manner. CTCs represent a source of tissue
19% of DA patients and 43% of placebo patients. A in SCLC that would enable us to accomplish these
3-point improvement in FACT-F score occurred in tasks.
54% of DA patients and 50% of placebo patients. Methods: We are conducting a phase II trial of
temozolomide for patients with relapsed sensitive
or refractory SCLC. Using the Veridex CellSearch
SystemTM , CTCs are being enumerated before
initiating temozolomide and at the time of repeat
imaging (at four weeks, eight weeks, and every eight
weeks thereafter). The number of CTCs is correlated
with clinical variables, including type of relapse SCLC II Thursday, 7 July 2011 12:30-14:00
(sensitive or refractory), line of treatment (second
or third) and sites of metastases; radiographic MO19.13 CLINICAL FEATURES OF
response; and survival. SURGICALLY RESECTED PATIENTS
Results: To date, 39 patients have had blood WITH SMALL CELL LUNG CANCER
evaluated for CTCs before and after temozolomide. ARISING FROM THE PERIPHERAL
Prior to starting therapy, the number of CTCs ranged LUNG
from zero (0) to 929: 7 patients had 0 CTCs detected Hiroshi Yokouchi1, Takashi Ishida1, Hiroyuki
(18%); 13 had between 1 and 4 CTCs (33%); and 19 Minemura1, Satoko Sekine1, Kengo Oshima1, Kenya
had 5 CTCs detected (49%). The number of CTCs Kanazawa1, Yoshinori Tanino1, Hiroyuki Suzuki2,
is higher in patients with liver metastases (21% < Mitsukazu Goto3, Mitsuru Munakata1
1
5 CTCs vs 79% 5 CTCs, p<0.001). Patients with Pulmonary Medicine, Fukushima Medical
new sites of metastases have signiÀcantly higher University/Japan, 2Thoracic Surgery, Fukushima
numbers of CTCs (60% 5 CTCs), compared to Medical University/Japan, 3First Department Of
those that progress at pre-existing sites of disease Surgery, Fukushima Medical University/Japan
(100% < 5 CTCs), p=0.008. At the end of cycle
1, the change in number of CTCs is correlated Background: Although it has been generally
to RECIST response (p=0.041). Increased CTCs accepted that the standard treatment for limited
at the end of cycle 1 are associated with worse disease (LD) small cell lung cancer (SCLC) is
overall survival, compared to stable or decreased chemoradiation, several small series have reported
CTCs (median: 5 vs 8 months, p=0.008). At favorable survival outcomes in patients who
disease progression with temozolomide, high CTC underwent surgical resection. One recent study using
numbers ( 5) are associated with worse overall a large population-based database in the US (SEER)
survival (median: 3 months), compared to low CTC demonstrated the use of surgery in selected patients
numbers (median survival, not reached), p=0.003. with LD-SCLC was associated with improved
At baseline, the number of CTCs is not predictive survival outcomes. However, the effective therapies
of response to treatment, nor associated with for patients with SCLC arising from the peripheral
progression-free and overall survival. No signiÀcant lung have yet to be determined. Thus we analyzed
correlations have been found between patient the date of those patients so as to elucidate the
characteristics (gender, age, Karnofsky performance clinical features and Ànd promising design for future
status, response to Àrst line therapy, previous lines prospective trials.
of treatment) and baseline CTCs. For patients with Methods: We retrospectively evaluated the clinical
brain and bone metastases, numbers of CTCs are courses of 25 patients with peripheral SCLC who
similar to those without metastases at these sites. underwent surgery in our institute from August, 1987
Conclusion: CTCs can be routinely enumerated through February, 2010.
in patients with SCLC during the course of Results: Of the 25 patients, 24 were men and the
treatment using the Veridex CellSearch System TM. average age was 66 (range, 47-82). Median smoking
A signiÀcantly higher number of CTCs is found index was 1,000 (500-2,400). Average tumor
in patients with liver metastases and those that diameter was 2.5 cm (0.7-11.5). Average serum
progress at new sites. Increased CTCs at the end of level of speciÀc tumor markers such as pro-gastrin-
cycle 1 and upon disease progression are associated releasing peptide (ProGRP) and neuron-speciÀc
with a poorer prognosis. enolase (NSE) were 35 pg/ml (17.2-763) and 8.2
Keywords: Veridex CellSearch System, circulating ng/ml (5-12.3), respectively. Sixteen patients (64%)
tumor cells, Small cell lung cancer, Temozolomide were diagnosed using bronchoscopy. Pathological
study demonstrated that 6 patients were diagnosed
as having combined SCLC (4 had adenocarcinoma
component, 1 had large cell carcinoma, and
another 1 had large and squamous cell carcinoma).
Twenty one patients underwent lobectomy and
another 4 underwent pneumonectomy. Clinical
stage (UICC TNM classiÀcation ver. 7) of IA/
IB/IIA/IIB/IIIA/IIIB was 13/1/4/1/3/3, and
pathological stage of IA/IB/IIA/IIB/IIIA/IIIB/IV was Methods: As of February 2002, a concurrent CRT

10/1/3/1/6/2/1, respectively. Adjuvant or neoadjuvant protocol was launched for patients with conÀrmed
chemotherapies all of which included platinum diagnosis of SCLC-LD. All patients treated in
compound were initiated for 19 patients (76%), accordance with the protocol were reviewed.
and the average number of chemotherapies was LD staging was documented by using computed
2.7. All but one patient who received neoadjuvant tomography (CT) scan of the chest, upper abdomen,
chemotherapy showed at least partial remission. and brain and, in most cases, 18F-deoxyglucose
After neoadjuvant chemotherapy, 1 patient archived positron emission tomography (PET). The CRT
complete remission and 1 was deÀned as having protocol consisted of thoracic radiotherapy delivered
pathological down staging from IIIA to IA. The up to a dose of 50 Gy in daily fractions of 2 Gy,
primary lesion, mediastinal lymph node, brain and starting concurrently with the second of four cycles
bone were the sites of major recurrence. Progression of platinum-based chemotherapy (cisplatin 60 mg/
free survival and overall survival were 55.7 and m2 d1, Q3w and etoposide 120 mg/m2 d1-3, Q3w).
73.7 months, respectively. Subgroup analyses Radiotherapy was given using IF-RT, targeted to
demonstrated that survival of the patients with the tumor, PET positive nodes and nodes >1cm in
c-stage IA was statistically longer than that of other smallest diameter on CT-scan. Response after CRT
stages (p=0.023). was evaluated with CT-scan. Patients with a (near)
Conclusion: Patients with peripheral SCLC showed complete response (nCR) received prophylactic
favorable prognosis, suggesting the potentiation cranial irradiation (PCI) up to 30Gy/2Gy within 6
of combined modalities including surgery with weeks after completion of CRT.
chemotherapy. These Àndings might provide Results: Between 2/2002 and 2/2009, 53 patients
valuable information for the management of the were treated according to this CRT protocol:
patients with peripheral SCLC. We are discussing female/male 15/38; median age: 58 years (range
our present study by comparing with previous reports 39-72); clinical TNM: cT1-4N0-3M0. Pathology
and proposing several designs of future prospective was obtained using bronchoscopy/TBNA (72%),
trial. mediastinoscopy (26%) or thoracotomy (2%). PET-
Keywords: Surgery, Chemotherapy staging was performed in 41/53 patients (77%): 33
isolated PET, 8 PET-CT. CRT was given according
to protocol in 50 patients, 2 received cisplatin-
SCLC II Thursday, 7 July 2011 12:30-14:00 pemetrexed as Àrst chemotherapy cycle, 1 started
radiotherapy with the 3rd chemotherapy cycle.
MO19.14 CONCOMITANT Median time between start of treatment and end
CHEMORADIOTHERAPY (CRT) USING of radiotherapy was 59 days (range 53-73). Of the
INVOLVED FIELD RADIOTHERAPY (IF- 32 patients in nCR, 30 received PCI 30Gy/2Gy,
RT) IN LIMITED DISEASE SMALL CELL 2 of them 30Gy/3Gy. Ten out of 21 patients in
LUNG CANCER (SCLC-LD): A TERTIARY partial remission (PR) received PCI (8: 30Gy/2Gy;
CENTER EXPERIENCE. 1:30Gy/3Gy; and 1: 20Gy/4Gy). Of the total group,
Emilie Dubaere1, Ans Pelgrims1, Yolande 20 patients did not relapse/progress. In the remaining
Lievens1, Johnny Moons2, Stephanie Peeters1, Elke 33 patients, site of Àrst relapse/progression was loco-
Vandenbroucke3, Johan Vansteenkiste4, Kristiaan regional in 10, distant in 15 and both combined in 8.
Nackaerts4, L. Leuven Lung Cancer Group5 Of the primary loco-regional relapses, 3 were in-Àeld
1
Radiation Oncology, University Hospitals Leuven/ (2 were salvaged by surgery) and 3 partially in- and
Belgium, 2Thoracic Surgery, University Hospitals out-of-Àeld. Only one patient developed an isolated
Leuven/Belgium, 3Pulmonology, AZ Monica/Belgium, out-of-Àeld relapse. Three PR patients progressed
4
Respiratory Oncology Unit, University Hospitals loco-regionally before developing metastases. After a
Leuven/Belgium, 5Leuven Lung Cancer Group, median (mean) follow-up of 24 (38) months, median
University Hospitals Leuven/Belgium overall and progression-free survival were 28,3 and
26 months, respectively. Overall survival at 1, 2 and
Background: To evaluate, in a tertiary referral 5 years was 81,1%, 58,4% and 40,6%. At the same
center, the results of CRT using IF-RT in SCLC-LD time points, respectively 85,5%, 63,1% and 52,6%
patients in terms of loco-regional tumor control, of patients were free of loco-regional recurrence,
survival and toxicity. respectively.
Conclusion: The outcome of concomitant Tumor histology was limited to either squamous cell
chemotherapy with IF-RT (up to 50Gy/2Gy) starting carcinoma (SC) or adenocarcinoma (AC). Five tumor
with the second chemotherapy cycle, compares groups based on the 7th edition TNM lung cancer
favorably with results from other series, which staging system (T1a 2cm, T1b > 2cm but 3cm,
may in part be due to the dedicated staging strategy T2a > 3cm but 5cm, T2b > 5cm but 7cm and T3
resulting in truly limited SCLC. The low number of > 7cm ) with clinical, demographic and tumor speciÀc
isolated local relapses seems to support the use of variables were analyzed to determine which variables
IF-RT, provided that PET is used for diagnosis and inÁuenced survival.
treatment planning. The observation that a relatively Results: Overall survival was reduced in larger
high proportion of patients fails to reach nCR, sized T3, T2a, and T2b subtypes compared with
suggests that higher radiotherapy doses may be the the smaller subtypes of T1a and T1b (P < 0.001). A
way to further improve the outcome. higher proportion of male patients had T3 disease
Keywords: Small-cell lung cancer, limited (74%, compared to 43.4% in T1a and 53.1% in T2b;
disease, involved Àeld radiotherapy, concomitant P< 0.001). All tumor subtypes tended towards right
chemoradiotherapy sided laterality (58%) and were predominately grade
II/II (88%). Larger tumors were more likely to be SC
A revised/updated abstract may be included in (T1a=14.5%, T1b= 20.65%, T2a=26.5%, T2b=35.5%
the Late Breaking Abstract Supplement, available and T3= 50%; p<0.001), while smaller tumors were
at the 14th World Conference on Lung Cancer. more likely to be AC (T1a= 85.5%, T1b=79.4%,
T2a=73.5%, T2b=64.5%, and T3=50%; p <0.001).
Survival estimates were found to correlate with tumor
Session MO20: Surgery - Outcome size, with worse survival in T3, followed by T2b, T2a,
and then T1b and T1a (Figure 1). After adjusting for
Thursday, 7 July 2011 important relevant confounders, T1a (Hazard Ratio
[HR) 0.53, 95% conÀdence interval [CI] 0.32 to 0.86;
P=0.011) and T1b (HR 0.54, 95% CI 0.33 to 0.88; P=
Surgery - Outcome Thursday, 7 July 2011 12:30-14:00 0.014) were both found to have decreased hazard of
death relative to T3. Negative predictors of survival,
MO20.01 SIZE OF PRIMARY TUMOR in addition to increasing tumor size, included age and
MATTERS IN THE CLINICAL OUTCOME male gender, while positive predictors included tumor
OF N2 POSITIVE STAGE IIIA PRIMARY grade I and upper lobe location.
LUNG CANCER AFTER LOBECTOMY
Steven Maximus1, Danh V. Nguyen2, Yi Mu2, Royce
F. Calhoun1, David T. Cooke1
1
Division Of Cardiothoracic Surgery, University Of
California, Davis Medical Center/United States Of
America, 2Department Of Public Health Sciences,
University Of California, Davis/United States Of
America
Background: Size of the primary lesion is important

in the prognosis of patients with early stage lung
cancer. Using a large United States national database,
we examined if size of the primary lesion was an Conclusion: Our study demonstrates that increased
independent risk factor of survival in patients undergoing size of tumor is an independent negative risk factor
lobectomy or similar procedure for N2 positive stage for survival in patients undergoing lobectomy or
IIIA non small cell lung cancer (NSCLC). similar procedure for N2 positive stage IIIA NSCLC.
Methods: This is a retrospective study querying the These results should help guide the oncology
Surveillance, Epidemiology and End Results database clinician on recommendations for post-therapy
to identify 1,971 surgical patients diagnosed with surveillance and enrollment in clinical trials.
N2 positive stage IIIA NSCLC from 1998 to 2007 Keywords: Lung cancer, Surgery, lobectomy, Stage
who underwent lobectomy or similar procedure. IIIA
Surgery - Outcome Thursday, 7 July 2011 12:30-14:00 for postoperative complications. All patients were
staged according to the 6th TNM classiÀcation.
MO20.02 PULMONARY RESECTION Results: The median age was 82 years (range, 80-
IN PATIENTS AGED 80 YEARS OR 91). Of the total patient number, 166 (27.6%) had
OVER WITH NON-SMALL CELL LUNG some form of comorbidity diagnosed preoperatively.
CANCER: A RETROSPECTIVE SURVEY Seventy-two (12.0%) patients presented with
OF 602 CASES IN A JAPANESE JOINT postoperative complications and the 30-day
COMMITTEE FOR LUNG CANCER operative mortality was 8 (1.3%). The 5-year
REGISTRATION STUDY survival rates were 64.3% for p-stage IA (N=224),
Jiro Okami1, Masahiko Higashiyama1, Noriyoshi 53.5% for p-stage IB (N=173), 62.9% for p-stage IIA
Sawabata2, Etsuo Miyaoka3, Hisao Asamura4, Yoichi (N=15), 27.2% for p-stage IIB (N=68), and 21.5%
Nakanishi5, Kenji Eguchi6, Masaki Mori7, Hiroaki for p-stage IIIA (N=55). In patients with completely
Nomori8, Yoshitaka Fujii9, Meinoshin Okumura2, resected c-stage I NSCLC, the 5-year survival
Kohei Yokoi10 rates were 55.7% for c-stage I, 62.0% for c-stage
1
General Thoracic Surgery, Osaka Medical Center IA, and 47.2% for c-stage IB patients (Figure).
For Cancer And Cardiovascular Diseases/Japan, Multivariate analyses were performed to elucidate
2
General Thoracic Surgery, Osaka University, prognostic factors and risk factors in this population.
Graduate School Of Medicine/Japan, 3Mathematics, Advanced pathological stage and comorbidity were
Science University Of Tokyo/Japan, 4Thoracic signiÀcant independent predictors of shortened
Surgery, National Cancer Center Hospital/ survival (P<0.0001 and P=0.032, respectively).
Japan, 5Clinical Medicine, Research Institute Comorbidity and mediastinal lymph node dissection
For Diseases Of The Chest, Graduate School were identiÀed as factors that increased the risk of
Of Medical Sciences, Kyusyu University/Japan, postoperative complications (P<0.0001 and P=0.036,
6
Respirology Medicine, Teikyo University School Of respectively). Survival rates were independent of the
Medicine/Japan, 7Pulmonary Medicine, Sapporo- extent of pulmonary resection (lobectomy or limited
kosei General Hospital/Japan, 8General Thoracic resection).
Surgery, Keio University School Of Medicine/Japan,
9
Surgery, Nagoya City University,graduate School
Of Medicine/Japan, 10Thoracic Surgery, Nagoya
University Graduate School Of Medicine/Japan
Background: The number of elderly lung cancer

patients is increasing rapidly worldwide. Comorbid
illness and adverse medical conditions due to aging
is a signiÀcant concern to treat elderly patients with
lung cancer. Surgeons often hesitate to recommend
surgery for elderly patients because of the higher
perioperative risks and uncertainty of long-term
beneÀt. More information regarding short- and long-
term postoperative outcomes would help surgeons
to select a subgroup of elderly patients suitable for Conclusion: Octogenarian patients in this study had
pulmonary resection. a satisfactory long-term outcome and low mortality
Methods: The Japanese Joint Committee of Lung rate. In c-stage I patients, comorbidity is a factor
Cancer Registry collated clinicopathological proÀles associated with both prognosis and operative risks.
and outcomes for 13,344 patients who underwent Another risk factor for postoperative complication
pulmonary resection for primary lung cancer in is mediastinal lymph node dissection in c-stage I
1999. Data of 602 patients aged 80 or over with patients. Therefore, to avoid unnecessary mediastinal
non-small cell lung cancer (NSCLC) were analyzed lymph node dissection based on an accurate
to assess the morbidity, mortality, and long-term preoperative nodal staging can be beneÀcial to
survival. Next, 367 patients who underwent complete decrease postoperative complications.
resection for stage I NSCLC were enrolled to the Keywords: Lung cancer, Surgery, Elderly
study to identify prognostic factors and risk factors
Surgery - Outcome Thursday, 7 July 2011 12:30-14:00 conÀrm signiÀcant pleural adhesions in any patient.
Furthermore, since there was no apparent SBRT-
MO20.03 SALVAGE LUNG RESECTION related change in the pulmonary structure, dissection
FOR NON-SMALL CELL LUNG around the vessels and bronchus was performed
CANCER AFTER STEREOTACTIC without difÀculties. There were no complications
BODY RADIOTHERAPY IN INITIALLY during surgery and postoperative course was also
OPERABLE PATIENTS uncomplicated in all cases. Pathological staging
Fengshi Chen1, Yukinori Matsuo2, Akihiko was pT1N0M0 in 2 patients, pT2N0M0 in 3, and
Yoshizawa3, Toshihiko Sato1, Takuji Fujinaga1, cT1-2N2M0 in 2. No adjuvant chemotherapy was
Tsuyoshi Shoji1, Makoto Sonobe1, Hiroaki Sakai1, performed except for 2 patients with pN2. Despite
Toru Bando1, Cheng-Long Huang1, Hiroshi Date1 a short follow-up time (5-47 months after salvage
1
Thoracic Surgery, Kyoto University Hospital/ surgery, median 21 months), all the patients are alive
Japan, 2Radiation Oncology And Image-applied without apparent recurrences.
Therapy, Kyoto University/Japan, 3Pathology, Kyoto Conclusion: During surgical extirpation, we did not
University/Japan Ànd any signiÀcant SBRT-related adhesions in any
of the patients. We found that surgical resection was
Background: Stereotactic body radiotherapy feasible after SBRT. More cases with longer follow-
(SBRT) is a recently developed radiotherapeutic up should be mandatory to evaluate the true meaning
method for early-stage non-small cell lung cancer of salvage lung resection for NSCLC after SBRT.
(NSCLC) and failure of local control is estimated Keywords: salvage resection, Non-small cell lung
to occur in around 10% of the patients treated cancer, stereotactic body radiotherapy
with SBRT. It has been reported that some patients
develop local recurrence after SBRT and are then
considered for salvage surgical resection. Herein, we Surgery - Outcome Thursday, 7 July 2011 12:30-14:00
retrospectively reviewed 7 such cases treated at our
institution to further understand the indications for MO20.04 REPEATED PULMONARY
salvage lung resection for NSCLC after SBRT. RESECTION FOR METASTATIC
Methods: Since 1998, three-dimensional conformal OSTEOSARCOMA: IS IT SAFE AND
SBRT has been performed in patients with solitary EFFECTIVE?
lung tumors at the Kyoto University Hospital. Hae Won Lee, Jinwook Hwang, Heejong Baek, Jong
The biological effective dose was 105.6 Gy at the Ho Park, Moon-Chul Kang
isocenter. The patients were followed up every 2 to Department Of Thoracic Surgery, Korea Cancer
3 months after SBRT. When local recurrence was Center Hospital/Korea
suspected from follow-up CT images, an FDG-PET
scan was performed and radiology peer review Background: Surgical resection has been considered
was undertaken. If local recurrence without distant as treatment of choice for pulmonary metastatic
metastasis was considered highly probable on the osteosarcoma. However, studies are insufÀcient to
basis of the review, the patient was referred to a establish any consensus on the safety and efÀcacy of
thoracic surgeon for possible salvage resection. We repeated pulmonary resection. The purpose of this study
encountered 7 patients who underwent salvage lung is to evaulate the clinical efÀcacy of repeated resection
resection for NSCLC after SBRT. for pulmonary metastatic osteosarcoma.
Results: All the patients were initially operable, Methods: We reviewed the medical records of 108
but they chose SBRT. After SBRT, the tumors consecutive patients who underwent operations
shrank initially in all patients, but increased in for pulmonary metastatic osteosarcoma from 1992
size within 16 months of SBRT in the case of 6 to 2008 in single institution. All the patients were
patients. In 1 case, the tumor relapsed more than 8 followed up and mean duration of follow-up was 47
years after SBRT. Clinical staging before salvage months. Preoperatively, we evaluated the patients with
surgery was cT1N0M0 in 3 patients, cT2N0M0 in MRI, PET-CT or CT scan for checking resectability
3, and cT2N2M0 in 1. The mean patient’s age at and extrathoracic metastasis. Selection criteria for
surgery was 75 years, ranging 64-86. As salvage pulmonary resection were the possibility of complete
surgery, lobectomy with lymph node dissection was resection, treatable or no longer present extrathoracic
performed in all patients. Surgical extirpation did not lesions and acceptable operative risks. Median
sternotomy or bilateral sequential thoracotomy were Keywords: pulmonary metastasis, osteosarcoma,

chosen for examination of bilateral lungs. We analyzed metastasectomy
the prognostic factors after repeated pulmonary
resection. In the prognostic factors, primary tumor
factors such as tumor size, resection margin of primary Surgery - Outcome Thursday, 7 July 2011 12:30-14:00
tumor and response to chemotherapy are included as
well as metastatic tumor factors. MO20.06 RESULTS OF SURGICAL
Results: From 1992 to 2008, 653 osteosarcoma RESECTION FOR SECOND PRIMARY
patients were treated at Korea Cancer Center LUNG CANCER
Hospital. Among these patients, pulmonary Takehiro Watanabe1, Tatsuhiko Hirono2, Nozomu
metastasis developed in 221 patients. One Motono2, Akira Okada2
1
hundred eight patients could receive pulmonary Division Of Chest Surgery, Nishi-Niigata Chuo
metastasectomy and 40 patients underwent the National Hospital/Japan, 2Nishi-Niigata Chuo
second pulmonary resection and 13 of these 40 National Hospital/Japan
patients had the third operation. There was no
signiÀcant morbidity and no mortality after operation Background: Recently, there are many patients who
in these patients. Five-year survival rates after underwent surgical resection for early non-small cell
1st, 2nd and 3rd resection were 37.5%, 37.1% and lung cancer in Japan. In the careful follow-up using
44.0%, and 1-year disease-free survival rates after high resolution CT, frequency of determining second
each metastasectomy were 55.6%, 40.0%, and primary lung cancer is increasing. But there is no
22.2%, respectively. Frequency of operation was standard treatment for second primary lung cancer.
not a negative prognostic factor. Primary tumor The aim of this study is to detail clinicopathological
size (p=0.003), primary tumor resection margin characteristics, surgical procedures, and the outcome
(p=0.006), the number of resected pulmonary of surgery for second primary lung cancer.
nodules (p=0.007) and completeness of resection Methods: A retrospective review of a prospective
(p=0.045) were signiÀcant prognostic factors. lung cancer database was carried out to identify
patients with second primary lung cancer. During
the time period 1996-2010, 900 patients underwent
surgical resection for primary lung cancer. Of the 900
patients, 70 (7.8%) had second primary lung cancer.
Among them, 57 patients underwent surgical resection
for second primary lung cancer, and these patients are
subject of this paper. Survival was calculated from
the time of the second primary lung cancer using the
Kaplan-Meier method, and differences in survival
were determined by log-rank analysis.
Results: There were 44 men and 13 women.
The average age at initial operation was 67. The
Conclusion: Primary tumor factors including size average age at the 2nd operation was 71. The initial
and resection margin are inÁuencing prognosis. pulmonary resection was lobectomy in 49 patients,
Patients with disease free interval less than one segmentectomy in 4 and wedge resection in 4.
year had worse prognosis but 5year survival rate The 2nd pulmonary resection was lobectomy in 10
of this group is as good as 33%. The number of patients, segmentectomy in 12 and wedge resection
metastatic nodules is a signiÀcant prognostic factor, in 35. Thirty-eight of 57 second primary lung cancers
but complete resection for a few patients with more were stage IA, 10 were IB, 1 was IIA, 3 were IIB, 2
than hundred metastatic nodules achieved good were IIIA and 3 were IIIB. Surgical complications
long term survival. And frequency of pulmonary occurred in 4, but there were no perioperative deaths.
metastasectomy was not a signiÀcant prognostic The 5 year survival rate for 2nd primary lung cancer
factor. These results suggest that repeated pulmonary was 59.9%. The 5 year survival rate for patients
resection can be done without severe morbidity and treated with wedge resection was 71.1%. The 5 year
mortality in properly indicated patients and improves survival rate of the patients with stage IA was 72.7%,
survival when complete resection is done. and that for patients with stage IB or more advanced
diseases was 32.9%(p=0.002). activity of all lesions decreased or deactivated.

Conclusion: The outcomes of aggressive surgical Among 202 patients with peripheral lung cancer
approach for second primary lung cancers are and chest wall invasion who complained chest
satisfactory. It is important to perform careful and pain pre-cryoablation, 40 patients(19.8%) showed
long-term follow-up for early detection of second complete pain relief after cryoablation and 124
primary lung cancer. It is linked with good outcome patients(61.4%) showed partially pain relief,
if the tumor is detected stage IA, when the possible respectively. The overall survival rates were
cure by performing wedge resection is promising. 70.2%% for 1-year and 54.1% for 2-year. The
Keywords: second primary lung cancer, wedge 1-year survival rate were 100.0%, 93.5%, 84.1%,
resection, Surgery 57.6% and 49.0%, and 2-year survival rate were
100.00%,81.36%,71.27%, 48.19% and 38.48% for
patients in stage I, stage II, stage III and stage IV
Surgery - Outcome Thursday, 7 July 2011 12:30-14:00 of primary lung cancer and metastatic lung cancer,
respectively. Tab. 1 Survival rate of lung cancer
MO20.07 THE EFFICACY OF CT GUIDED patient treated by cryoablation
CRYOABLATION IN LUNG CANCER
Li Z. Niu, Li H. He, Hai B. Li, Feng Mu, Bing H. N 1-year survival rate(%) 2-year survival rate(%)
Wu, Ke C. Xu Stage I 46 100.0(44/44) 100.0(21/21)
Oncology, Fuda Cancer Hospital/China Stage II 137 92.6(100/108) 83.6(51/61)
Stage III 296 81.7(/156/191) 70.8(84/104)
Stage IV 206 57.3(75/174) 48.2(25/52)
Background: Lung cancer has been the commonest
Metastatic 131 47.1(56/119) 33.0(13/40)
cause of cancer death, with a very poor survival lung cancer
rate. By the time of diagnosis, most cases are at an
advanced stage. In recent years, little progress has Conclusion: CT guided cryoablation showed some
been in improving the quality of life of patients efÀcacy in controlling the progress of lung cancer
with advanced lung cancer. While the possiblity and may contribute to pain relief and prolong
of surgery has been limited, the other palliative survival for lung cancer patients.
measures must be considered. Keywords: Lung cancer, CT-guided, EfÀcacy,
Methods: From Jan 2002 to Apr 2006, 816 Cryoablation
patients(568 male and 248 female) at an median age
of 64±1.2 years old(range from 12 to 95 years old) A revised/updated abstract may be included in
with primary or metastatic lung cancer were treated the Late Breaking Abstract Supplement, available
with cryoablation, including 46 patients in I, 137 in at the 14th World Conference on Lung Cancer.
stage II, 296 in stage III and 206 in stage IV and 131
patients with metastatic lung cancer.A total of 1139
cryoablations were done for 1014 lesions, which with Surgery - Outcome Thursday, 7 July 2011 12:30-14:00
mean diameter of 6.3±0.4 cm (ranged from 1.0 to
25.0cm). According to the size, shape and location of MO20.08 BILOBECTOMY FOR
the lesion, 2-8 cryo-probes were inserted as following: LUNG CANCER: INDICATIONS,
1-2 cryo-probes for the tumor smaller than 2 cm in POSTOPERATIVE RESULTS AND LONG-
diameter, 2-4 cryo-probes for tumor with 2-4 cm TERM OUTCOMES
in diameter, and 5-8 cryo-probes for tumor up to 5 Domenico Galetta, Piergiorgio Solli, Alessandro
cm or more. Freeze-thaw cycle was set as 15 min of Borri, Roberto Gasparri, Francesco Petrella, Stefano
freezing at -140±10 Celsius degree with argon and 5 Donghi, Alessandro Pardolesi, Lorenzo Spaggiari
min of thawing at 15±5 Celsius degree with helium. Division Of Thoracic Surgery, European Institute Of
Three freeze-thaw cycles were performed during each Oncology/Italy
cryoablation. Recheck CT or PET/CT and reappraise
Karnofsky Performance Status(KPS) every 1-3 Background: Bilobectomy for lung cancer is
monthes, and followed up every 3 months. considered a high risk procedure for the increased
Results: 1006 lesions (68.3%) decreased in size postoperative complication rate and for the negative
with mean size reducing from 4.7±0.3 cm to impact on survival. The aim of this study is to
3.5±0.4 cm in diameter, CR+PR was 97.2%. Tumor analyze if bilobectomy is a safety operation and the
1
oncologic results of this procedure. Thoracic Surgery, Hospital Clínico San Carlos/
Methods: We retrospectively reviewed a prospective Spain, 2Pathology, Hospital Clínico San Carlos/
electronic database of patients who underwent Spain, 3Preventive Medicine, Hospital Clínico San
bilobectomy for lung cancer between 1998 and Carlos/Spain
2009. Age, gender, bilobectomy type and indication,
complications, pathology, stage, and survival were Background: Controversy persists in relation to the
analyzed. indications and results of surgery in the treatment
Results: Bilobectomy was performed on 146 patients of patients with stage pIIIA-N2 non-small cell lung
(101 men; mean age, 62 years) with lung cancer. cancer (NSCLC). The objective of this study was to
There were 77 upper-middle and 69 middle-lower analyze the overall survival of a multicenter series
bilobectomies. Indications for bilobectomy were tumor of these patients and the factors that may inÁuence
extending across the Àssure in 27 (18.5%) patients, survival after complete surgical resection.
endobronchial tumor in 39 (26.7%), extrinsic tumor or Methods: A retrospective study was made of 287
nodal invasion of bronchus intermedius in 66 (45.2%), patients with stage pIIIA-N2 NSCLC submitted to
and vascular invasion in 14 (9.6%). An extended complete resection. Patients were taken from the
resection was performed in 24 patients (16.4%). multi-institutional database of the Bronchogenic
Induction therapy was performed in 43 patients Carcinoma Cooperative Group of the Spanish
(29.4%). Istology was squamous cell carcinoma in Society of Pneumology and Thoracic Surgery,
45 patients, adenocarcinoma in 51, other pathologies including 2,994 prospectively collected consecutive
in 50. Thirty-day mortality was 1.4% (n=2). Overall patients who underwent surgery for lung cancer.
morbidity was 47.2%. Mean chest tube persistence was Adjuvant treatment (chemotherapy – CT – and/or
7 days (range, 6-46 days) and mean hospital stay was radiotherapy – RT –) was administered in 238 cases
9 days (range, 5-174 days). The overall 5-year survival (82.9%). We analyzed age, gender, histological type
was 58%. SigniÀcance differences in survival were and adjuvant treatment (CT and/or RT).
observed among the different stages (stage I, 70%; Results: The 5-year survival was 23.9% with a
stage II, 55%; stage III, 40%; p=.0003) and the N status median survival of 22 months. Survival stratiÀed
(N0, 69%; N1, 56%; N2, 40%; p=.0005). An extended by adjuvant treatment was 26.5% with adjuvant
procedure (p=.0003) and a superior bilobectomy treatment versus 10.7% without (p = 0.069). No
(p=.0008) adversely inÁuence 5-year survival. signiÀcant difference was found with respect
Multivariate analisys demonstrated that an extended to gender. However age modiÀed the effect of
resection (p=.01) and an upper-mild lobectomy (p=.02) adjuvant treatment on survival (interaction p =
adversely affected prognosis. 0.049). In patients under 70 years of age, adjuvant
Conclusion: These date demonstrate that treatment reduced the mortality rate by 37% (HR
bilobectomy is associated with a low mortality and 0.63 CI 95% 0.42-0.95; p = 0.036) adjusted for
with an increased morbidity. Survival relates to histological type and induction treatment.
disease stage and N factor. Optimal prognosis is Conclusion: Our series shows that complete
obtained in patients with a lower-middle lobectomy surgical resection in patients with stage pIIIA-N2
without extension of the resection. NSCLC leads to a 5-year survival of 23.9%,
Keywords: NSCLC, Bilobectomy, Surgery which increases to 26.5% with adjuvant treatment.
Patients under 70 years of age with epidermoid
cancer who have received neoadjuvance
Surgery - Outcome Thursday, 7 July 2011 12:30-14:00 chemotherapy, reach a signiÀcantly greater survival
when receiving adjuvant treatment after pulmonary
MO20.09 WHAT AFFECTS THE resection.
SURVIVAL OF PATIENTS WHO Keywords: Stage IIIA, Complete resection,
UNDERGO COMPLETE RESECTION NSCLC, N2-disease
FOR STAGE IIIA-N2 NON-SMALL CELL
LUNG CANCER?
Ana M. Gomez1, Florentino Hernando1, Antonio
J. Torres1, Jose A. López García-Asenjo2, Cristina
Fernández3, Joaquín Calatayud1, Jose R. Jarabo1,
Elena Fernandez1
Surgery - Outcome Thursday, 7 July 2011 12:30-14:00 p=0.191), and they were intermediate between pN0
(n=1113, 5-ys; 83.7%) and pN2 patient survival rates
MO20.11 PROGNOSTIC IMPACT OF (n=243, 5-ys; 32.0%).
NODE INVOLVEMENT PATTERN IN
PN1 NON-SMALL CELL LUNG CANCER
PATIENTS
Masayuki Nakao1, Junji Yoshida1, Genichiro Ishii2,
Akikazu Kawase1, Ryo Maeda1, Keiju Aokage1,
Tomoyuki Hishida1, Mitsuyo Nishimura1, Kanji Nagai1
1
Division Of Thoracic Surgery, National Cancer
Center Hospital East/Japan, 2Pathology Division,
Research Center For Innovative Oncology, National
Cancer Center Hospital East/Japan
Background: Although it is possible that the

prognostic effect of direct node involvement by the
primary tumor may be different from that of node
involvement separated from the primary tumor,
nothing regarding this possibility is suggested in the
current TNM ClassiÀcation on N1 (peribronchial,
interlobar, or perihilar) lymph node involvement
patterns. We evaluated the prognostic impact of
node involvement patterns in pN1 non-small cell Conclusion: Node involvement patterns had
lung cancer (NSCLC) patients, with special attention signiÀcant prognostic impact in pN1 NSCLC
given to any differences between squamous cell patients. This impact was different between SCC
carcinoma (SCC) and adenocarcinoma (AD). and AD cases. The subclassiÀcation of N1 based on
Methods: We reviewed 324 consecutive patients node involvement pattern is of signiÀcance for SCC
who underwent complete resection of pN1 NSCLC patients but not for AD patients.
from July 1992 through December 2005 and Keywords: Non-small cell lung cancer, lymph node
classiÀed them into 2 groups based on their node involvement, direct involvement
involvement patterns: directly or separately involved
N1 groups. To compare survival rates, 1545 pN0
patients and 330 pN2 patients were also investigated. Surgery - Outcome Thursday, 7 July 2011 12:30-14:00
Results: The median length of overall follow-up
period for the censored patients was 8.6 years. MO20.12 ROLE OF POSITRON
Univariate and multivariate analyses showed that EMISSION TOMOGRAPHY
the node involvement pattern was signiÀcantly (PET), MUTATION STATUS AND
associated with pN1 NSCLC patient outcome. The PREDOMINANT HISTOLOGIC SUBTYPE
directly involved N1 group (n=130) had a much AS PREDICTORS OF SURVIVAL IN
better 5-year overall survival rate (5-ys) of 61.0% PATIENTS WITH STAGE IIIA(N2)
compared with 43.4% for the separately involved RESECTED NON SMALL CELL LUNG
N1 group (n=194). In SCC patients, the directly CARCINOMA (NSCLC).
involved N1 group (n=80, 5-ys; 68.4%) showed Stephen A. Barnett1, Prudence A. Russell2, Marzena
an overall survival similar to pN0 patients (n=302, Walkiewicz3, Zoe Wainer4, Gavin M. Wright1, Simon
5-ys; 63.9%, p=0.561), while overall survival of the Knight5, Siven Seevanayagam5, Julian Gooi5, Naveed
separately involved N1 group (n=40, 5-ys; 33.5%) Alam1, Matthew Conron6, Richard A. Williams2,
was identical to that of pN2 patients (n=59, 5-ys; Rochelle Wynne7, Thomas John3
1
25.6%, p=0.870), and their survival rates were Department Of Thoracic Surgery, St Vincent’s
signiÀcantly different (p<0.001). In AD patients, Hospital/Australia, 2Department Of Anatomical
however, the survival rates were marginally different Pathology, St Vincent’s Hospital/Australia, 3Austin
between the directly (n=33, 5ys=49.6%) and Health, Ludwig Institute For Cancer Research/
separately involved N1 groups (n=135, 5-ys; 42.9%, Australia, 4Department Of Surgery, University Of
Melbourne/Australia, 5Department Of Thoracic

Surgery, Austin Health/Australia, 6Department
Of Respiratory Medicine, St Vincent’s Hospital/
Australia, 7School Of Health Sciences, University Of
Melbourne/Australia
Background: Overall survival (OS) in resected

NSCLC with metastasis to mediastinal lymph nodes
(pN2) is poor, with 5-year OS ranging from 13-
42%. Prognostic information known preoperatively
allows avoidance of a futile thoracotomy or
stratiÀcation to induction therapy. Addition of
prognostic information known postoperatively may
inform adjuvant treatment choices. Predominant
histologic subtype and mutation status correlate with
survival in early stage disease. 18F-FDG avidity of
mediastinal nodes is an emerging prognostic variable
possibly more strongly associated with survival than
avidity of the primary tumour. In a cohort of resected
pN2 patients, we identiÀed factors associated with
survival, focusing on 18F-FDG avidity of mediastinal Conclusion: In pN2 patients, 18F-FDG avidity of
nodes, histologic subclassiÀcation, genetic mediastinal nodes identiÀes preoperatively patients
mutations. with poor OS and may guide treatment paradigm.
Methods: Patients with pre-operative PET and Post-operatively, in locoregionally advanced
pN2 on Ànal pathology were identiÀed. N2 nodal NSCLC, KRAS mutations correlate with poorer OS
status based on original PET report was recorded independent of known prognostic variables.
as avid or not. Tumours were classiÀed according Keywords: NSCLC, PET, Kras, Predominant
to 2004 WHO or IASLC/ATS/ERS ClassiÀcations. histologic subtype
Predominant subtype was circled on the slide, a core
punched from the parafÀn block, DNA isolated and
mutational proÀling performed using Sequenom’s Surgery - Outcome Thursday, 7 July 2011 12:30-14:00
MassArray platform. Univariate and multivariate
models examined predominant subtype, mutation MO20.13 FACTORS AFFECTING
status, 18F-FDG avidity of mediastinal nodes and OS. VARIATIONS IN INTRA-OPERATIVE
Results: Between 1993 and 2010, 108 patients were STAGING FOR LUNG CANCER
identiÀed. On univariate analyses 18F-FDG avidity RESECTION
of mediastinal nodes, male sex, pneumonectomy, Annabel Sharkey, Justine Downing, David
T-stage and mediastinal nodal predominant subtype Hopkinson, Timothy Locke, Jagan Rao, John
correlated with poorer OS (Table, Fig.). On Edwards
multivariate analysis of factors potentially known Cardiothoracic Surgery, Northern General Hospital/
preoperatively, 18F-FDG avidity of mediastinal United Kingdom
nodes (HR=2.25[1.28-3.97],p=0.005), KRAS
mutation (HR=2.13[1.13-4.00],p=0.019), and age Background: Systematic lymph node dissection
(HR=1.03[1.01-1.06],p=0.023) correlated with (SLND) is recommended by the European Society
OS. On multivariate analysis of factors known of Thoracic Surgeons as the gold-standard for intra-
postoperatively, 18F-FDG avidity of mediastinal nodes operative staging of non-small cell lung cancer
(HR=2.21[1.24-3.93],p=0.007), KRAS mutation (NSCLC). The aim of this study was to investigate
(HR=1.94[1.01-3.72],p=0.046), pneumonectomy the differences in intra-operative staging between
(HR=2.86[1.54-5.26],p=0.001) and age four consultant surgeons in a single institution.
(HR=1.03[1.00-1.06],p=0.023) correlated with OS. Methods: Retrospective analysis of histopathology
reports from 350 consecutive patients from 11/06/08
to 30/03/10 who underwent resections for conÀrmed
1
or suspected NSCLC. Comparisons in the lymph Oncology, Asan Medical Center/University Of
node stations reported by the pathologist were made Ulsan/Korea, 2Pathology, Asan Medical Center/
between surgeons. University Of Ulsan/Korea
Results: Twenty-eight patients without NSCLC
proven at or after surgery were excluded from Background: Epidermal growth factor receptor
subsequent analysis. Anatomical resection tyrosine kinase inhibitors (EGFR TKI) have not been
was in 290 (90.1%) (87.5% lobectomy/8.3% fully evaluated regarding their efÀcacy for brain
pneumonectomy/4.1% segmentectomy), wedge metastasis related to adenocarcinoma of the lung.
resection performed in 32 (9.9%). Sixty one of 322 Methods: This is a prospective study of patients
(18.9%) patients did not have separate N2 lymph with histologically conÀrmed adenocarcinoma of
nodes sent for staging (range between surgeons 0% the lung, EGFR mutations of either exon 19 or 21,
to 58.7%, p<0.0001). Only one patient with no N2 and documented brain metastatic lesions without
nodes sent was pN1, 46 were pN0 and 14 were pNx. prior therapy including radiotherapy or radiosurgery
The median number of N2 nodal stations reported or surgical resections. Either erlotinib 150 mg or
varied from 0 to 3 between surgeons (p<0.0001). geÀtinib 250 mg was administered every day. EGFR
The percentage of cases with Station 7 nodes sent mutations were genotyped by direct sequencing.
for histopathology varied between 17.4% and 91.0% Results: A total of 23 patients were enrolled. Median
(p<0.0001). The percentages of patients with three or age was 57 years (range 37-77). Female accounted
more N2 stations reported ranged from 2.2% to 56.2% for 61% (14/23) and ECOG PS 0-1 74% (17/23).
(p<0.0001) and the range for lobe-speciÀc SLND Fourteen patients (61%) had mutations in exon 19
was 0% to 25.8% (p<0.0001). The sub-speciality and 9 (39%) exon 21. Synchronous brain metastasis
of the surgeon (p<0.001) and whether surgery was documented in 15 patients (65%). Seventeen
was performed by thoracotomy (p=0.001) were patients used EGFR TKI as second line therapy. Six
independent predictors of three or more N2 stations patients (26%) received erlotinib and 17 geÀtinib.
dissected in multivariate linear regression analysis, but Response rate was 70.0%. Median PFS and OS were
PET nodal positivity and patient age were not. 6.6 months (95% CI: 0.0-14.7) and 19.8 months
Conclusion: There were signiÀcant differences (14.1-25.6). Drug modiÀcation related to toxicities
between the intra-operative staging practices of occurred in 4 patients (17.4%). Patients with exon
consultant surgeons. Lobe-speciÀc lymph node 19 mutations had longer PFS than those with exon
dissection rates were generally low. The sub-speciality 21 mutations (14.0 months vs 4.6 months; P=0.031);
of the surgeon and route of surgical access were however, no difference in OS was seen (exon 19 15.9
factors affecting nodal dissection strategy. months, exon 21 19.8 months; P=0.498). Patterns of
Keywords: Lymph nodes, Non small cell lung cancer treatment failure included progression of intracranial
lesions (42%, 5/12), extracranial lesions (25%,
3/12) and both intra- and extracranial lesions(33%,
Session MO21: Medical Oncology III 4/12). Following progression, 6 patients underwent
gamma-knife radiosurgery and 2 patients whole
Thursday, 7 July 2011 brain radiation.
Conclusion: EGFR TKI were effective in NSCLC
patients with brain metastasis harboring either
Medical Oncology III Thursday, 7 July 2011 12:30-14:00 exon 19 or 21 mutations. Exon 19 mutations
were associated with better disease control when
MO21.01 EFFICACY OF EPIDERMAL compared to exon 21.
GROWTH FACTOR RECEPTOR Keywords: Brain Metastasis, EGFR mutations,
TYROSINE KINASE INHIBITORS FOR EGFR TKI
BRAIN METASTASIS IN NON-SMALL
CELL LUNG CANCER PATIENTS
HARBORING EITHER EXON 19 OR 21
MUTATIONS
Kyu-Pyo Kim1, Dae-Ho Lee1, Jungshin J. Lee1,
Cheolwon Suh1, Sang-We Kim1, Jae Cheol Lee1,
Chang-Min Choi1, Se Jin Jang2, Jene Choi2
Medical Oncology III Thursday, 7 July 2011 12:30-14:00 December 2010, 26 pts had intracranial PD; 16 pts
had non-PD and continued on erlotinib; and 5 pts
MO21.02 ERLOTINIB AS 2ND-LINE stopped erlotinib due to extracranial PD. Median
TREATMENT IN ADVANCED NON- PFS was 10.1 months (95% CI 8.97–13.966) overall;
SMALL-CELL LUNG CANCER (NSCLC) for pts with 3 or >3 BM, median PFS was 10.2
PATIENTS (PTS) WITH ASYMPTOMATIC and 8.3 months, respectively (p=0.35); for pts with
BRAIN METASTASES (BM) AND ITS EGFR mutation, wild-type or unknown, median PFS
BIOMARKER ANALYSIS - A PHASE 2 was 23.2, 8.2 or 15.1 months respectively (p=0.06).
STUDY (CTOMG0803) ORR considered both intracranial and extracranial
Yi-Long Wu1, Caicun Zhou2, Ying Cheng3, Shun Lu4, lesions: 2 pts (4.2%) had a CR and 25 (52.1%) had
Gongyan Chen5, Cheng Huang6, Yi-Sheng Huang1, a PR, giving an ORR of 56.3%. Six-month and
Hong-Hong Yan1, Jin-Ji Yang1 1-year OS rates were 87% and 74%, respectively.
1
Guangdong Lung Cancer Institute, Guangdong Adverse events (AEs) occurred in 72.9% (35/48) of
General Hospital & Guangdong Academy Of pts; 7.3% of AEs were grade 3/4 and no SAEs have
Medical Sciences/China, 2Shanghai Pulmonary been reported to date. The most common AE was
Hospital, Tongji University/China, 3Jilin Cancer rash (64.6%). No unexpected AEs or ILD-like events
Hospital, Jilin Cancer Hospital/China, 4Shanghai were reported.
Chest Hospital, Jiaotong University/China, 5The Conclusion: Erlotinib as monotherapy after 1st-
Cancer Hospital Of Harbin Medical University, line CT for NSCLC pts with asymptomatic BM has
Harbin Medical University/China, 6Medical promising efÀcacy and is well tolerated. The best
Department, The Cancer Hospital Of Fujian/China PFS was seen in EGFR mutant patients.
Keywords: NSCLC, Brain Metastasis, erlotinib,
Background: About 20–30% of all pts with Clinical trial
NSCLC develop BM, leading to a poor prognosis
and a median survival of <6 months after whole
brain radiotherapy. The role of systemic CT in the Medical Oncology III Thursday, 7 July 2011 12:30-14:00
management of BM is limited and controversial. The
CTONG0803 study (NCT00663689) was designed to MO21.03 RATES OF CENTRAL NERVOUS
evaluate 2nd-line erlotinib in NSCLC pts with BM. SYSTEM (CNS) METASTASES IN
Methods: Eligible pts had conÀrmed PATIENTS WITH ADVANCED NON-
adenocarcinoma or activating EGFR mutation- SMALL CELL LUNG CANCER (NSCLC)
positive NSCLC and asymptomatic BM (1 lesion AND SOMATIC EGFR MUTATIONS
of 10mm diameter or 3 lesions of <10mm); INITIALLY TREATED WITH
without extracranial progressive disease (PD) after GEFITINIB OR ERLOTINIB VERSUS
2–6 cycles of 1st-line platinum-doublet CT; aged CHEMOTHERAPY
18–75y with ECOG PS of 0–2, and life expectancy Stephanie Heon1, Beow Yeap2, Neal I. Lindeman3,
>3 months. Pts received erlotinib 150mg/d until Michael S. Rabin1, David M. Jackman1, Bruce E.
radiologically-veriÀed intracranial PD or clinically Johnson1
1
symptomatic BM. The primary endpoint was PFS Medical Oncology, Dana-Farber Cancer Institute/
(time from starting erlotinib to occurrence of either United States Of America, 2Cancer Center,
clinically symptomatic BM or conÀrmed intracranial Massachusetts General Hospital/United States
PD). Secondary endpoints included ORR, 6-month Of America, 3Pathology, Brigham And Women’s
and 1-year OS rates and safety. EGFR mutation was Hospital/United States Of America
detected by DNA direct sequencing.
Results: From June 2008 to April 2010, 48 pts Background: The impact of tumor genotype and
were enrolled in the study; 1 pt withdrew consent treatment with targeted therapies on the control and
to receive erlotinib after 7 days, without efÀcacy development of CNS metastases from NSCLC has
assessment. Demographics were: median age not been extensively studied. We recently reported
56y (range 21–75y); male/female: 19/29; PS 1/2: a lower than expected rate of CNS progression in
18/30; adeno/BAC/other: 45/1/2; no. of BM: 3/>3 patients with advanced NSCLC and somatic EGFR
23/25; non-smoker/smoker/unknown: 38/8/1; mutations initially treated with the EGFR tyrosine
EGFR mutant/wild-type/unknown: 7/15/26. As of kinase inhibitors (TKIs), geÀtinib or erlotinib. This
retrospective study was undertaken to investigate the Conclusion: Our data suggest lower rates of CNS
impact of geÀtinib or erlotinib versus chemotherapy progression in patients with advanced NSCLC
on the outcome of CNS progression in EGFR mutant and somatic EGFR mutations initially treated
advanced NSCLC patients. with geÀtinib or erlotinib compared with upfront
Methods: Patients with stage IV or relapsed chemotherapy. Additional patients with advanced
metastatic NSCLC with somatic EGFR mutations NSCLC initially treated with chemotherapy are
seen at the Dana-Farber Cancer Institute between undergoing EGFR sequencing to increase the number
08/2000 and 02/2010 who were initially treated of EGFR mutant patients treated with chemotherapy.
with geÀtinib or erlotinib or chemotherapy without Keywords: Secondary brain neoplasms, Secondary
receiving geÀtinib or erlotinib for at least 6 months meningeal neoplasms, Non-small cell lung cancer,
following treatment initiation were identiÀed Epidermal growth factor receptor tyrosine kinase
from a prospective trial. The cumulative risk of inhibitors
CNS progression was calculated using death as a
competing risk. CNS progression included both
newly developed brain or leptomeningeal metastases Medical Oncology III Thursday, 7 July 2011 12:30-14:00
and progression of preexisting brain lesions.
Results: One hundred and twenty-nine patients with MO21.04 CEREBROSPINAL FLUID
somatic EGFR mutations were eligible for inclusion CONCENTRATION OF GEFITINIB IN
in this analysis (99 EGFR-TKI, 30 chemotherapy). PATIENTS WITH CENTRAL NERVOUS
Twenty-one patients (21%) in the EGFR-TKI group SYSTEM METASTASES OF NON-SMALL
and 9 patients (30%) in the chemotherapy group had CELL LUNG CANCER
brain metastases at the time of diagnosis of advanced Yaping Xu1, Shenglin Ma2, Nengming Lin3, Yang
NSCLC (P=0.331); twenty-eight of the 30 patients Yu3, Luo Fang3, Xiaojiang Sun3, Hao Jiang3
1
received CNS therapy before initiating systemic Department Of Radiotherapy, Zhejiang Cancer
treatment. Thirty patients (30%) in the EGFR-TKI Hospital/China, 2Hangzhou Cancer Hospital/China,
3
group and 15 patients (50%) in the chemotherapy Zhejiang Cancer Hospital/China
group developed CNS progression after a median
potential follow-up of 49 months (P=0.040). The 1- Background: Although there have been several
and 2-year cumulative risk of CNS progression was reports in which central nervous system (CNS)
5% (95% CI, 2–11%) and 21% (95% CI, 13–30%), metastases of non-small cell lung cancer (NSCLC)
respectively, in the EGFR-TKI group compared with were improved by geÀtinib, however, very little is
corresponding rates of 24% (95% CI, 10–40%) and known about the CNS penetration and exposure to
31% (95% CI, 15–48%) in the chemotherapy group. this drug. We measured plasma and cerebrospinal
Progression-free survival was prolonged in patients Áuid(CSF) concentrations of geÀtinib. The another
initially treated with geÀtinib or erlotinib (median purpose of this study was to demonstrate the
11.5 v 6.9 months; P<0.001), whereas there was no beneÀcial effect of geÀtinib in the treatment of CNS
difference in overall survival (median 32.2 v 36.2 metastasis for a select group of NSCLC patients who
months; P=0.366). had a sensitive EGFR mutation or good predictive
clinical factors for EGFR TKI treatment.
Methods: We administered 250 mg geÀtinib daily
concurrently with whole brain radiotherapy (in 3Gy
fraction Àve times weekly to a total dose of 30 Gy) to
six patients with NSCLC who had CNS metastases,
and we investigated plasma and CSF concentrations
of geÀtinib on day 8, when steady-state plasma
concentrations of geÀtinib were assumed to be
achieved. Objective response rate according to the
RECIST criteria was recorded and performence
status (PS) was evaluated using Zubrod-ECOG-
WHO(ZPS) score.
Results: In all cases, plasma and CSF concentrations
of geÀtinib data on day 8 were similar to those
previously reported. The CSF penetrations of Smilow Cancer Hospital/United States Of America,
2
geÀtinib in patients with NSCLC who had CNS City Clinical Hospital/Ukraine, 3Leningrad
metastases were approximately 2.4% (Table 1). Regional Clinical Hospital/Russian Federation,
4
Five of 6 patients showed overt improvement in Oddzial Chemioterapii/Poland, 5University Of
ECOG performance status. The overall response Mediterranée - Assistance Publique Hopitaux De
rate was 100% (Table 2). Table 1. Plasma and CSF Marseille/France, 6Christian Medical College/
concentrations of geÀtinib in six patients India, 7Department Of Hematology, Oncology
And Pneumology, Johannes Gutenberg-university
Case Plasma concentration CSF concentration CSF penetration Medical Center Mainz/Germany, 8Bristol-myers
ng/mL nmol/L ng/mL nmol/L rate (%) Squibb/United States Of America, 9Hospital
1 31.73 70.99 0.91 2.03 2.86 Grosshansdorf/Germany
2 107.12 239.69 4.81 10.77 4.49
3 56.90 127.33 0.89 1.98 1.56 Background: Ipilimumab, a fully human
4 28.15 62.98 0.68 1.52 2.41 monoclonal antibody, augments T cell activation
5 35.43 79.27 0.53 1.18 1.48 by selectively inhibiting cytotoxic T-lymphocyte
6 23.27 52.07 0.40 0.89 1.71
antigen-4. Ipilimumab signiÀcantly improved overall
survival (OS) in a phase 3 study of previously treated
Table 2. Clinical Characteristics of the Patients, patients with metastatic melanoma; principal adverse
Tumor Response events (AEs) were immune-mediated and managed
using drug-speciÀc treatment-guidelines (N Eng J
Case Age Sex Cigarettes/ Histology EGFR Change Tumor Med 2010;363:711). We conducted a phase 2 study
(yr) year Mutation of PS Response (CA184-041) of ipilimumab plus paclitaxel and
1 43 F Never Ad + 1 to 1 PR carboplatin (P/C) as Àrst-line treatment in non-small
2 64 M Never Ad + 1 to 0 CR
cell lung cancer (NSCLC) or extensive-disease small
3 60 F Never Sq + 2 to 1 PR
cell lung cancer. Imunohistochemical evaluation
4 35 F Never Ad + 2 to 0 CR
indicates that T-cell inÀltration level may correlate
5 23 M <400 Ad - 1 to 0 PR
with NSCLC histology (Br J Cancer 2006;94:275).
6 37 F Never Ad + 2 to 1 PR
Given this, we report our analysis of NSCLC cohort
by histology (squamous/non-squamous).
Conclusion: The CSF penetrations of geÀtinib in Methods: Patients were randomized 1:1:1 to
patients with NSCLC who had CNS metastases were receive: concurrent ipilimumab+P/C, (4 doses
approximately 2.4%. GeÀtinib are effective in the of ipilimumab+P/C followed by 2 doses of
treatment of CNS metastases from NSCLC when placebo+P/C); phased ipilimumab+P/C, (2
patients were selected properly. doses of placebo+P/C followed by 4 doses of
Keywords: Cerebrospinal Áuid, Non-small cell lung ipilimumab+P/C); or P/C alone, (placebo+P/C).
cancer, geÀtinib, Central nervous system metastases Ipilimumab (10 mg/kg), paclitaxel (175 mg/
m2) and carboplatin (AUC=6) were administered
intravenously every 3 weeks for a maximum of 6
Medical Oncology III Thursday, 7 July 2011 12:30-14:00 doses. Patients without disease progression who
tolerated treatment received ipilimumab (ipilimumab
MO21.06 IPILIMUMAB IN arms) or placebo (P/C alone arm) every 12 weeks in
COMBINATION WITH PACLITAXEL maintenance phase.
AND CARBOPLATIN AS FIRST- Results: As reported previously, 204 untreated
LINE TREATMENT IN NON-SMALL NSCLC (57 squamous; 147 non-squamous) patients
CELL LUNG CANCER: ANALYSIS BY were randomized. The study met its primary
BASELINE HISTOLOGY IN A PHASE 2 endpoint of immune-related PFS (irPFS) with irPFS,
TRIAL mWHO-PFS and OS being more favorable for
Thomas Lynch1, Igor Bondarenko2, Alexander Luft3, phased schedule. Analysis by histology in phased
Piotr Serwatowski4, Fabrice Barlesi5, Raju Chacko6, ipilimumab+P/C arm suggests greater improvements
Martin Sebastian7, Jonathan Siegel8, Jean-Marie in PFS versus P/C alone among patients with
Cuillerot8, Martin Reck9 squamous NSCLC [HR= 0.40 (95%CI, 0.18-0.87)
1
Department Of Oncology, Yale Cancer Center And for squamous and HR=0.81 (95%CI, 0.53-1.26)
1
for non-squamous vs P/C alone]. Similar results Department Of Oncology, Istituto ScientiÀco San
were noted with OS [HR= 0.48 (95%CI, 0.22-1.03) Raffaele/Italy, 2Istituto Nazionale Tumori/Italy,
3
for squamous and HR=1.17 (95%CI, 0.74-1.86) Lung Cancer Unit, National Institute For Cancer
for non-squamous vs P/C alone]. In the concurrent Research/Italy, 4Clinical Development, Molmed/Italy
ipilimumab+P/C arm, however, PFS and OS were
similar among squamous and non-squamous patients Background: NGR-hTNF is a highly selective
when compared to P/C alone [PFS:HR= 0.87 vascular targeting agent consisting of human tumor
(95%CI, 0.42-1.81) for squamous and HR=0.88 necrosis factor (hTNF) fused with the NGR peptide,
(95%CI, 0.57-1.35) for non-squamous vs P/C alone; which is able to bind to a CD13 overexpressed on
OS: HR= 1.02 (95%CI, 0.50-2.08) for squamous and tumor blood vessels. By damaging tumor vasculature
HR= 0.96 (95%CI, 0.60-1.53) for non-squamous vs and decreasing tumor interstitial pressure, NGR-
P/C alone]. Overall safety in NSCLC patients was hTNF improves penetration of cytotoxic agents
previously reported with grade3/4 AEs being 57%, within the tumor.
54% and 40% in concurrent ipilimumab+P/C, phased Methods: Chemo-naive, stage IIIb-IV NSCLC
ipilimumab+P/C, and P/C alone arms, respectively. patients, including patients with brain metastasis,
Hematologic abnormalities observed were those stratiÀed by histology (nonsquamous vs squamous)
generally expected with P/C. Two treatment-related and PS (0 vs 1), were randomly assigned to
deaths were reported, one each in concurrent receive and cisplatin 80 mg/m2 day 1 plus either
ipilimumab+P/C and P/C alone arms. Most common gemcitabine 1,250 mg/m2 days 1 and 8 for squamous
(>5% in any arm) treatment-related grade3/4 AEs histology or pemetrexed 500 mg/m2 day 1 for
(concurrent vs phased vs P/C alone) were: fatigue nonsquamous histology for up to six cycles plus
(10% vs 7% vs 6%) and diarrhea (10% vs 7% vs 4%) NGR-hTNF 0.8 ƫg/m2 day 1 until progression (arm
among non-squamous patients; nausea (0% vs 5% vs A) or chemotherapy alone (arm B). Primary study
7%), vomiting (0% vs 5% vs 7%) and dyspnoea (0% objective was progression-free survival (PFS).
vs 0% vs 7%) among squamous patients. Assuming a 15% absolute increase in PFS rate
Conclusion: In NSCLC patients, a statistically (ơ=20% and 1-sided Ơ=10%), a sample size of 102
signiÀcant improvement (phase 2 criteria) in irPFS patients was calculated.
and PFS was previously reported with phased Results: Of the 86 patients recruited so far, 64
ipilimumab+P/C versus P/C alone. Analysis patients (32 in each arm) were presently assessed
by histology suggests greater improvements in for safety and preliminary activity. Baseline
squamous NSCLC with phased schedule. AE characteristics were (arm A/B): median age: 63/62
proÀle in ipilimumab arms was generally similar in years; PS of 1: 11/9; squamous histology: 8/8. A total
squamous and non-squamous patients. While sample of 180 cycles (range 1-17) were administered in arm
size precludes deÀnitive conclusions, these results A and 133 cycles (range 1-6) in arm B. Treatment-
are encouraging and warrant exploration in a larger related grade 3-4 toxicities for arm A vs B were
clinical trial. 23% vs 34% for all adverse events and included:
Keywords: ipilimumab, CTLA-4, NSCLC, Lung neutropenia 13% vs 15%; thrombocytopenia 3% vs
cancer 6%; fatigue 3% vs 12%; renal or respiratory failures
0% vs 6%; thromboembolism 6% vs 0%. Grade
1-2 hypertension was 3% in arm A and 11% in arm
Medical Oncology III Thursday, 7 July 2011 12:30-14:00 B. No grade 3 or 4 toxicities related to NGR-hTNF
were observed, while 31% of patients, as espected,
MO21.07 RANDOMIZED PHASE II TRIAL experienced NGR-hTNF-infusion related grade 1
OF NGR-HTNF AND CHEMOTHERAPY transient chills. Neither pulmonary hemorrhage nor
IN CHEMO-NAIVE PATIENTS WITH bleeding were reported in both arms. Median follow-
NON-SMALL CELL LUNG CANCER up time was 8.6 months in arm A and 5.5 months
(NSCLC): PRELIMINARY RESULTS. in arm B. In patients with nonsquamous histology
Vanesa Gregorc1, N. Zilembo2, Francesco Grossi3, (n=48), PFS rates at eight months were 38% in arm
Gilda Rossoni1, Filippo Pietrantonio2, Erika Rijavec3, A and 18% in arm B. In nonsquamous patients who
Alessandra Bulotta1, Milena Vitali2, Giulia Barletta3, achieved disease control (partial response plus stable
Luca Bergamaschi2, Marco Platania2, Antonio disease; n=36), PFS rates at eight months were 51%
Lambiase4, Claudio Bordignon4 in arm A and 21% in arm B. Among patients with
squamous histology (n=16), 2 partial responses, normal tissue antigens. On this basis, the MAGE-A3
5 stable diseases and 1 progressive disease in arm Antigen-SpeciÀc Cancer Immunotherapeutic
A and 1 partial response, 4 stable diseases and 3 (ASCI) (recombinant MAGE-A3 protein + an
progressive diseases in arm B were observed. immunostimulant AS15) has been developed
Conclusion: NGR-hTNF and chemotherapy can be and is currently under evaluation in a double-
safely combined in NSCLC regardless of histology blind, randomized, placebo-controlled Phase III
showing promising antitumoral activity. study, the MAGRIT trial (NCT00480025) as
Keywords: NSCLC, Chemotherapy, NGR-hTNF adjuvant treatment in patients with MAGE-A3
positive stage IB-IIIA resected non-small cell lung
cancer (NSCLC). We present here the tumor and
Medical Oncology III Thursday, 7 July 2011 12:30-14:00 patient characteristics associated with MAGE-A3
expression.
MO21.08 PATIENT AND TUMOR Methods: Univariate logistic regression analysis
CHARACTERISTICS IMPACTING ON was performed with tumor and patient characteristics
MAGE-A3 EXPRESSION: SCREENING (including age, race, region, sex, stage, T stage,
DATA FROM THE MAGRIT PHASE III N stage, histopathology and tumor size) to select
TRIAL variables that impact signiÀcantly on MAGE-A3
Joo-Hang Kim1, Jae Ill Zo2, Haruhiko Nakayama3, expression (based on available information for 8470
Tommaso De Pas4, Jubrail Dahabreh5, Marcin of the 9347 screened patients, data from 06 Dec
Zielinski6, Nasser Altorki7, Tonu Vanakesa8, 2010). This was also done separately for squamous
Keunchil Park9, Herjan Leszek10, Kenji Suzuki11, and non-squamous tumors. Variables associated with
János Strausz12, Emilio Esteban González13, Tetsuya MAGE-A3 expression in the univariate analysis
Mitsudomi14, Sumitra Thongprasert15, Lecia were then used to build a multivariate model to
Sequist16, K robert Shen17, Bart Spiessens18, Channa predict MAGE-A3 expression by histopathology.
Debruyne19, Johan Vansteenkiste20 Results: The overall rate of MAGE-A3 expression
1
Oncology, Yonsei Cancer Center/Korea, 2Center was 33.4%. We observed major differences between
For Lung Cancer, National Cancer Center/Korea, MAGE-A3 expression in squamous (47.5%) and
3
Thoracic Oncology, Kanagawa Cancer Center/ non-squamous tumors (25.7%). For squamous
Japan, 4European Institute Of Oncology/Italy, tumors, none of the tested independent variables
5
Medical Center/Greece, 6Szpital Chorob Pluc/ had a clinically relevant predictive capacity for
Poland, 7Weil Medical College, Cornell University/ MAGE-A3 expression (MAGE-A3 expression in the
United States Of America, 8North Estonia Medical different subcategories ranged from approximately
Center/Estonia, 9Samsung Medical Center, 40-50%). For non-squamous tumors, the independent
Sungkyunkwan University School Of Medicine/ variables signiÀcantly associated with MAGE-A3
Korea, 10Wojewodzki Szpital/Poland, 11Juntendo expression were race (Asian: 18.3%; others: 28.2%),
University Hospital/Japan, 12Koranyi National region (East Asia: 18.9%; Europe: 29.5%; North
Institute For Pulmonology/Hungary, 13Hospital America: 24.4%; Other International: 24.6%), sex
Central De Asturias/Spain, 14Aichi Cancer Center (male: 29.6%; female: 20.6 %); stage (IA: 11.0%;
Hospital/Japan, 15Maharaj Nakorn Chiangmai IB: 25.5%; IIA: 21.0%; IIB: 28.8%; IIIA: 25.9%;
Hospital, Chiangmai University/Thailand, IIIB: 29.6%), T category (T1: 20.1%, T2: 25.5%;
16
Massachusets General Hospital Cancer Center/ T3: 34.6%; T4: 27.9%), and size of tumor ( < 4 cm:
United States Of America, 17Mayo Clinic/United 21%; 4cm: 31.5%%). In a multivariate model for
States Of America, 18Glaxosmithkline Biologicals/ non-squamous tumors (based on 5326 patients for
Belgium, 19Gvd, Glaxosmithkline Biologicals/ whom all required information was available), the
Belgium, 20Univ. Hospital Gasthuisberg/Belgium variables race, sex and tumor size were signiÀcantly
associated with MAGE-A3 expression. To illustrate
Background: Active immunization against the variation, among non-squamous histopathologies
MAGE-A3 tumor antigen is currently under cancers, MAGE-A3 expression was signiÀcantly
investigation. MAGE-A3 belongs to the cancer- lower in Asian female with a tumor size < 4 cm
germline shared tumor antigens also called cancer- (8.8%), compared to male from “non-Asian” regions
testis tumor-speciÀc antigens, which are appealing and with a tumor size 4cm. (36%).
because they have little crossover with accessible Conclusion: In patients with stage IB-IIIA
resected NSCLC; we observed major differences Solid Tumors. Adverse events were graded according
in MAGE-A3 expression between squamous and to National Cancer Institute Common Toxicity
non-squamous tumors. For squamous tumors, the Criteria (version 3.0).
overall expression rate was 47.5% and other clinical Results: Between 1998 and 2010, 43 patients were
variables had little impact on predicting MAGE-A3 treated with dendritic cell-based vaccines, and 26
expression. However, among non-squamous tumors, patients (60.5%) with mean age of 61.1 years (range,
three factors have been identiÀed as signiÀcant 39-77 years) were assessable for response. Among
predictors for MAGE-A3 expression: non-Asian these assessable patients, 1 partial response and no
race, male sex, and larger tumor size. complete responses were obtained, giving an overall
Keywords: MAGE-A3, Antigen-SpeciÀc Cancer response rate of 4.7%. Fifteen patients (57.7%) had
Immunotherapeutic, Non-small cell lung cancer stable disease, yielding an overall disease control
rate of 61.5%. Seven patients had progressive disease
as the best response. Survival of those patients was
Medical Oncology III Thursday, 7 July 2011 12:30-14:00 evaluated in 19 patients. Of them, 5 patients were
still alive for more than 6 months, and 14 were dead,
MO21.09 MUC1-TARGETING with mean survival time of 12.2 months after the
DENDRITIC CELL-BASED VACCINE vaccines. Adverse events related to the vaccines were
IMMUNOTHERAPY IN PATIENTS WITH mild, and grade 1-2 of fever/chill was observed in 10
ADVANCED LUNG CANCER patients (21.7%).
Koji Teramoto, You Kawaguchi, Tesuo Hori, Shoji Conclusion: MUC1-targeting dendritic cell-based
Kitamura, Jun Hanaoka, Norikai Tezuka vaccine immunotherapy is feasible, and has a
Department Of Surgery, Shiga University Of Medical potential to control the diseases in patients with
Science/Japan treatments-refractory lung cancer.
Keywords: immunotherapy, MUC1, Advanced Lung
Background: MUC1, a tumor antigen, has been Cancer, dendritic cell
considered to a promising target antigen for cancer
immunotherapy because it possesses a strong
immunogenicity. It is processed and presented by Medical Oncology III Thursday, 7 July 2011 12:30-14:00
antigen-presenting cells in a MHC-unrestricted
pattern. Dendritic cell-based vaccine immunotherapy MO21.11 TREATMENT WITH TKI
can elicit antigen-speciÀc cytotoxic T lymphocytes BEYOND PROGRESSION IN LONG
in tumor-bearing hosts, and activated cytotoxic TERM RESPONDERS TO ERLOTINIB IN
T lymphocytes are expected to attack cancer ADVANCED NSCLC
cells. In this study, we evaluated the efÀcacy and Martin Faehling1, Robert Eckert2, Sabine Kuom1,
feasibility of MUC1-targeting dendritic cell-based Werner Spengler3
1
vaccine immunotherapy in patients with advanced Klinikum Esslingen, Klinik Für Kardiologie
treatments-refractory lung cancer. Und Pneumologie (TESS)/Germany,
2
Methods: The eligibility criteria of this Onkologische Schwerpunktpraxis Wendlingen/
immunotherapy were as follows: histologic or Germany, 3Medizinische Klinik II (Onkologie),
cytologic evidence of lung cancer that have been Universitätsklinik Tübingen/Germany
proven to express MUC1 abundantly; an Eastern
Cooperative Oncology Group performance status of Background: Some patients with advanced
0-2; advanced stage of diseases refractory for other inoperable NSCLC show prolonged disease
cancer treatments. The dendritic cells were prepared stabilization on the EGFR-tyrosine kinase inhibitor
from peripheral blood mononuclear cells with (TKI) erlotinib. It is so far not clear how to treat
cytokines interleukin-4 and granulocyte macrophage patients who progress after prolonged response to
colony stimulating factor, were pulsed with MUC1 erlotinib. From a pathophysiological point of view,
peptides, and subsequently administered to patients it might be better, to continue TKI therapy beyond
subcutaneously. The vaccinations were repeated progression and add further therapy as appropriate
bi-weekly, and assessable patients were received at rather than to discontinue TKI and use standard
least 6 vaccinations. Tumor response was assessed therapy alone.
according to the Response Evaluation Criteria in Methods: We retrospectively analyzed all NSCLC
patients treated with erlotinib at our institutions since Keywords: Tyrosine kinase inhibitor, NSCLC,
February 2004 who progressed after stable disease advanced, erlotinib
on erlotinib for at least 6 months.
Results: Of 43 patients, those 28 who were treated
with TKI beyond progression had a signiÀcantly Medical Oncology III Thursday, 7 July 2011 12:30-14:00
longer overall survival (OS)than those 15 who did
not receive further TKI treatment after progression. MO21.12 RETREATMENT WITH
The two groups did no differ signiÀcantly with ERLOTINIB FOR PATIENTS WITH
respect to progression-free survival (PFS) on TKI, NSCLC WHO BENEFITTED FROM
ECOG or age at progression. Of the 28 patients PREVIOUS EGFR-TKI TREATMENT.
treated beyond progression, 24 received erlotinib, Laurence M.M. Crombag, Annemarie Becker, Atie
whereas 4 were switched to the second generation W. Van Wijk, Pieter E. Postmus, Egbert F. Smit
TKI afatinib (LUX-LUNG5 trial). 12 patients on Pulmonary Diseases, Vrije Universiteit Medical
erlotinib beyond progression received 1 further Centre/Netherlands
line of chemotherapy, 6 patients received 2 lines
(15 pemetrexed, 7 gemcitabine, 1 vinorelbine, Background: Tyrosine kinase inhibitors (TKIs)
1 carboplatin). Treatment with erlotinib and of the epidermal growth factor receptor (EGFR)
chemotherapy was well tolerated with no increase in are globally approved as treatment in any line of
grade 3 and 4 toxicities. non-small-cell lung cancer (NSCLC). Patients with
an activating mutation who despite an initially
impressive response to EGFR TKI’s invariably
relapse. For these patients few treatment options are
available after additional progression during or after
chemotherapy. The aim of this retrospective study
is to study whether acquired resistance to an EGFR-
TKI is reversible after a drug holiday.
Methods: We retrospectively reviewed the medical
records of 14 patients with stage IV NSCLC who
progressed after previously achieved long term
disease control on treatment with EGFR-TKI’s, were
subsequently treated with standard chemotherapy
and at renewed progression retreated with TKI .
TKI beyond No TKI beyond SigniÀcance Treatment was continued until radiographic tumor
progression progression (p)
progression. All patients were retreated with erlotinib
n 28 15 -
(two in combination with cetuximab) at the maximal
OS after progression on 9 2 0.0002
TKI (months) tolerated dose. Tumor response was evaluated by
OS from start of TKI 25.5 14.5 0.019 radiologic examinations according to the Response
therapy (months) Evaluation Criteria in Solid Tumors (RECIST).
PFS from start of TKI 13 11.75 n.s. (0.49)
therapy (months)
Progression-free survival was deÀned as the period
Age at progression 65.1 67.8 n.s. (0.37) from the start of treatment until disease progression.
Patients receiving 18 (64.3%) 8 (53.3%) Results: 14 patients (5 male, 9 female, median age
Chemotherapy after 55 years (39-70 years), ECOG PS 0-1) received
progression
Patients receiving 7 (25%) 3 (20%)
retreatment with erlotinib. The median interval
Radiotherapy after from the discontinuation of EGFR-TKI to the
progression 2nd episode was 9.5 months (3-36 months). With
Patients receiving BSC 3 (10.7%) 5 (33.3%)
after progression
erlotinib retreatment 36% (n=5) received partial
response, 50% had stable disease (n=7) and 14%
Conclusion: In long-term erlotinib responders, had progressive disease (n=2) as their best response.
treatment with TKI beyond progression in addition Median follow up is 9 months (1,5- 16+ months)
to chemotherapy or radiotherapy is feasible and well and median PFS is 6,5 months (1- 16+ months).
tolerated. TKI-treatment beyond progression may 7 patients are still on therapy without signs of
lead to prolonged OS. progression. Toxicity of treatment consisted of grade
1-3 skin rash, grade 2 hair loss, grade 1 diarrhea, Methods: We analyzed four hundred and seventeen
grade 2 constipation and grade 1 esophagitis NSCLC patients who showed partial response or
(CTCAE v 3.0). Dose reduction was often necessary. complete response at the Àrst 2 months evaluation and
Conclusion: Our Àndings suggest that retreatment with stable disease for more than 6 months after the initiation
erlotinib is an option for patients with NSCLC who of geÀtinib. All clinical data were obtained from 9 centers
initially beneÀtted from previous EGFR-TKI treatment of Korean Molecular Lung Cancer Group (KMLCG).
and recurred after standard cytotoxic chemotherapy. The time to progression, overall survival, clinical
Keywords: NSCLC, EGFR-TKI retreatment manifestations, and EGFR genotype were analyzed in
the aspect of acquired resistance development.
Results: The median time to the development
Medical Oncology III Thursday, 7 July 2011 12:30-14:00 of acquired resiatance to geÀtinib (time to
progression) was 10.2 months and overall survival
MO21.13 RETROSPECTIVE ANALYSIS was 20.8 months. Survival analysis of the patients
FOR CLINICAL CHARACTERISTICS OF experienced acquired resistance to geÀtinib showed
ACQUIRED RESISTANCE TO GEFITINIB signiÀcant predominance in female, non-smoker,
IN NON-SMALL CELL LUNG CANCER and adenocarcinoma histology and these trend was
PATIENTS more prominent in responder group (CR/PR) than
Hye Ryun Kim1, Jae Chol Lee1, Young Chul Kim2, in stable disease group. EGFR genotype does not
Kyu Sik Kim2, In Jae Oh2, Hee Jung Ban3, Sung affect the developmemt of acquired resistance to
Yong Lee3, Tae Won Jang4, Kyeong Cheol Shin5, geÀtinib even though EGFR genotyping data was
Gwan Ho Lee5, Jeong Seon Ryu6, Seung Hoon Jang7, obtained in only 30% of the patients. At the time
Jeong Eun Lee8, Sun Young Kim8, Hee Joung Kim9, of acquired resistance, 35.3 % of the patients were
Kye Young Lee9 asymptomatic. The incidence of primary tumor
1
Internal Medicine, Korea Cancer Center Hospital/ progression was 53.2% and CNS failure was noted
Korea, Democratic People’s Republic Of, 2Chonnam in 17.1% of the patients. Median time to death after
National University Medical School, Hwasun acquisition of resistance was 8.9 months (7.4 – 10.4)
Hospital/Korea, Democratic People’s Republic Of, and multivariate analysis showed signiÀcantly high
3
Guro Hospital, Korea University Medical School/ risk in smoker, poor performance status, CNS failure
Korea, Democratic People’s Republic Of, 4Kosin and chemotherapy after acquisition of resistance.
University Medical College/Korea, Democratic Conclusion: These retrospectively analyzed clinical
People’s Republic Of, 5Yeungnam University data for the clinical characteristics of acquired
College Of Medicine/Korea, Democratic People’s resistance to geÀtinib will support to set up the
Republic Of, 6Inha University School Of Medicine/ clinical deÀnition of acquired resistance to EGFR-
Korea, Democratic People’s Republic Of, 7Hallym TKI and the strategy to overcome the acquired
University School Of Medicine/Korea, Democratic resistance
People’s Republic Of, 8Choongnam National Keywords: Non small cell lung cancer, acquired
University Hospital And Cancer Research Institute/ resistance, geÀtinib, EGFR mutations
Korea, Democratic People’s Republic Of, 9Internal
Medicine, Konkuk University Hospital/Korea,
Democratic People’s Republic Of Medical Oncology III Thursday, 7 July 2011 12:30-14:00
Background: The NSCLC patients who experienced MO21.14 HER2 MUTATIONS IN

good clinical responses to epidermal growth NON-SMALL CELL LUNG CANCER:
factor receptor tyrosine kinase inhibitos (EGFR- PRELIMINARY EFFICACY OF
TKIs) such as geÀtinib or erlotinib will inevitably TARGETED THERAPY WITH
develop acquired resistance. Molecular mechanisms NERATINIB + TORISEL ON A PHASE I
including T790M secondary mutation and c-Met TRIAL.
have been suggested,but the clinical deÀnition and Leena Gandhi1, Mohit Butaney1, Alice T. Shaw2,
characteristics of acquired resistance to EGFr-TKIs Rastislav Bahleda3, Kathleen Fiel1, Andrew
is not clearly established. Herein, we investigated Wolanski1, Kathleen Turnbull4, Anna Berkenblit4,
the clinical characteristics of acquired resistance to Bruce E. Johnson1, Pasi A. Janne1, Jean-Charles
geÀtinib in NSCLC retrospectively. Soria3, Geoffrey Shapiro1
1
Medical Oncology, Dana-Farber Cancer Institute/ disease control rate on neratinib + temsirolimus
United States Of America, 2Cancer Center, despite signiÀcant prior treatment, suggesting HER2-
Massaschusetts General Hospital/United States Of mutant NSCLC, like other molecular subgroups,
America, 3Institut Gustave Roussy/France, 4PÀzer, may be uniquely sensitive to the appropriate targeted
Inc/United States Of America therapy. An expansion cohort of 12 NSCLC pts has
been initiated.
Background: Distinct populations of patients (pts) Keywords: HER2, neratinib, torisel, lung
with non-small cell carcinoma (NSCLC) carry
somatic activating mutations uniquely sensitive
to speciÀc targeted therapies. Human Epidermal Session MO22: Biomarkers VIII
Growth Factor Receptor 2 (HER2) mutations were
Àrst identiÀed in NSCLC in 2004, but the clinical Thursday, 7 July 2011
signiÀcance of these mutations is still unclear.
Preclinical data have demonstrated that mutant
HER2 activates the Akt/mTOR pathway and is Biomarkers VIII Thursday, 7 July 2011 12:30-14:00
oncogenic in vitro and in vivo. In a HER2-driven
transgenic murine model of lung cancer, synergistic MO22.01 TUMOR IMMUNE
anti-tumor activity was seen with the combination MICROENVIRONMENT IN STAGE I
of a HER family inhibitor and an mTOR inhibitor LUNG ADENOCARCINOMA (LAC):
compared to either drug alone. STROMAL FOXP3/CD3 RATIO, TUMOR
Methods: A phase I clinical trial of neratinib (HER2 IL7R, AND IL12Rȕ2 ARE INDEPENDENT
inhibitor) + temsirolimus (mTOR inhibitor) was PREDICTORS OF RECURRENCE
designed in part to assess the clinical efÀcacy of Kei Suzuki1, Kyuichi Kadota2, Camelia S. Sima3,
this combination in selected molecular cohorts of Valerie W. Rusch1, Michel Sadelain4, William D.
NSCLC. Sequencing across HER2 Exon 20 was Travis2, Prasad S. Adusumilli1
1
conducted on tumor samples from non-squamous Department Of Surgery, Thoracic Service,
cell carcinoma pts under an IRB-approved protocol. Memorial Sloan-Kettering Cancer Center/United
Eligible pts with identiÀed HER2 mutations States Of America, 2Pathology, Memorial Sloan-
were enrolled to the phase I trial of neratinib + Kettering Cancer Center/United States Of America,
3
temsirolimus and assessed for best response. Epidemiology And Biostatistics, Memorial Sloan-
Results: As part of a comprehensive genotyping Kettering Cancer Center/United States Of America,
4
effort of non-squamous lung cancer at Dana-Farber Center For Cell Engineering, Memorial Sloan-
Cancer Institute, Àfteen pts with tumors harboring Kettering Cancer Center/United States Of America
HER2 mutations were identiÀed from 509 tumors
sequenced from July 2009-December 2010 (3%). Background: The NIH Director’s Challenge multi-
The majority was women (60%) and had no (60%) institutional gene proÀling study identiÀed immune-
or limited (33%) smoking history (< 10 pack-years). related genes with prognostic signiÀcance in LAC.
Six pts with HER2-mutated NSCLC (including one The aims of this study are to investigate in stage
not of this cohort) with progressive disease after a I LAC: (a) immune microenvironment (immune
median of 3 prior therapies were treated on the phase cell inÀltration, chemokines, interleukins, and their
I study of neratinib + temsirolimus. Pts were treated receptors) in the tumor nest and the tumor-associated
at dose levels of neratinib ranging from 120-240 stroma and (b) assess the strength of immune
mg daily and temsirolimus ranging from 15-75 mg markers in predicting recurrence in a multivariate
weekly. Four of six patients showed some tumor analysis.
regression (2 partial response and 2 stable disease). Methods: Stage I LAC tissue microarrays (n=479,
Median progression-free survival among evaluable 1995-2005, median follow-up 4.3 years) were
patients was 5 months (1.7, 10.5). constructed, and immunohistochemistry was
Conclusion: Systematic genotyping of NSCLC performed for immune cell inÀltration (CD3,
pts identiÀed those who were eligible for HER2- CD4, CD8, CD20, FoxP3), chemokines/receptors
targeted therapy. These pts share similar clinical (CXCL12, CXCR4, CCR7), and interleukin
characteristics to epidermal growth factor receptor receptors (IL7R and IL12Rơ2). Stains were analyzed
(EGFR) mutation-carriers. We observed a 67% for tumor and stromal immune cell inÀltration (low
versus high) as well as immune marker expression IL12Rơ2. Prognostic ability of two markers even in
(sum of intensity and distribution). Log-rank tests tumors 2cm underscores the signiÀcance of tumor-
and Cox proportional hazard models were used to immune interactions in the progression of early
analyze the association between each marker and LAC.
recurrence-free survival (RFS). Keywords: early lung adenocarcinoma, tumor
Results: The 5-year RFS for the entire cohort was stroma, tumor immunology, prognostic marker
82%. No prognostic signiÀcance was demonstrated
for the immune cells independently. However, a
relative ratio of stromal FoxP3 (regulatory T-cells) Biomarkers VIII Thursday, 7 July 2011 12:30-14:00
and CD3 (total T-cells) was a signiÀcant predictor
of recurrence (Figure 1A). Univariate analysis MO22.02 PROGRAMMED DEATH-1
identiÀed tumor expression of IL7R (Figure 1B) LIGAND MRNA LEVELS MAY PREDICT
and IL12Rơ2 (Figure 1C) as signiÀcant predictors SURVIVAL AND RELAPSE IN NON-
of recurrence. IL12Rơ2 and stromal FoxP3/CD3 SMALL CELL LUNG CANCER
ratio were prognostic even within tumors 2cm Yi-Hui Wu1, Ming-Ching Lee2, Chih-Yi Chen3, Huei
(Table 1A). In a multi-variate analysis including Lee1
1
gender, stage (IA and IB), and lymphatic invasion, Division Of Environmental Health And
these three immune markers were independently Occupational Medicine, National Health Research
associated with recurrence (Table 1B). Institutes/Taiwan, 2Divison Of Thoracic Surgery,
Department Of Surgery, Taichung Veteran General
Hospital/Taiwan, 3Department Of Surgery, China
Medical University Hospital/Taiwan
Background: Programmed death-1 ligand (PD-L)

involved in PD-1/PD-L1 pathway has been shown
to associate with tumor progression via suppression
of T-cell immunity. However, the prognostic value
of PD-L1 in non-small cell lung cancer (NSCLC)
remains unclear, especially in human papillomavirus
(HPV)-infected lung cancer.
Methods: Two hundred and twenty one lung tumors
surgically resected from NSCLC patients were
enrolled to determine PD-L1 mRNA expression by
real-time RT-PCR. HPV 16/18 E6 expression in lung
tumors was examined by immunohistochemistry.
The role of E6 on PD-L1 expression was examined
by E6-knockdown and E-overexpression in HPV16
E6-positive lung cancer cells. Kaplain-Meier and
Multivariate Cox regression analysis were used to
verify whether PD-L1 mRNA levels may predict
overall survival (OS) and relapse free survival (RFS)
in NSCLC, especially in patients with E6-positive
tumors.
Results: PD-L1 mRNA levels in E6-positive TL-1
and TL-2 cells were remarkably higher than E6-
negative A549, H23, H1355, TL-4, TL-5, TL-6 lung
Conclusion: In this study of the largest dataset- cancer cells. PD-L1 expression was decreased in
to-date of stage I LAC tumor and stromal E6-knockdown TL-1 and TL-2, and increased in E6-
immune microenvironment characterization overexpression A549 and TL-4 cells compared with
by immunohistochemistry, we identiÀed three their control cells. Patients with low PD-L1 mRNA
independently associated with recurrence: stromal levels had poorer OS and RFS than those with high
FoxP3/CD3 ratio, tumor expression of IL7R and PD-L1 mRNA levels. Among patients with high
PD-L1 mRNA levels, the hazard ratio (HR) of E6- the percentage of tumor cells that stained at each
positive patients was elevated to 1.89 (95% CI, 1.17- intensity, respectively. The score median value was
2.66, P = 0.003) compared with that of E6-negative a priori chosen as the cutoff point for classifying
patients (HR, 1.31, 95% CI, 1.07-1.58, P = 0.007). tumors as CTLA-4-negative (score 20) and
Conclusion: PD-L1 mRNA levels may predict positive (>20). In addition, IHC expression proÀles
survival and relapse in NSCLC. We suggest that PD- were correlated with clinicopathological features.
L1 may be a potential immunotherapeutic target in Results: The median follow-up time was 41 months
NSCLC, especially in patients with HPV infection. (range 28-54), and 27 deaths were observed. CTLA-
Keywords: Lung cancer, PD-L1, HPV 4 expression was positive in 48% of tumors and
similar in males and females (47 vs 47%), age
70 and > 70 (46 vs 49%), ex-never smokers and
Biomarkers VIII Thursday, 7 July 2011 12:30-14:00 current smokers (46 vs 47%), whereas was higher in
non-squamous than in squamous carcinoma (53 vs
MO22.03 EVALUATION OF CTL 36%). Cox’s multiple regression analysis identiÀed
ANTIGEN 4 (CTLA-4) EXPRESSION AS stage and CTLA-4 expression as the only variables
PROGNOSTIC FACTOR IN NON-SMALL associated with survival. The hazard ratio (HR) was
CELL LUNG CANCER (NSCLC) 2.76, (95%CI, 0.9-8.3; p= 0.07) and 6.61 (95%CI,
Francesco Grossi1, Sandra Salvi2, Domenico F. 2.6-16.8; p 0.001 ) for tumor stage II and III
Merlo2, Erika Rijavec2, Giulia Barletta2, Maria compared to stage I respectively, and 0.39 (95%CI,
Giovanna Dal Bello2, Carlo Genova2, Edoardo 0.2-0.9; p= 0.03) for CTLA-4 score >20.
Margallo2, Simona Boccardo2, Anna Morabito2, Conclusion: Clinical trials with CTLA-4 inhibitors
Stefania Laurent2, Marco Mora2, Matilde Mannucci2, (ipilimumab and tremelimumab) in NSCLC
Giovanni Battista Ratto2, Paolo Pronzato2, Mauro combined with chemotherapy or alone in unselected
Truini2, Maria Pia Pistillo2 population showed promising results encouraging
1
S.S. Tumori Polmonari, Istituto Nazionale Per La further investigations. Our results demonstrate
Ricerca Sul Cancro/Italy, 2Istituto Nazionale Per La an association between CTLA-4 expression and
Ricerca Sul Cancro/Italy increased overall survival in NSCLC pts suggesting
a prognostic role for CTLA-4 in NSCLC. An
Background: CTLA-4, a close homologue to CD28, increased CTLA-4 expression may contribute to
is a vital negative regulator of T-cell activation NSCLC progression by modulating the interaction of
and proliferation. Preclinical studies and clinical microscopic disease with CTLA-4 ligand-expressing
trials have demonstrated that the administration cells leading to NSCLC cell death.
of antibodies that block CTLA-4 can provoke the Keywords: CTLA-4, NSCLC, tissue microarray,
elimination or reduction of established tumors. prognostic factor
We previously reported that CTLA-4 is expressed
by NSCLC cell lines providing evidence of its
involvement in apoptosis induction upon engagement Biomarkers VIII Thursday, 7 July 2011 12:30-14:00
with soluble CTLA-4 ligands (Contardi E, Int J
Cancer 2005). The present study examined the MO22.04 T LYMPHOCYTE SUBSET
expression of CTLA-4 on tumor tissues of patients MICROLOCALIZATION IS A STRONG
(pts) with radically resected stage I-IIIA NSCLC. PREDICTOR OF CLINICAL OUTCOME
Methods: Tumor tissue samples from 82 pts IN SURGICALLY RESECTED NON-
who underwent surgery between 7/2005-3/2007 SMALL CELL LUNG CANCER.
were analyzed for expression of CTLA-4 using Dermot S. O’Callaghan1, Elton Rexhepaj2, Kathy
immunohistochemistry (IHC). Viable tumor was Gately1, Liam Gallagher2, Kenneth J. O’Byrne1
1
sampled in triplicate for tissue microarray analysis, Thoracic Oncology Research Group, Trinity College
and slides were stained by IHC with 14D3 mAb Dublin/Ireland, 2University College Dublin/Ireland
(eBioscence, San Diego, CA, USA). All tissue arrays
were independently scored by two observers (M.T. Abstract under Embargo - will be presented in a
and S.S.), blinded to the patients. CTLA-4 score press conference during WCLC 2011.
was calculated using the following formula: (1 +
I) x PC, where I is the staining intensity and PC
Biomarkers VIII Thursday, 7 July 2011 12:30-14:00 DNA; and is sensitive enough to use with small
samples such as core needle biopsies (CNB), Àne
MO22.06 MALDI-TOF MS MUTATION needle aspirates (FNA), and CTCs. We developed a
ANALYSIS FOR NSCLC CIRCULATING lung cancer assay panel of 12 genes/135 mutations
TUMOR CELLS (including AKT1, BRAF, CTNNB1, EGFR, ERBB2,
Heidi S. Erickson1, Nana E. Hanson1, Katherine KRAS, MEK1, NRAS, PIK3CA, PIK3R1,PTEN,
Stemke-Hale2, Hector G. Galindo3, Uma Giri1, and STK11) to test for somatic mutations in genes
Christina Mcdowell1, Luc Girard4, J.J. Lee5, Roy representing multiple pathways known to be
Herbst1, John D. Minna4, Hai Tran1, Gordon B. involved in lung cancer. All assays can detect a
Mills2, Edward Kim1, John V. Heymach1, Ignacio mutation in < 25% of a sample.
Wistuba6 Results: In the effort to analyze CTCs, we Àrst
1
Thoracic / Head & Neck Medical Oncology, Ut MD analyzed 57 NSCLC cell lines with known mutations
Anderson Cancer Center/United States Of America, and conÀrmed known mutation status. Next, we
2
Systems Biology, Ut MD Anderson Cancer Center/ successfully analyzed DNA from 90 frozen and
United States Of America, 3Pathology, Ut MD matched FFPE NSCLC resected tissues. Analysis
Anderson Cancer Center/United States Of America, of unampliÀed and matched WGA cell line DNA
4
Hamon Center For Therapeutic Oncology Research, quantity CNB and FNA equivalents gave the
University Of Texas Southwestern Medical Center/ same mutational status results. Moving to CTC
United States Of America, 5Biostatistics, University equivalents, we successfully analyzed cell line DNA
Of Texas M.D. Anderson Cancer Center/United and matched WGA DNA equivalents of 100-1000
States Of America, 6Pathology And Thoracic/head & cells with known EGFR L585R and KRAS G34A
Neck Medical Oncology, UT MD Anderson Cancer mutations and negative control DNA (negative for
Center/United States Of America all assays). Next, WGA methodology for direct
CTC cell lysate DNA ampliÀcation was developed
Background: Circulating tumor cells (CTC) using CTC cell number equivalents (3 – 200 cells)
associated with solid tumors are being studied for obtained from a typical clinical blood sample CTC
their diagnostic and prognostic value. In patients preparation. Then, we directly compared unampliÀed
with metastatic tumors, CTC presence in the blood and matched ampliÀed CTC cell equivalents (50,
has been putatively associated with short survival. 100, and 200 cells). Analysis of both unampliÀed and
Since blood collection is relatively non-invasive, ampliÀed CTC cell equivalents reported identical
CTC molecular analysis opens up the possibility mutation status results. Thus, we demonstrated that
of monitoring genotypic changes during cancer we are able to study mutations in multiple genes
treatments. Unfortunately, CTCs are not present using small amount of DNA from CTC cell numbers
in large numbers, often at rates as low as one cell in a high-throughput manner.
per 106-107 leukocytes. Thus, to perform genotypic Conclusion: We developed a robust method for
biomarker analysis on CTCs, methodologies must accurately determine cancer-associated genetic
be developed to using highly speciÀc and sensitive mutations in NSCLC CTC cell number equivalent
technologies and an enrichment step to increase lysates using MALDI-TOF MS SNP analysis which
analytes to detectable levels. can be applied to better understand the molecular
Methods: We developed a methodology for characteristics of lung cancer during treatment and
detecting mutations in multiple oncogenes and progression. As clinical NSCLC CTC samples are
chemotherapy resistance genes in non-small cell collected, we will apply this methodology to assess
lung cancer (NSCLC) CTC specimens using CTC mutation status as potential diagnostic and/or
high-throughput matrix-assisted laser desorption/ prognostic markers.
ionization time-of-Áight mass spectrometry Keywords: mutation analysis, circulating tumor
(MALDI-TOF MS) single nucleotide polymorphism cells, Non-small cell lung cancer, MALDI-TOF MS
(SNP) analysis (MASSarray; Sequenom, Inc.) to
determine cancer-associated genetic mutations in
lung cancer specimens. This system allows for up
to 10 different somatic mutations to be assayed per
well in a 384-well format; requires very little DNA;
can be used with whole genome ampliÀed (WGA)
Biomarkers VIII Thursday, 7 July 2011 12:30-14:00 Cytokeratins) and mesenchymal markers (Vimentin
and N-Cadherin) were heterogeneously expressed
MO22.07 MOLECULAR in CTCs and CTM within and between lung cancer
CHARACTERISTICS OF CIRCULATING patients. E-Cadherin expression was absent,
TUMOUR CELLS AND CIRCULATING cytoplasmic or nuclear but only rarely expressed
TUMOUR MICROEMBOLI IN PATIENTS at the surface of contiguous cells within CTM.
WITH LUNG CANCER Vimentin was expressed in a subpopulation of CTCs
Jian-Mei Hou1, Matt Krebs1, Tim Ward1, Robert but was observed in the majority of cells within
Sloane1, Lynsey Priest1, Fiona Blackhall2, Caroline CTMs. There were subpopulations of apoptotic and
Dive3 of proliferating solitary CTCs but neither cell death
1
Clinical & Experimental Pharmacology, Paterson nor proliferation was observed in cells comprising
Institute For Cancer Research/United Kingdom, CTM.
2
Department Of Medical Oncology, The Christie Conclusion: We have for the Àrst time revealed the
NHS Foundation Trust/United Kingdom, 3Paterson substantial heterogeneity of CTCs and CTM in lung
Institute For Cancer Research/United Kingdom cancer patients with respect to EMT markers. The
different proÀles of apoptosis and proliferation in
Background: Enhanced cell migration, a key CTCs and CTM are consistent with our hypothesis
change in cellular behaviour during Epithelial to of CTM possess a survival advantage and the lack
Mesenchymal Transition (EMT) involves loss of of proliferation may render them relatively resistant
cell-cell contacts, and is widely reported to facilitate to conventional cytotoxic drugs that preferentially
invasion and metastasis. However, collective kill proliferating cells. CTCs and CTM have been
migration of tumour cells also occurs where the demonstrated as a useful research tool and a potential
cells maintain cell-cell contacts. We have observed surrogate tissue to further our understanding of
circulating tumour cells (CTCs) and circulating metastasis biology for lung cancer.
tumour microemboli (CTM, clusters of tumour Keywords: Molecular characteristics, Circulating
cells) in peripheral blood samples from patients tumour cells, Circulating Tumour microemboli, Lung
with small cell lung cancer (SCLC) and non-small cancer
cell lung cancer (NSCLC). It is thought that only
0.1% tumour cells in the circulation survive. We A revised/updated abstract may be included in
hypothesise that maintenance of cell-to-cell survival the Late Breaking Abstract Supplement, available
signals may confer a survival advantage on CTM at the 14th World Conference on Lung Cancer.
over single CTCs. Here, we have characterised the
expression proÀle of EMT markers in CTCs and in
CTM of SCLC and NSCLC patients. The apoptosis Biomarkers VIII Thursday, 7 July 2011 12:30-14:00
and proliferation status of CTCs and CTM have
also been explored to address the hypothesis of the MO22.08 MICRORNA BIOMARKERS OF
survival advantage of CTM. LUNG CANCER IN WHOLE BLOOD
Methods: A Àlter-based size exclusion approach Santosh K. Patnaik1, Sai Yendamuri1, Eric Kannisto1,
(ISET, RareCell) and an epithelial marker (EpCam Anil Vachani2
1
and cytokeratins) dependent platform (CellSearch, Department Of Thoracic Surgery, Roswell Park
Veridex) have been utilised for detection and Cancer Institute/United States Of America,
2
isolation of CTCs and CTM from patients with Division Of Pulmonary Medicine, University Of
SCLC and NSCLC. Expression of EMT markers Pennsylvania/United States Of America
(cytokeratins, E-Cadherin, Vimentin, N-Cadherin) in
CTCs and CTM isolated by ISET was assessed by Background: Development of simple non-invasive
single marker immunohistochemistry (IHC) staining. assays to diagnose lung cancer is of signiÀcant
Apoptotic cells were identiÀed via fragmented and clinical importance. In this study, we explored the
condensed, DAPI stained, nuclear morphology using utility of microRNA expression in whole blood for
the CellSearch technology. The proliferation marker identifying biomarkers of lung cancer.
Ki67 was evaluated in ISET isolated CTCs and CTM Methods: PAXgeneTM blood RNA kit (Qiagen®)
using IHC. was used to collect blood and isolate RNA from
Results: Epithelial markers (E-Cadherin, 22 cases of non-small cell lung adenocarcinoma at
pathologic stage IA-IIIB, and 23 clinically-relevant blood-based assays for diagnosing lung cancer.
controls at a high risk of developing lung cancer Studies using larger cohorts are needed to further
either because of smoking or because of the presence develop and validate such microRNA biomarkers.
of pulmonary nodules later found to have a benign Keywords: Lung cancer, MicroRNAs, Blood
pathology. Two-color microarrays were used to
quantify microRNAs in each sample. ClassiÀcation
analyses were done using linear kernel support Biomarkers VIII Thursday, 7 July 2011 12:30-14:00
vector machines (SVM) and top-scoring pair (TSP)
methods, and classiÀers were tested in internal cross- MO22.09 A PROSPECTIVE STUDY OF
validations. SERIAL MEASUREMENTS OF CELL-
Results: Cases and controls were evenly matched FREE DNA IN PLASMA, RADIOGRAPHIC
for demographic, clinical, and pathologic variables RESPONSE, AND SURVIVAL IN
(Table 1). After data pre-processing, 387 of the PATIENTS WITH METASTATIC NON-
1268 (31%) human microRNAs on the platform SMALL CELL LUNG CANCER (NSCLC)
were considered expressed, 89 (23%) of which were Christopher G. Azzoli1, Christopher Mcginn1,
differentially expressed between the two cohorts Melissa Johnson1, Meier Hsu2, Camelia S.
with Benjamini-Hochberg-adjusted P values <0.05 Sima2, Janine Cooc3, Kathleen Danenberg4, Peter
based on moderated t-statistics. Forty differentially Danenberg3, Valerie W. Rusch5, Mark G. Kris1
1
expressed microRNAs had a >1.25 fold-change in Medicine, Memorial Sloan-kettering Cancer
mean expression level between groups. In leave-one- Center/United States Of America, 2Epidemiology
out cross-validation, the TSP classiÀcation method And Biostatistics, Memorial Sloan-kettering Cancer
had a prediction accuracy, sensitivity, speciÀcity, Center/United States Of America, 3Department Of
positive predictive value (PPV) and negative Biochemistry, University Of Southern California,
predictive value (NPV) of 95.6%, 90.9%, 100%, Keck School Of Medicine/United States Of America,
4
100%, and 92%, respectively. Values with SVM Response Genetics/United States Of America,
5
were 91.1%, 90.9%, 91.3%, 90.9%, and 91.3%, Department Of Surgery, Thoracic Service, Memorial
respectively. Areas under curve of 0.95 and 0.97 Sloan-kettering Cancer Center/United States Of
in receiver operating characteristics analysis were America
obtained respectively for the TSP and SVM methods
(Figure 1). Similar results were obtained in Monte Background: Radiologic response by RECIST
Carlo cross-validations. category (PR, SD, PD) and progression-free
survival (PFS) are surrogates for overall survival
(OS) in phase II, and some phase III trials of
chemotherapy for patients with metastatic NSCLC.
Most patients have SD at their Àrst follow-up scan,
and discriminatory biomarkers for this subgroup are
sorely needed. Levels of cell-free DNA in plasma are
higher in patients with metastatic NSCLC compared
to early-stage patients, and healthy controls.
Published data suggest that high levels of cell-free
DNA in plasma predict worse survival, and that
changes in DNA over time may be used to predict
the efÀcacy of therapy.
Methods: We conducted a prospective study to
measure cell-free DNA in the plasma of patients
with metastatic NSCLC. 182 patients had pre-
treatment blood collected in citrated tubes containing
Ficoll Hypaque density Áuid and a polyester gel
barrier, kept on ice, and processed within 1 hour
Conclusion: This pilot study suggests that whole of collection. Tubes were spun at 1800 RCF for 20
blood microRNA expression proÀles can be used minutes at room temperature. Plasma was removed
for developing biomarkers for use in non-invasive without disturbing the mononuclear cell layer, and
frozen at -80°C. DNA was extracted from a Àxed Background: Secreted proteins and those released
volume of plasma, and measured using quantitative from tumors and surrounding tissues contain
PCR of the ơ-Actin gene. Radiologic response important information that could enable early cancer
was recorded by RECIST, including sum longest diagnosis. However, there is great difÀculty in
diameter of measurable lesions. Additional blood quantifying such signals for large numbers of low
was collected coincident with up to 3 radiologic abundance proteins. Immunoassays are sensitive but
response assessments during chemotherapy (until assays are difÀcult to multiplex at the level (100s
PD). Progression-free and overall survival was to 1000s of analytes) required to discover novel
analyzed by Cox regression. biology. Mass spectrometry measures many proteins,
Results: 128 patients had at least one follow-up but throughput is low and the technology cannot
CT scan and plasma DNA level. Baseline plasma easily quantify low abundance proteins.
DNA levels were highly variable (baseline range SomaLogic therefore created a highly multiplexed
0.2-5128 ng/mL, median 7.7 ng/mL). Clinical proteomic assay which is continuously expanding
characteristics did not correlate with baseline DNA in breadth. It currently measures >1000 proteins
level (smoking history, gender, performance status, simultaneously from 10ul blood, with throughput
prior chemotherapy, prior XRT, sites of metastases). of 300 samples/day. The median lower limit
In follow-up, median percent change in DNA was of quantiÀcation is below 1 pM with a median
-12% for PR (n=21), +6% for SD (n=86), +6% coefÀcient of variation for each protein below 5%.
for PD (n=21), p=0.06. For Cox regression, a log This assay performance arises from the selection
transformation was performed to minimize the effect of high afÀnity SOMAmers that bind selectively to
of extreme values of DNA on the estimates of the their target proteins with slow off-rates.
hazard ratios. Neither DNA levels at baseline and Methods: We have applied this proteomic
follow-up, nor % change in DNA, were associated technology to discover blood and tissue protein
with PFS, or OS. biomarkers for NSCLC detection. A multi-center
Conclusion: In this large, prospective study, pre- case-control study was conducted in archived serum
treatment levels of cell-free plasma DNA were not samples from 1,326 subjects from four independent
prognostic of outcome in patients with metastatic studies of non-small cell lung cancer (NSCLC) in
NSCLC. Changes in cell-free plasma DNA over time long-term tobacco-exposed populations. Samples
were not predictive of PFS or OS, and did not add were divided into 75% training and 25% blinded
discriminatory value to radiologic response. Ongoing veriÀcation prior to analysis. We then calculated
efforts focus on detection of speciÀc oncogene the Kolmogorov-Smirnov (KS) statistic to quantify
mutations (EGFR or KRAS mutation) in the plasma the difference in the populations for each protein,
as opposed to quantitative assays of total DNA. developed Bayesian classiÀers and veriÀed with 10-
Supported by R01-CA092315. fold stratiÀed cross validation prior to analyzing the
Keywords: plasma DNA, radiologic response, blood blinded sample set. In addition, to investigate the
biomarker, RECIST connection between serum and tissue biomarkers,
we analyzed homogenates prepared from NSCLC
resected tumor tissue and compared the proteomic
Biomarkers VIII Thursday, 7 July 2011 12:30-14:00 proÀle with adjacent and distal tissue from the same
individuals. The Mann-Whitney test for signiÀcance
MO22.11 LARGE SCALE APPLICATION was applied to compare adjacent to distant, adjacent
OF SOMAMER PROTEOMIC to tumor and distant to tumor protein proÀles.
TECHNOLOGY FOR EARLY DETECTION Results: We identiÀed 44 candidate serum
OF LUNG CANCER: BIOLOGICAL biomarkers and developed a 12-protein panel and
INSIGHTS FROM SERUM AND TISSUE naive Bayes classiÀer that distinguished NSCLC
Rachel Ostroff1, Deborah Ayers1, Geoffrey Baird2, from controls with 91% sensitivity and 84%
Nebojsa Janjic1, Thale Jarvis1, Michael R. Mehan1, speciÀcity in a training set and 89% sensitivity and
Alex Stewart1, Sheri K. Wilcox1, Wei Xiong2, 83% speciÀcity in a blinded, independent veriÀcation
Stephen Williams1 set. In the tissue homogenate analysis, 36 proteins
1
Medical, Somalogic, Inc./United States Of America, were most signiÀcantly different between the
2
Univ Of Washington/United States Of America NSCLC tumor and adjacent or distant non-tumor
tissue. Of these, 20 were elevated in the tumor and
16 were lower. There was considerable overlap SDF1a were analyzed by blinded duplicate ELISA
between proteins elevated in tumor tissue and the (sensitivity ~3-70 pg/ml). Cut-points (VEGF-A:<
identiÀed serum biomarkers. or 1ng/ml, sVEGFR2: < or 11ng/ml, sVEGFR3:
Conclusion: Proteomic analysis of serum and tissue < or 35.5ng/ml and SDF-1a: or > 3.5ng/ml)
taken from NSCLC patients agreed with many of were determined using graphical methods based on
the Àndings in the literature and uncovered new Martingale residuals derived from the prognostic
biomarkers and biological insights. The role of these model for placebo pts, & the estimated baseline
proteins in angiogenesis, growth and metabolism, cumulative hazard and coefÀcients. Changes in
inÁammation and apoptosis, and invasion and biomarker levels from baseline to post-treatment
metastasis provide a comprehensive view of the were categorized into decreased >10%, stable within
complex proteomic changes associated with the 10%, or increased >10%. Cox regression models
development and progression of NSCLC. Based were used to correlate biomarker data with pt
on these discoveries, we have initiated clinical characteristics and PFS.
validation studies for early detection in populations Results: There were no signiÀcant differences in
at risk for lung cancer. Additional application of the baseline pt characteristics for 149 pts with baseline
multidimensional SOMAmer proteomic technology biomarker values compared to those without (147).
may provide insights into therapeutic target PFS was longer in the marker vs no-marker cohort
identiÀcation and characterization of individual (p=0.03), but hazard ratio (HR) for PFS beneÀt
therapeutic response. from cediranib was similar in both (HR 0.81, 95%
Keywords: Aptamer, Tissue proteomics, proteomics, C.I. 0.54-1.24 with and HR 0.81, 95% C.I. 0.56-
Early Detection 1.17 without marker data, interaction p=0.84). High
baseline sVEGFR2 levels were prognostic for better
PFS in the placebo arm (aHR 0.40, 95% C.I. 0.20-
Biomarkers VIII Thursday, 7 July 2011 12:30-14:00 0.70, p=0.0008), while low baseline sVEGFR2 and
sVEGFR3 were predictive of increased beneÀt from
MO22.12 CIRCULATING PLASMA cediranib in univariate analysis. However, following
ANGIOGENIC FACTORS AND SOLUBLE multivariate analysis, only low baseline sVEGFR3
RECEPTORS IN NCIC CTG BR.24 remained statistically signiÀcant (interaction
Glenwood D. Goss1, Christina L. Addison2, p=0.05). Correlation between changes in plasma
Keyue Ding3, Huijun Zhao2, Aurelie Le Maitre3, biomarker levels from baseline to post-treatment and
Scott Laurie1, Frances A. Shepherd4, Penelope A. PFS are currently being analyzed and will also be
Bradbury3, Lesley Seymour5 presented.
1
Medical Oncology, The Ottawa Hospital Cancer
Center/Canada, 2Oncology, The Ottawa Hospital Biomarker-Level Placebo (n) Cediranib (n) HR (95% C.I.) p-value Interaction
Research Institute/Canada, 3Lung, NCIC Clinical Baseline Biomarker Level-Progression Free Survival
VEGF-low 5.6m (59) 6.9m (52) 0.86 (0.53-1.42), p=0.56
Trials Group/Canada, 4Medical Oncology And p=0.46
VEGF-high 5.5m (19) 5.7m (19) 0.69 (0.30-1.60), p=0.38
Hematology Division, Department Of Medicine, sVEGFR2-low 4.3m (33) 6.6m (33) 0.52 (0.28-0.97), p=0.04
University Health Network, Princess Margaret sVEGFR2-high 6.6m (45) 6.8m (38) 1.07 (0.60-1.92), p=0.82
p=0.06
Hospital And University Of Toronto/Canada, 5NCIC sVEGFR3-low 5.6m (60) 6.9m (53) 0.60 (0.36-0.99), p=0.04
p=0.05
Clinical Trials Group/Canada sVEGFR3-high 6.2m (18) 4.4m (18) 1.79 (0.80-4.01), p=0.15
SDF-1a-low 5.5m (72) 6.6m (61) 0.71 (0.45-1.12), p=0.13
p=0.22
SDF1a-high 6.4m (6) 3.3m (10) 1.69 (0.54-5.21), p=0.36
Background: BR.24 randomized 296 NSCLC (IIIB/
IV) patients (pts) to placebo or cediranib (30 or 45
mg/kg) in combination with 6 cycles paclitaxel Conclusion: While high sVEGFR2 was prognostic
(200mg/m2) and carboplatin (AUC 6) q3 weeks for better PFS, only low baseline sVEGFR3 was
followed by placebo/cediranib. Improved response signiÀcantly predictive for PFS beneÀt from
and progression free survival (PFS) was observed in cediranib after adjusting for confounding factors.
the cediranib vs placebo arm. We examined potential Our results suggest that analysis of soluble receptor
predictive or prognostic biomarkers at baseline or levels may assist in identifying pt populations
post-treatment and their correlation with PFS. most likely to respond to cediranib treatment, and
Methods: Pretreatment baseline or post-treatment prospective studies validating these Àndings are
(4-10 weeks) VEGF-A, sVEGFR2, sVEGFR3 and planned.
Biomarkers VIII Thursday, 7 July 2011 12:30-14:00

Note: *Fisher Exact Probability
MO22.13 EGFR MUTATION STATUS IN Conclusion: Plasma samples can be used as an
PAIRED PLASMA AND TISSUE SAMPLES alternative of or supplement to tissue samples
OF 93 NSCLC PATIENTS FROM CHINA in EGFR mutation detection. Only 50% patients
Xiao Zhao, Meng Z. Wang harboring EGFR mutations can be detected both in
Respiratory Medicine, Peking Union Medical plasma and in tissue samples. We found that one in
College Hospital/China Àve patients with EGFR mutations would be missed
by tissue sample analysis. The positive consistence
Background: EGFR-TKIs are playing an increasingly in female, non-squamous cell lung cancer and late
important role in treating patients with active EGFR stage patients were higher. The results suggest that
mutations. The golden standard of detection EGFR blood test for EGFR mutation analysis could be used
mutations is using tissue samples. However, tissue in female, non-squamous cell lung cancer and late
samples are unavailable or limited for mutation stage patients. For squamous cell lung cancer and
analysis at some occasions. The aims of this study early stage patients, detection of EGFR mutations
were to compare the mutation status in plasma with from plasma is not a wise choice..
in tissue, and thus to determine the speciÀc group of Keywords: NSCLC, EGFR, Mutation, plasma
patients who may be the best candidates for EGFR
mutation analysis using blood circulating DNA.
Methods: 93 paired formalin-Àxed, parafÀn-embedded Biomarkers VIII Thursday, 7 July 2011 12:30-14:00
tissues and blood samples were collected. Tissue
samples were derived from percutaneous lung biopsy MO22.14 VELOCITY OF RISE IN PLASMA
(9), bronchial mucosal biopsy (55), operation (27) and OSTEOPONTIN DIFFERENTIATES NON-
others (5). Nest PCR was used to amplify exon 19 and SMALL CELL LUNG CANCERS FROM
21 fragments. After the Àrst round, Mse I and Msc I were CONTROLS IN A CT SCREENING TRIAL
used to digest wild type fragments of exon 19 and 21, Jessica S. Donington1, Ryan Harrington2, Dawn
respectively. Subsequent sequencing results were for Walter2, Amanda Beck2, Tyler Litton2, Nathalie
mutation analysis. Hirsch2, Judith Goldberg2, Justin D. Blasberg2,
Results: 3 tissue samples (all from bronchial mucosal William Rom2, Harvey I. Pass2
1
biopsy) and 1 plasma sample failed to give any target Cardiothoracic Surgery, NYU School Of Medicine/
product after nest PCR. Mutations were found in 37.6% United States Of America, 2NYU School Of
patients (35/93). In 90 tissue samples, exon 19 mutation Medicine/United States Of America
rate was 17.8% (16/90), exon 21 mutation rate was
14.4%(13/90); in 92 plasma samples, exon 19 mutation Background: Determining cancers from benign
rate was 17.4%(16/92), exon 21 mutation rate was nodules on CT scan can be difÀcult. As CT screening
10.9%(10/92). The consistence of EGFR mutation status initiatives are integrated into non-small cell lung
in 89 paired plasma and tissue samples was 80.9%, and it cancer (NSCLC) care additional variables that
was analyzed for gender, pathology and disease stage. further guide clinicians are essential to decrease
frequency of unnecessary biopsies. Osteopontin
Total N
Overall Positive Negative
Mutation
rate in
Mutation
rate in
P value (OPN) is a secreted phosphoprotein and plasma OPN
consistence consistence consistence (mutation
(pairs)
(%) (%) (%)
plasma
(%)
tissue
(%)
rate) levels are known to be elevated in patients with early
Gender male 63 84.1 41.2 82.1 19 19 0.0006 stage NSCLC. We hypothesize that the absolute
female 26 73.1 58.8 37.5 46.2 57.7 0.0171* change or velocity of change in plasma OPN levels
P (between
group)
0.2278 can differentiate NSCLC patients from high risk
Pathology
Non-
59 74.6 51.6 65.1 35.6 44.1 0.0002
patients without cancer in a CT screening population.
Squamous
Squamous 30 93.3 33.3 93.1 10 3.3 0.1*
Methods: A nested case-control trial was performed
P (between
0.0333
to evaluate plasma OPN as a biomarker within
group)
Disease
a large phase II CT screening trial for the early
I-IIIA 31 77.4 12.5 76.7 9.7 19.4 0.4883*
Stage detection of NSCLC. Current or former smokers
IIIB-IV 58 82.8 61.5 76.2 36.2 36.2 <0.0001
over the age of 50 with at least a 20 pack year
P (between
group)
0.5415
smoking history and without previous cancer were
Total 89 80.9 50 76.4 27 30.3 0.5335
eligible for screening. Incidence cancers with serial
banked plasma and 2-4 matched controls for each Session MO23: Cancer Biology
cancer were identiÀed. Controls were matched for
age, sex, pack years, character of nodules, and time Thursday, 7 July 2011
interval for surveillance and plasma collection.
Plasma OPN was measured by ELISA (Arbor
Assays, Ann Arbor MI). The initial and Ànal OPN Cancer Biology Thursday, 7 July 2011 12:30-14:00
levels prior to nodule removal, the scanning interval
and the velocity of rise in plasma OPN over time MO23.01 TARGETING TUMOR-
were evaluated. ASSOCIATED MACROPHAGES AS
Results: 10 incidence cancers and 33 matched A THERAPEUTIC APPROACH IN
controls with banked serial plasma samples were MALIGNANT MESOTHELIOMA
identiÀed. Median number of months of evaluation V. Courtney Broaddus1, Sailaja Battula1, Dario
was similar between cancers and controls (22.9 Barbone1, Collin Blakely2, Nikita Kolhatkar2,
vs. 25.5, p=0.60). At initiation of surveillance Raphael Bueno3, David J. Sugarbaker3, David M.
the average plasma OPN levels were similar in Jablons4, Lisa M. Coussens2
1
the cancers and controls (46.6 ng/ml vs. 53.6 ng/ Medicine, University Of California San Francisco/
ml, p=0.57), but at completion of surveillance the United States Of America, 2Pathology, University
average plasma OPN level in the cancer cases was Of California San Francisco/United States Of
slightly higher than controls (80.8 ng/ml vs. 62.9 America, 3Surgery, Brigham & Women’s Hospital/
ng/ml, p=0.07). The velocity of rise in plasma OPN United States Of America, 4Surgery, University Of
levels over time were signiÀcantly greater in cancers California San Francisco/United States Of America
than controls (2.92 ng/ml/month vs. 0.34 ng/ml/
month, p=0.03) Background: Mesothelioma is highly resistant
to chemotherapy. One feasible approach could be
to harness the immune system to undermine the
chemoresistance of mesothelioma. We studied
the chemoresistance of mesothelioma cells in a
spheroid model wherein mesothelioma cells acquire
multicellular apoptotic resistance that resembles that
of the solid tumor.
Methods: Immunohistochemistry and Áow
cytometry were used to analyze the leukocyte
compositions of human mesotheliomas.
Macrophages, either derived from human
mesothelioma, THP-1-derived or matured from
Conclusion: Although OPN is a central regulator peripheral blood monocytes, were polarized to
of pathogenesis in NSCLC, OPN plasma elevations a Th1 or Th2 phenotype by exposure for 48 h to
are not unique to NSCLC and have been reported cytokines (IFN-gamma & LPS or IL-4 respectively).
for infectious processes. This case controlled Polarized macrophages were then grown with
trial provides preliminary evidence for the utility mesothelioma cells either together in heterotypic
of monitoring serial changes plasma OPN to 3-dimensional spheroids or in a Transwell system
differentiate cancers from benign etiologies in a in which macrophages were grown separately
high-risk screening population. The velocity of rise from mesothelioma spheroids by a 3 micron Àlter.
in plasma OPN was greater in NSCLC cancer cases After 24 h, mesothelioma spheroids with and
than controls. Further evaluation of this biomarker in without macrophages were treated with TRAIL plus
larger CT screening populations is warranted. gemcitabine or carboplatin plus pemetrexed for 48
Keywords: biomarker, Non-small cell lung cancer h and studied for apoptosis by analysis of Hoescht-
(NSCLC), osteopontin, CT screening stained nuclear morphology.
Results: We found that all subtypes of mesothelioma
A revised/updated abstract may be included in harbor a large macrophage population (31±4.6% of
the Late Breaking Abstract Supplement, available the inÁammatory cell population [CD45+]). Indeed,
at the 14th World Conference on Lung Cancer. the percentage of macrophages in mesotheliomas
exceeded that found in other thoracic malignancies approaches that may further enhance the anti-tumour
thus far evaluated (NSCLC cancer, 9%; esophageal, activity of this platinum drug. This is essential in
4%). We found that Th1-polarized macrophages elucidating the mechanisms underlying this drug-
increased the response of mesothelioma spheroids resistant phenotype. Cancer stem cells (CSC’s)
to TRAIL plus gemcitabine by 155% and to are rare, drug-resistant, stem-like tumour cells that
carboplatin plus pemetrexed by 47.6% respectively, drive tumour progression and metastasis through
compared to Th2 polarization. The pro-apoptotic aberrant self-renewal and differentiation. Although
effect was similar whether macrophages were grown CSC’s have been described in leukaemia, breast,
together with or separately from the mesothelioma brain and colon cancer, little is currently known
cells, suggesting the mediation of macrophage- about the biology of CSC’s in lung cancer. There
derived cytokines. The pro-apoptotic effect of is increasing evidence showing that CSC’s may be
Th1 polarization depended on the presence of resistant to the cytotoxic effects of chemotherapy
macrophages: mesothelioma spheroids without due to their low proliferation rate and resistance
macrophages exposed to Th1 cytokines showed no mechanisms. The aim of this study was to generate
increase in apoptosis. and characterise a clinically relevant, isogenic
Conclusion: Polarization of macrophages within model of cisplatin resistance in a panel of NSCLC
mesothelioma tumors to an Th1 phenotype could cell lines. Furthermore, a preliminary study
enhance the efÀcacy of standard and novel therapies. examining potential stem-like markers present in
This work was supported by grants from the NCI and the chemoresistant cell lines generated, was carried
a DoD Mesothelioma Program grant PR080717 to out using the lung cancer stem cell markers, CD133
Broaddus and Coussens (Prominin-1) and aldehyde dehydrogenase (ALDH).
Keywords: heterotypic, trail, gemcitabine, Methods: Dose-response curves were generated to
Carboplatin determine IC50 concentrations of cisplatin (0.1M-
100M) in a panel of NSCLC cell lines (A549,
A revised/updated abstract may be included in SKMES-1, MOR and H460). Cells were treated
the Late Breaking Abstract Supplement, available with cisplatin (IC50) for 72h and allowed to recover.
at the 14th World Conference on Lung Cancer. Over a period of twelve months, cisplatin resistant
(CisR) cell lines were derived from original, age-
matched parent cells (PT) and were maintained
Cancer Biology Thursday, 7 July 2011 12:30-14:00 in the continuous presence of cisplatin (IC50) to
generate a resistant subpopulation. Characterisation
MO23.02 GENERATION AND studies were performed between PT and CisR
CHARACTERISATION OF CISPLATIN- cell lines. Proliferation (MTT) and clonogenic
RESISTANT NON-SMALL CELL LUNG survival assays (crystal violet) were carried out on
CANCER CELL LINES DISPLAYING PT and CisR cells. Cellular response to cisplatin-
STEM-LIKE FEATURES induced apoptosis and cell cycle distribution were
Martin P. Barr1, Dean A. Fennell2, Kenneth J. examined by FACS analysis. Expression of the
O’Byrne1 lung cancer stem cell marker CD133 and aldehyde
1
Clinical Medicine, St. James’ Hospital/trinity dehydrogenase (ALDH) activity were examined by
College Dublin/Ireland, 2Centre For Cancer FACS.
Research And Cell Biology, Queen’s University Results: A panel of NSCLC cell lines with a
Belfast/United Kingdom cisplatin resistant phenotype were generated and
characterised based on their decreased proliferative
Background: Lung cancer is the leading cause capacity in response to cisplatin, increased resistance
of cancer-related mortality worldwide and is to cisplatin-induced cell death, cell accumulation
typically characterised by low treatment response in the G0/G1 phase of the cell cycle and enhanced
rates and poor overall prognosis. Unfortunately, clonogenic survival ability. Chemoresistant
the outcome of cisplatin therapy in NSCLC has cells displayed characteristic stem-like features,
reached a plateau, with the development of resistance demonstrating signiÀcantly increased expression of
being a major obstacle in the use of this drug. An CD133+ cells and increased ALDH activity relative
understanding of the mode of action of cisplatin is to their corresponding parent cells.
therefore warranted in order to reÀne therapeutic Conclusion: We have developed a clinically
relevant, isogenic model of cisplatin resistance in a of VPA (0.1mM-1mM) for 72 hrs and assayed
panel of NSCLC cell lines and characterised these for global epigenetic changes by western blot.
based on a number of functional cellular parameters Similarly treated cells were measured for gene
relative to their original parental cell lines. The expression changes by qRT-PCR. Chromatin-
presence and enrichment of speciÀc stem-cell immunoprecipitation experiments for H3K9/14-Ac,
markers in cisplatin resistant cells further supports H3K9me3, H3K4me3, HeK27me3, H4K20me3 are
the presence of a chemoresistant population with being conducted.
stem-like properties and may be useful as a model Results: Long-term carcinogen exposure of 3kt cells
for studying mechanisms of cisplatin resistance in leads to anchorage-independent colony formation.
NSCLC. The methylation status of several genes is affected
Keywords: NSCLC, Cisplatin resistance, stem cells by long-term carcinogen exposure as assayed by
MSP. Treatment of these carcinogen-exposed cells
with 0.1mM-0.5mM VPA signiÀcantly decreased
Cancer Biology Thursday, 7 July 2011 12:30-14:00 anchorage-independent colony formation. VPA
treatment of carcinogen exposed cells increased
MO23.03 ROLE OF HDAC INHIBITION global levels of gene-activation associated histone
IN THE REVERSAL OF EPIGENETIC marks H3K9/K14-Ac and H3K4-me2, but had
GENE SILENCING IN LUNG little effect on gene-repressive marks H3K9-me3
CARCINOGENESIS. and H3K27-me3. Protein levels of DMNT1 and
Seth A. Brodie, Adam El-Kommos, Suresh H3K9methyltransferase G9a are up-regulated in
Ramalingam, Fadlo R. Khuri, Johann C. Brandes carcinogen exposed cells, but are rescued to normal
Hematology & Medical Oncology, Emory levels by VPA. The effect of HDAC inhibition
University-Winship Cancer Institute/United States Of on DNMT1 levels is through a post-translational
America modiÀcation mediated by HDAC1&2. G9A however
is transcriptionally regulated by VPA. Lastly, VPA
Background: We present a model by which treatment of established NSCLC lines with known
epigenetic therapy with HDAC inhibitors prevents hyper-methylation patterns and gene suppression
smoke-carcinogen induced bronchial epithelial cell causes partial promoter demethylation and re-
transformation. Epigenetic alterations have been expression of suppressed genes.
identiÀed as a key event in the pathogenesis of Conclusion: We have established a model of
NSCLC. In addition to DNA methylation, aberrantly early-stage carcinogenesis in human bronchial
silenced promoter regions are characterized by epithelial cells. Treatment of these cells with the
loss of the active histone marks H3K4 di-and HDAC inhibitor valproate (VPA) ameliorates these
tri-methylation (me2-3), histone H3 K9/K14- transformative events. Our evidence points to global
acetylation and acquisition of the repressive epigenetic changes mediated by HDAC inhibition,
histone mark H3K9-trimethylation (me3). Our data which reach far beyond a merely increase in
show a profound induction of H3-acetylation and acetylated histones. Taken together, VPA is a HDAC
H3K4me2-3 after exposure to the HDAC inhibitor inhibitor which has potential as a chemopreventive
valproate (VPA) and downregulation of DNMT1 agent to reprogram epigenetic changes associated
and the H3K9 methyltransferase G9A, resulting in with early carcinogenesis.
HDAC inhibition mediated reversal of gene silencing Keywords: chemoprevention, Tobacco Carcinogen,
in lung carcinogenesis. HDAC inhibitor, epigenetics
Methods: Human bronchial epithelial cells
immortalized with hTERT/cdk4 (HBEC-3kt) were A revised/updated abstract may be included in
treated with methylnitrosourea (MNU) and benz- the Late Breaking Abstract Supplement, available
a-pyrene (BaP) for 24 hours/ week over numerous at the 14th World Conference on Lung Cancer.
passages. Anchorage-independent colony formation
was assayed in the presence or absence of VPA by
soft agar method. Methylation status of several genes
were assayed by methylation speciÀc PCR (MSP) in
later-passage cells. Normal and carcinogen-exposed
3kt cells were treated with clinical concentrations
Cancer Biology Thursday, 7 July 2011 12:30-14:00 that AXL is the main resistant mechanism in H820.
Conclusion: Axl activation was involved in the
MO23.04 THE ROLE OF AXL IN acquisition of erlotinib-resistance suggesting the
ACQUIRED RESISTANCE TO EGFR role of Axl as a bypass signal for survival like MET.
TYROSINE KINASE INHIBITORS Axl should be considered as a new therapeutic target
Jae Cheol Lee1, Se Jin Jang2, Chang-Min Choi1, Kyu- to overcome the resistance to EGFR-TKIs in lung
Pyo Kim1, Dae-Ho Lee1, Sang-We Kim1, Jung-Shin cancer.
Lee1, Woo Sung Kim3 Keywords: Lung cancer, EGFR, AXL, Resistance
1
Oncology, Asan Medical Center/Korea, 2Pathology,
Asan Medical Center/Korea, 3Pulmonary And
Critical Medicine, Asan Medical Center/Korea Cancer Biology Thursday, 7 July 2011 12:30-14:00
Background: Axl has been considered as one of MO23.06 CLINICAL AND

receptor tyrosine kinases collaterally activating BIOLOGICAL SIGNIFICANCE OF
signals for cancer cell growth and survival if the CD157 IN MALIGNANT PLEURAL
major oncogenic signal pathway is blocked by MESOTHELIOMA.
targeted agent in gastrointestinal stromal tumor and Simona Morone1, Erika Ortolan1, Alice Giacomino1,
breast cancer. We investigated whether the Axl also Rossella Parrotta1, Nicola Lo Buono1, Ida Rapa2,
contributes to the resistance to EGFR tyrosine kinase Luisella Righi2, Marco Volante2, Enrico RufÀni3,
inhibitors (EGFR-TKIs) in lung cancer cells with Sara Demichelis4, Giulia Rovere2, Silvia Novello4,
EGFR sensitizing mutations. Fabio Malavasi1, Ada Funaro1
1
Methods: Sublines resistant to erlotinib (HCC827/ Department Of Genetics, Biology And Biochemistry,
ER) were established by chronic, repeated Lab Of Immunogenetics/Italy, 2Department Of
exposure in HCC827 lung cancer cell line with Clinical And Biological Science, University Of Turin/
deletion mutation on exon 19. RT-PCR, Western Italy, 3Thoracic Surgery Department, San Giovanni
blots and immunoprecipitation were used to Battista Hospital/Italy, 4Thoracic Oncology Unit,
evaluate AXL expression. To modulate AXL, University Of Turin/Italy
siRNA and adenovirus-AXL transfection were
performed. Response to drugs and combination Background: Malignant pleural mesothelioma
effect were determined by MTT, 3D culture assay (MM) is an asbestos-related tumor with poor
and combination index by CalcuSyn software, prognosis, difÀcult to diagnose and treat effectively.
respectively. Understanding the mechanisms of MM development
Results: HCC827/ER cells showed approximately and invasiveness, and identifying potential
1000-fold higher resistance to erlotinib than parental biomarkers are intrinsic to the prevention, screening
cells. The basal phosphorylation of receptor HER and effective therapies.
family was signiÀcantly decreased and erlotinib Recently, we have demonstrated that CD157, a
failed to suppress Akt and ERK activation despite glycosylphosphatidylinositol-anchored NADase/
effective inhibition of EGFR. HCC827/ER cells ADP-ribosyl cyclase-related molecule regulating
showed the induction of Axl activation and increase leukocyte diapedesis, plays a pivotal role in the
of migratory and invasive capability. XL880, a control of ovarian cancer cell migration and
MET and Axl inhibitor, effectively down-regulated peritoneal invasion and represents a marker of poor
Axl phosphorylation, which made HCC827/ER prognosis in serous ovarian cancer.
cells more susceptible to erlotinib regarding cell Here we investigated the clinical and biological
proliferation and survival. Axl silencing by siRNA signiÀcance of CD157 in MM analyzing i) the
in combination with erlotinib completely suppressed expression of CD157 in tissue sections from
sustained Akt and ERK activation and enhanced surgical samples of MM in correlation to clinical-
apoptosis via caspase-3 activation and PARP-1 pathological features and outcome and ii) its
cleavage. Further, we found AXL activation in biological effects in both native and engineered
H820, another erlotinib-resistant lung cancer cell mesothelioma cell lines.
line harboring T790M and MET ampliÀcation. Methods: CD157 expression was examined by
The sensitivity to erlotinib was restored through immunohistochemistry in tissue sections from
inhibition of Axl by XL880 or Axl siRNA suggesting surgically resected MM (n = 81), quantiÀed by
histological score (H-score), categorized as at/above Keywords: Malignant mesothelioma, CD157,

or below the median value of 60, and compared with biomarker
clinical parameters.
Native and engineered MM cell lines were analyzed A revised/updated abstract may be included in
for CD157 expression using Áow cytometry, Western the Late Breaking Abstract Supplement, available
blot and RT-PCR. Cell proliferative activity, tumor at the 14th World Conference on Lung Cancer.
cell migration and invasion were studied using
conventional in vitro cell-based assays. Soluble
CD157 in serum and pleural effusion was detected Cancer Biology Thursday, 7 July 2011 12:30-14:00
by means of a novel enzyme-linked immunosorbent
assay. MO23.07 RELATIONSHIP OF BRCA1
Results: Immunohistochemical analysis revealed MRNA EXPRESSION PATTERNS WITH
that CD157 is expressed in 85% (69/81) of the EGFR/KRAS MUTATION STATUS IN A
specimens analyzed at varying levels and with LARGE LUNG CANCER COHORT
discrete localization patterns. CD157 H-score did not Philip C. Mack1, Karen Kelly1, Xu Huang2, Primo N.
associate with patient age at surgery, sex, histological Lara1, Kathleen Danenberg2, David R. Gandara1
1
type, IMIG disease stage, or asbestos exposure, Internal Medicine, UC Davis Cancer Center/United
whereas, it was statistically associated with outcome States Of America, 2Response Genetics/United States
on follow up in patients with biphasic MM (P Of America
= 0.034, n=43). Univariate analysis of patients
with biphasic MM demonstrated that patients Background: Differential expression of DNA repair
with CD157-H-score 60 and those with CD157 proteins plays a role in drug sensitivity, and may
immunostaining localized at the cell membrane be inÁuenced by the mutational status of signal
had signiÀcantly shorter survival then patients with transduction oncogenes such as EGFR and KRAS
CD157-H-score <60 (log-rank test: P = 0.037) or (Gandara JTO 2010). BRCA1, which participates
with cytoplasmic staining (log-rank test: P = 0.038), in homologous recombination, has emerged as a
respectively. Multivariable Cox regression showed potential biomarker for chemosensitivity (Rosell
that CD157 H-score and membrane localization were CCR 2011). To examine the distribution of BRCA1
powerful independent prognostic factors of poor expression in NSCLC, relative to other key NSCLC
prognosis in biphasic MM. factors (EGFR, KRAS, ERCC1, histology and
In vitro studies highlighted that CD157 is expressed patient demographics), we quantiÀed BRCA1 mRNA
in selected cell lines; moreover, forced expression of levels in specimens from the extensive Response
CD157 in the CD157-negative MSTO-211H biphasic Genetics Inc (RGI) tumor collection.
MM cell line i) signiÀcantly increased the rate of Methods: RNA from microdissected formalin-Àxed
tumor cell proliferation, ii) enhanced cell motility parafÀn-embedded lung cancer specimens in the
and, iii) increased the ability of tumor cells to invade RGI database were analyzed for BRCA1 mRNA
the extracellular matrix . expression by RT-PCR, reported as a ratio of gene
Preliminary results indicated that CD157 is expression to ơ-actin. The data was correlated to
released in the serum and in the pleural effusion patient demographics, ERCC1 mRNA levels and
of patients with mesothelioma. The evaluation of mutational status of KRAS and EGFR.
soluble CD157 potential clinical signiÀcance and/or Results: 425 tumor specimens with known ERCC1
prognostic utility deserves further investigation. expression levels were analyzed for BRCA1
Conclusion: These Àndings indicate that CD157 expression. Patient demographics: Median age - 66
could represent a novel biomarker in MM since (range 34-90 ); Gender - 53% female; Stage- early
it is expressed by the majority of MM tissues and 4%, late 96%; Histology-adenocarcinoma (Adeno)
its expression level and localization are associated 60%, squamous cell (SCC) 15% and (not otherwise
with shorter survival in patients with biphasic MM. speciÀed/other 25%; The median BRCA1 mRNA
Moreover, CD157 expression promotes proliferation expression level was 0.81 with a range of 0 – 12.05.
and motility and increases the invasive potential of There was no association between age or gender and
MM cells. BRCA1 levels but there was a signiÀcant association
This study was supported by the Regione Piemonte, with histology. Median BRCA1 gene expression was
Ricerca Sanitaria Finalizzata (2009) to A. Funaro. higher in SCC at 2.39 vs 0.57 for adeno (p.<0.0001).
When dichotomized at the medians, there was a airway epithelial (Clara) cells leads to progressive
small but statistically signiÀcant positive correlation bronchiolization of alveoli (BOA) in CC10-hASH1
between BRCA1 and ERCC1 expression (P<0.001). transgenic (TG) mice, which mimics metaplastic
This relationship was retained when using the and potentially premalignant BOA lesions in human
clinically established cutpoint of 1.7 for ERCC1 lungs. In the TG mice, hASH1 also attenuates
(p<0.001). In a subset of samples where EGFR and pulmonary NE cell maturation during injury repair
KRAS mutational status were available (n = 386), following exposure to naphthalene. In small cell lung
BRCA1 mRNA levels were signiÀcantly higher in cancer, hASH1 regulates NE features and enhances
wild-type tumors compared to either mutant form tumor-initiating capacity. Taken together, the results
(p=0.0092 ANOVA). EGFR mut-positive tumors suggest that ASH1 is important in maintaining a
(n=60) had a median BRCA1 level of 0.55 (range 0 phenotype that promotes renewal of both NE and
to 4.73); KRAS mut (n =113) had a median BRCA1 epithelial (non-NE) cells. However, little is known
level of 0.59 (range 0 to 7.22); WT tumors (n = about the contribution of ASH1 into the ‘stemness’
213) had a median BRCA1 level of 0.91 (range 0 to in the airway epithelium. Aims We investigated
12.05). whether hASH1 regulates stem cell features that
Conclusion: BRCA1 expression levels are might contribute to BOA formation and possible
signiÀcantly higher in SCC compared to adeno and mechanisms.
modestly correlate with ERCC1 expression levels. Methods: We used CC10-hASH1 TG mice, human
BCRA1 levels were signiÀcantly higher in WT immortalized bronchial epithelial (BEAS2B)
tumor compared to either EGFR or KRAS mutant, cells, immunohistochemistry (IHC), qRT-PCR,
albeit with signiÀcant variance. To further evaluate laser capture microdissection (LCM), Áuorescence
these associations and their impact on treatment activated cell sorting (FACS) and cell culture.
outcome, a clinical trial is planned. Results: Microscopic analysis of TG mice revealed
Keywords: BRCA1, EGFR mutation, KRAS that BOA localized at the proposed stem cell niche
mutation bronchioalveolar junction (BADJ) in the peripheral
lung. There was a 2-4 fold increase in the expression
A revised/updated abstract may be included in of stem cell marker CD133, CD44, Sca-1, Msi1
the Late Breaking Abstract Supplement, available and Nanog mRNAs in the lungs of TG mice. Using
at the 14th World Conference on Lung Cancer. LCM we were able to demonstrate an increased
expression of the stem cell marker nestin mRNA
in BOA lesions. By IHC ALDH1 was also highly
Cancer Biology Thursday, 7 July 2011 12:30-14:00 expressed in the terminal bronchioli (TB). The assay
to mark the retention of bromodeaoxiuridine (BrdU)
MO23.08 PRONEURAL TRANSCRIPTION in DNA, indicating the presence of an ‘immortal’
FACTOR ACHAETE-SCUTE HOMOLOG strand of DNA over many divisions revealed label-
1 REGULATES STEMNESS IN THE retention in only 2.1+0.5% of TB cells in control
AIRWAY EPITHELIUM THROUGH mice, in contrast to 6.9+0.9 and 14.8+1.1 % in
ACTIVATION OF THE WNT/ȕ-CATENIN TBs and BOAs of TG mice, respectively. This is
PATHWAY consistent with the asymmetric division property
Ilona Linnoila1, Xiaoyang Wang2, Kathleen M. of stem cells. To further study the role of hASH1
Keefe2, Sandra M. Jensen-Taubman2, Abeba in Clara cells, we sorted the CC10+ (positive) and
Demelash2 CC10- (negative) populations from control and TG
1
Exp. Pathology Section, CCBB, NCI, NIH/United lungs by FACS. Our results showed that the mRNA
States Of America, 2NCI, NIH/United States Of expression of CD133, CD44, Sca1 and nestin was
America dramatically increased in TG CC10+ population
compared with one derived from control animals.
Background: Achaete-scute complex homolog 1 To explore molecular mechanisms, we focused on
(ASH1 or ASCL1) is a critical transcription factor the WNT pathway. IHC revealed nuclear relocation
that regulates the development of pulmonary of ơ-catenin and a decrease in the WNT inhibitor
neuroendocrine (NE) cells. It also promotes DKK1 expression in the airways of TG mice,
proliferation and prevents apoptosis. Constitutive consistent with pathway activation. Furthermore,
expression of human ASH1 (hASH1) in the overexpression of hASH1 in human BEAS2B cells
activated the T-cell transcription factor which drives epithelia as well as lung cancer cells. Repression
the WNT pathway, detected by TopFlash® luciferase of miR-487b in these cells persisted for several
reporter assay. weeks following cessation of CSC exposure.
Conclusion: Proneural ASH1 regulates many airway Expression levels of miR-487b were signiÀcantly
stem cell features, potentially contributing to the down-regulated in a panel of resected lung cancers
formation of BOA through activation of the WNT relative to adjacent normal tissues; the magnitude
pathway. of miR-487b repression was more pronounced in
Keywords: Ascl1, stem cell, Wnt, premalignant tumors from active or former smokers relative to
non-smokers. Software-guided analysis revealed
numerous potential targets for miR-487b including
Cancer Biology Thursday, 7 July 2011 12:30-14:00 Wnt5a, encoding a noncanonical Wnt ligand, as well
as SUZ12 and BMI1, which encode components
MO23.09 CIGARETTE SMOKE of polycomb repressor complexes implicated in
ENHANCES POLYCOMB EXPRESSION aberrant silencing of Wnt signaling antagonists
AND ACTIVATES WNT SIGNALING IN such as Dickkopf-1 (Dkk-1), SFRP1, SFRP4, and
NORMAL RESPIRATORY EPITHELIA WIF-1 in lung cancer cells. Constitutive over-
AND LUNG CANCER CELLS VIA expression of miR-487b mediated ~3 - 11 fold
EPIGENETIC REPRESSION OF MIR-487B reductions in Wnt5a, SUZ12 and BMI1 expression
David S. Schrump1, Sichaun Xi1, Hong Xu2, Jigui in SAEC, HBEC, Calu-6 and H841 cells; depletion
Shan3, Yongguang Tao2, Mary Zhang1, Suzanne of endogenous miR-487b induced Wnt5a, SUZ12
Inchauste1, Leandro Mercedes1, Julie A. Hong1 and BMI1 expression in these cells. Constitutive
1
Thoracic Oncology, National Cancer Institute/ expression of miR-487b up-regulated Dkk-1, SFRP1,
United States Of America, 2Laboratory Of Cancer SFRP4, and WIF1, and down-regulated Wnt5A,
Prevention, National Cancer Institute/United States Wnt3A, TCF7, LRP6, and LRF1 in SAEC and/or
Of America, 3Advanced Biomedical Computing Calu-6 cells. CLIP experiments conÀrmed direct
Center, National Cancer Institute/United States Of interference of miR-487b with Wnt5a, SUZ12 and
America BMI1 transcripts. Repression of miR-487b coincided
with recruitment of SUZ12 and BMI1 to Dkk-1,
Background: Limited information is available SFRP1, SFRP4, and WIF-1 promoter regions, and
regarding the mechanisms by which miRNA down-regulation of these genes in normal respiratory
alternations contribute to initiation and progression epithelia and lung cancer cells. CSC enhanced CpG
of tobacco-induced lung cancers. methylation, decreased occupancy of TCF-1, and
Methods: Array techniques were used to assess reduced H2AZ levels within the miR-487b genomic
miRNA expression proÀles in normal small airway locus in SAEC and Calu-6 cells; deoxyazacytidine
epithelial cells (SAEC) and immortalized human (DAC) mediated demethylation of the miR-487b
bronchial epithelial cells (HBEC), as well as Calu-6 promoter region, induced miR-487b expression,
and H841 lung cancer cells cultured in normal media and markedly attenuated CSC-mediated repression
(NM) with or without cigarette smoke condensate of miR-487b in SAEC and Calu-6 cells. Over-
(CSC). Quantitative RT-PCR, Super-Array, Western expression of miR487b inhibited proliferation and
blot, and RNA cross-link immunoprecipitation tumorigenicity of H841 and Calu-6 lung cancer cells.
(CLIP) techniques were used to evaluate expression Conclusion: CSC-mediated repression of miR-
of miR-487b and target genes. Chromatin 487b promotes pulmonary carcinogenesis, via
immunoprecipitation (ChIP) and sodium bisulÀte activation of genes encoding proteins implicated in
sequencing experiments were used to examine modulation of cancer stem cell signaling. These data
chromatin structure within the miR-487b promoter may account in part for clinical observations linking
region. MTT assays and nude mouse xenograft cigarette smoking with aggressive phenotype of lung
experiments were used to assess proliferation and cancers, and poor outcome of patients with these
tumorgenicity of lung cancer cells constitutively malignancies.
expressing miR-487b or control sequences.
Results: Under relevant exposure conditions, CSC A revised/updated abstract may be included in
consistently mediated ~2.5-7.5 fold decreases in the Late Breaking Abstract Supplement, available
miR-487b expression in cultured normal respiratory at the 14th World Conference on Lung Cancer.
Cancer Biology Thursday, 7 July 2011 12:30-14:00 compared the allelic frequencies between T790M
and the activation mutation. As shown in Table 1,
MO23.11 FREQUENCY OF DE NOVO T790M was found to be present in similar frequency
T790M GATE-KEEPER MUTATION IN to L858R in cases 1. However in cases 2 and 3,
EGFR TKI-TREATMENT NAïVE LUNG T790M was present at lower frequencies and
ADENOCARCINOMAS DETECTED BY suggested that in some instances, T790M might be a
DIRECT SEQUENCING. secondary mutation occurred in a sub-clone of TKI-
Ka F. To1, Joanna H. Tong1, Shuk L. Chau1, Peggy P. treatment naïve cancer cells.
Law1, Raymond W. Lung1, Wei Kang1, Ching Y. So1,
Tony Mok2 Case No. Mutation
Wild type Mutant Total
Mutant%
T790M/Activation
1 allele allele clones mutation
Anatomical And Cellular Pathology, The Chinese 1 T790M 61 38 99 38% 1.2
University Of Hong Kong/Hong Kong, 2Department L858R 51 23 74 31%
Of Clinical Oncology, The Chinese University Of
Hong Kong/Hong Kong 2 T790M 59 8 67 12% 0.5
L858R 73 25 98 26%
Background: Lung adenocarcinomas harboring

3 T790M 87 6 93 6% 0.1
activation mutations in epidermal growth factor Del2235-2249 44 67 111 60%
receptor (EGFR) gene are sensitive to EGFR-
tyrosine kinase inhibitors (TKI). However, almost
all patients that initially responded would develop Conclusion: T790M mutation occurs alone or
resistance. The T790M gate-keeper mutation on coexist with other activation EGFR mutation can be
EGFR contributes to ~50% of acquired resistance detected in a small subset of EGFR-TKI treatment
to TKI-therapy. De novo T790M mutation has been naïve adenocarcinomas by direct sequencing. T790M
reported in the absence of TKI therapy. However, mutation often occurs in cis to EGFR activation
the prevalence of T790M mutation in EGFR-TKI mutation. It can also present as minor clones in some
treatment naïve patients varies from 1% to 38% instances. Determination of T790M status is essential
which partly related to the detection methods for the clinical management of patients with lung
employed. Here we report our experience of the adenocarcinoma and may have implications in the
frequency of de novo T790M mutation in EGFR optimal design and interpretation of clinical trials.
TKI-treatment naïve lung cancers detected by direct Keywords: EGFR, Tyrosine kinase inhibitor, lung
sequencing. adenocarcinoma
Methods: DNA from 689 EGFR-TKI treatment
naïve adenocarcinoma samples was used for
detection of both EGFR-activation and T790M Cancer Biology Thursday, 7 July 2011 12:30-14:00
mutations by PCR-direct sequencing. The allelic
frequencies for the activation and/or T790M MO23.12 STAT3 IS ACTIVATED BY JAK2
mutations were determined by sub-cloning method. INDEPENDENT OF KEY ONCOGENIC
Results: T790M mutation was detected in 8 DRIVER MUTATIONS IN NSCLC
out of 689 (1.2%) EGFR-TKI treatment naïve Glen J. Weiss1, Brendan D. Looyenga2, Danielle
adenocarcinoma samples by PCR-direct sequencing. Hutchings2, Irene Cherni3, Chris Kingsley4, Carlos D.
Of 8 cases that harbored T790M mutations, 2 Lorenzo3, David K. Edwards V3, Shravan Sridhar3,
harbored T790M only and 6 had additional EGFR Jeffrey P. Mackeigan2
1
activation mutations (L858R in 5 cases, and in-frame Medical Oncology, Virginia G. Piper Cancer Center
deletion Del2235-2249 in 1 case). To determine At Scottsdale Healthcare/tgen/United States Of
whether the double mutations were in cis or trans America, 2Systems Biology, Van Andel Research
to each other, we used RT-PCR to amplify cDNA Institute/United States Of America, 3Lung Cancer
fragments spanning the 2 mutations in 2 cases (both Unit, The Translational Genomics Research Institute
carried L858R and T790M mutations) where frozen (TGEN)/United States Of America, 4Diabetes,
tumor tissues were available. Sequencing analysis Cardiovascular & Metabolic Diseases Division, The
indicated that L858R and T790M mutations occurred Translational Genomics Research Institute (TGEN)/
on the same allele in both cases. In another 3 cases United States Of America
where only parafÀn sections were available, we
Background: Constitutive activation of STAT3 clinically-annotated TMA derived from community-

is common in cancer. While somatic mutations based early-stage NSCLC may be useful for
to JAK2 are responsible for STAT3 activation in meaningful exploratory research on other key
hematologic malignancies, these mutations are rare signaling pathways in NSCLC.
or lacking in non-small cell lung cancer (NSCLC). Keywords: stat3, jak2, Non-small cell lung cancer,
Instead, STAT3 activation can be induced by tyrosine kinase inhibitors
autocrine cytokine signaling or activated growth
factor receptors. We sought to investigate the
interaction between well-characterized oncogenic Cancer Biology Thursday, 7 July 2011 12:30-14:00
“driver” mutations in NSCLC and STAT3 activation.
Methods: STAT3 activation was assessed in seven MO23.13 GENE EXPRESSION
well-characterized NSCLC cell lines with known PROFILING OF ASBESTOS-RELATED
oncogenic “driver” mutations. The effects of a SQUAMOUS CELL CARCINOMAS
JAK1/2 inhibitor, siRNA knockdown of JAK2, and Casey M. Wright1, Santiyagu M.F. Savarimuthu1,
gp-130 neutralizing antibody blockade on p-STAT3 Maxine Tan2, Maria Martins2, Nick K. Hayward3, Ian
were determined. Drug dose response with EGFR, A. Yang2, Rayleen Bowman2, Kwun M. Fong2
1
MEK, PDGFR, or ALK/MET tyrosine kinase School Of Medicine, University Of Queensland/
inhibitors (TKI) on MAPK and STAT3 was assessed Australia, 2Department Of Thoracic Medicine, The
in selected NSCLC cells in 2D culture and 3D assays Prince Charles Hospital/Australia, 3Oncogenomics
with and without a JAK1/2 inhibitor, ruxolitinib. Laboratory, Queensland Institute Of Medical
In addition, stage I-II NSCLC clinically-annotated Research/Australia
tumor samples collected from a community hospital
were immunohistochemically (IHC) stained and Background: Asbestos-related lung cancer
scored for STAT3, p-STAT3, and JAK2. EGFR exon accounts for 4–12% of all lung cancers worldwide.
19 deletion and KRAS mutation analysis was also Since putative mechanisms of carcinogenesis
performed on the same samples. The relationship differ between asbestos and tobacco induced lung
between IHC staining intensities, mutational status cancers, tumours induced by the two agents may
and various patient statistics was analyzed using an be genetically distinct. We previously reported
array of statistical tests. analysis of high dimensional gene expression data
Results: STAT3 is constitutively activated for asbestos-related lung adenocarcinoma. Since the
independent of activating KRAS or tyrosine major lung cancer subtypes, adenocarcinoma and
kinase mutations in all of the NSCLC cell lines we squamous cell carcinoma, are emerging as distinct
analyzed. We also found that STAT3 was tyrosine diseases with markedly different susceptibilities to
phosphorylated in 22% of human NSCLC tumor molecularly targeted therapies, the aim of this work
samples independent of mutations in the EGFR was to identify expression biomarkers of asbestos-
or KRAS oncogenes. As with randomized clinical related squamous cell carcinoma of lung.
trial patients, in this cohort of early-stage NSCLC Methods: Gene expression proÀling by Illumina’s
patients, EGFR and KRAS mutations are not HumanHT-12 v3 arrays was performed on a total of
signiÀcantly associated with progression-free or 56 tumours with squamous cell carcinoma histology;
overall survival. Inhibition or blockage of the gp130/ 26 cases with lung asbestos body counts above
JAK2 signaling pathway disrupts STAT3 activation levels associated with urban dwelling (ARLC-
in vitro. Interestingly, treatment of NSCLC cells with SCC: asbestos-related lung cancer-squamous cell
the JAK1/2 inhibitor ruxolitinib has no effect on cell carcinoma) and 30 controls with no lung asbestos
proliferation and viability in 2D culture, but prevents bodies (NARLC-SCC: non-asbestos related lung
anchorage-independent growth of these cells in 3D cancer - squamous cell carcinoma). Data was feature
assays. extracted using proprietary software (GenomeStudio,
Conclusion: JAK2/STAT3 signaling operates Illumina, Hayward, CA) and normalised to the 75th
independent of known driver mutations in NSCLC percentile using GeneSpring (GeneSpring, Agilent
and plays critical roles in tumor cell behavior Technologies, CA, USA). Supervised analysis based
that may not be effectively inhibited by drugs on lung asbestos body content was used to identify
that selectively target these mutations, suggesting differentially expressed genes which were then
a potential role for combination therapy. Our prioritized on p-value (P<0.001) and fold change
(>2-fold). The Expression Analysis Systematic Biochemistry And Cell Biology/China, 2Institute Of
Explorer (EASE) Online Interface was used to Biochemistry And Cell Biology/China, 3Department
identify important gene ontologies. Technical and Of Thoracic Surgery, Fudan University Shanghai
biological validation was performed on the training Cancer Center/China, 4Brigham And Women’s
set and three independent test sets (in-house data Hospital/United States Of America, 5Dana-farber
and two public datasets). Candidate genes of Cancer Institute/United States Of America,
6
interest were sequenced to identify possible somatic Laboratory Of Molecular Cell Biology, Institute Of
mutations and single nucleotide polymorphisms. Biochemistry And Cell Biology, Shanghai Institutes
Results: Differential expression analysis identiÀed For Biological Sciences, Chinese Academy Of
six putative candidates of biological and statistical Sciences/China
signiÀcance (p<0.001) with known function. Expression
of two of these six candidate genes (MS4A1 and Background: Over 90% of lung cancer patients
CARD18) was replicated by the qRT-PCR method. die from metastasis. We have previously shown
Expression of MS4A1, but not CARD18, was that somatic mutation of a serine/threonine kinase
consistently up-regulated in independent data of LKB1 frequently occurs in lung cancer and promotes
phenotypic relevance to asbestos related squamous the metastasis process for unknown reason (Ji et al
cell carcinoma of lung. Integration of MS4A1 gene Nature ’07). Through the integrative bioinformatic
expression, copy number, and methylation showed analysis on microarray datasets from either human
no evidence that methylation or DNA copy number cell lines or murine lung tumors with LKB1
alterations were factors responsible for the differential deÀciency, we here identify lysyl oxidase (LOX)
expression observed in a subset of asbestos related SCCs. as a downstream target negatively regulated by
No somatic mutations were observed for MS4A1. LKB1. LOX is an extracellular copper residues
Conclusion: There are distinct genomic proÀles in precursors. We plan to investigate the detailed
for asbestos and non-asbestos related squamous mechanism how LKB1 modulates the process
cell carcinoma of the lung. Microarray proÀling has of lung cancerigenesis through LOX. We aim to
identiÀed one candidate gene MS4A1 consistently identify biomarkers for diagnosis or prognosis
up-regulated across independent datasets. Integration purpose as well as therapeutic targets in lung cancer.
of gene expression, methylation and copy number Methods: Over-expression or knockdown of LKB1
data failed to show a signiÀcant relationship with gene in human lung cancer cell lines was performed to
expression suggesting that these processes are not major conÀrm the regulation of LOX expression by LKB1
regulators of expression ARLC-SCC. It is possible that assessed by real-time PCR and western blot. The
other regulatory processes including microRNAs may function of LOX in lung cancer progression was
be responsible.Further validation studies are required investigated through a series of in vitro functional
to conÀrm involvement of candidate genes in asbestos- studies including cell proliferation, soft agar colony
related lung carcinogenicity. formation, three-dimensional matrigel invasion
Keywords: asbestos, squamous cell carcinoma, gene and wound healing assay. The impact of LOX
expression proÀling inhibition upon cancer progression in vivo was tested
using treatment of a pharmacological inhibitor,
b-aminoproprionitrile, in a previously established
Cancer Biology Thursday, 7 July 2011 12:30-14:00 lung cancer mouse model with Lkb1 deÀciency.
Immuno-Áuorescence staining on three-dimensional
MO23.14 IDENTIFICATION OF LYSYL cell culture was carried out to study the contribution
OXIDASE AS A DIAGNOSIS AND of collagen and b1 integrin signaling to cell polarity
PROGNOSIS BIOMARKER AND A disruption and cell proliferation promoted by
THERAPEUTIC TARGET IN LUNG increased LOX expression. A published microarray
CANCER dataset of a cohort of 111 lung cancer patients
Yijun Gao1, Qian Xiao2, Huimin Ma2, Li Li2, with survival information was used for studying
Jun Liu2, Yan Feng2, Zhaoyuan Fang2, Jing Wu2, the correlation of LOX expression with prognosis.
Xiangkun Han2, Junhua Zhang3, Yihua Sun3, To test if LOX serves as diagnosis biomarker, its
Gongwei Wu2, Robert Padera4, Haiquan Chen3, serum activity was measured in a cohort of 80 lung
Kwok-Kin Wong5, Gaoxiang Ge2, Hongbin Ji6 adenocarcinoma patients and 28 healthy subjects by
1
Laboratory Of Molecular Cell Biology, Institute Of enzyme assay for Áuorescence detection in Hitachi
F-2000 Áuorescence spectrophotometer. tomography (PET-CT) can detect up to 15% of these;

Results: Lysyl oxidase is negatively regulated by nevertheless it has a low sensibility in detecting
LKB1 through mTOR-HIF-1Ơ signaling axis and cerebral metastases. Clinical guidelines recommend
mediates lung cancer progression. Inhibition of performing MRI only if there are neurological
LOX activity dramatically alleviates lung cancer symptoms. The aim of this study was to assess the
malignancy progression. Up-regulated LOX role of MRI in detecting silent brain metastasis in the
expression triggers excess collagen deposition in initial staging of NSCLC.
Lkb1-deÀcient lung tumors, and thereafter results in Methods: Retrospective analysis of newly diagnosed
enhanced cancer cell proliferation and invasiveness cases of NSCLC without distant metastasis by PET-
through activation of ơ1 integrin signaling. High TC over a ten month period (January - October
LOX expression and increased serum LOX activity 2010). MRI was performed in all of NSCLC patients
correlates with metastatic status and poor prognosis. as initial work up, except those in stage IV, according
Moreover, in contrast to healthy population, serum to the protocol of the Institution. A multivariate
from lung cancer patients have a signiÀcant increase statistical analysis was performed to determine those
of LOX activity. clinical variables associated to the presence of brain
Conclusion: We have identiÀed a novel mechanism metastasis with or without neurological symptoms.
involving extracellular matrix remodeling in lung Results: Cerebral MRI was performed in 95 patients
cancer metastasis elicited by LKB1 loss. LOX may with lung cancer. 85% were men, 93% had a history
serves as a target for lung cancer therapy as well as a of smoking and a mean age of 65 years. 39% had a
prognosis biomarker. More importantly, serum LOX squamous cell carcinoma, 40% had adenocarcinoma
activity serves as a potential diagnosis biomarker for (ADK) and 21% had other histology. 20% were
lung cancer. stage I, 21% were stage II and 59% were stage III.
Keywords: lysyl oxidase, extracellular matrix, Brain metastasis were diagnosed by MRI in 11,6%
LKB1, lung cancer metastasis (11/95) of the patients, and six of them (6/95,
6,35%), did not present neurological symptoms. A
stratiÀed binary logistic regression analysis showed
Session MO24: New Imaging Techniques that there were not any clinical variable associated
and New Applications of Established with the presence of silent brain metastasis in the
Imaging Techniques in Thoracic asymptomatic subgroup, whereas central tumours
Malignancies (p=0,005) and ADK (p= 0,01) were more frequently
associated to brain metastasis in patients with
neurological symptoms. In both subgroups, staging,
Thursday, 7 July 2011 SUVm, tumour size and mediastinal lymph nodes
were not statistically indicative of brain metastasis.
New Imaging Techniques and New Applications of Established

Imaging Techniques in Thoracic Malignancies Thursday, 7 July 2011
12:30-14:00
MO24.01 PREVALENCE OF SILENT

BRAIN METASTASIS (BM) IN THE
INITIAL STAGING OF NON-SMALL
CELL LUNG CARCINOMA (NSCLC)
Daniel Huertas, Lisbeth Marizell Pari, Susana
Padrones, Nuria Gonzalez, Samantha Aso, J. Ignacio
Martínez-Ballarin, Jordi Dorca, Antoni Rosell
Pulmonology, Hospital Universitari De Bellvitge/
Spain
Background: Distant metastases are a common Conclusion: Prevalence of silent brain metastasis at
event and a determining factor in the treatment initial staging is 6,35% in our study. Neither clinical
strategy for lung cancer. Positron emission nor radiological variables could predict silent brain
metastasis. Thus, we concluded that cerebral MRI retrospectively enrolled. Patients with multiple lung
is justiÀed as a routine diagnostic procedure in all tumors and/or who received induction chemotherapy
NSCLC patients without distant metastasis in the were excluded. From three institutions, 199 patients
PET-TC. Partially funded by SOCAP. (99 men, 100 women) who underwent surgery from
May 2004 through December 2009 were enrolled.
A revised/updated abstract may be included in Patients had pathological stage IA (n=133) or stage
the Late Breaking Abstract Supplement, available IB (n=66) adenocarcinoma. Patient age ranged from
at the 14th World Conference on Lung Cancer. 32 to 84 years old (average, 67 years old). Tumor
size ranged from 0.6 to 5.0 cm (average, 2.3 cm).
Surgical procedures included lobectomy (n=177;
New Imaging Techniques and New Applications of Established 88.9%) and limited resection (segmentecotmy and
Imaging Techniques in Thoracic Malignancies Thursday, 7 July 2011 wedge resection; n=22; 11.1%). The corrected SUV
12:30-14:00 was deÀned as the SUV index, which was calculated
as the ratio of tumor SUVmax to liver SUVmean.
MO24.02 STANDARDIZED UPTAKE Associations between disease-free survival (DFS)
VALUE CORRECTED BY MEAN and the following factors were analyzed: gender,
LIVER STANDARDIZED UPTAKE age, smoking history (+ or -), CEA level ( 5.0 or >
VALUE (SUV INDEX) IS A MARKER 5.0 ng/ml), SUV index, tumor size, lymphovascular
FOR PREDICTING RECURRENCE IN invasion (+ or -), pleural invasion (+ or -), and
STAGE I LUNG ADENOCARCINOMA: A surgical procedure (lobectomy vs. segmentectomy
RETROSPECTIVE STUDY OF PATIENTS and wedge resection).
AT THREE INSTITUTIONS: JAPANESE Results: Median follow-up was 46 months. The
NORTHERN EAST AREA THORACIC SUV index ranged from 0 to 12.4 (average, 2.0;
SURGERY STUDY GROUP (JNETS) median, 1.4). The overall 5-year survival rate after
Satoshi Shiono1, Hirotsugu Notsuda2, Hiroyuki surgery was 92.3%. Twenty-Àve patients (12.6%)
Suzuki3, Masami Abiko1, Toru Sato1, Chiaki Endo2, experienced recurrence after surgery. The 5-year
Motoyasu Sagawa4, Takashi Kondo2 DFS rate was 84.7%. Multivariate analysis showed
1
Department Of Thoracic Surgery, Yamagata that SUV index (P=0.02) was independent predictive
Prefectural Central Hospital/Japan, 2Department factors for recurrence. ROC curve analysis identiÀed
Of Thoracic Surgery, Institute Of Development, an optimal cut-off value of 2.24 for lung cancer
Aging, And Cancer, Tohoku University/Japan, recurrence. Even in stage IA patients, SUV index
3
First Department Of Surgery, Fukushima Medical was an independent predictive marker for recurrence
University/Japan, 4Department Of Thoracic Surgery, (P=0.01), and an optimal cut-off value was 1.73 for
Kanazawa Medical University/Japan lung cancer recurrence. Notably, no patients with an
SUV index < 1.0 experienced recurrence.
Background: F-18 Áuorodeoxyglucose (FDG) Conclusion: This study revealed that SUV index
positron emission tomography (PET) has become can be used as a predictive factor for recurrence.
an important staging tool for patients with lung Although this was a small and retrospective study,
cancer, and determination of the standardized uptake we found that SUV index is a signiÀcantly predictive
value (SUV) is the most widely used method for marker for recurrence in pathological stage I
evaluating patients. Although SUV is recognized lung cancers. Many additional cases need to be
as a powerful surrogate marker for lung cancer prospectively evaluated to conÀrm the utility of SUV
outcomes, SUV standardization and reproducibility index in this setting.
in clinical practice remain major concerns. This Keywords: SUV, PET, Lung cancer,
study was conducted to evaluate the signiÀcance Adenocarcinoma
of standardized uptake value corrected by mean
liver standardized uptake value (SUV index) and
to investigate the possibilty of using PET results in
clinical trials.
Methods: This was a retrospective study.
Pathological stage I lung adenocarcinoma patients
who underwent curative resection after PET-CT were
New Imaging Techniques and New Applications of Established PET-CT showed signiÀcant uptake in 24 of 25
Imaging Techniques in Thoracic Malignancies Thursday, 7 July 2011 cases of carcinoid tumours . 18F FDG/PET-CT
12:30-14:00 showed uptake in only 18 of 25 cases of carcinoids
. 68Ga DOTATOC/PET-CT had 100% sensitivity in
MO24.03 ROLE OF 68 GA DOTATOC/ predicting presence of typical carcinoid and 85.71%
PET-CT AND 18 F FDG/PET-CT IN in predicting atypical carcinoids. 68Ga DOTATOC/
THE EVALUATION OF SUSPECTED PET-CT could even predict the metastasis into
BRONCHO-PULMONARY CARCINOIDS mediastinal lymph nodes in one case. Two cases of
Balasubramanian Venkitaraman1, Tarun Jindal1, Ectopic ACTH producing tumors were localized
Roman Dutta1, Arvind Kumar1, Rakesh Kumar2, using 68Ga DOTATOC/PET-CT. Based on the
A. Malhotra2, G. C. Khilani3, Randeep Guleria3, results the efÀcacy of 68Ga DOTATOC/PET-CT
Rajinder Parshad1 and 18F FDG/PET-CT in evaluation of suspected
1
Department Of Surgical Disciplines, All India bronchopulmonary carcinoids was assesed and
Institute Of Medical Sciences/India, 2Department compared(Table-1) (Table-1)Comparison of
Of Nuclear Medicine, All India Institute Of Medical efÀcacies of 68Ga DOTATOC/PET-CT & 18F
Sciences/India, 3Department Of Medicine, All India FDG/PET-CT in the evaluation of suspected
Institute Of Medical Sciences/India bronchopulmonary carcinoids
Background: Broncho-pulmonary neuroendocrine 68

Ga DOTATOC/PET-CT 18
F FDG/PET-CT
tumors are a subset of broncho-pulmonary Sensitivity 96 72
neoplasms that share a distinctive basic microscopic SpeciÀcity 83.3 25
appearance, resembling Neuro-endocrine tumours Positive predictive
92.31 66.67
value
found elsewhere in the body. Diagnosis of Broncho- Negative predictive
pulmonary carcinoids by non invasive techniques is 90.90 20
value
largely limited due to the lack of deÀnitive diagnostic
features. Structural imaging like CT/MRI, lack the Conclusion: 68Ga DOTATOC/PET-CT was found
ability to assess the functional activity of carcinoids. to be an effective investigation in evaluation of
Functional imaging like 111In-Pentetreotide Broncho-Pulmonary carcinoid. It was found to be
scintigraphy although can assess the activity of effective, not only in localising the primary tumour,
the tumour, lack spatial resolution. Low metabolic but also the metastatic spread. 18F FDG/PET-CT
activity of carcinoids, limit the use of 18F FDG/ had low sensitivity and speciÀcity in differentiating
PET-CT(2-[Áuorine-18]-Áuoro-2-deoxy-D-glucose/ carcinoid from other tumours. Absence of uptake on
PET-CT), as a diagnostic entity. 68Ga DOTATOC/ 68
Ga DOTATOC practically rules out the possibility
PET-CT(1, 4, 7, 10 e Tetraazacyclododecane - NI, of typical carcinoid according to our study.
NII, NIII , NIIII, - tetra acetic acid (D) ePhe1-thy3- Keywords: Bronchopulmonary carcinoid, 68Ga
octreotide /PET-CT) has the advantage of combining DOTATOC/PET-CT
spatial resolution with assessment of functional
status of carcinoids. Use of 69Ga DOTATOC/PET-CT
as primary investigating modality in gastrointestinal New Imaging Techniques and New Applications of Established
carcinoids is well documented. However there are Imaging Techniques in Thoracic Malignancies Thursday, 7 July 2011
no large studies evaluating its efÀcacy in broncho- 12:30-14:00
pulmonary carcinoids .
Methods: A prospective evaluation of 37 patients, MO24.04 DETECTION OF PLEURAL
who presented in surgical outpatient department with LYMPHATIC FLOW BY INDOCYANINE
clinically/radiologically suspicious bronchopulmonary GREEN FLUORESCENCE IMAGING IN
carcinoid tumours was done using 68GaDOTATOC/ PATIENTS WITH LUNG CANCER
PET-CT and 18 F FDG/PET-CT , between July 2007 Kazuhiro Imai, Yoshihiro Minamiya, Hajime Saito,
and Jan 2011. The nuclear imaging studies of the Taku Nakagawa, Manabu Ito, Hiroshi Toda, Hayato
patients were compared, considering histopathological Konno, Junichi Ogawa
tissue diagnosis as gold standard. Department Of Chest, Breast And Endocrinologic
Results: Of the 37 patients, 25 were positive for Surgery, Akita University Graduate School Of
carcinoid on histopathology. 68Ga DOTATOC/ Medicine/Japan
Background: Lymphatic spread of carcinoma of

the lung to the mediastinum is an essential factor
determining prognosis. To the knowledge, in
lymph Áow from the pulmonary segment to the
mediastinum, there is direct drainage of mediastinal
lymph node without hilar lymph node. This
phenomenon has been called skip metastasis. We
studied the lymphatic Áow from the subpleural area
to the mediastinum using indocyanine green (ICG)
by invisible near-infrared Áuorescence imaging
system (Hamamatsu Photonics, Hamamatsu, Japan)
(Fig.1).
Conclusion: In this report, we Àrst observed the
direct lymphatic Áow from the pulmonary segment
to the mediastinum without passing hilum pulmonis
by invisible near-infrared Áuorescence imaging
system using ICG. These results might be a clue for
investigating the mechanism of skip metastasis to the
mediastinal lymph node.
Keywords: skip metastasis, Indocyanine green,
Lung cancer, pleural lymph Áow
Methods: 17 patients with lung cancer suspected
were enrolled in this study between March 2008
and December 2008 after obtaining written New Imaging Techniques and New Applications of Established
informed consent. 25 mg of ICG (Diagnogreen; Imaging Techniques in Thoracic Malignancies Thursday, 7 July 2011
Daiichi Pharmaceutical, Tokyo, Japan) in a total 12:30-14:00
of 5 ml of distilled water was prepared. After
induction of thoracotomy, 0.3ml of ICG was MO24.06 IFCT-0504 TRIAL: IMPACT
injected at the subpleural site near the primary OF EARLY CT-SCAN EVALUATION
tumor. Direct lymphatic Áow by Áuorescence image IN FIRST-LINE TREATMENT OF
from the injected site to the mediastinum was ADVANCED BRONCHIOLOALVEOLAR
observed for 5 minutes. Correlations of anatomic CARCINOMA (BAC), BY ERLOTINIB (E)
segment of the primary tumor with the direct OR CARBOPLATIN/PACLITAXEL (C/P)
lymphatic Áow to the mediastinum were examined. Jacques Cadranel1, Radj Gervais2, Marie Wislez3,
Results: There were no complications or adverse Patrick Merle4, Denis Moro-Sibilot5, Virginie
effects associated with ICG injection. The Westeel6, Laurence Bigay-Gamé7, Elisabeth Quoix8,
lymphatic vessels draining from the injected Sylvie Friard9, Fabrice Barlesi10, Marc Zaegel11,
site were visualized by bright Áuorescence (Fig Lionel Moreau11, Isabelle Monnet12, Jean-Paul
.2). Lymphatic vessels were detected in 14 of 17 Duhamel13, Gérard Oliviero14, Pierre Jean Souquet15,
patients (82.4%). Direct lymphatic Áow drained Luc Thiberville4, Laurence Baudrin16, Franck
from the injected site to the mediastinum was Morin16, Gérard Zalcman17
1
conÀrmed in 3 of 14 patients (21.4%). There were Pneumologie, AP-HP Hopital Tenon/France,
2
3 failure cases in detecting lymph Áow due to Oncology, Centre François Baclesse/France,
3
invasion of the primary tumor to the pleura. AP-HP Hopital Tenon/France, 4Pneumologie,
CHU/France, 5Chest Medicine Department,
Grenoble University Hospital/France, 6Chest
Medicine Department, Besançon University
Hospital/France, 7Thoracic Oncology, Toulouse
University Hospital/France, 8Pulmonary Medicine
Department, Strasbourg University Hospital/France,
9
Pneumologie, Hôpital Foch/France, 10Oncologie
Multidisciplinaire Et Innovations Thérapeutiques, (p=0.02), respiratory symptoms score (p=0.004)

Hôpital Nord/France, 11Pneumologie, CH/France, and with treatment arms (p=0.03). Although PFS
12
Service De Pathologie Respiratoire, CHI/France, improved with P/C compared to E (HR=0.667
13
Hôpital Privé De L’estuaire/France, 14Service De [0.461-0.966], p=0.03), OS did not differ between
Pathologie Respiratoire, CHR/France, 15Service the two arms (21.0 [15-33] and 16.4 [12-29] for
De Pneumologie Dr Souquet, Hôpital Lyon Sud, E and C/P, respectively). Finally, an independent
Hospices Civils De Lyon/France, 16IFCT/France, interaction (p=0.035) was observed for the PFS,
17
Chest Medicine Department, Caen University between treatment arms and cytological subtypes.
Hospital/France Increased risk of progression was observed with E
compared to C/P for M-BAC (HR=2.7 [1.4-5.1],
Background: First-line EGFR-TKI in advanced p=0.003), but not for NM-BAC (HR=0.90 [0.51-
BAC yielded a 2.9 to 4-month PFS in Phase II 1.54]).
trials. We and others have suggested that EGFR- Conclusion: IFCT-0504 trial showed that: 1) C/P is
TKI had a reduced activity in M-BAC but that C/T effective in both M- and NM-BAC; 2) Early tumoral
and pemetrexed could have some effect, in both evaluation is not pertinent to select the best strategy,
cytological BAC subtypes. Furthermore, IFCT-0401 and 3) E is as effective as P/C in NM-BAC, but
trial has suggested that patients with M-BAC should less in M-BAC. Finally, it suggested that strategy
early progress after EGFR-TKI administration. To including C/P and E contributed to improve survival
determine the best therapeutic strategy for advanced in advanced BAC.
BAC, we conducted a multicentric randomized phase Keywords: Adenocarcinoma, bronchiolo-alveolar,
II trial to evaluate in Àrst-line treatment E (150 mg/d) EGF-R, paclitaxel
or C/P (AUC 6 d1 / 90mg/m² d1,8,15 four-weekly)
with a cross-over at progression and pemetrexed
in third-line. A secondary objective was also to New Imaging Techniques and New Applications of Established
investigate the impact of an early CT-scan evaluation Imaging Techniques in Thoracic Malignancies Thursday, 7 July 2011
i.e. at week 4, on the DCR at 4 months. 12:30-14:00
Methods: Inclusion criteria: previously untreated,
cyto/pathologically proven advanced BAC. Primary MO24.07 THE DIAGNOSTIC VALUE
objective: 4-month disease control rate (DCR) OF INCREASED F-18 FDG UPTAKE IN
>30% and PFS >3.0 months. Secondary objectives: SURRENAL GLANDS
impact of 4-weeks CT-Scan evaluation on 4-month Tar×k Sengoz1, Canan Karaman2, Ozhan Ozdogan3,
evalution, tolerance, QOL, OS and subgroups Erdem Surucu3, Sadet Ayhan3, Yusuf Demir3, Oya
analyses by arms, cytological subtypes and It×l2, Atilla Akkoclu2, Berna Degirmenci Polack3
1
predeÀned biomarkers. Department Of Nucleer Medicine, Dokuz Eylul
Results: From 09/06 to 07/09, 130/133 patients were University, School Of Medicine/Turkey, 2Department
eligible: median age (68 yrs), PS <2 (87%), females Of Cheast Diseases, Dokuz Eylul University School
(39%), never smokers (27%), stage IIIB-IV (91%), Of Medicine/Turkey, 3Department Of Nuclear
NM (46%), M (41%) and undetermined (13%) Medicine, Dokuz Eylul University, School Of
BAC. DCR was 46% (37-55), PFS=3.5 months (2.6- Medicine/Turkey
5.6) and OS=19.5 months (12.1-28.7). Grade 3
toxicity (>5%): skin for E and hematological/febrile Background: F-18 FDG PET-CT has been reported
neutropenia and neuropathy for C/T; 1 death-related as a valuable tool in determining surrenal gland
toxicity with E. Early evaluations by investigators metastasis in different types of tumors. Increased
showed early progression for 14 patients in E F-18 FDG uptake in surrenal glands has been
(31%) and 13 in P/C (28%). Among these 37 early determined as a frequent Ànding in PET-CT scans.
progressive patients at 4 weeks, 4-month DCR We aimed to investigate the diagnostic value of
was observed in 25% and 22% in E and P/C arms, increased F-18 FDG in surrenal glands and to Ànd a
respectively. Finally, DCR was independently cut-off SUVmax value in differentiating malignant
associated with smoking (p=0.008 and p=0.02), and benign lesions.
respiratory symptoms score (p=0.01), and age >70 Methods: A total of 119 surrenal glands that have
yrs (p=0.03), but not with early CT-Scan evaluation. been reported to have increased F-18 FDG uptake in
PFS was independently associated with smoking 98 patients were included in the study. The PET scan
was performed after at least 12 hours of fasting state. New Imaging Techniques and New Applications of Established
Blood glucose levels of patients were less than 200 Imaging Techniques in Thoracic Malignancies Thursday, 7 July 2011
mg/dl during the injection. A low dose-non enhanced 12:30-14:00
CT was performed preceding a PET scan which was
obtained in 7-8 bed positions (1 bed position/1.5 MO24.08 OSTEOBLASTIC BONE ‘FLARE’
minute) using PET-CT scanner with time-of- IN RESPONDING PATIENTS WITH
Áight technology 60 minutes after FDG injection. EXTENSIVE STAGE SMALL CELL LUNG
SUVmax values were obtained for all lesions. Final CANCER: OBSERVATIONS FROM A
decision on surrenal lesions were performed by PROSPECTIVE RANDOMIZED PHASE II
using histopathological evaluation, MRI imaging or TRIAL (EORTC 08062)
clinical follow-up. Mann-Whitney U test, Wilcoxon Christian Fink1, Mary O’Brien2, Jan P. Van
Signed Rank test and ROC curve analysis were Meerbeeck3, Krzystof Konopa4, Paul Lorigan5,
performed for statistical analysis. Lionel Bosquée6, Ernest Marshall7, Frederique
Results: A total of 70 lesions were evaluated as Bustin8, Sabine Margerit9, Jos A. Stigt10, Anne-Marie
benign. The mean SUVmax for benign lesions was C. Dingemans11, Baktiar Hasan9, Paul Baas12
1
3.03 ± 1.14. Patients without any primary malignancy Institute Of Clinical Radiology And Nuclear
had 16 benign surrenal lesions (SUVmax: 3.37 ± Medicine, University Medical Center Mannheim/
1.43). Patients with a primary malignancy had 54 Germany, 2Lung Unit, Royal Marsden Hospital/
surrenal benign lesions (SUVmax: 2.93 ± 1.03). There United Kingdom, 3University Hospital Ghent/
was no statistically signiÀcant difference in SUVmax Belgium, 4Medical University Gdansk/Poland,
5
values between these groups (p: 0.54) with benign The Christie NHS Foundation Trust, Manchester/
surrenal lesions. There were 49 metastatic surrenal United Kingdom, 6CHU Sart-Tilman, Liège/Belgium,
7
lesions with a mean SUVmax of 8.77 ± 5.37. Forty- Clatterbridge Centre For Oncology, Wirral/
one of these malignant lesions were in patients with United Kingdom, 8Centre Hospitalier Regional
diagnosis of nonsmall cell lung cancer (NSCLC) and De La Citadelle, Liege/Belgium, 9Headquarters,
6 lesions were in patients diagnosed to have small European Organisation For Research And Treatment
cell lung cancer (SCLC), 1 with unknown primary Of Cancer/Belgium, 10Isala Klinieken Zwolle/
and the last with submandibular adenocarcinoma. The Netherlands, 11Academic Hospital Maastricht/
mean SUVmax value of surrenal lesions in patients Netherlands, 12Thoracic Oncology, NKI AVL/
with NSCLC was 9.12 ± 5.60 and for SCLC was 6.62 Netherlands
± 3.62. The SUVmax values of surrenal metastasis
in patients with NSCLC were signiÀcantly higher Background: Bone metastasis is common in lung
than the SUVmax values of surrenal metastasis in cancer and affects approximately 30% of patients
patients with SCLC (p<0.05). The SUVmax values during the course of the disease. In other tumour
of all malignant surrenal lesions were signiÀcantly types a well-known response pattern of bone marrow
higher than the SUVmax values of all benign lesions metastasis is osteoblastic bone Áare
(p<0.001). A ROC curve was generated. A sensitivity Methods: Observations summarized in this report
ratio of % 73.5 and a speciÀcity % 94.3 was obtained are based on a preplanned, independent, blinded,
using the SUVmax: 5.45 as a cut-off value for the centralized, radiological review of a randomized
differentiation of a benign from a malignant surrenal study of single agent amrubicin (A), amrubicin
lesions. combined with cisplatin (AP), and etoposide
Conclusion: F-18 FDG PET study can diagnose a combined with cisplatin (PE) as Àrst line treatment
surrenal metastasis with a sensitivity of 75.5% and in extensive disease (ED) small cell lung cancer
speciÀcity of 94.3% using a SUVmax 5.45 as a cut- (SCLC). CT scans of the chest and upper abdomen
off value. In our study we demonstrated that using of 71/88 patients who had an investigator reported
a SUVmax value smaller than 5.45 can differentiate CR, PR or SD as best response were reviewed
benign surrenal lesions with a speciÀcity of 94.3 %. by one blinded radiologist using RECIST 1.0.
Metastatic surrenal lesions in patients with NSCLC In 11/71 patients review was not assessable due
demonstrated statistically higher SUVmax values to missing image data. The radiologic reports
than SCLC. were retrospectively analysed to assess previous
Keywords: SUVmax, surrenal glands, F-18 FDG knowledge of bone involvement.
PET-CT Results: In this group of patients, 3 had bone
metastases as a site of disease at baseline and 2/3 Background: Tumours invading the mediastinum
developed new osteoblastic lesions. In 11 patients can often be resected en-bloc with neighbouring
there were no baseline/pre-existing/documented structures, however extensive invasion of the
bone lesions, but new osteoblastic lesions developed superior vena cava (SVC), pulmonary artery (PA)
on follow up scans. The 13 patients who developed trunk, aortic wall, atria or ventricular wall require
new osteoblastic bone lesions on follow-up CT adequate preoperative planning and are often
scans were treated with A, AP and PE in 4, 5 and 4 considered a limit. As the identiÀcation of a surgical
cases, respectively. All 13 patients were responders resection plane if often doubtful on CT scans, we
(had PR as assessed by both independent reviewer tested if cine-Magnetic Resonance (CMR) would
and local investigators). We cannot comment on allow for a better differentation between contact and
bone metastasis in the patients who had progressive inÀltration of vital structures.
disease to their primary chemotherapy as they were Methods: Sites of contact between tumour and
excluded from the radiological review. mediastinal structures on CT scans were individually
assessed by CMR. The CMR study protocol included
3 orthogonal stacks of Steady State Free Precession
(SSFP) sequences after administration of contrast
medium. We deÀned inÀltration as absence of sliding
motion and/or absence of chemical shift (seen as a
dark line) between tumour and adjacent structures.
Surgical Àndings (presence or absence of a resection
plane) were reported postoperatively for each
individual site.
Results: Twelve patients with mediastinal tumours
Conclusion: In this study new developing (8 males and 4 females, age 23-72), in whom a
osteoblastic bone lesions were observed in a total 59 contact sites were identiÀed by CT scans,
surprisingly large number of responding patients were preoperatively assessed by CMR. Histology
indicating a high prevalence of occult bone was lung cancer in 5, thymoma-thymic carcinoma
marrow metastasis in SCLC and did not represent in 5, sarcoma in 1, and theratoma in 1. Surgical
progressive disease. To our knowledge this is the Àrst procedures were: pneumonectomy 5, mediastinal
report of osteoblastic bone ‘Áare’ in SCLC patients mass resection 5, extrapleural pneumonectomy 1,
with previously unknown bone metastasis. Staging and exploratory thoracotomy 1 in one. The negative
of SCLC should therefore include imaging tests predictive value was 0.94, positive predictive
sensitive for bone marrow metastasis (e.g. MRI or value 0.80, sensitivity 0.91, speciÀcity 0.86, and
PET). accuracy 0.88. CMR imaging always correctly
Keywords: Imaging, Osteoblastic bone Áare, CT, anticipated or excluded invasion of SVC (6 cases),
SCLC supra-aortic vessels (2), aortic wall (7), PA trunk
(2), atrial wall (7), ventricular wall (3), oesophagus
(2), and pericardium (9) but was less reliable
New Imaging Techniques and New Applications of Established for intrapericardial pulmonary vessels and left
Imaging Techniques in Thoracic Malignancies Thursday, 7 July 2011 anonymous vein.
12:30-14:00 Conclusion: Preoperative CMR imaging allows
for an accurate selection and surgical planning
MO24.09 PREOPERATIVE ASSESSMENT of complex resections in patients with advanced
OF TUMOURS INVADING THE tumours in contact with mediastinal structures.
MEDIASTINUM BY CINE-MAGNETIC Keywords: MRI, Preoperative assessment,
RESONANCE (CMR) IMAGING Mediastinal mass, Surgery
Maurizio V. Infante1, Lorenzo Monti2, Catherine
Depretto2, Alberto Testori1, Umberto Cariboni1,
Daniel Solomon1, Luca Balzarini2, Marco Alloisio1
1
Thoracic And General Surgery Dept., Istituto
Clinico Humanitas/Italy, 2Radiology Dept, Istituto
Clinico Humanitas/Italy
New Imaging Techniques and New Applications of Established FLT SUVpeak 3.1 had a signiÀcantly better overall
Imaging Techniques in Thoracic Malignancies Thursday, 7 July 2011 survival (15.67 months [95% CI 6.4 to 25 months])
12:30-14:00 compared to patients with an SUVpeak >3.1 (3.2
months [95% CI 0 to 8.2 months]) (p=0.008, log
MO24.11 COMPARISION OF [18F] rank). For FDG, the OS groups divided by the
FLUORO-L-THYMIDINE (FLT) AND [18F] median (6.3) were 9.79 months (0-27.03 months,
FLUORO-D-GLUCOSE (FDG) UPTAKES 95% CI) vs 4.89 months (1.77-8.03 95% CI)
IN BASELINE POSITRON EMISSION (p=0.042). Of the clinical parameters, only age was
TOMOGRAPHY (PET) AND THEIR signiÀcantly associated with OS (p=0.046). Both
PROGNOSTIC IMPACTS IN PATIENTS FLT and and FDG baseline values were signiÀcant
WITH ADVANCED NON-SMALL CELL prognostic factors in multivariate analysis with age
LUNG CANCER (NSCLC) TREATED (p=0.020 and p=0.033, respectively).
FIRST-LINE WITH ERLOTINIB Conclusion: The uptake of both tracers of the most
Matthias SchefÁer1, Thomas Zander1, Lucia active tumor manifestation site are strong prognostic
Nogova2, Carsten Kobe3, Deniz Kahraman3, Markus markers for overall survival among patients with
Dietlein3, Erich Stoelben4, Walburga Engel-Riedel4, advanced NSCLC treated with erlotinib Àrst-line.
Bernd Neumaier5, Jurgen Wolf2 Keywords: NSCLC, FLT-PET, FDG-PET, Prognosis
1
Lung Cancer Group Cologne, University Hospital
Of Cologne/Germany, 2Lung Cancer Group Cologne,
Dep.I Of Internal Medicine, Center For Integrated New Imaging Techniques and New Applications of Established
Oncology, University Hospital Cologne/Germany, Imaging Techniques in Thoracic Malignancies Thursday, 7 July 2011
3
University Hospital Cologne, Clinic For Nuclear 12:30-14:00
Medicine/Germany, 4Lung Clinic Merheim/Germany,
5
Max-Planck-Institute For Neurological Research/ MO24.12 CHARACTERISATION AND
Germany PROGNOSTIC SIGNIFICANCE OF
GLOBAL AND REGIONAL HYPOXIA IN
Background: Imaging tools gain in importance for MESOTHELIOMA USING 18F-MISO PET/
assessment of pharmacodynamics, prognosis and CT IMAGING
prediction of therapeutic outcome. We evaluated Tatiana M.L. Segard1, Anna K. Nowak2, Y.C.
the prognostic value of 3’-deoxy-3’-[18F]Áuoro- Gary Lee3, Michael Millward4, Laurence M.J.A.
L-thymidine (FLT) and 2’-deoxy-2’-[18F]Áuoro- Morandeau5, Elaine M. Campbell1, Roslyn J.
D-glucose (FDG) uptake measured by positron Francis2
1
emission tomography (PET) with regards to the Nuclear Medicine, Sir Charles Gairdner Hospital/
prognosis in patients with metastatic non-small cell Australia, 2School Of Medicine And Pharmacology,
lung cancer (NSCLC) prior to systemic therapy with University Western Australia/Australia, 3Pleural
erlotinib. Disease Unit, Lung Institute Of Western Australia/
Methods: FLT and FDG uptake were analyzed in 41 Australia, 4School Of Medicine And Pharmacology
chemonaive patients with advanced NSCLC (stage (m503), The University Of Western Australia/
IV) treated with erlotinib Àrst-line prior to systemic Australia, 5Medical Technology & Physics, Sir
therapy. The median peak SUV of the lesion with Charles Gairdner Hospital/Australia
the highest SUV (SUVpeak) for both FLT and FDG
was used for dichotomizing the patients into two Background: Malignant pleural mesothelioma
groups. Both were analyzed in univariate analysis (MPM) is a relatively chemoresistant cancer with a
using Kaplan-Meier statistics and log rank for poor prognosis. Compelling evidence now suggests
the association with survival and compared with that the presence of hypoxia induces tumour
clinical parameters (age, gender,histology, ECOG aggressiveness and confers cellular resistance
performance state). Multivariate analysis was to both chemotherapy and radiation treatment.
performed using Cox regression. The aim of this pilot study was to determine the
Results: Median follow-up was 21.9 months. As activity of the hypoxia imaging agent (18)F-labeled
expected, the baseline values of FLT and FDG Áuoromisonidazole (FMISO) using positron
were strongly correlated with each other (p 0.0001, emission tomography/computed tomography
Pearson). In univariate analysis, patients with an (PET-CT) in MPM and to compare FMISO
activity with glucose metabolism reÁected by (18) New Imaging Techniques and New Applications of Established
F-Áuorodeoxyglucose (FDG). Imaging Techniques in Thoracic Malignancies Thursday, 7 July 2011
Methods: Consenting patients with histologically 12:30-14:00
or cytologically conÀrmed MPM not currently
receiving systemic or local treatment underwent MO24.13 DIFFUSION-WEIGHTED
both FMISO and FDG PET-CT scans as part of a MAGNETIC RESONANCE IMAGING
prospective study from March 2010 to December IN PERIPHERAL AND SMALL LUNG
2010. The study had Human Research Ethics ADENOCARCINOMA
(HREC) and Radiological Council approval. Patients Ryota Tanaka1, Yoshimasa Nakazato2, Tomoyuki
received 300 MBq/m2 of FMISO with an uptake Goya1
1
phase of 2 hours prior to imaging. FDG PET was Department Of Surgery, Kyorin University School
performed as per standard clinical protocol (6 hour Of Medicine/Japan, 2Division Of Diagnostic
fast, 200 MBq/m2 FDG, 60 minute uptake phase). Pathology, Gunma Prefectural Cancer Center/Japan
FMISO and FDG PET-CT scans were analysed by
two independent PET physicians. Regions of interest Background: We reported results which evaluated
were drawn on the FDG and FMISO images at the the clinical value of MRI for differentiating among
sites of maximal tumour activity. The maximum the invasiveness of lung adenocarcinoma in patients
standardized uptake value (SUVmax) was used to by comparing the MRI Àndings with the pathological
depict FDG activity, and SUVmax and tumour to Àndings in WCLC 2009. In the near future, MRI
background (muscle) ratio were used to quantify with the several sequences may thus be valuable
FMISO activity. as additional modality for evaluating the grade of
Results: Eleven patients (all male) have completed invasiveness in the lesions. Diffusion-weighted
FDG and FMISO PET-CT scans. Visual analysis magnetic resonance imaging (DWI) represents the
demonstrated that FMISO activity was detected in 10 biological characteristics of tissue. DWI reÁects the
of 11 patients. One patient had no evidence of FDG random thermal motion of molecules (Brownian
or FMISO activity in tumour (previously treated motion). The Brownian motion of protons in
mesothelioma in remission). In the 10 patients with bulk water are considered to mainly contribute to
FDG and FMISO activity in tumour the average the signal in DWI. We retrospectively evaluated
tumour SUVmax was 5.7 (range 1.9 to 10.0) for the usefulness of DWI for differentiating among
FDG activity and 2.2 (range 1.4 to 3.3) for FMISO different types of invasiveness in small-sized lung
activity. FMISO tumour to background ratios in adenocarcinomas by comparing the DWI Àndings
the 10 patients visually assessed to have signiÀcant with the pathologic Àndings.
FMISO activity was 1.6 (range 1.2-1.9). There was Methods: MRI was performed on a 1.5T system
a positive correlation between intensity of metabolic (Magnetom Avanto; Siemens, Erlangen, Germany)
activity on FDG PET-CT and hypoxia on FMISO with high-performance gradients and total imaging
PET-CT as assessed by SUVmax (r=0.89, p<0.001) matrix (Tim). All MRI images were posted on a
and between FDG SUVmax and FMISO tumour to Picture Archiving and Communication System
background activity (r=0.78, p=0.008). (PACS) workstation for review by the radiologists.
Conclusion: MPM demonstrates areas of hypoxia From May 2005 to June 2008, forty-six patients
as assessed by FMISO. Tumours exhibiting a higher with lung adenocarcinoma measuring 2 cm or less
SUVmax on FDG PET also had more hypoxia. The across the greatest dimension underwent a surgical
relationship of tumor hypoxia to treatment response operation including preoperative MRI study in
(chemotherapy and/or radiotherapy) should be Gunma prefectural Cancer Center. Of all the tumors,
assessed prospectively. 14 were bronchioloalveolar carcinoma (so-called
Keywords: mesothelioma, PET/CT, Noguchi’s type A and B; type A+B group), 26 were
Fluoromisonidazole, Hypoxia adenocarcinomas with mixed subtypes (so-called
Noguchi’s type C; type C group) and 6 were the
other histological subtypes of adenocarcinoma
(Noguchi’s type D, E and F in this study; type
D+E+F group). The signal intensities of a lesion
(DWI) and the spinal cord (SC) were severally
analyzed in the region of interests (ROIs), and the
DWI/SC ratio was calculated with the value of DWI cases, and radiation alone in 11. The mid-radiation
divided by the value of SC. scans were performed when patients had received
Results: The calculated mean DWI/SC ratio for 30-36 Gy. The gross tumor volume and maximum
the lesions were as follows: 0.448 ± 0.261 (mean standardized uptake value (SUVmax) at each
± standard deviation) for type A+B group, 0.963 ± imaging time point were recorded. Age, stage, and
0.465 for type C group, and 0.816 ± 0.291 for type Karnofsky performance status (KPS) were also
D+E+F group. The mean DWI/SC ratio of type A+B recorded as potential prognostic factors. Endpoints
group was signiÀcantly lower than those type C analyzed were local (within the radiation Àeld)
(p=0.0005) and type D+E+F group (p=0.0117). and distant (out-of-Àeld) progression, and overall
Conclusion: DWI is therefore considered to be survival. Progression was deÀned as biopsy-proven
a useful diagnostic modality for differentiating recurrence or progression by imaging sufÀciently
the subtypes of lung adenocarcinomas. MRI suspicious to warrant a change in treatment.
Àndings may be used to help characterize lung Results: Median follow-up from the time of
adenocarcinomas, and these Àndings may provide radiotherapy simulation was 16.4 months. The
useful supplementary information before regular median age was 69 years (range 47-90). Stage
medical checkups or decisions of surgical procedures distribution was 7 stage I-II, 33 stage III, 4 stage IV
such as limited resection. (oligometastatic), 10 recurrence after prior treatment.
Keywords: magnetic resonance imaging, Median KPS was 80. Median radiation dose was
diffusion weighted imaging, lung adenocarcinoma, 66 Gy. On multivariate Cox proportional hazards
bronchioloalveolar carcinoma analysis, lower KPS (p<0.001), higher pre-radiation
tumor volume (p=0.003), and higher mid-radiation
SUVmax (p=0.05) were signiÀcantly associated with
New Imaging Techniques and New Applications of Established shorter overall survival after controlling for age and
Imaging Techniques in Thoracic Malignancies Thursday, 7 July 2011 stage. Higher mid-radiation SUVmax also correlated
12:30-14:00 signiÀcantly with shorter time to any progression
(p<0.001) and distant progression (p=0.01), and
MO24.14 MID-RADIATION THERAPY insigniÀcantly but with a trend with shorter time to
PET CORRELATES WITH SURVIVAL IN local progression (p=0.09).
LOCALLY ADVANCED NSCLC
Billy W. Loo1, Christine Chang1, Julian Hong1, Kaplan-Meier survival plots stratiÀed by tertiles of
Heather Wakelee2, Quynh Thu Le1, Wendy Y. mid-radiation SUVmax demonstrate its impact on
Hara1, Andrew Quon3, Peter G. Maxim1, Edward E. overall survival (Figure 1) and distant progression
Graves1, Maximilian Diehn1, Michael Olson1 (Figure 2).
1
Radiation Oncology, Stanford University & Cancer
Center/United States Of America, 2Oncology,
Stanford University/United States Of America,
3
Radiology, Stanford University/United States Of
America
Background: Results of chemoradiotherapy for

locally advanced non-small cell lung cancer (LA-
NSCLC) are suboptimal. We studied mid-radiation
PET as a potential early response prediction
biomarker that would be valuable for individualized
therapy adaptation at a time point when additional
intervention is possible.
Methods: We retrospectively studied the outcomes
of 54 consecutive patients who were treated with
deÀnitive radiation therapy for LA-NSCLC from
October 2005 to July 2009 and who also received
both pre- and mid-radiation PET-CT scans.
Concurrent chemoradiotherapy was given in 43
Conclusion: Mid-radiation PET is a strong

prognostic factor for progression and survival in LA-
NSCLC treated with deÀnitive chemoradiotherapy.
It may be useful as a risk-stratiÀcation biomarker
and perhaps ultimately to guide individual therapy
adaptation.
Keywords: Radiation Therapy, PET-CT, Early
response prediction
POSTER SESSIONS DNMT1, MeCP2, MBD1 and HDAC1 by ENU. IP6

protected the alterations at three months and also the
tumor development at eight months. Other changes
Session P1: Poster Session 1 before and after the tumor development will also be
discussed.
Monday, 4 July 2011 Conclusion: The alterations in the epigenetic
machinery were observable before the appearance of
tumor and were responsive to the anticancer agent
Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15 as well. DNA methylation appeared to be involved
in the development and progression of tumors and
P1.001 TARGETING THE EPIGENETIC methylation of promoter CpG islands is a mechanism
SIGNATURES AS EARLY EVENT for inactivation of tumor-suppressor genes, p16. We
FOR THE CONTROL OF TUMOR suggest that these epigenetic signatures are involved
DEVELOPMENT even before the tumor is developed and through
Krishna P. Gupta, Manuraj Pandey these changes IP6 modulates the gene expression.
Carcinogenesis, Indian Institute Of Toxicology They can be targeted for the timely management/
Research/India prevention of the tumor development by anticancer
agents.
Background: Lung cancer is among the major Keywords: Epigenetic, Lung tumor, Prevention,
causes of death due to cancer. There is need to Inositol hexaphosphate
detect the cancer at an early stage by developing
the newer targets and its control by newer agents.
Epigenetic changes are among the earliest changes Poster Session 1 – Cancer Biology 1 Monday, 4 July 2011 12:15-14:15
in tumorigenesis. Epigenetics / methylation precede
neoplasia and if they are responsive to anticancer P1.002 IN VIVO INHIBITION OF
agents that could be used as an early marker for the LUNG CANCER BY PYRROLIDINE
assessment or detection of cancer. The study is to DERIVATIVES: A NOVEL HUMAN
assess the early changes for the detection and control CYTOSOLIC PHOSPHOLIPASE A2Į
of tumor development. INHIBITOR
Methods: We used mouse model for lung tumor Soundarapandian Kannan, Shenbagamoorthy
development. A studied was done at the time of Sundarraj
no tumors i.e. three months and another study Zoology, Bharathiar University/India
was after the tumors were developed i.e. at eight
months. 3 ip injections of ethylnitosourea (ENU) Background: Cytosolic phospholipase A2Ơ
were administered weekly at the dose of 40 mg/kg. (cPLA2Ơ) produces free arachidonic acid and
2% inositol hexaphosphate (IP6) was used as anti lysophospholipds, contributes to the production
tumor agent in drinking water. At the end lungs were of eicosanoids and platelet activating factors. We
isolated and were used for the histopathological aim to determine the level of cPLA2Ơ expression in
analysis, genes expression and methylation study. lung cancer cell lines and the effect of pyrrolidine-1
Results: There were no tumors but hyperplasia and targeting cPLA2Ơ in vitro and in vivo.
lymphocytic inÀltrations were observed at three Methods: The expression of cPLA2Ơ was
months and tumors were present at eight months determined in selected mammalian cancer
after the ENU exposure. To pick up the early cell lines by RT-PCR, Western blot, and
changes, detailed study was carried out in the three immunocytochemistry. Growth inhibition and
months exposure samples. Tumor suppressor gene, cPLA2Ơ activity were determined after inhibition
p16, was down regulated by ENU at the level of with pyrrolidine-1. Cytosolic PLA2Ơ inhibitor
protein and mRNA both. IP6 tried to revert this down namely pyrrolidine-1 was also administered to lung
regulation. At the same time, ENU down regulated cancer xenograft mouse models and assessed the
the global DNA methylation and up regulated the inhibitory level in both in vitro and in vivo.
p16 gene promoter CpG methylation. Thereafter, we Results: cPLA2Ơ is expressed in all the selected
observed the up regulation of the critical events of mammalian cancer cell lines. The cPLA2Ơ
epigenetic machinery in terms of the expressions of expression was increased in A549 cells when
compared to other selected cell lines. Pyrrolidine-1 3SDs of the normal controls. Seropositivity was
inhibitory assay revealed a signiÀcant reduction not evaluated in three subgroups of lung cancer patients-
only in cell proliferation rate but also in cPLA2Ơ smokers, exsmokers, nonsmokers. Exsmokers were
activity in the lung cancer cells. The inhibitory deÀned as former smokers with at least one year
assay clearly demonstrating that the approximately abstinence from smoking.
38% of A549 xenograft growth was inhibited when Results: There were no signiÀcant sex differences
compared with the respective control. in the antibody production. 37,5% (12 lung cancer
Conclusion: In conclusion, Cytosolic PLA2Ơ patients) produced at least one of three investigated
is present in cancer cell lines. These levels are tumor antigen speciÀc antibodies: 31,25% (10
increased in A549 lung cancer cell lines. Cytosolic patients) had antibodies against NY-ESO-1,
PLA2Ơ may play a role in lung cancer cell 25,00% ( 8 patients patients) had antibodies against
proliferation and apoptosis, and its inhibition results MAGE A4 and 18,75% ( 6 patients) against HER2
in decreased cell growth. The drug pyrrolidine-1 neu. Production of tumor speciÀc antibodies has
seems to act speciÀcally through the cPLA2Ơ cumulative character- 50% of patients produce
enzyme. These Àndings are replicated in vivo, both NY-ESO and MAGE A4 antibodies, 40%
with pyrrolidine-1 treatment. Cytosolic PLA2Ơ is a produce NY-ESO together with HER 2 neu speciÀc
potentially effective target for therapy of lung cancer. antibodies. There was no correlation between the
Keywords: Cytosolic phospholipase A2 Alpha presence of tumor speciÀc antibodies and the stage
protein (cPLA2Ơ), Nonsmall cell lung cancer cells, of the disease or tumor histology. Interestingly,
Phyllanthus niruri, Pyrrolidine-1 the presence of tumor antigen speciÀc antibodies
strongly correlated with the history of smoking
and with the elevated levels of CRP (a negative
Poster Session 1 – Cancer Biology 1 Monday, 4 July 2011 12:15-14:15 prognostic factor). There was a signiÀcant difference
in the frequency of NY-ESO-1, MAGE-A4 and
P1.003 SMOKING HISTORY AFFECTS HER 2/neu antibodies. The frequency of tumor
THE PRODUCTION OF TUMOR speciÀc antibodies is signiÀcantly higher in smokers
ANTIGEN SPECIFIC ANTIBODIES IN and sharply declines in the groups of ex- and non-
PATIENTS WITH LUNG CANCER smokers.
Dagmar Myšíková1, Anna Fialová2, Radek Špíšek2,
Robert Lischke1 Smoker Exsmoker Nonsmoker Signi¿cance
1 n=18 n=9 n=5 level
3rd Deptartment Of Surgery, University Hospital
NY-ESO 50%, n=9 11,11%, n=1 0%, n=0 p=0,014
Motol/Czech Republic, 2Institute Of Immunology, positive
University Hospital Motol/Czech Republic HER 2 neu 33,33%, n=6 0%, n=0 0%, n=0 p=0,019
positive
Background: Understanding the characteristics and MAGE A4 33,33%, n=6 11,11%, n=1 20%, n=1 p=0,048
positive
importance of tumor speciÀc immune responses
is a prerequisite for the development of cancer
immunotherapy strategies. In order to evaluate Conclusion: We show that the history of active
the clinical relevance of tumor speciÀc immune smoking has a profound impact on the frequency
responses, we prospectively analyze the presence of tumor antigens speciÀc antibodies in the serum
of cellular and humoral tumor speciÀc immune of lung cancer patients. The ethiology of this
responses in lung cancer patients. In this study, we phenomenon and its clinical relevance remains
compared the differences in the frequency of tumor unknown and requires further studies. Antibody
antigen speciÀc antibodies according to the patients´ production and higher CRP levels in smokers
smoking history. might indicate the chronic inÁammatory state that
Methods: Serum from patients with non-small cell potentiates the development of tumor speciÀc
lung cancer (n=32) and normal controls (n=19) was immune response.
analyzed for the presence of antibodies against three Keywords: effect of smoking history, tumor antigen
tumor antigens HER2 neu, NY-ESO-1 and MAGE speciÀc antibodies
A4 by enzyme-linked immunosorbent assay. Cut-
off point of positive seroreactivity was deÀned as
an optical density value greater than the mean plus
Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15
P1.004 SECRETORY PHOSPHOLIPASE

A2 INHIBITION PROMOTES APOPTOSIS
IN LUNG CANCER CELLS AND
MODULATES ERK 1/2 ACTIVATION
Jessica A. Yu1, Miral R. Sadaria2, Xianzhong Meng2,
David A. Fullerton2, Michael J. Weyant2
1
Division Of Cardiothoracic Surgery, University Of
Colorado Denver School Of Medicine/United States
Of America, 2University Of Colorado Denver School
Of Medicine/United States Of America
Background: Lung cancer remains the leading

cause of cancer death in the world with limited
options for prevention or treatment. We recently
identiÀed secretory phospholipase A2 (sPLA2) as
integral to the invasive potential of lung cancer cells.
SPLA2 has also been demonstrated to inÁuence
proliferation and viability in numerous cancer cell
types though the mechanism of this has not been
well elucidated. ERK 1/2 has been implicated in
regulating proliferation and apoptosis in cancer. We
hypothesize a link between sPLA2 activity, ERK 1/2 Conclusion: Secretory phospholipase A2 inhibition
activation, and tumor cell viability and proliferation. attenuates proliferation and viability in lung cancer
We propose that inhibition of sPLA2 modulates ERK cells by promoting apoptosis. The effect of sPLA2
1/2 activation in lung cancer cells and promotes on growth and proliferation is mediated in part by
apoptosis. ERK 1/2 intracellular signaling. These Àndings
Methods: A549 and H358 cells were treated justify further evaluation of secretory phospholipase
with a speciÀc inhibitor of group IIa secretory A2 as a potential therapeutic target in lung cancer.
phospholipase A2. Apoptosis was evaluated Keywords: secretory phospholipase A2, Lung
by Áow cytometric detection of annexin V and cancer
propidium iodide. Cell viability and proliferation
were measured with 3-(4,5-dimethylthiazol-2- A revised/updated abstract may be included in
yl)-2,5-diphenyltetrazolium bromide (MTT) the Late Breaking Abstract Supplement, available
and bromodeoxyuridine (BrdU) incorporation at the 14th World Conference on Lung Cancer.
assays, respectively. Cell necrosis was evaluated
by LDH assay. The effect of sPLA2 inhibition on
phosphorylation of ERK 1/2 was detected by western Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15
blot.
Results: Inhibition of group IIa secretory P1.005 MICRORNA-145 SUPPRESSES
phospholipase A2 resulted in a signiÀcant dose- LUNG ADENOCARCINOMA INITIATING
dependent increase in apoptosis in both A549 and CELLS PROLIFERATION BY
H358 cells (p<.001, Figure 1). Proliferation and TARGETING OCT4
viability also decreased signiÀcantly in both cell Rong Yin, Shuai Zhang, Yaqin Wu, Feng Jiang, Lin Xu
lines in a dose-dependent manner without causing Thoracic Surgery, Cancer Hospital Of Jiangsu
cell necrosis (p<.001). These effects were associated Province/China
with a dose-dependent decrease in phosphorylation
of ERK 1/2 (p<.001, Figure 2). Background: Recent studies demonstrated that
microRNA-145 was downregulated in human
cancer cells and may function as a tumor suppressor.
However, its role in the tumorigenesis of lung
cancer remains unclear. Here we demonstrated that accumulating data indicate that some miRNAs can
upregulation of miR-145 suppressed the cancer function as tumor suppressors or oncogenes and are
initiating cells proliferation of the human lung important in cancer development. Deletion or loss
adenocarcinoma A549 cell line via targeting Oct4 of function of a tumor-suppressing miRNA results
mRNA. in overexpression of target oncogenes. Conversely,
Methods: A549 cells were transfected by miR-145 activation or overexpression of an oncogenic miRNA
mimics, inhibitors, and their negative controls. Cell results in silencing of tumor-suppressing target
Counting Kit-8 assay was employed for evaluating genes. According to miRNA proÀles on microarray,
proliferation capacity. Cell migration capacity miR-99b was down-expressed in Korean lung cancer.
was evaluated by using the matrigel and millicell FGFR-3 is predicted target of miR-99b through two
chambers. Flow cytometry was used for cell cycle public algorithms. FGFR-3 has been demonstrated to
and CD133 phenotype analysis. Oct4 protein level be involved in the RAS/RAF/MEK/MAPK pathway
was also analyzed by western blot. Tumorspheres through activation of p90 ribosomal S6 kinase.
were cultured in a serum-free medium with the It has been reported that FGFRs are frequently
support of providing growth factors. Finally, overexpressed in NSCLC cell lines, suggesting that
the targeting gene of miR-145 was predicted by an FGFR-dependent autocrine signaling pathway
bioinformatics analysis and validated by a luciferase may operate in a subset of NSCLCs.
reporter system. Methods: We studied expression of miR-99b and
Results: Overexpression of miR-145 by transfecting FGFR-3 using quantitative reverse transcription
mimics can signiÀcantly suppress A549 cells PCR (qRT-PCR) in lung cancer tissue. To examine
proliferation and migration capacity, decrease whether miR-99b could regulate FGFR-3 in lung
the percent of S phase cells, the ratio of CD133+ cancer, we performed transient transfection of
initiating cells and the Oct4 protein level, as well as pre-miR-99b into lung cancer cell line, then we
inhibiting the capacity of tumorspheres formation. performed qRT-PCR and western blot in HCC1438,
Oct4 mRNA is directly targeted by miR-145 which HCC95, and H522 cells for analysis of FGFR-
was validated by the luciferase reporter system. 3 expression. Luciferase reporter gene assays
Conclusion: It is therefore conÀrmed that miR- were performed to identify miR-99b targets. We
145 can impair the proliferation of human lung hypothesized the miR-99b has a role of inhibitor cell
adenocarcinoma initiating cells via targeting OCT4 growth in lung cancer. To test this hypothesis, we
and then lead to lung cancer development inhibition. performed cell proliferation assay.
Keywords: cancer initiating cells, proliferation, lung Results: miR-99b was down-regulated and FGFR-3
adenocarcinoma, microRNA was up-regulated in lung cancer. Over-expression
of miR-99b induced marked reduction of FGFR-3
mRNA levels and protein level. The signal from a
Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15 luciferase reporter was signiÀcantly decreased at
one miR-99b target site at the 3’UTR of FGFR3,
P1.006 MICRORNA-99B INHIBITS suggesting that miR-99b directly regulates FGFR3.
LUNG CANCER GROWTH THROUGH The growth rate in miR-99b precursor treated cell
REGULATION OF FIBROBLAST was lower than in negative control of miR treated
GROWTH FACTOR RECEPTOR 3 cell.
Yumi Lee1, Soo Young Lee2, Sun Jung Kwon1, Conclusion: Abnormal down-regulation of miR-99b
Eugene Choi1, Moon Jun Na1, Young Jin Kim3, Hyun could lead to the over-expression of FGFR-3 in lung
Min Cho3, Jae Ku Kang4, Ji Woong Son1 cancer. miR-99b may be a potent tumor suppressor
1
Internal Medicine, Konyang University Hospital/ and may be a potential candidate of therapeutic tool
Korea, 2Myunggok Research Institute For Medical in lung cancer.
Science, Konyang University/Korea, 3Department Keywords: microRNA, FGFR-3, tumor suppresor
Of Thoracic Surgery, Konyang University Hospital/ gene, Lung cancer
Korea, 4Department Of Pharmacology, College Of
Medicine, Konyang University/Korea
Background: Dysregulation of miRNA expression

has been identiÀed in a number of cancers and an
Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15 bladder and mesothelial cells of tunica vaginalis
produced intelectin-1 partially. In adrenal cortex and
P1.007 IMMUNOHISTOCHEMICAL renal collecting tubule, intelectin-1 was detected
EVALUATION OF INTELECTIN-1 weakly. Intelectin-1 in epithelial MPMs was detected
EXPRESSION, A MESOTHELIOMA in cytoplasm. In mucinous type adenocarcinomas,
MARKER, IN NON-NEOPLASTIC AND intelectin-1 was showed in mucus of the goblet
NEOPLASTIC TISSUES. cells and in cytoplasm of epithelial cells. Lung
Kota Washimi1, Shoutaro Tsuji2, Tomoyuki Yokose1, non-mucinous adenocarcinomas did not produce
Yohei Miyagi3, Mitsuyo Yoshihara3, Rurika intelectin-1.
Hamanaka4, Miki Ohe4, Chikako Hasegawa1, Conclusion: In non-neoplastic tissues, only limited
Kimitoshi Nawa4, Tetsukan Woo4, Yoichi Kameda1 cells produced intelectin-1. In mucinous type
1
Department Of Pathology, Kanagawa Cancer adenocarcinoma (stomach, colon, pancreas, lung,
Center/Japan, 2Cancer Therapy Division, Kanagawa uterine body), intelectin-1 was partially detected in
Cancer Center Research Institute/Japan, 3Molecular mucus of goblet cells and in cytoplasm of epithelial
Pathology And Genetics Division, Kanagawa Cancer cells. However, in histologically, it is not difÀcult to
Center Research Institute/Japan, 4Department Of differentiate MPM from these metastatic mucinous
Thoracic Oncology, Kanagawa Cancer Center/ type adenocarcinoma in pleura. Lung non-mucinous
Japan adenocarcinomas, which is difÀcult to differentiate
from MPM, did not produce intelectin-1. Therefore,
Background: Recently, malignant pleural we consider intelectin-1 is useful for diagnosing
mesothelioma (MPM) patients have increased. MPM.
Since a pathological diagnosis of MPM is Keywords: intelectin-1, immunohistochemistry,
difÀcult, improvement of MPM diagnosis has malignant pleural mesothelioma
been required. We previously reported that human
intelectin-1, host defense lectin is secreted by A revised/updated abstract may be included in
epithelial MPM cells (S Tsuji et al. Br J Cancer the Late Breaking Abstract Supplement, available
2010;103:517-523). Intelectin-1 may become at the 14th World Conference on Lung Cancer.
an useful immunohistochemical markers for a
differential diagnosis of epithelial MPM. However,
intelectin-1 expression in human tissues has not been Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15
investigated in detail. In this study, we examined
intelectin-1 expression in non-neoplastic and P1.008 RELATION OF LUNG CANCER
neoplastic tissues by immunohistochemistry. HISTOLOGY TO PERIPHERAL
Methods: Anti-intelectin-1 monoclonal antibody, MICROVASCULAR SATURATION
15:3G9, was used for immunohistochemical MEASURED BY OPTICAL
assessment of intelectin-1 expression. Non- SPECTROSCOPY
neoplastic tissues were prepared as a tissue Cor Van Der Leest1, Hendricus Sterenborg2, Paul
microarray (TMA). The 264 cores of non-neoplastic Mulder2, Remco Djamin1, Henk Hoogsteden3,
tissues were made from six cases for which Joachim Aerts1
1
pathological autopsies were conducted at Kanagawa Pulmonary Diseases, Amphia Hospital/Netherlands,
2
Cancer Center between 2006 and 2010. Intelectin-1 Erasmusmc/Netherlands, 3Erasmus Medical Center/
expression was also analyzed in epithelial MPM Netherlands
(two cases) , lung adenocarcinoma (three cases) and
mucinous type adenocarcinoma (stomach, colon, Background: Lung cancer is historically divided
pancreas, lung, breast, uterine endocervix, uterine into Non-Small Cell Lung Cancer (NSCLC) and
body; two cases, respectively). Small Cell Lung Cancer (SCLC), due to differences
Results: In non-neoplastic tissues, goblet cells in treatment options and prognosis. Hypoxia is a
and their surrounding cells in gastric metaplastic well known parameter in many solid tumors and
epithelium ,duodenal epithelium, and colonic has been related to high metastatic rate and poor
mucosal epithelium produced intelectin-1 protein prognosis. Whether hypoxia is different between the
largely. Reactive mesothelial cells on the pulmonary histological subtypes of lung cancer is unknown.
pleura and peritonea, the umbrella cells of urinary The aim of the study was to compare spectroscopic
determined saturation levels of endobronchial proliferation, oncogenesis and cancer progression.

NSCLC and SCLC tumors and relate this to survival. Currently, a combination of cisplatin + etoposide is
Methods: Differential pathlength spectroscopy the standard Àrst-line therapy for SCLC. Hence, we
(DPS) was used during bronchoscopy. Hereby wanted to test whether increased GLI1 expression
peripheral microvascular saturation data were contributes to cisplatin and etoposide resistance in
obtained in vivo in different histological subtypes SCLC.
of lung tumors. DPS data were correlated with Methods: H69 cells (H69-wt) were transduced with
endobronchial tumors histology corrected for stage GLI1 over-expressing vector to create H69-GLI1.
of disease. Proliferation assays and drug dose response to
Results: In 98 patients DPS data could be correlated combination of cisplatin +/- etoposide was conducted
to histological-conÀrmed endobronchial tumor on H69-wt and H69-GLI1 cells and on four
tissue. No differences in microvascular saturation additional SCLC lines: H146, H187, H345, H1688.
between NSCLC and SCLC were established. We mined the literature to identify genes previously
Adenocarcinomas and squamous cell carcinomas been described as GLI1 targets or shown as
had a signiÀcant better peripheral oxygenation, associated with GLI1. Subsequently, the expression
StO2 65% (sd 20,0) and 58% (sd 28,9) respectively, of these candidate genes was validated by qRT-PCR.
compared to large cell carcinoma and SCLC, StO2 Results: Proliferation assays showed no signiÀcant
42% (sd 28,9) and 38% (sd 28,2) respectively. No differences in H69-wt vs. H69-GLI1 cells. Drug
relation between peripheral microvascular tumor dose response experiments showed at least 1.5
saturation and survival could be established. fold increase in cisplatin resistance in H69-GLI1
Conclusion: Although differences in peripheral compared to H69-wt cells and similar trend was
microvascular saturation, measured during observed in cisplatin/etoposide combination
bronchoscopy, between the histological subtypes of dosing. In other SCLC cell lines a positive trend
lung cancer can be observed, no relation was found was observed where increased GLI1 expression
to survival. correlated with elevated cisplatin resistance. From
Keywords: Lung cancer, Differential pathlength literature review search, we identiÀed two genes,
spectroscopy, microvascular saturation, histology SFRP1 and FOXA2, which have been associated
with GLI1. We tested their expression in H69-wt and
H69-GLI1 cells and found that both genes are over-
Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15 expressed in H69-GLI1, which is in concordance
with previously published data. Interestingly,
P1.009 CONNECTING GLI1 WITH microRNA 21 (miR-21) was over-expressed in H69-
CHEMORESISTANCE IN SMALL CELL GLI1 cells. This is intriguing, as miR-21 expression
LUNG CANCER has previously been related to chemoresistance in
Glen J. Weiss1, Kristi E. Allen2, David K. Edwards various other cancers. We are currently performing
V2, Irene Cherni2, Carlos Lorenzo2, Shilpi Arora2 GLI1 knockdown experiments using siRNA to
1
Medical Oncology, Virginia G. Piper Cancer validate the role of GLI1 in chemoresistance and
Center At Scottsdale Healthcare/tgen/United also conÀrm that SFRP1, FOXA2 and miR21
States Of America, 2Cancer And Cell Biology, The are its effectors and contribute to GLI1’s role
Translational Genomics Research Institute (TGEN)/ in chemoresistance. We are also testing GLI1’s
United States Of America expression in tumors from SCLC patients to see if
there is a correlation between GLI1 expression and
Background: Small cell lung cancer (SCLC) de novo chemoresistance
accounts for ~15% of all lung cancers. Drug Conclusion: GLI1 plays an important role in
resistance to chemotherapeutic drugs is particularly conferring cisplatin + etoposide resistance in H69
crippling in SCLC. We examined gene expression SCLC cells and once validated its expression could
in cisplatin-resistant SCLC cell line H69, and be used to predict chemotherapy response in SCLC
found aberrant expression of a subset of Hedgehog patients.
Signaling (Hh) Pathway-related genes, among which Keywords: microRNA, Small cell lung cancer,
GLI1 was signiÀcantly elevated. GLI1 is a known GLI1, chemoresistance
transcription factor that is involved with regulation
of a number of key genes in cell fate determination,
Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15 not increased in PC-14/lung, PC-14/kidney, PC-
14/bone, and PC-14/muscle. They appeared to be
P1.010 MICROARRAY ANALYSIS candidate for the genes that inÁuence organotropism
TO DETECT GENES PREDICTING of lung cancer adrenal metastasis.
ORGANOTROPISM OF LUNG CANCER Conclusion: Microarray analysis was applied to
ADRENAL METASTASIS. Ànd the gene expression inÁuencing organotropism
Tatsuya Yoshimasu, Shoji Oura, Fuminori Ohta, of lung cancer adrenal metastasis. Our study
Yoshimitsu Hirai, Koma Naito, Rie Nakamura, results detected 19 genes as the candidates. This
Haruka Nishiguchi, Sayoko Hashimoto, Mitsumasa experimental method seems to be promising. Further
Kawago, Yoshitaka Okamura experiments using additional cell lines will be
Department Of Thoracic And Cardiovascular needed to deÀne them precisely.
Surgery, Wakayama Medical University/Japan Keywords: adrenal metastasis, microarray analysis,
organotropism
Background: Lung cancer easily metastasizes to
multiple organs, such as bone, lung, brain, liver,
and adrenal gland. The frequency of the distant Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15
metastasis usually appears to be dependent on the
volume of each target organ. However, metastasis P1.011 MASS SPECTROMETRY
to the adrenal gland is frequently observed in spite ANALYSES OF KAPPA AND LAMBDA
of its small volume. We hypothesized that some FRACTIONS OF IGG RESULT
organotropic mechanisms exist in lung cancer IN INCREASED NUMBER OF
adrenal metastasis. We applied microarray analysis to COMPLEMENTARITY DETERMINING
Ànd the gene expression inÁuencing organotropism REGIONS IDENTIFICATIONS
of lung cancer adrenal metastasis. Ingrid Broodman1, Dominique De Costa2, Christoph
Methods: Human non-small cell lung cancer cell Stingl3, Lennard J.M. Dekker3, Martijn M. Vanduijn3,
line PC-14 was used. The cell was cultured for 7 Jan Lindemans1, Rob J. Van Klaveren2, Theo M.
days on the fresh tissue slice of athymic mouse Luider3
1
(Balb/c-nu/nu) adrenal gland. After that, proliferated Clinical Chemistry, Erasmus Medical Center/
cancer cells were collected from the surface of Netherlands, 2Pulmonology, Erasmus Medical
adrenal gland and cultured in the Áask again. This Center/Netherlands, 3Neurology, Erasmus Medical
process was repeated 5 times. The cells conditioned Center/Netherlands
in this manner, which was named as PC-14/adrenal,
showed higher organotropism to adrenal gland than Background: Antibodies against tumor associated
original PC-14 cells when they were inoculated to antigens in early stage lung cancer have been
the athymic mice. The same procedure was also identiÀed before the tumor was detectable by a
applied to the other organs, such as lung, kidney, CT scan. SpeciÀc amino acid sequences of the
bone, and muscle. Then the conditioned cells PC- complementarity determining regions (CDRs)
14/lung, PC-14/kidney, PC-14/bone, and PC-14/ in the antigen-binding fragment (Fab) of these
muscle were obtained. These 4 subclones were used antibodies have potential as biomarkers for early
as control cells against PC-14/adrenal. Microarray detection of lung cancer. IdentiÀcation of CDRs
analysis was applied to these 6 cells including depends on the sensitivity of the mass spectrometry
original PC-14 cells. to detect these very low-abundant CDR peptides.
Results: Expressions of 28869 genes were evaluated However, ion suppression in the mass spectrometer
in each cell using microarray analysis. Expression especially for complex peptide mixtures can reduce
was signiÀcantly higher in 20, 57, 70, 29, and 23 the sensitivity. Reducing the complexity decreases
genes in PC-14/adrenal, PC-14/lung, PC-14/kidney, ion suppression and leads to a signiÀcantly higher
PC-14/bone, and PC-14/muscle, respectively, when sensitivity to detect CDR peptides. Our aim was
they were compared with original PC-14 cells. to molecular dissect IgG into kappa and lambda
Increase in DUSP1 was commonly observed in all 5 fragments to reduce the complexity and thereby
conditioned cells. This alteration of DUSP1 seemed identify substantially more CDRs than by just total
to be derived from this experimental method itself. Fab isolation.
The other 19 genes increased in PC-14/adrenal were Methods: In this pilot study, we puriÀed Fab, Fab-Ʃ,
Fab-ƪ, Ʃ and ƪ light chains of IgG from serum from Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15
10 stage I lung adenocarcinoma patients and 10
matched controls from current and former smokers P1.012 DYNAMIC MOLECULAR
of the Dutch Belgian randomized lung cancer CHANGES ASSOCIATED WITH
screening trial (NELSON). After puriÀcation, the EPITHELIAL-MESENCHYMAL
immunoglobulin fragments were enzymatically TRANSITION AND SUBSEQUENT
digested and measured by nanoLC Orbitrap mass MESENCHYMAL-EPITHELIAL
spectrometry. Label-free quantiÀcation of MS data TRANSITION IN THE EARLY PHASE OF
was performed by Progenesis software. Peptide METASTATIC TUMOR FORMATION
sequences were identiÀed by a Mascot search Keiju Aokage1, Genichiro Ishii2, Tomoyuki Hishida1,
against the NCBInr human database and de novo Junji Yoshida1, Mitsuyo Nishimura1, Kanji Nagai1
1
sequencing by Peaks software. CDRs were identiÀed Division Of Thoracic Oncology, National Cancer
by using the IMGT/DomainGapAlign tool. Finally, Center Hospital East/Japan, 2Pathology Division,
we compared the number of CDRs identiÀed in Research Center For Innovative Oncology, National
these immunoglobulin fragments with the number Cancer Center Hospital East/Japan
of CDRs identiÀed in the Fab fragments. Statistical
tests were performed using Microsoft Excel 2007, Background: Metastatic tumor formation via vessel
VassarStats and Stata. route begins with cancer cell extravasation from
Results: Our method provided reproducible vessel lumen, migration into the connective tissue
separations (CV%<5) with high recovery rates surrounding vessels, and invasion into target organ
(>90%). In addition, a normal Ʃ:ƪ ratio was parenchyma. Epithelial-mesenchymal transition
measured in both cases and controls. Cases and (EMT) and mesenchymal-epithelial transition
controls revealed 1663 CDR peptides of Fab, 1422 (MET) have been recognized to play an important
of Fab-Ʃ, 971 of Fab-ƪ, 859 of Ʃ and 991 of ƪ. The role in these metastatic processes, however, how
non-parametric Kruskal-Wallis test (two-sided) and where these biological changes take place in the
showed a signiÀcantly (p<0.001) higher CDR3 ratio early phase of metastatic tumor development has
in the three Fab fractions (Fab, Fab-Ʃ, Fab-ƪ) than in never been clariÀed. The aim of this study was to
the light chain fractions (Ʃ and ƪ). On average, 1.73 determine how the biological features of tumor cells
times more CDRs were found in the combination change dynamically during early metastatic tumor
of Fab-Ʃ, Fab-ƪ, Ʃ and ƪ than in Fab. Pearson Chi- development.
square tests with odds ratios revealed no statistically Methods: Examination of the surgical specimens
signiÀcant difference (p>0.50) between cases and of the 3161 consecutive patients who underwent
controls in the number of CDRs identiÀed in the surgical resection of a primary lung cancer at our
individual and combined IgG fractions compared hospital between July 1992 and October 2008
with that of Fab. The mean additional number of revealed intrapulmonary metastasis by the NSCLC
unique CDRs (mean%) to the Fab fraction was for in 222 of them. We extracted the cases of primary
Ʃ 320 CDRs (23.1%), ƪ 501 CDRs (36.0%), Fab-Ʃ adenocarcinoma of the lung alone and evaluated
679 CDRs (48.7%) and Fab-ƪ 315 CDRs (22.7%). the 233 metastatic tumors in the 129 patients
Combined Ʃ and ƪ fractions resulted in 804 (57.8%), with a pulmonary metastasis less than 10 mm in
and combined Fab-Ʃ and Fab-ƪ fractions in 978 diameter. An intrapulmonary metastatic tumor
(70.3%) additional unique CDRs. In addition, these was judged to have formed by the lymphogenic
four fractions combined showed an additional 1683 mechanism if all of the following criteria were
unique CDRs (121.0%) to Fab. In total, twice as met: both the primary tumor and metastatic tumor
many CDRs were identiÀed when Fab-Ʃ, Fab-ƪ, Ʃ positive for lymphatic permeation and presence of
and ƪ (3330) were combined than in the Fab (1663) a metastatic focus in the lung parenchyma adjacent
fraction alone. to a bronchovascular bundle involved by lymphatic
Conclusion: Molecular dissection of IgG identiÀes permeation. So we extracted 34 lymphogenic
signiÀcantly more CDRs, which will increase the intrapulmonary metastases, immunostained them
likelihood of Ànding early lung cancer-related CDR for 13 molecular markers of EMT and MET and
proÀles. scored the immunostaining intensity of cancer
Keywords: CDRs, lambda, Kappa, cells Áoating in lymphatic vessels (LV), migrating
immunoglobulins into the connective tissue surrounding vessels
(bronchovascular bundle; BVB), and growing in Research/United Kingdom, 4Paterson Institute

lung parenchyma (LP). For Cancer Research/United Kingdom, 5Medical
Results: The mean staining score ± standard Oncology, Christie Hospital/United Kingdom
deviation (S.D.) for E-cadherin in LV, BVB, and
LP was 1.03 ± 0.45, 0.6 ± 0.32, and 0.82 ± 0.36, Background: Small cell lung cancer (SCLC)
respectively. The mean staining score ± S.D. for is an aggressive neuroendocrine tumour that
ơ-catenin in LV, BVB, and LP was 1.09 ± 0.67, 0.44 shows early metastasis and eventual resistance
± 0.33, and 1.07 ± 0.58, respectively. The E-cadherin to chemotherapy. Currently both epithelial and
and ơ-catenin expression levels in BVB were neuroendocrine biomarkers can provide information
signiÀcantly lower than in LV (E-cadherin: p<0.001; on the diagnosis/prognosis of SCLC. However it
ơ-catenin: p<0.001) and LP (E-cadherin: p=0.011; is not clear whether the tumour cells express both
ơ-catenin: p<0.001). The mean staining score ± S.D. neuroendocrine and epithelial markers or if there
for Laminin 5Ƣ2 in LV, BVB, and LP was 0.07 ± are distinct cell sub-populations in the primary
0.11, 0.3 ± 0.4, and 0.05 ± 0.16, respectively, and tumour, in metastases and/or in circulating tumour
the Laminin 5Ƣ2 expression levels in BVB were cells (CTCs). The aims of this study were to
signiÀcantly higher than in LV (p=0.037) and LP investigate the expression of neuroendocrine (pro-
(p=0.001). SigniÀcantly more Geminin-positive opiomelanocortin, POMC, the precursor of ACTH)
cells per 100 tumor cells were detected in LV (mean and epithelial markers (cytokeratin) in vitro, in vivo
± S.D.; 15.9 ± 11.8) and LP (10.4 ± 8.0) than in in primary tumours from SCLC xenografts and their
BVB (5.9 ± 4.6) (LV vs. BVB: p<0.001; BVB vs. metastases and in patient samples.
LP: p=0.037). The mean staining score ± S.D. of Methods: A SCLC cell line (DMS 79) and a
MMP7 in LV, BVB, and LP was 0.05 ± 0.12, 0.15 ± negative control, non SCLC cell line (A549), were
0.26, and 0.05 ± 0.1, respectively, and The MMP7 grown in culture (1) and prepared as cytospins.
expression level in BVB was signiÀcantly higher Cells were stained using immunoÁuorescence with
than in LV (p=0.046) and LP (p=0.038). antibodies for POMC (2), cytokeratin (pan CK,
Conclusion: Our results suggested that in the early Sigma) and DAPI (nuclear stain, DAKO). For the
phase of metastatic tumor formation cancer cells xenograft model (1) nude mice injected with DMS
undergo dynamic phenotypic change associated with 79 cells were left until the tumour reached 4 times
EMT and subsequent MET. Further understanding the relative tumour volume (approximately 800mm3).
of tumor cell behavior during the early metastatic The tumours and metastatic sites were excised and
process will provide insight into therapeutic sections were stained for POMC and cytokeratin
strategies to overcome metastasis. using a DAB stain.
Keywords: Metastasis, lymphogenic, epithelial Results: SCLC cells (DMS 79) release POMC and
mesenchymal transition, mesenchymal epithelial cytokeratin in culture. ImmunoÁuorescent staining
transition of these cells showed some were positive for POMC,
some for cytokeratin and some positive for both
markers. The epithelial non-SCLC control cell line
Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15 (A549) was negative for POMC and positive for
cytokeratin. Xenografts stained positive for both
P1.013 NEUROENDOCRINE AND CK and POMC. Terminal POMC concentrations in
EPITHELIAL PHENOTYPES IN SCLC IN the circulation of the xenografted mice were highly
VITRO AND IN VIVO: IMPLICATIONS elevated (mean values 2850pmol/l vs 150pmol/l
FOR METASTASIS IN PATIENTS WITH at baseline, p<0.001). Seven mice had evidence
SMALL CELL LUNG CANCER of liver metastases and 4 had evidence of brain
Rachel Stovold1, Suzanne Meredith1, Muhammad metastases. In both the brain and liver, metastases
Babur2, Jessica Booth3, Brian Telfer2, Caroline Dive4, stained positive for POMC. In 25 patients with
Kaye Williams2, Fiona Blackhall5, Anne White2 SCLC, plasma POMC levels correlated with
1
Faculty Of Life Sciences, University Of Manchester/ circulating tumour cell (CTC) number and poor
United Kingdom, 2Faculty Of Medical And prognosis. The markers will also be measured to
Human Sciences, University Of Manchester/ assess neuroendocrine and epithelial characteristics
United Kingdom, 3Clinical And Experimental in clinical CTC samples.
Pharmacology, Paterson Institute For Cancer Conclusion: Our results provide evidence that SCLC
cells in vitro comprise a mixture of cell populations the media compared to controls. Overexpression of
consisting of those with a neuroendocrine or OPNa (p<.002) and exposure to OPNa conditioned
epithelial phenotype and those that express both media (p<.002), each signiÀcantly increased invasion
characteristics. It is possible that the contribution compared to controls and the effects were additive.
of each cell type to metastasis and chemoresistance Over expression of OPNc and exposure to OPNc
varies, and understanding the role of each type may conditioned media decreased invasion compared to
help to drive new targeted treatment strategies. controls. (Figure) OPNc conditioned media differed
References: 1 Sommer et al 2010, ERC 17 (1) p203- from that of OPNa and control most notably by the
13 2 Stevens et al 2011 Eur J Pharmacology in press lack of CD44 detection.(Table)
Keywords: SCLC, Neuroendocrine, POMC,
Cytokeratin
P1.014 EXTRACELLULAR MEDIATION

OF DIVERGENT EFFECTS OF
OSTEOPONTIN SPLICE VARIANTS IN
NON-SMALL CELL LUNG CANCER
Jessica S. Donington, Chandra M.V. Goparaju,
Nathalie Hirsch, Ryan Harrington, Justin D.
Blasberg, Harvey I. Pass
Cardiothoracic Surgery, NYU School Of Medicine/
United States Of America pcmv2 OPNa OPNc
galactin-3-binding protein osteopontin isoform a precursor osteopontin precursor
agrin precursor galectin-3-binding protein galectin-3-binding protein
Background: Osteopontin (OPN) is a secreted laminin B2 chain agrin precursor Alpha-enolase
phosphoprotein with an important but poorly amyloid-like protein 2 14-3-3 protein zeta/delta syndecan-4 precursor
understood role in non-small cell lung cancer syndecan-4 precursor syndecan-4 precursor 14-3-3 protein zeta/delta
(NSCLC) pathogenesis. We previously demonstrated proactivator polypeptide a proactivator polypeptide a unnamed protein product
golgi membrane protein CD44
that OPN splice variants have divergent patterns
amyloid beta A4 precursor Myosin-9
of expression and impact on invasion in NSCLC. calmodulin
OPNa, which is selectively up regulated in tumors basigin isoform 1 precursor
and cell lines, increases invasion, while OPNc is CD44
not expressed in tumors or cell lines, but decreases

invasion when overexpressed.We hypothesize Conclusion: The divergent impact of OPN splice
that these divergent effects on NSCLC invasion variants on invasion in NSCLC is mediated
are mediated extracellularly through associated extracellularly. The effects of overexpression can be
difference in secreted proteins. mimicked by isoform speciÀc conditioned media.
Methods: cDNA plasmids speciÀc to OPNa, Alterations in cellular attachment related to CD44
OPNc and pcmv empty vector controls (Origene, represents possible pathway of effect. These Àndings
Rockville, MD) were transfected into NSCLC cell increase the likelihood of being able to target
lines H358 and H460. At 24H cells were washed and isoform-speciÀc differences for therapy of NSCLC.
placed in serum free media. Conditioned media was Keywords: osteopontin, Non-small cell lung cancer,
harvested at 48H. OPN levels in conditioned media Invasion, splice variants
were measured by ELISA (IBL, Yuma, Japan) and
proteomics analysis performed using NanoLC-MS/ A revised/updated abstract may be included in
MS peptide sequencing (Prottech, Fairview Village, the Late Breaking Abstract Supplement, available
PA). Invasion assay was performed with pooled at the 14th World Conference on Lung Cancer.
populations of transfected cells in OPNa, OPNc and
control conditioned media.
Results: Overexpression of either OPNa or OPNc
signiÀcantly increased the OPN concentration of
Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15 EpCAM knockdown dramatically inhibited growth
of shZEB1-expressing ACC-MESO-1 but only
P1.015 TRANSIENT BUT NOT STABLE modestly inhibited growth of shGFP-expressing
ZEB1 KNOCKDOWN DRAMATICALLY ACC-MESO-1 cells, supporting our hypothesis.
INHIBITS GROWTH OF MALIGNANT Conclusion: ZEB1 knockdown may be a promising
PLEURAL MESOTHELIOMA CELLS: therapeutic strategy for MPM, but the possibility of
IMPLICATION OF EPCAM UP- EpCAM up-regulation induced by ZEB1 knockdown
REGULATION INDUCED BY ZEB1 must be taken account in the development of ZEB1-
KNOCKDOWN targeted therapeutics.
Mihoko Horio1, Mitsuo Sato1, Yoshihiro Takeyama1, Keywords: mesothelioma, EMT, ZEB1, EpCAM
Tetsunari Hase1, Elshazley Momen1, Kenya Yoshida1,
Yoshitaka Sekido2, Masashi Kondo1, Adi F. Gazdar3,
John D. Minna3, Yoshinori Hasegawa3 Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15
1
Respiratory Medicine, Nagoya University Graduate
School Of Medicine/Japan, 2Division Of Molecular P1.016 CLINICAL IMPACT OF THE DNA
Oncology, Aichi Cancer Center Research Institute/ METHYLATION LEVEL IN NON-SMALL
Japan, 3Hamon Center For Therapeutic Oncology CELL LUNG CANCER DETERMINED
Research, University Of Texas/United States Of USING A PYROSEQUENCING METHOD
America Riichiroh Maruyama1, Yasunori Shikada1, Tsukihisa
Yoshida1, Yosuke Morodomi1, Kensaku Ito1, Akira
Background: ZEB1, a master epithelial-to- Haro1, Mitsuhiro Takenoyama1, Tokujiro Yano1,
mesenchymal transition (EMT) regulator gene, Hiroyuki Kitao2, Yoshihiko Maehara1
1
contributes to several important malignant properties Surgery And Science, Kyushu University/Japan,
2
in a wide variety of epithelial malignancies. Department Of Molecular Oncology, Graduate
However, its role in malignancies of mesodermal School Of Medical Sciences, Kyushu University/
origin including malignant pleural mesothelioma Japan
(MPM) is unclear.
Methods: Eighteen MPM cell lines and the Background: Given the aging of society in Japan,
normal immortalized pleural mesothelial cell line the number of elderly patients with lung cancer is
MeT-5A were used. The expression of ZEB1, expected to increase. It is necessary to distinguish
E-cadherin, vimentin and epithelial cell adhesion the epigenetic differences between elderly and young
molecule (EpCAM) was determined by quantitative patients in order to develop more speciÀc population-
real-time PCR and /or western blotting. RNA based treatment strategies. Global hypomethylation
interference-mediated knockdown of ZEB1 and and the hypermethylation of gene promoter regions
EpCAM was done in two MPM cell lines (ACC- are common events in tumor DNA. Because of their
MESO-1, H2052). Cellular growth was evaluated high frequency in the genome, Long interspersed
by colorimetric proliferation and liquid and soft agar nuclear element 1 (LINE-1) methylation serves as a
colony formation assays. useful surrogate marker of global methylation. The
Results: Most MPM cell lines expressed ZEB1 at p16 tumor suppressor gene is an important signaling
higher levels than MeT-5A. Transient knockdown of molecule involved in cell cycle regulation. Down-
ZEB1 with short interfering RNA in ACC-MESO-1 regulation of p16 by promoter hypermethylation
and H2052 signiÀcantly suppressed their growth. occurs early in lung carcinogenesis, such as during
Unexpectedly, stable ZEB1 knockdown with a acquisition of abnormal proliferative potential. The
short hairpin (sh) ZEB1-expressing vector had only aim of the present study was to quantitate the LINE-
modest or no effects on the growth of these cell lines. 1 and p16 methylation levels using bisulÀte-PCR
EpCAM, which functions as a mitogen activator, was and a pyrosequencing analysis, and to analyze their
up-regulated in shZEB1-expressing ACC-MESO-1 relationship with the clinicopathological features in
and H2052 and thus we hypothesized thatEpCAM a large series of unselected NSCLC and matching
up-regulation counteracts the ZEB1 knockdown- normal lung tissues.
induced growth inhibition. To test this hypothesis Methods: From May 2008 to May 2009, 57 patients
we examined whether EpCAM knockdown inhibits underwent surgical resection in our department.
the growth of shZEB1-expressing ACC-MESO-1. Genomic DNA was isolated from frozen tissues
of 57 resected non-small cell lung cancer, and Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15
DNA methylation was quantitated using bisulÀte-
PCR and pyrosequencing (PyroMark® Q24). The P1.017 YAP TRANSCRIPTION
clinicopathological characteristics of the patients COACTIVATOR INDUCES
are shown in Table. Corresponding normal lung MALIGNANT MESOTHELIOMA CELL
tissues were available for 56 of these patients. PROLIFERATION BY UP-REGULATING
Methylation of long interspersed nuclear elements 1 CELL CYCLE PROGRESSION
(LINE-1) was used as a surrogate marker for global Tetsuya Mizuno1, Hideki Murakami1, Makiko Fujii1,
hypomethylation. Hypermethylation of the p16 Futoshi Ishiguro1, Yutaka Kondo1, Shinya Akatsuka2,
promoter region was also evaluated. Shinya Toyokuni2, Kohei Yokoi3, Hirotaka Osada1,
Table Clinicopathological characteristics of the Yoshitaka Sekido1
1
patients Division Of Molecular Oncology, Aichi Cancer
Center Research Institute/Japan, 2Department
Parameter No. % Of Pathology And Biological Responses, Nagoya
Age (years), median (range) 70 (47-85) University Graduate School Of Medicine/Japan,
Gender Female Male 21 36 37 63 3
Division Of Thoracic Surgery, Nagoya University
Smoking status Brinkmann Smoking
Index, median (range) Never Ex-smoker 500 (0-2160) 22 15 20 39 26 35 Graduate School Of Medicine/Japan
Current smoker
Histological type Adenocarcinoma
41 10 6 72 18 10
Squamous cell Carcinoma Others Background: Malignant mesothelioma (MM) is
Pathological stage IA IB IIA IIB IIIA
29 14 3 3 5 2 1 51 24.5 5 5 9 3.5 2 highly refractory to conventional therapies including
IIIB IV
cytotoxic chemotherapy, radiotherapy and surgery.
Although comprehensive understanding of key
Results: Tumor tissue showed signiÀcantly lower genetic/epigenetic alterations underlining MM
LINE-1 methylation levels compared with normal development/progression is limited, inactivating
lung tissue, but higher p16 methylation levels. deletion or mutation of p16INK4a/p14ARF and
The methylation level of LINE-1 has a negative neuroÀbromatosis type2 (NF2) genes are frequently
correlation with the p16 methylation level (r=-0.269, detected. While recent studies have shown that the
p=0.043) and age (r=-0.233, p=0.08) as determined Hippo signal transduction cascade plays a key role in
using Pearson’s product moment correlation organ size control by regulating cell proliferation and
coefÀcient. Of the 57 patients examined, 5 (8.8%) apoptosis, Merlin (a product of NF2) has also been
had hypermethylation of the p16 gene. All Àve shown to be one of the upstream regulators of this
cases with hypermethylation were squamous cell tumor suppressive cascade. Furthermore, the Hippo
carcinomas, while there was no association between signaling regulates cell proliferation by suppression
smoking status and the methylation levels of p16. of the activity of YAP, a transcriptional coactivator,
Conclusion: These results suggest that global and we also found YAP gene ampliÀcation in a
hypomethylation, as well as hypomethylation subset of MM specimens. Our Àndings and those of
of LINE-1 in tumor tissues is linked to the others suggest a signiÀcant involvement of the Hippo
hypermethylation of p16, one of the tumor signaling pathway inactivation and subsequent
suppressor genes. A higher age also correlated with activation of YAP for MM cell development/
a lower methylation level of LINE-1. Patients with progression. However, the detailed roles of YAP in
an abnormal methylation status may thus be suitable MM cell growth/survival remain unclear. The aims
candidates for novel antimethylation therapeutic of this study are to delineate the biological effects of
strategies in future studies. YAP on MM cell proliferation and progression, to
Keywords: LINE-1, p16, Non-small cell lung reveal key transcriptional target genes of YAP.
cancer, DNA methylation Methods: Two MM cell lines (NCI-H290,
Y-MESO-27) were knocked-down for YAP with a
lentivirus-mediated system, and the effects of the
knockdown on cell proliferation, motility, invasion
of MM cells were evaluated. Microarray based-
expression proÀling and subsequent gene ontology
(GO) analyses were performed to identify potential
transcriptional targets of YAP. Luciferase reporter
assay and chromatin immunoprecipitation (ChIP) family of proteins. These proteins participate both
assay and were performed for selected target genes in constitutive and alternative pre-mRNA splicing.
to determine the transcriptional activities and binding Owing to their numerous serine residues, the SR
of YAP on their promoter regions. proteins are phosphorylated and this phosphorylation
Results: YAP knockdown decreased the motility controls their activity. The purpose of this study was
and invasion activities by 60-80% and proliferation to analyze the status of the SR proteins SRSF1 and
by ~50% in two MM cells. Expression proÀling SRSF2 as well as of the SR-phosphorylating kinases
analyses detected 236 genes whose expression SRPK1 and SRPK2 in a large series of non small cell
levels were decreased less than 0.5-fold by YAP lung carcinoma (NSCLC).
knockdown. GO analysis revealed signiÀcant Methods: One hundred and seventeen NSCLC
expression changes of a subgroup of genes that were and 25 associated normal lung parenchyma were
involved in cell cycle machinery. Among them, included in this study. Tumors consisted of 58
expressions of cyclin D1 (CCND1) and forkhead box adenocarcinoma (ADC) and 59 squamous cell
M1 (FOXM1) were decreased to 0.1-0.5 and 0.2-0.4- carcinoma (SCC). The expression of SRSF1,
fold by YAP knockdown, respectively. Luciferase SRSF2 and its phosphorylated form P-SRSF2,
reporter assay showed that YAP transduction SRPK1 and SRPK2 proteins was studied by
strongly induced their promoter activities. The immunohistochemistry. Results were conÀrmed
promoter activities of CCND1 and FOXM1 were by western blotting using a small number of
further enhanced by combined transduction of representative samples.
TEAD. ChIP assay conÀrmed the binding of YAP to Results: As compared to normal lung tissues, we
their promoter regions. showed that SRSF1 is overexpressed in 70% of
Conclusion: YAP plays an oncogenic role in MM NSCLC, with the same frequency in ADC (71%,
cells by regulating a subgroup of genes which are p<0.0001) and SCC (69%, p<0.0001). We observed a
involved in cell cycle progression. Among them, signiÀcant correlation between SRSF1 upregulation
CCND1 and FOXM1 were direct transcriptional and the appearance of distant metastasis (p=0.02).
target genes of YAP. Regarding SRSF2 and P-SRSF2 status, we showed
that SRSF2 and P-SRSF2 proteins are overexpressed
in 80% (p<0.0001), and 62% (p<0.0001) of NSCLC,
Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15 respectively. High levels of SRSF2 and P-SRSF2
were more frequent in SCC than in ADC (91% and
P1.018 THE SPLICING FACTORS SRSF1 66% versus 69% and 59%, respectively) and were
AND SRSF2 AND THEIR REGULATORS, clearly associated in both ADC (p=0.0008) and
THE KINASES SRPK1 AND SRPK2, ARE SCC (p=0.02). Interestingly, SRSF2 and P-SRSF2
OVEREXPRESSED IN NON SMALL CELL overexpression was detected in ADC displaying
LUNG CARCINOMA low pTNM stage (stages I-II; p=0.01) whereas it
Stephanie Gout1, Elisabeth Brambilla1, Christian was associated with SCC of higher pTNM stage
Brambilla1, Sylvie Gazzeri2, Beatrice Eymin2 (III-IV; p=0.01). These results indicated that SRSF2
1
Team 2, Inserm U823/France, 2Institut Albert and P-SRSF2 proteins could play a distinct role
Bonniot, Inserm U823/France depending on the histological sub-type. Finally, and
consistent with the accumulation of a phosphorylated
Background: Alternative splicing of pre-mRNA SRSF2 product, we found that SRPK1 and SRPK2
plays a dominant role in regulating gene expression are upregulated in 89% of ADC (p<0.0001) and
and affects the expression of about 90% of human 77% of SCC (p<0.0001) and mainly display a
genes. Through the generation of aberrant transcripts, nuclear staining pattern. We also noticed a clear
it is a widespread source of human diseases, such association between P-SRSF2 accumulation and
as cancer. Although mutations in cis-acting splicing SRPK2 overexpression in ADC (p=0.03). Again, the
elements occur in cancer, changes in the expression upregulation of SRPK1 and SRPK2 was detected
of trans-acting splicing regulators are thought to in ADC displaying low pTNM stage while it was
contribute to tumor progression. However, only a associated with late stage of carcinogenesis in SCC
few studies have veriÀed this hypothesis in human (p=0.04).
tumors. A key role in splice site choice regulation Conclusion: To conclude, we provide the Àrst
is played by members of the SR (Ser/Arg-rich) evidence that the critical splicing factors SRSF1,
SRSF2 and its phosphorylated form as well as their prediction tools. Quantitative real-time PCR was used
regulators, the kinases SRPK1 and SRPK2, are to assess the expression levels of the miRNAs. The
upregulated in a large series of non small cell lung reference gene RNU6B was used for normalization.
carcinoma, thereby indicating that deregulation of An immunohistochemical (IHC) staining with 5
pre-mRNA splicing patterns is likely to occur during antibodies (STAT1, pSTAT1(Ser727), STAT3, SOCS1,
lung tumorigenesis. PIAS1) was performed on tissue microarray sections
Keywords: SRSF1, SRSF2, SRPK, splicing factors to correlate it with the results of the miRNA detection.
Results: MiR-106a (targeting STAT3) expression was
A revised/updated abstract may be included in increased in 63% of cases. MiR-155, miR-19a, and
the Late Breaking Abstract Supplement, available miR-30d* (targeting SOCS1, SOCS1 and STAT1,
at the 14th World Conference on Lung Cancer. respectively) were downregulated in all cases. Due
to very low expression levels, miR-196a*, miR-608
and miR-765 (targeting SOCS6, PIAS1, SOCS3
Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15 respectively) were not detected. Positive IHC staining
was achieved for STAT1, pSTAT1(Ser727), STAT3
P1.019 STAT SIGNALING IN MALIGNANT and PIAS1. STAT1 was higher expressed than STAT3;
MESOTHELIOMA: IS DEREGULATION SOCS1 was not detected by IHC. This conÀrms
OF STAT1 AND STAT3 CAUSED BY results of a previous study in mesothelioma cell lines,
MICRORNAS? where we could demonstrate STAT1 overexpression
Lisa Arzt1, Hannelore Kothmaier1, Franz as well as downregulated PIAS1 and SOCS1 proteins.
Quehenberger2, Iris Halbwedl1, Helmut H. Popper1 Conclusion: Total STAT1 is upregulated in
1
Institute Of Pathology, Medical University Graz/ mesotheliomas and - to a lesser degree - even pSTAT1
Austria, 2Institute For Medical Informatics, Statistics (Ser727). The inverse correlation between pSTAT1
And Documentation, Medical University Graz/ (Ser727) and miR-30d* (p = 0,014) indicates a
Austria regulatory effect of this miRNA. MiR-30d* may
even have a regulatory effect on nonphosphorylated
Background: Human malignant mesothelioma STAT1 (p = 0,062). The semi-quantitative assessment
(MM) is an aggressive cancer due to former asbestos done by immunohistochemistry might explain the
exposure, with little knowledge about predictive discrepancy between pSTAT1 and STAT1. Therefore
factors of outcome and resistance to conventional additional investigations using other techniques will
chemotherapy. Little is known about the mechanisms be performed to clarify this. STAT3 is downregulated
regulating proliferation and apoptosis in MM, but it but not affected by miR-106a (p = 0,53). However, the
was reported previously that STAT1 is up- whereas upregulation in 63% of cases implicates an important
STAT3 is downregulated in this particular cancer. In role of this miRNA in MM like it is reported for
a current study we found that the negative feedback different solid cancers. Additional targets (JAK1,
loop of STAT1 is deregulated: SOCS1, the inhibitor SOS1 and OSM) of miR-106a have been selected
of STAT1 activation, was undetectable in MM. which are currently under investigation.
PIAS1 acts in the nucleus and inhibits DNA binding Keywords: mesothelioma, STAT signaling,
of pSTAT1 and was found to be downregulated microRNA
too. It is known that the developmental timing of
protein expression is controlled by non-coding
RNAs; microRNAs (miRNA) are one class. They are Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15
typically about 22 nucleotides in size and regulate
the expression of target mRNAs. In addition they are P1.020 APOPTOSIS AND GROWTH
expected to act as oncogenes or tumor suppressors. INHIBITION BY SPROUTY2 IN NON-
Therefore we aimed to quantify selected miRNAs SMALL CELL LUNG CANCER
in MM which are thought to be involved in the Byoung Chul Cho, Joo-Hang Kim
regulation of the STAT signaling pathway. Medical Oncology, Yonsei Cancer Center/Korea
Methods: RNA was obtained from 35 formalin-Àxed
and parafÀn-embedded tumor tissue samples; only Background: Sprouty2 proteins function as
tumor areas with more than 85% of tumor cells were inhibitors of receptor tyrosine kinase signaling
included. MiRNAs were selected via in silico target mainly by interfering with the Ras/Raf/mitogen-
activated protein kinase cascade, a pathway capacity, and growth inhibition by enhancing JNK-
frequently deregulated in human non-small cell mediated mitogen-activated protein kinases pathway.
lung cancer (NSCLC). The aim of the study Results of this study implicate that sprouty2
was to investigate the role of sprouty2 in anti- represents a tumor suppressor in NSCLC and suggest
proliferation, pro-apoptosis, tumor suppression, sprouty2 re-expression as a promising therapeutic
and antiangiogenesis in NSCLC. Furthermore, target against NSCLC.
we examined the role of sprouty2 in modulating Conclusion: Overexpression of sprouty2 promotes
responses to therapies, such as chemotherapy and cellular apoptosis and inhibits tumor cell migration
EGFR inhibitors, in NSCLC. and cell cycle progression via activation of c-Jun NH
Methods: NSCLC cell lines and normal embryonic (2)-terminal kinase and in NSCLC. Furthermore,
lung Àbroblasts were used. Western blot analysis overexpression of sprouty2 showed synergistic
was performed to investigate signal transduction antitumor effects in combination with geÀtinib.
pathway. Cell viability and cell cycle assays were Sprouty2 overexpression suppressed tumor growth
done to see the effects of sprouty2 expression on and VEGF production in H1975 xenograft model.
apoptosis and cell cycle. To examine the effects on Keywords: sprouty2, Epidermal growth factor
migration, Boyden chamber assay was performed. receptor, Non-small cell lung cancer
Yeast two hybridization experiments was done for
identiÀcation of binding partner of sprouty2. The
effects of sprouty2 overexpression was examined in Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15
vivo xenograft model.
Results: In this study, it was shown that sprouty2 P1.021 DELETIONS OF 11Q22.3-Q25 ARE
protein expression was consistently downregulated ASSOCIATED WITH ATYPICAL LUNG
in NSCLC. Analysis of sprouty2 using ONCOMINE CARCINOIDS AND POOR CLINICAL
data set further indicated that sprouty2 was OUTCOME
downregulated in NSCLC tissues compared Dorian R.A. Swarts1, Sandra M.H. Claessen1,
with normal lung tissues. Ectopic expression Yvonne M.H. Jonkers1, Robert-Jan Van Suylen2,
of sprouty2 not only induced cell death in an Anne-Marie Dingemans3, Wouter W. De Herder4,
apoptotic manner but also resulted in cell cycle Ronald R. De Krijger5, Egbert F. Smit6, Frederik B.
arrest in various NSCLC cell lines. Furthermore, Thunnissen7, Cornelis A. Seldenrijk8, Aryan Vink9,
sprouty2 overexpression substantially reduced Aurel Perren10, Frans C.S. Ramaekers1, Ernst-Jan M.
migratory capacity in H1975 cells. Overexpression Speel1
1
of sprouty2 did not interfere with activation of the Molecular Cell Biology, Maastricht University/
major downstream targets of epidermal growth Netherlands, 2Pathology, Maastricht University
factor receptor (EGFR) including extracellular Medical Center/Netherlands, 3Pulmonology,
signal–regulated kinase, Akt, and signal transducer Maastricht University Medical Center/Netherlands,
4
and activator of transcription 3/5. Instead, sprouty2 Internal Medicine, Erasmus MC/Netherlands,
5
overexpression promoted apoptosis in H1975 cells Pathology, Erasmus MC/Netherlands, 6Pulmonology
via activation of c-Jun NH (2)-terminal kinase Department, Vrije Universiteit Medical Centre/
(JNK). The transfection of H358 cells with sprouty2 Netherlands, 7Pathology, Vumc/Netherlands,
8
siRNA decreased phosphorylation of JNK, which Pathology, St. Antonius Hospital/Netherlands,
9
further suggested the speciÀcity of sprouty2 on the Pathology, University Medical Center Utrecht/
activation of JNK. In addition, sprouty2 expression Netherlands, 10Pathology, University Of Bern/
in combination with geÀtinib, a small molecule Switzerland
EGFR inhibitor, synergistically induced apoptosis
via augmented activation of JNK in NSCLC Background: Lung carcinoids are neuroendocrine
cells. Finally, sprouty2 expression resulted in the tumors that can be subclassiÀed as typical (TC) or
regression of H1975 tumor xenograft in vivo due atypical (AC) carcinoids. ClassiÀcation is difÀcult and
to the combined effects on tumor cell proliferation, its reliability to predict disease outcome is variable.
survival and tumor angiogenesis. In conclusion, Methods: To identify genetic alterations which can
sprouty2 expression is generally repressed in improve prediction of prognosis we investigated 34
NSCLC, and overexpression of sprouty2 contributes lung carcinoids (18 TCs, 15 ACs, 1 unclassiÀed)
to induction of apoptosis, reduced migratory by array comparative genomic hybridization (array
CGH) on 3.7 k genomic BAC arrays (resolution 1 Background: Pulmonary carcinoids are
Mb). Results were correlated with clinical patient neuroendocrine tumors (NETs) that can be
data and long term follow-up. histopathologically classiÀed as typical (TC) or
Results: When comparing ACs with TCs our data atypical (AC) carcinoids. Despite the fact that ACs
revealed: 1) a signiÀcant difference in the average generally show more often malignant behavior
number of chromosomal alterations (10 Mb) (9.6 and have a lower 5-year survival rate compared to
versus 4.2, respectively, p=0.036), with a subgroup of TCs, more reliable indicators of poor prognosis are
Àve ACs with 15 chromosomal alterations; 2) in required. MEN1 mutations and associated LOH of
25% of ACs multiple gains (1 Mb) at chromosomes 11q13 have been implied in tumorigenesis. Our aim
8pq, 9q, and 17pq, and losses at 1p, 2q, 10q, and was to examine MEN1 promoter hypermethylation
11q; and 3) deletions in 8/15 of ACs vs. 1/18 of TCs and gene expression and their correlation with
(p=0.004), which was conÀrmed by Áuorescence in clinical outcome.
situ hybridization. The four critical regions of interest Methods: We determined MEN1 mRNA expression
in 45% of ACs comprised 11q14.1, 11q22.1-q22.3, (exon 2/3 PCR product) relative to the housekeeping
11q22.3-q23.2 and 11q24.2-q25, all telomeric of genes ß-Actin and cyclophilin A for 20 ACs, 31 TCs
MEN1 at 11q13. There was a strong association of and 10 NE carcinomas by quantitative RT-PCR. In
11q22.3-q25 loss with a poorer prognosis, alone or in addition, normal tissue and 9 neuroendocrine cell
the combination with absence of 9q34.11 alterations lines (including the Bon-1, H720 and H727 carcinoid
(p=0.0022 and p=0.00026, respectively). cell lines) were included for comparison. Genomic
Conclusion: A subgroup of ACs can be identiÀed DNA from these and 29 additional tumors (15 ACs,
harboring 11q22.3-q25 deletions, with a signiÀcantly 11 TCs and 3 NE carcinomas) were analyzed for
poorer prognosis as compared to carcinoids without MEN1 promoter hypermethylation by Methylation
these 11q deletions. SpeciÀc PCR, and the carcinoid cell lines were also
Keywords: 11q loss, pulmonary carcinoids, Array examined by next-generation sequencing. Deletion
CGH, MEN1 of the MEN1 gene was determined for a subset of
cases with Áuorescence in situ hybridization (FISH)
with a MEN1 gene-speciÀc BAC probe. Results
Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15 were correlated with clinical outcome.
Results: Quantitative RT-PCR revealed that the
P1.022 REDUCED MEN1 GENE average MEN1 mRNA expression is lower in (1)
EXPRESSION IN PULMONARY lung carcinomas than carcinoids (0.25 vs. 0.36;
CARCINOIDS IS ASSOCIATED WITH p=0.024), (2) ACs than TCs (0.28 vs. 0.36) and (3)
METASTATIC DISEASE AND POOR carcinoids with a poor prognosis (0.17 vs. 0.36,
PROGNOSIS p=0.0078). Relative MEN1 expression 0.15
Dorian R.A. Swarts1, Mieke E. HenÁing1, Annick correlated with (1) distant metastasis, both within
Haesevoets1, Robert-Jan Van Suylen2, Anne-Marie the group of lung carcinoids (p=0.0017) and within
Dingemans3, Marco Volante4, Aurel Perren5, Marie- ACs (p=0.0077), and (2) a poor prognosis, both
Louise F. Van Velthuysen6, J A. Burgers7, Wim Van within the complete group of lung NETs (p=0.00064)
Criekinge8, Kim Wouters2, Jürgen Veeck2, Frans C.S. and within carcinoids (p=0.042). MEN1 promote r
Ramaekers1, Manon Van Engeland2, Ernst-Jan M. hypermethylation was not detected in lung NETs.
Speel1 This was conÀrmed by next-generation sequencing
1
Molecular Cell Biology, Maastricht University/ analysis of methylation-bound genomic DNA
Netherlands, 2Pathology, Maastricht University showing MEN1 hypermethylation neither in the
Medical Center/Netherlands, 3Pulmonology, promoter region of the Bon-1, H720 and H727
Maastricht University Medical Center/Netherlands, carcinoid cell lines, nor in other tumors and normal
4
Pathology, University Of Turin At San Luigi tissue (> 50 samples). Deletion of the MEN1 locus
Hospital/Italy, 5Pathology, University Of Bern/ (11q13) was identiÀed in 3/28 cases (2 with a MEN1
Switzerland, 6Pathology, The Netherlands Cancer mutation and 1 unknown), of which 2 showed low
Institute/Netherlands, 7Thoracic Oncology, and 1 intermediate gene expression.
The Netherlands Cancer Institute/Netherlands, Conclusion: We identiÀed correlations of reduced
8
Molecular Biotechnology, University Of Ghent/ MEN1 gene expression with both metastatic disease
Belgium and lower 10-year survival in lung carcinoid
patients, independent of promoter hypermethylation. Am J Pathol 2010), cell lines could be classiÀed into
Because a considerable number of cases with low two groups: Group I (n=26) was characterized by
MEN1 expression also lack deletion of the MEN1 high activation proÀles of EGFR and MET, and high
gene locus (and thus most probably do not have a expressions of E-Cadherin, MET, lamininC2, and
MEN1 mutation), other mechanisms must underlie COX2, while Group II (n=15) was characterized by
the decreased MEN1 gene expression during tumor low expression and activation of EGFR and MET
progression, which remains to be examined. and high expressions of vimentin and FGFR1. All
Keywords: Promoter hypermethylation, Bronchial Group I cells formed round or spheroid colonies,
carcinoids, Menin, Multiple Endocrine Neoplasia while all cell lines forming grape-like or stellate-
Type I shaped aggregates belonged to Group II. Most EGFR
mutant (n=6) belonged to Group I and formed round
spheroid. In contrast, KRAS mutant (n=11) were
Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15 heterogeneous: 5 of them belonged to Group I and
they all formed round spheroid, while 4 of the 6 cell
P1.023 THREE DIMENSIONAL CULTURE lines that belonged Group II formed grape-like or
REVEALS GENETIC-MORPHOLOGIC stellate-shaped aggregates. All MET-ampliÀed cell
CORRELATIONS THAT MAY BE lines (n=3) belonged to Group I and formed round
RELEVANT TO CLASSIFICATION OF colonies. Strikingly, most of KRAS mutant that
LUNG ADENOCARCINOMAS belonged to Group II showed loss of expression of
Toshiro Niki1, Daisuke Matsubara1, Shumpei p16 and LKB1. Abnormalities of LKB1 were not
Ishikawa2, Masashi Fukayama2 found in EGFR mutants.
1
Pathology, Jichi Medicaluniversity/Japan, 2Human Conclusion: Lung adenocarcinomas show genetic-
Pathology, The University Of Tokyo/Japan morphologic correlations in three dimensional
culture. The results reinforce the genetic-histologic
Background: We have recently reported that correlations previously documented in primary
lung cancer cells can be classiÀed into two groups tumors. Inactivation of p16 and LKB1 that occurs
(Group I and Group II) according to (1) genetic in KRAS mutant tumor may result in alterations of
alterations and activation status of epidermal growth morphology in three dimensional culture.
factor receptor (EGFR) and MET, and (2) gene Keywords: EGFR, MET, Kras, E-cadherin
expression proÀles, and further demonstrated that
this classiÀcation reÁects sensitivities to geÀtinib,
MET inhibitor (PHA6657852), and cisplatin Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15
(Matsubara et al. Am J Pathol 2010; Matsubara et al.
J Thorac Oncol 2010). In this study we analyzed the P1.024 GENOME-WIDE ASSOCIATION
relationship among (1) gene expression proÀles, (2) STUDY IDENTIFIES SUSCEPTIBILITY
mutation and copy number alterations of epidermal LOCI FOR LUNG CANCER IN CHINESE
growth factor receptor (EGFR), MET, and KRAS, HAN POPULATION
and (3) morphology of colonies formed on Matrigel Shun Lu1, Yun Liu2, Xiaomin Niu1, Zhiwei Chen1,
Methods: We analyzed a panel of cell lines Daizhan Zhou3, Yongyong Shi4, Ziming Li1,
consisting of 35 adenocarcinomas, 4 large cell Yongfeng Yu1, Lin He4
1
carcinomas, and one adenosquamous cell carcinoma. Department Of Shanghai Lung Cancer Center,
The cell lines included 6 cell lines with EGFR Shanghai Chest Hospital, Jiaotong University,
mutation, 11 cell lines with KRAS mutation, and 3 Shanghai/China, 2Institutes Of Biomedical Sciences,
cell lines with MET ampliÀcation. The cells were Fudan University/China, 3Institute For Nutritional
plated on Matrigel (BD Biosiences) and colony Sciences, Shanghai Institutes For Biological
shapes at day 3-4 were classiÀed according to Bissell Sciences, Chinese Academy Of Sciences/China,
4
et al. with minor modiÀcations (Mol Oncol 2007). Bio-x Center, Jiaotong University, Shanghai/China
Results: On Matrigel cell lines formed either round
(n=32), grape-like (n=4) or stellate-shaped (n=5) Background: Lung cancer is the most common
colonies. All cell lines with high thyroid transcription cause of cancer mortality worldwide. Although
factor-1 (TTF-1) and/or E-cadherin formed round smoking is known to be the most important risk
colonies. As reported previously (Matsubara et al. factor, there is a signiÀcant genetic predisposition
to be responsible for lung tumorigenesis. Recently Pulmonary And Critical Care Medicine, Vanderbilt
the availability of genome-wide association study University/United States Of America, 4Cancer
(GWAS) across the whole genome allows for Biology, Vanderbilt University/United States Of
efÀcient and comprehensive analysis for lung cancer. America
Methods: To identify genetic loci which are related
to the risk of lung cancer in Chinese Han population, Background: Small-cell lung cancer (SCLC) is
we do a GWAS of lung cancer using Affymetrix SNP the most aggressive subtype of lung cancer with no
6.0 chips. Totally, about 1 million single-nucleotide early detection strategy or targeted therapy currently
polymorphisms (SNPs) in a series of 400 lung available. We hypothesized that the identiÀcation
cancer cases and 1000 controls were genotyped. The of membrane-associated proteins speciÀc to
association with lung cancer risk was estimated by SCLC may lead to the discovery of new candidate
the odds ratio and 95% conÀdence interval using diagnostic or therapeutic biomarkers and advance
the multivariate unconditional logistic regression our understanding of SCLC biology.
by PLINK software. Study matching variables of Methods: Quadruplicate membrane-associated
smoking status, age and gender were included in the protein lysates were independently prepared
regression as covariates. from three SCLC, three non-small cell lung
Results: The GWAS identiÀed several genomic cancer (NSCLC) and three immortalized normal
locations as potentially associated with lung cancer bronchial epithelial cell lines. The 36 samples
risk in Chinese Han population in the discovery were co-analyzed by two-dimensional difference
phase. In particular, three loci were strongly gel electrophoresis (DIGE) using a mixed-sample
identiÀed exceeding the genome-wide signiÀcance internal standard on each of the 18 DIGE gels.
level of P=10-6, including 3p14.3 (representative Subsequent protein identiÀcation was performed
SNP, P=6.34×10ï6; odds ratio for patients vs. using mass spectrometry (LTQ-Orbitrap) and
controls, 1.71); 6p21.32 (representative SNP, database interrogation. IdentiÀed proteins were
P=4.56×10ï6; odds ratio for patients vs. controls, investigated further using Ingenuity Pathway
2.92); 9q33.1 (representative SNP, P=1.41×10ï7; Analysis (IPA).
odds ratio for patients vs. controls, 2.14). Results: Principle Component Analysis on the global
Conclusion: Further replications of these most DIGE dataset demonstrated that the four replicates
signiÀcant associations with lung cancer risk from derived from each of the nine cell lines clustered
GWAS are being done in an additional case-control very closely, as did samples within each histological
database. These Àndings will provide new insight group. A total of 135 distinct protein features were
into the pathogenesis of lung cancer. Further studies differentially expressed (ANOVA p<0.0001) in
to elucidate their function will aid the understanding SCLC as compared to NSCLC and normal samples
of the etiology of lung cancer. combined. They included 137 different proteins
Keywords: Lung cancer, risk genetic loci, genome- identiÀed by mass spectrometry. IPA revealed that
wide association study these proteins were overrepresented in the cellular
assembly, organization, morphology and tissue
morphology networks. Of the proteins that were
Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15 upregulated in SCLC, membrane-associated and
part of interesting networks or with relevant cellular
P1.025 ANALYSIS OF MEMBRANE- functions, Àve have been selected to be investigated
ASSOCIATED PROTEINS BY DIGE further.
REVEALED NEW CANDIDATE Conclusion: Using DIGE to analyze the membrane-
BIOMARKERS OF SMALL-CELL LUNG associated subproteome, we identiÀed 137 proteins
CANCER differentially expressed in SCLC. These proteins
Sebahat Ocak1, David B. Friedman2, Mohamed were overrepresented in the cellular assembly,
Hassanein3, Jamie A. Ausborn4, Pierre P. Massion3 organization, morphology and tissue morphology
1
Medicine, Pulmonary Division, Cliniques networks. Five proteins have been selected for
Universitaires Ucl De Mont-godinne/Belgium, validation as candidate diagnostic or therapeutic
2
Department Of Biochemistry, Mass Spectrometry biomarkers in an independent tumor dataset and for
Research Center, Vanderbilt University/United investigation of their functional relevance.
States Of America, 3Medicine, Division Of Allergy,
Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15 Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15
P1.026 THE PROTEOME ANALYSIS P1.027 THE CLINICAL SIGNIFICANCE

OF HUMAN LUNG LARGE CELL OF PLASMA DNA QUANTIFICATION IN
NEUROENDOCRINE CARCINOMA NSCLC
Hiroaki Komtsu, Noritoshi Nishiyama, Koshi Adam Szpechcinski1, Michal Skronski1, Krystyna
Nagano, Nobuhiro Izumi, Keiko Tei, Shoji Hanada, Maszkowska-Kopij2, Wãodzimierz Kupis3,
Hideki Wanibuchi, Shigefumi Suehiro Jolanta Zaleska4, Elzbieta Radzikowska4, Elzbieta
Thoracic Surgery, Osaka City University/Japan Puscinska5, Pawel Sliwinski6, Tadeusz Orlowski3,
Kazimierz Roszkowski-Sliz4, Joanna Chorostowska-
Background: In terms of prognosis, large cell Wynimko1
1
neuroendocrine carcinoma(LCNEC) differs Laboratory Of Molecular Diagnostics And
distinctively from other non small cell lung Immunology, National Institute Of Tuberculosis And
carcinoma, with prognosis of LCNEC being poor, Lung Diseases/Poland, 2Outpatient Clinic, National
even for early-stage disease.Improvements in Institute Of Tuberculosis And Lung Diseases/Poland,
3
survival require a new biomarker for early detection, Dept. Of Thoracic Surgery, National Institute Of
deÀning cancer risk, prognosis, and therapy targets. Tuberculosis And Lung Diseases/Poland, 4Iii Dept.
The purpose of this study was to investigate the Of Lung Diseases, National Institute Of Tuberculosis
molecular background of lung carcinogenesis and And Lung Diseases/Poland, 5Ii Dept. Of Lung
to search useful biomarkers for clinical treatment Diseases, National Institute Of Tuberculosis And
including early detection and prognosis prediction Lung Diseases/Poland, 6Department Of Diagnosis
of lung LCNEC by performing proteome analysis of And Treatment Of Respiratory Failure, National
human lung LCNEC. Institute Of Tuberculosis And Lung Diseases/Poland
Methods: Subjects were cases with primary lung
LCNEC on which surgical resection was performed. Background: The increased amount of free-
Tumor and adjacent non-tumor tissue sample circulating DNA is present in peripheral blood of
were collected and proteome analysis was carried non-small cell lung cancer (NSCLC) patients, most
out using QSTAR Elite LC-MS/MS with iTRAQ likely due to up-regulated cell death processes.
technology and validated the expression of target We believe that dynamics of plasma DNA changes
proteins by immunohistochemistry in 38 cases monitored throughout treatment and follow-up
with lung carcinomas, which included 25 SCLC, 6 period might prove useful for assessment of therapy
LCNEC, and 7 large cell carcinomas. effectiveness in NSCLC.
Results: All through the examined cases, several Methods: We analyzed plasma DNA concentrations
proteins were found overexpressed in tumor tissue in 50 NSCLC patients prior and following the
compared to adjacent non-tumor tissue, and these radical treatment (stage I-IIIA) or chemotherapy
proteins were thought as novel potential biomarkers (IIIB), using qPCR method. In order to determine
associated with lung LCNEC. Especially, one of the a potential contribution of chronic respiratory
proteins showed immunohistochemical staining. inÁammation to this phenomenon the levels of
We assessed the statistical signiÀcance of the plasma DNA were analyzed in 30 COPD, 30
associations between expression level of this protein sarcoidosis and 30 persistent asthma patients as well.
and clinicopathologic variables, and found that Control group consisted of 30 healthy individuals.
this protein had possibility to be a novel predictive Results: Only resectable NSCLC (12.1 ng/ml), but
biomarker of prognosis in lung LCNEC. not advanced NSCLC (4.4 ng/ml) group, showed
Conclusion: This study enables the indentiÀcation signiÀcantly higher mean plasma DNA concentration
of biomarker candidates for novel tumor markers and with respect to patients with chronic respiratory
therapetic targets that will eventually lead to early inÁammation (3.9 ng/ml) and healthy controls (2.8
detection, prevention and treatment of cancer. ng/ml; p<0.001). Furthermore, a drastic increase
Keywords: komatty, 818, komatty818, 0818 in plasma DNA levels up to mean 68.74 ng/ml was
observed a week after primary tumor resection or
24/48 hours after chemotherapy administration
(16.4 ng/ml). Most resected NSCLC patients with
no disease recurrence during 6-12 month follow-up
demonstrated reduced plasma DNA levels (2.4 ng/ examined and four tumor areas were selected; two
ml) with respect to their presurgical values. tumor areas representative of the peripheral area of
Conclusion: Increased plasma DNA level in the tumor close to the border of normal lung tissue
NSCLC patients is due to the cancer but not chronic and two areas representative of more central areas.
inÁammatory process. Drastic raise in plasma The location of the core samples on the TMA were
DNA levels observed after radical therapy is most blinded until immunohistochemical scoring was
likely due to the surgical trauma. Importantly, a Ànished. The distribution of the staining was scored
trend towards reduction of free-circulating DNA using a 4-category scoring-scheme for p53, p63,
concentration was observed in relapse-free patients. CK7, TTF1 and Napsin A. The interpretation of the
The effect of chemotherapy on plasma DNA in scores was as follows: 0 (1%), 1 (>1% and 10%),
NSCLC IIIB patients is currently analyzed. 2 (>10% and 50%), and 3 (>50%). For p53, p63,
Keywords: free-circulating DNA, Biomarkers, CK7, TTF1 and Napsin A, a positive staining were
genetics, real-time PCR regarded to be score 2 and 3.
Results: The data for the central and peripheral
A revised/updated abstract may be included in cores were concordant (weighted Kappa 80%) for
the Late Breaking Abstract Supplement, available all markers (Table 1). However, the disconcordance
at the 14th World Conference on Lung Cancer. (McNemar´s test) was highest between the two
peripheral cores for CK7, TTF1 and Napsin A
respectively, compared to the central cores and
Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15 between central versus peripheral cores. For p53 the
disconcordance were high between the peripheral
P1.028 TISSUE MICROARRAYS cores (McNemar´s p=0.04) versus the central cores
IN NON-SMALL CELL LUNG (McNemar´s p=1.00). Table 1. Comparison of
CANCER (NSCLC): A STUDY OF immunohistochemical staining results. Only samples
INTRATUMORAL HETEROGENEITY OF with all four readings were used
IMMUNOHISTOCHEMICAL MARKER
EXPRESSION.
Mette Poehl1, Karen E. Olsen2, Henrik J. Ditzel3,
Olfred Hansen1
1
Department Of Oncology, Odense University
Hospital/Denmark, 2Department Of Pathology,
Odense University Hospital/Denmark, 3Department
Of Cancer And InÁammation Research, Institute
Of Molecular Medicine, University Of Southern
Denmark/Denmark
Background: The use of tissue microarray (TMA)

for biomarker studies has several advantages.
However, heterogeneous expression of certain Conclusion: Immunohistochemical marker
markers may cause the staining read-out of small expressions of TMAs are valid, with a high
tissue cores not to be representative of that of larger correlation between the TMAs within the same
tissue sections. Further, it is not clear whether tumor. The disconcordance is highest among the
different tumor areas; peripheral versus central, peripheral cores, which could be an indication
exhibit different biomarker expressed. To our of a higher degree of intratumoral heterogeneity
knowledge this issue has not been examined in in the peripheral parts of a tumor. In general it is
NSCLC. In this retrospective study we have focused recommended to use 2-4 cores per tumor to avoid
on evaluating the staining pattern of antibodies sampling error due to intratumoral heterogeneity.
directed against p53, p63, CK7, TTF1 and Napsin A This also reduces the number of cases not evaluable
and the extent of the intratumoral heterogeneity. because of loss of samples during processing, and it
Methods: A total of 178 formalin Àxated and enhances the conÀdence of the read-out of TMAs.
parafÀn embedded operated NSCLC specimens Keywords: Non-small cell lung cancer, NSCLC,
were collected. Routinely-stained slides were Tissue microarrays, intratumoral heterogeneity
Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15 LR-IKKơ). It also signiÀcantly reduced the number
of visible tumors on the lung surface of CC-LR
P1.029 ROLE OF AIRWAY mice by >60% (2.6-fold) after inducing COPD-like
INFLAMMATION IN LUNG airway inÁammation using weekly NTHi exposure
CARCINOGENESIS: A MECHANISTIC for 8 weeks (156 ± 9 in CC-LR NTHi treated vs
DISSECTION 60 ± 8 in CC-LR-IKKơ NTHi treated). We also
Cesar E. Ochoa1, M. Miguelina De La Garza1, genetically ablated IL-6 in CC-LR mice, which not
Seyedeh Golsar Mirabolfathinejad1, Nelly Torres only inhibited intrinsic lung cancer development
Garza2, Alejandra Garza Flores2, Burton F. Dickey1, (1.7-fold, 41%), but also inhibited the promoting
Seyed Javad Moghaddam1 effect of extrinsic COPD-like airway inÁammation
1
Pulmonary Medicine, Ut MD Anderson Cancer (2.6-fold, 62%). Then we targeted expression of TNF
Center/United States Of America, 2Tecnologico De under the control of the mouse Clara cell secretory
Monterrey School Of Medicine/Mexico protein (CCSP) promoter in a C57BL/6 background
(CCSP- TNF overexpressing transgenic mouse) then
Background: Worldwide, lung cancer is the leading crossed it with a CC-LR mouse. This resulted in
cause of cancer mortality and cigarette smoking is severe inÁammatory cell inÀltration of the airway
the principal cause of it. However, several studies wall and peribronchovascular lymphoid aggregates,
have found that smokers with chronic obstructive increased levels of TNF, IL-6, and total neutrophil
pulmonary disease (COPD), an inÁammatory numbers in BALF. Furthermore, TNF overexpression
disease of the lung, have an increased risk of lung resulted in a 1.8-fold increase in lung surface tumor
cancer compared to smokers without COPD. This numbers compared to age and sex matched control
suggests a strong link between COPD-related CC-LR mice (50 ± 2 in CC-LR vs 91 ± 9 in CC-LR/
airway inÁammation and lung cancer promotion TNF-Tg).
independent of smoking, however, the precise Conclusion: We conclude that there is a clear
mechanistic link in not known. Importantly, speciÀcity for the nature of inÁammation in lung
lung inÁammation persists even after cessation cancer promotion, and the NF-kB pathway has
of cigarette smoking among former smokers an essential role in this phenomenon. Therefore,
with COPD. One possible explanation is chronic suppression of NF-kB and more selectively its target
colonization of the lungs by microbial pathogens, genes could be a tool to protract the premalignant
such as non-typeable Haemophilus inÁuenzae phase in patients with COPD and inhibit lung cancer
(NTHi). progression in patients with early stage lung cancer.
Methods: We have established a mouse model of Keywords: NF-kB, InÁammation, TNF, IL-6
COPD-like airway inÁammation through repeated
aerosol challenge to a lysate of NTHi, and we have
shown that this type of airway inÁammation, but Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15
not asthma-like airway inÁammation, promotes
lung cancer 3.2 fold in a K-ras mutant mouse model P1.030 “MECHANISM OF PAI-1 ANTI-
(CCSPCre/LSL–K-rasG12D or CC-LR). This was PROLIFERATIVE ACTIVITY TOWARDS
associated with NF-kB pathway activation, and up- LUNG AND PROSTATE CANCER CELLS”
regulation of its downstream target genes including Adriana Roŧy1, Marta Kĕdzior1, Joanna
IL-6, and TNF. Therefore, we further studied the role Chorostowska-Wynimko1, Paulina Jaguŋ1, Michal
of NF-kB in lung cancer promotion by COPD-like Skronski1, Adam Szpechcinski1, Ewa Skrzypczak-
airway inÁammation by targeting its expression in jankun2, Jerzy Jankun2
1
airway epithelium. CC-LR mice were crossed with Laboratory Of Molecular Diagnostics And
IKK-ơf/f mice to develop a mouse with lack of NF- Immunology, National Institute Of Tuberculosis And
kB in airway secretory cells (CC-LR-IKKơ mice). Lung Diseases/Poland, 2Urology Research Center,
Results: NF-kB deÀciency in the airway epithelium University Of Toledo Health Science Campus/United
changed the bronchoalveolar lavage Áuid (BALF) States Of America
cellular component of CC-LR mice, and resulted in
a ~70% (3.4-fold) reduction in lung surface tumor Background: Plasminogen activator inhibitor type
number compared to age and sex matched control 1 (PAI-1) plays an important role in tumor growth
CC-LR mice (44 ± 6 in CC-LR vs 13 ± 4 in CC- and metastasis formation, directly via speciÀc
urokinase complexing or indirectly due to its afÀnity University Of Toledo Health Science Campus/United
to vitronectin. The aim of this study was to analyze States Of America
the impact of the mutant forms of PAI-1: very long
half-life (VLHL PAI-1) or devoid of afÀnity towards Background: Acquisition of ability to uncontrolled
vitronectin (Vn neg PAI-1) and wild form (wPAI -1) migration is one of the fundamental properties of
on proliferation of lung cancer (A549 and H1299) and cancer cells, enabling them to inÀltrate tissues and
prostate cancer (LNCaP and DU145) cells characterized metastasize. PAI-1 is the major physiological inhibitor
by different proteinase (urokinase) production. of urokinase (uPA), which plays a key role in migration
Methods: Proliferative activity of cancer cells after and invasion of tumor cells. The aim of present study
addition of PAI-1 was evaluated after 24, 48 and was to analyze the impact of increasing concentrations
72 hours using a commercial kit EZ4Y cytotoxicity of PAI-1 mutated forms: VLHL PAI-1 with very long
assay (Biomedica). The analysis was performed half-life time, Vn neg PAI-1 - devoid of afÀnity towards
according to the manufacturer’s recommendations. vitronectinand wPAI -1 on lung (A549, NCI-H1299)
Results: The dose- and time-dependent inhibition of and prostate (LNCaP, DU145) cancer cells invasive
cell proliferation in the presence of VLHL PAI-1 was activity. Selected cell lines are characterized by
evident in A549 and LNCaP cultures. In H1299 cells different (normal and high) urokinase production.
inhibitory effect was only dose-depended (p<0.001), Methods: The impact of PAI-1 proteins on
while in DU145 only 100 ƫg/ml of VLHL PAI-1 invasiveness of cancer cells A549, H1299, LNCaP,
in 72 hrs cultures suppresed prostate cancer cells DU145 was examined by using commercial kit
proliferative activity (p <0.001). No signiÀcant effect QCMTM 96-Well Cell Invasion Assay (ECM
of Vn neg PAI-1 on the proliferation of A549 and 555 - Chemicon, Europe) in accordance with the
H1299 was observed while in prostate cancer lines manufacturer’s recommendations.
(DU145, LNCaP) only the inhibitory effect of the Results: No effect of PAI-1 proteins on invasiveness
highest Vn neg PAI-1 concentration (100 ƫg/ml) was of lung cancer cells was observed, while dose-
evident (p <0.001) but not time-dependent. wPAI-1 dependent signiÀcant inhibition was demonstrated
did’t affect A549 and LNCaP proliferation while in in both prostate cancer lines (DU145 and LNCaP)
highest concentration it had the stimulating effect on cultured with VLHL PAI-1 (respectively p<0,05 and
H1299 and Du145 (24,48 hrs cultures). p<0,01) and Vn PAI-1 neg (p<0,05). Not surprisingly
Conclusion: PAI-1 is a negative regulator of cancer wPAI-1 signiÀcantly stimulated prostate cancer cells
cells proliferation due to its anti-proteinase activity. invasiveness in all concentrations.
Its biological effect on lung cancer cells is time and Conclusion: PAI-1 inhibitory effect on prostate cancer
dosage-dependent. invasive activity is associated with anti-proteinase
Keywords: Cancer, PAI-1, cell proliferation, activity. Lung cancer cells invasiveness regulation
urokinase seems not to be PAI-1-urokinase regulated.
Keywords: PAI-1, invasiveness, urokinase, Cancer
the Late Breaking Abstract Supplement, available A revised/updated abstract may be included in
at the 14th World Conference on Lung Cancer. the Late Breaking Abstract Supplement, available

P1.031 “PAI-1 REGULATES PROSTATE
CANCER BUT NOT LUNG CANCER P1.032 PROTEOME ANALYSIS AND
CELLS INVASIVENESS” TISSUE ARRAY FOR PROFILING
Adriana Roŧy1, Marta Kĕdzior1, Joanna PROTEIN MARKERS ASSOCIATED
Chorostowska-Wynimko1, Paulina Jaguŋ1, Michal WITH THYMOMA CLASSIFICATION
Skronski1, Adam Szpechcinski1, Ewa Skrzypczak- Sun Qiangling1, Sha Huifang1, Fang Wentao2
Jankun2, Jerzy Jankun2 1
Basic Research Laboratory, Shanghai Chest Hospital
1
Laboratory Of Molecular Diagnostics And AfÀliated To Shanghai Jiaotong University/China,
2
Immunology, National Institute Of Tuberculosis And Department Of Surgery, Shanghai Chest Hospital
Lung Diseases/Poland, 2Urology Research Center, AfÀliated To Shanghai Jiaotong University/China
Background: The histologic classiÀcation of thymoma tissues. For the Àrst time, differentially
thymoma has been attracting more controversy expressed proteins between type B1 and B2
on account of morphological variation and tumor thymoma tissues were explored by comparative
epithelial heterogenicity for the past several decades. proteomic analysis. Increases in alteration of
Molecular proÀling at protein levels may elucidate GSTP1 and ezrin were found to be signiÀcantly
the biological variance of tumors and contribute to associated with poorly differentiated histology and
the pathological classiÀcation system that correlates higher clinical stage. The techniques of proteomic
better with biological, clinical and prognostic analysis tissue microarray provide us a dramatic
parameters. The recent application of two- tool for screening of key molecules for helping with
dimensional electrophoresis (2-DE) coupled with thymoma histological classiÀcation.
mass spectrometry (MS) to the study of thymoma Keywords: GSTP1, Thymoma, proteomics, tissue
allows the characterization of global alterations in array
protein expression in thymoma classiÀcation.
Methods: In this study, proteins extracted from 12
thymoma tissue specimens (six type B1 and six type Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15
B2 thymoma) were analyzed by two-dimensional
electrophoresis (2-DE) coupled with MALDI-TOF- P1.033 A GIANT SOLITARY
MS. Some of the differentially expressed proteins MESOTHELIOMA / FIBROUS TUMOUR
identiÀed by proteomics analysis were detected ARISING FROM VISCERAL PLEURA OF
by tissue microarray with immunohistochemistry THE LUNG.
staining to access the clinicopathological K. V.V. Kumar
characteristics in different histologic types of Surgical Oncology, Kidwai Memorial/India
thymomas.
Results: Twenty proteins were found to be Background: A Giant solitary mesothelioma /
differentially expressed between type B1 and B2 Fibrous tumour arising from visceral pleura of
thymoma tissue. GSTP1 and ezrin were identiÀed the lung is rare and sometime produces diagnostic
to be over expressed in type B2 thymoma. The difÀculties. Surgical excision is the treatment of
statistical analysis demonstrated that type B2, B3 choice and is curative.
group had signiÀcantly higher positive expressions Methods: I am reporting a case of giant
of GSTP1 than B1 group (type B2 vs B1: Z=-2.582, Àbroadenoma / mesothelioma arising form visceral
P=0.010; type B3 vs B1: Z=-4.012, P=0.000). pleura of lung. I present the clinical scenario,
Moreover, the results showed signiÀcantly investigations and our management.
correlation between GSTP1 and WHO classiÀcation Results:
from type B1 to type B3 (Spearman’s correlation
coefÀcients: 0.633, P=0.000). There was existed
statistically signiÀcant difference in the positive
rate of ezrin between type B1 thymoma and type B3
thymoma (Z=-2.963, P= 0.003). However, there is no
difference between ezrin expression in type B1 and
B2 thymoma (Z=-1.814, P=0.070) or between type
B2 and B3 (Z=-1.047, P=0.295). The ezrin showed
a tendency to be expressed in higher classiÀcation
tumors from type B1 to B3. There is correlation
between ezrin and WHO classiÀcation from type
B1 to type B3 (Spearman’s correlation coefÀcients:
0.515, P=0.002). Statistical analysis showed
that there is correlation between GSTP1 or ezrin
expression and clinical stage (Spearman’s correlation
coefÀcients, Ezrin: 0.481, P=0.032; GSTP1: 0.484,
P=0.002).
Conclusion: To our knowledge, this study is the
Àrst report on proteomic approach towards human
P1.035 CO-TRANSFECTION OF
MRP AND BCL-2 ANTISENSE
S-OLIGODEOXYNUCLEOTIDES
REDUCES DRUG RESISTANCE IN
CISPLATIN-RESISTANT LUNG CANCER
Final diagnosis was based on histopathology and CELLS
immuno histochemistry. Shiying Zheng1, Hong Li2, Dong Jiang1
1
Conclusion: Lesions arising from the visceral pleura Department Of Cardio-thoracic Surgery, The First
of the lung are reviewed. AfÀliated Hospital Of Soochow University/China,
2
Department Of Geriatrics, The First AfÀliated
Hospital Of Soochow University/China
Background: To detect the inÁuence of antisense
P1.034 CASTLEMAN’S DISEASE OF THE s-oligodeoxynucleotides](S-ODNs) of bd-2 and
PLEURA: A CASE REPORT multidrug resistamce-associated protein (MRP)
K. V.V. Kumar1, Rajaram Burrah2, Vijayalakshmi genes multidrug resistance-associated protein gene
Deshmane2, Sayed Althaf2, Srinivasalu Yapamakula2, and bcl-2 antisense S-oligodeoxynucleotides on
Sathyanarayana Kurubabala2, Anand Hanumaiah2 cisplatin-resistant lung adenocarcinoma cell line
1
Surgical Oncology, Kidwai Memorial/India, A549DDPwhich overexpresses both bcl-2 and MRP.
2
Surgical Oncology, Kidwai Memorial Institute Of Methods: A549DDPcells were treated with sense
Oncology/India and antisense S-ODN mediated by lipofection.
Expression of MRP and bcl-2 mRNA and protein
Background: Castleman’s disease is a rare benign in the treated cells was measured by RT-PCR and
non-clonal disease of the lymphnodes.It can occur Áow cytometry (FCM), respectively. Apoptosis was
in the mediastinum, neck, axilla & abdomen. identiÀed by DNA electrophoresis and terminal
Castleman’s disease arising from the pleura is deoxynucleotidyl transferase (TdT)-mediated biotin
very rare.In our case, the lesion was found arising dUTP nick end-labeling(TUNEL). The degree of
from the parietal pleura & was completely excised. drug resistance of the treated cells was detected
Histopathological & immunohistochemistry (IHC) by a cell viability 3’-4,5-dimethylthiazol-2-y-2,5-
examination revealed it to be a hyaline vascular diphenyl-tefrazolium bromide thiazolylblue (MTT)
variant of Castleman’s disease.We describe the assay.
presentation & management of our patient and Results: Expression of bcl-2 and MRP signiÀcantly
review the litrature. decreased in the cells treated with bcl-2 or/and MRP
Methods: Surgical excision when feasible appears to antisense S-ODN for 48h as compared to the cells
provide good results.We encountered a patient who untreated and sense-treated (P<0.05). Resistance
had the disease arising from the parietal pleura. to cisplatin in the cells treated with bcl-2 or/and
Results: Castleman’s disease of the pleura is a rare MRP antisense S-ODN decreased by 60.6% (6.5
disorder.Though it is a benign disorder a small risk times), 56.4% (7.2 times) and 71.0% (4.8 times),
of malignant transformation has been described in respectively, which paralleled the decrease of bcl-2
other sites. and MRP expression. Similarly, the resistance to
Conclusion: The surgical resection would aapear etoposide and epirubicin in antisense-treated cells
to be the optimal treatment modality when feasible. also reduced in parallel to decreases of the two
The prognosis following complete surgical resection gene expressions. The drug resistance in sense-
appears to be good.Minimal invasive surgery may be treated cells was similar to that in untreated cells.
attempted in experienced centres. Statistically signiÀcant dose-and concentration-
dependent increases of apoptotic cells were observed
in the groups exposed to 100 ƫmol/L cisplatin for 48
h after treatment by bcl-2 or/and MRP antisense.
Conclusion: Bcl-2 and MRP were at least additive
and possibly synergistic in conferring drug resistance
in a cisplatin-resistant lung adenocarcinoma cell line. as spheres within 20 days (neuroendocrine) and
Antisense S-ODN could attenuate drug resistance 3 months (SCC). Injection of spheres derived
by promoting cells apoptosis, which might lead from two adenocarcinomas into the right lung of
to a new treatment for patients with non-small immunodeÀcient mice was also followed by tumor
cell lung cancers (NSCLCs) who are refractory to growth within 1 month. CICs and differentiated cells
conventional chemotherapy. were further analysed by Áow cytometry.
Keywords: A549 and A549DDP cell lines, Results: The percentage of CD133 positive cells
drug resistance, apoptosis, antisense•S- was variable with a mean of 5,1% within a range
oligodeoxynucleotide of 0,1-40%. In three cultures the expression of
CD133 showed a tendency to increase (from 3%
A revised/updated abstract may be included in to 18%) after three weeks of CICs culture, and
the Late Breaking Abstract Supplement, available the % of CD133+ cells was particularly high in
at the 14th World Conference on Lung Cancer. the neuroendocrine tumor (40%). The EPCAM
molecule and ATP-binding cassette transporter
(ABC), involved in drug resistance, ABCB1 and
Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15 ABCG2 were expressed at higher levels in CICs
than in the cells from the same tumors maintained in
P1.036 IN VITRO AND IN VIVO differentiating conditions (standard medium + FCS).
CHARACTERIZATION OF HUMAN Conclusion: These data suggest that a higher level of
LUNG CANCER–INITIATING CELLS drug resistance is associated with an undifferentiated
Angela Alama1, Anna Maria Orengo2, Francesco phenotype. Indeed, the cytotoxic activity of cisplatin
Grossi1, Silvano Ferrini2, Rosaria Gangemi2 was lower in CICs than in differentiated cultures,
1
Lung Cancer Unit, National Institute For Cancer in agreement with Áow cytometry results. We are
Research/Italy, 2Immunotherapy Unit, National presently investigating the functional relationship
Institute For Cancer Research/Italy between ABC transporters and cisplatin resistance
in CICs as well as the possible in vivo growth
Background: Lung cancer is the most deadly cancer advantage of subpopulations selected by EPCAM,
worldwide. Non small cell lung cancer (NSCLC) CD133 and ABC phenotypic markers.
accounts for about 85% of all lung cancers. The Keywords: drug resistance, cancer initiating cells,
current 5-year survival rate for all stages of NSCLC Lung cancer
is only 15%. Recent evidence indicates that tumors
contain a small population of cancer-initiating cells A revised/updated abstract may be included in
(CICs) that are responsible for tumor maintenance, the Late Breaking Abstract Supplement, available
resistance to chemotherapy and spreading. The at the 14th World Conference on Lung Cancer.
purpose of our study is the characterization of
CICs derived from human lung cell carcinomas
and the development of a mouse model of human Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15
lung carcinoma by orthotopic xenotransplants.
The in vivo model will allow the identiÀcation of P1.037 ESTABLISHMENT OF
molecules involved in the control of tumor growth MULTIDRUG RESISTANCE LUNG
and spreading, in the natural immune response and to ADENOCARCINOMA CELL LINE A549/
study therapeutic approaches at preclinical level. ADM AND INVESTIGATION OF THE
Methods: Cell suspensions and tumor spheres, REVERSAL OF DRUG RESISTANCE BY
were obtained in non-differentiating culture AZITHROMYCIN.
conditions (operationally deÀned as CICs), from Yin Li1, Shiying Zheng2, Dong Jiang3
1
24 samples of NSCLC (17 adenocarcinomas, 6 Department Of Thoracic Surgery, The Tumor
squamous carcinomas (SCC) and 1 neuroendocrine Hospital Of Henan ,zhengzhou/China, 2The First
carcinoma. Xenotransplantation experiments were AfÀliated Hospital Of Soochow University, The First
performed with cells derived from 4 tumors (1 AfÀliated Hospital Of Soochow University/China,
3
SCC, 2 adenocarcinoma and 1 neuroendocrine Department Of Cardio-thoracic Surgery, The First
cancers). Xenografts were obtained after AfÀliated Hospital Of Soochow University/China
subcutaneous injection of all the tumors injected
Background: To establish a multidrug-resistant cell Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15
line A549/ADM induced by azithromycin in vitro
and investigate the reversal effect of azithromycin to P1.038 CHEMOTHERAPY RESISTANCE
A549/ADM. Methods A549 cells were treated with AND ONCOGENE EXPRESSION IN NON–
adriamycin ADM. SMALL CELL LUNG CANCER
Methods: The cells were treated with low Yin Li1, Shiying Zheng2, Dong Jiang2
1
concentration of ADM Àrstly and then gradually Department Of Thoracic Surgery, The Tumor
increased concentration of ADM intermittently. Hospital Of Henan ,zhengzhou/China, 2Department
The expressions of P-GP and MRP in A549 and Of Cardio-thoracic Surgery, The First AfÀliated
A549/ADM were conÀrmed by Áow cytometry Hospital Of Soochow University/China
FCM. The 50% restrain concentration (IC50) of
four drugs to A549 and A549/ADM were evaluated Background: Empiric chemotherapy for patients
with MTT assay. Same methods were used to A549/ with non–small cell lung cancer who have
ADM when treated with azithromycin AZM. The undergone resection is recommended without
inhibition rates of different concentration of AZM knowledge of the tumor’s speciÀc biologic
to A549/ADM were also evaluated with MTT assay. characteristics, and many patients may not beneÀt.
The Áuorescence intensity of ADM in A549 and In vitro chemotherapy resistance is associated
A549/ADM with or without AZM added were also with clinical unresponsiveness in some tumors,
evaluated with FCM. and in lung cancer, chemotherapy resistance is
Results: The expressions of P-GP and MRP in prevalent. Multiple-agent chemotherapy resistance
A549 were 2.3% and 2.5% respectively, but those of and association of chemotherapy resistance with
A549/ADM were 33% and 46.3% respectively.The molecular markers are described.
resistance index of A549/ADM to ADM was 17.80 Methods: Chemotherapy resistance to doublets—
times higher than that of A549 and the cells showed carboplatin and paclitaxel, cisplatin and navelbline,
resistant to DDP, VCR and MTX incoordinately. cisplatin and docetaxel, and cisplatin and
With AZM added 5ƫg/ml, the sensitivities of A549/ gemcitabine—was analyzed in 4571 non–small
ADM to ADM were 2.81 times higher than before cell lung cancer tumors with the extreme drug
and sensitivities to DDP,VCR and MTX increased resistance assay. Chemotherapy resistance is deÀned
by 1.86, 3.78 and 3.86 times respectively. The as follows: extreme drug resistance, 1 SD above the
sensitivities of A549/ADM to these drugs were much median chemotherapy resistance; intermediate drug
higher when treated with 10ƫg/ml of AZM. With the resistance, between the median and extreme drug
same treatment, the Áuorescence intensities in A549, resistances; and low drug resistance, 1 SD below
A549/ADM and A549/ADM were 121.4, 51.2 and the median. Chemotherapy resistance was compared
96 respectively. with DNA ploidy measured by Áow cytometry, and
Conclusion: A549/ADM were multidrug- markers p53 and epithelial growth factor receptor
resistantMDR.The high expressions of P-GP and were assayed by immunohistochemistry.
MRP might play an important role in MDR. AZM Results: Tumors with extreme or intermediate
could reverse the MDR of A549/ADM through drug resistance were noted in 30% to carboplatin-
increase the accumulation of drugs in cells and the paclitaxel, in 24% to cisplatin-navelbline, in 42%
effection of reversal correlates with concentration. to cisplatin-gemcitabine, and in 27% to cisplatin-
Keywords: A549/ADM, multidrug resistance docetaxel. Extreme or intermediate drug resistance
(MDR), Azithromycin, Reversal to at least one drug occurred in 74% to carboplatin-
paclitaxel, in 68% to cisplatin-navelbline, in
A revised/updated abstract may be included in 88% to cisplatin-gemcitabine, and in 68% to
the Late Breaking Abstract Supplement, available cisplatin-docetaxel. More intermediate plus extreme
at the 14th World Conference on Lung Cancer. chemotherapy resistances occurred in aneuploid
tumors to etoposide (53% vs 36%, P = .0002) and
topotecan (48% vs 36%, P = .0094), with less
intermediate or extreme chemotherapy resistance
to gemcitabine (88% vs 81%, P = .0345). p53-
Positive tumors had more intermediate or extreme
resistance to etoposide (57% vs 44%, P = .0009)
and doxorubicin (73% vs. 58%, P = .0324) and less and tumorigenicity were tested for SP and non-
intermediate or extreme resistance to cisplatin (44% SP (NSP) cells. Tumors were characterized by
vs 54%, P = .0125), to carboplatin (47% vs 57%, mesothelin, calretinin, N-cadherin, D2-40 and Wilms
P = .0129), to taxol (47% vs 57%, P = .0056), and tumor 1 (WT-1) immunohistochemistry. Surface
to gemcitabine (78% vs 87%, P = .0108). Fewer expression of mesenchymal stem cell markers CD90,
epithelial growth factor receptor–positive tumors CD73 and CD105 was investigated in SP and NSP
were extremely drug resistant to cisplatin (13% vs cells.
26%, P = .0074) and carboplatin (13% v. 30%, P = Results: We identiÀed SP cells with self-renewal
.0008). properties and increased chemoresistance in MPM
Conclusion: Multi-drug chemotherapy resistance cell lines and tumor derived primary cell cultures.
in non–small cell lung cancer tumor cultures is Compared to the non-SP fraction (NSP), the SP
common, and associations between molecular fraction led to the development of tumors with
markers and in vitro chemotherapy resistance are mesothelium precursor phenotype characterised by
noted. Clinical validation through integration of such mesenchymal morphology, being WT1 negative
testing into clinical trials seems warranted. but podoplanin positive, and having a tendency
Keywords: non–small cell lung cancer, of increased tumorigenicity. The same phenotypic
chemotherapy resistance;, P53 shift was observed in patients with relapsing tumors
after chemotherapy. Furthermore the SP cells were
A revised/updated abstract may be included in enriched in CD105 -/low expressing cells which
the Late Breaking Abstract Supplement, available were small sized and had increased tumorigenicity
at the 14th World Conference on Lung Cancer. compared to CD105 high cells.
Conclusion: Taken together our results support the
hypothesis that MPM CD105-/low, chemoresistant,
Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15 small sized SP cells may constitute the cellular
pool out of which recurrence develops. Further
P1.039 PLEURAL MESOTHELIOMA SIDE characterization of mechanisms of chemoresistance
POPULATIONS HAVE A PRECURSOR and self-renewal should lead to targets speciÀc for
PHENOTYPE AND ARE SIMILAR TO this subpopulation in MPM patients.
PATIENT’S RELAPSES Keywords: mesothelioma, side population,
Emanuela Felley-Bosco1, Claudia Frei2, Isabelle chemoresistance, tumor relapse phenotype
Opitz2, Alex Soltermann2, Bruno Fischer2, Ubiratan
Moura2, Hubert Rehrauer2, Walter Weder3, Ralf
Stahel1 Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15
1
Zurich University Hospital, Laboratory Of
Molecular Oncology/Switzerland, 2Zurich P1.040 HIF1 MODULATES CARCINOGEN
University/Switzerland, 3Thoracic Surgery, METABOLISM AND DNA DAMAGE:
University Hospital Zurich/Switzerland IMPLICATIONS FOR LUNG CANCER
Roland Chiu, Marten Schults, Roger Godschalk,
Background: Inhaled asbestos Àbres accumulating Frederik Jan Van Schooten
in the pleural cavity confer both chronic tissue repair Toxicology, Maastricht University/Netherlands
as well as oncogenic damage to the mesothelial
lining cells, ultimately leading to malignant pleural Background: A ten times increased risk for lung
mesothelioma (MPM). We hypothesized that cancer is observed in smokers with an associated
such damage may primarily occur in mesothelial chronic obstructive pulmonary disease (COPD).
precursor cells, recruited to repair tissue injury and We hypothesized that low oxygen concentrations
that this subpopulation would be associated with in COPD affected lung tissues may be involved
chemoresistance and tumor recurrence. in the enhanced risk. Benzo[a]pyrene (B[a]P) is
Methods: DyeCycleViolet was used to set up an important mutagen present in tobacco smoke
the side population (SP) functional assay aimed and recently we demonstrated that hypoxia related
at identifying subpopulations of tumor cells with activation of hypoxia-inducible factor 1 (HIF1a)
chemoresistance phenotype associated with ABCG2 ampliÀes the B[a]P induced mutagenic phenotype. It
transporter activity. Self-renewal, chemoresistance appears that HIF1a sequester a critical cofactor for
carcinogen detoxiÀcation, HIFb/ARNT. Reduced anti-EGFR monoclonal antibody, and geÀtinib, a

availability of this cofactor for coupling with the tyrosine kinase inhibitor, in non-small cell lung cancer
aryl hydrocarbon receptor (AhR) leads to decreased (NSCLC) in vitro and in vivo.
expression of carcinogen metabolising enzymes. Methods: Two NSCLC cell lines, A549 and SPC-A-1
Although we observed a 3 fold increase in mutation were treated with cetuximab (1 n mol/L,5n mol/L,25n
frequency at the hprt locus in cells after B[a]P mol/L,125n mol/L,625n mol/L), geÀtinib (0.2
exposure following HIF1a induction, the changes in ƫmol/L,1ƫmol/L,5 ƫmol/L,25 ƫmol/L,125ƫmol/L)
DNA adduct formation are minimal. This suggests or a combination of both at a range of concentrations.
that other cellular response pathways are modiÀed PI marked and the cells were observed using Áow
concurrently with HIF1a activation. cytometry apoptosis, CCK8 measured the inhibition
Methods: We have identiÀed three mechanisms that may of cell proliferation in each group; under the power
be involved. These are changes in metabolism of B[a]P; to change the status of apoptosis, downstream protein
the transmembrane transport of B[a]P or its metabolites; expression of EGFR, p-EGFR, and p-Akt were
or the capacity to repair the subsequent DNA damage. evaluated by Western blot. The in vivo effects of
Results: First, under conditions of low oxygen, cetuximab and geÀtinib on tumor cell growth were
the B[a]P-9,10-dihydrodiol metabolites decreased examined using a xenografted nude mouse model and
while the B[a]P-7,8-dihydrodiol and 3-OH-B[a]P tumor growth analyses.
metabolites are formed in higher quantities compared to Results: The combined treatment with geÀtinib and
normoxia. Furthermore, when HIF1a was upregulated cetuximab resulted in a synergistic effect on cell
under hypoxic conditions (0.2% O2 or CoCl2), the proliferation and in superior inhibition of EGFR-
extracellular concentrations of the parent B[a]P dependent signaling and induction of apoptosis (p<0.05).
compound were dramatically increased compared In the combination-treated tumors, there was a superior
with cells treated under higher (20% and 5%) oxygen inhibition of EGFR, mitogen-activated protein kinase,
concentrations. And Ànally, using a modiÀed comet and Akt phosphorylation, as well as greater inhibition of
assay to determine the DNA repair capacity, we cell proliferation and enhanced apoptosis. A combination
observe that cells in which HIF1a is dysregulated (VHL of geÀtinib and cetuximab signiÀcantly inhibited
mutants) have an approximately 10 fold decrease in the tumor growth and caused a substantial growth delay in
ability to repair B[a]P-DNA adducts. vivo models of both cell lines while each single-agent
Conclusion: These results show that all three exposure caused no delay of tumor growth.
processes may in part be responsible for the Conclusion: Our Àndings suggest combined therapy
enhanced mutagenic phenotype under hypoxia. with geÀtinib and cetuximab can add the potency of
Insight into these pathways may provide further EGFR signaling inhibition, however, selective targeting
understanding of the intrinsic risks for mutagenic of distinct molecular pathways is required for effective
exposures and provide new targets and tools for clinical response.
therapies directed against cancer.
Keywords: benzo[a]pyrene, Hypoxia, HIF, COPD A revised/updated abstract may be included in
P1.041 ANTICANCER EFFICACY Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15
OF CETUXIMAB COMBINED WITH
GEFITINIB IN THE TREATMENT OF P1.042 EFFECTS OF ANTIANGIOGENIC
NON-SMALL CELL LUNG CANCER AGENTS PLUS EP REGIMEN ON SMALL
Ziming Li, Shun Lu, Zhiwei Chen CELL LUNG CANCER(SCLC) CELL LINE
Department Of Shanghai Lung Cancer Center, NCI-H446
Shanghai Chest Hospital, Jiaotong University, Zhiwei Chen1, Xiang-Yun Ye1, Ziming Li2, Xiaomin
Shanghai/China Niu1, Yongfeng Yu1, Shun Lu2
1
Department Of Shanghai Lung Cancer Center,
Background: The purpose of this study was to Shanghai Chest Hospital, Jiaotong University,
evaluate the anticancer efÀcacy of EGFR pathway Shanghai/China, 2Shanghai Chest Hospital, Jiaotong
inhibition achieved by combining cetuximab, an University/China
Background: Despite the characters of broad- development of promising investigational regimens

spectrum effects on different tumors and low- for the treatment of patients with SCLC.
toxicity, antiangiogenic therapy is also effective on
neuroendocrine tumors and has a synergistic effect A revised/updated abstract may be included in
when administered with chemotherapy concurrently. the Late Breaking Abstract Supplement, available
As small cell lung cancer (SCLC) is a cancer at the 14th World Conference on Lung Cancer.
of higher growth ability and with higher tumor
angiogenesis, we hypothesize that antiangiogenic
agents plus EP regimen would be more effective than Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15
the currently-used EP regimen, which needs to be
further investigated by both laboratory and clinical P1.043 THE SYNTHETIC EFFECT
studies. Here, we evaluated the effects of three OF AROMATASE INHIBITOR
different antiangiogenic agents in combination with ANASTROZOLE IN COMBINATION
EP regimen on proliferation inhibition and apoptosis WITH EGFR TYROSINE KINASE
of SCLC cell line NCI-H446, respectively. INHIBITOR GEFITINIB IN NON-SMALL
Methods: NCI-H446 cells were treated with CELL LUNG CANCER CELL LINES
Bevacizumab (Avastin, Roche), Recombinant Lan Shen1, Shun Lu2, Fei Y. Zhang1, Ziming Li2
1
Human Endostatin Injection (Endostar, Xiansheng), Shanghai Lung Tumor Clinical Medical Center,
a multi-targeted agent(SoraÀnib, Bayer) respectively Shanghai Chest Hospital, Shanghai Jiaotong
and in combination with EP regimen(VP16+DDP). University/China, 2Department Of Shanghai Lung
The growth-inhibitory activities and apoptosis of Cancer Center, Shanghai Chest Hospital, Jiaotong
single-agent and combinations of EP and individual University, Shanghai/China
antiangiogenic agents, were evaluated using a PI
labelled Áow cytometer. Each two-drug combination Background: Several studies implicated that lung
was studied over a range of concentrations at a Àxed cancer progression was governed by the interaction
ratio corresponding to the ratio of the IC5 values of between estrogen receptor(ER) and epidermal
the individual agents. Transwell invasion assays were growth factor receptor(EGFR) signaling pathways.
performed to detect in vitro invasion and metastasis So combined targeting of EGFR and ER may have
of NCI-H446 cells. ELISA were performed to detect the synthetic effect in lung cancer treatment. The
the expression of VEGF in different groups. aim of this study was to explore the potential utility
Results: Compared with EP group, all three of targeting these two pathways with combination
antiangiogenic agents(Avastin, Endostar and of Anastrozole and GeÀtinib in non-small cell lung
SoraÀnib) in combination with EP can enhance the cancer cell lines.
growth activities of NCI-H446 cells to some extent. Methods: The expression levels of ERs(ER-Ơ and
The results of Áow cytometer showed that single ER-ơ) in lung cancer cell lines (A549,H460,SPC-
agent of all three antiangiogenic drugs(Avastin, A-1,H1299) and normal bronchus epithelial cell
Endostar and SoraÀnib) could signiÀcantly induce BEAS-2B were detected using Real-time PCR and
cell apoptosis respectively( EP: 0.02 Avastin 1.07 Western-blot(WB).Immunohistochemistry(IHC)
Endostar:0.41 soraÀnib 8.27 P<0.05). Moreover, was used to locate ER-Ơ and ER-ơ in cell lines with
SoraÀnib plus EP induced more apoptosis than EP highest ERs expression levels. The cell lines were
regimen only EP+soraÀnib 17.82 soraÀnib 8.27 P treated with Anastrozole or GeÀtinib alone or in
0.05 . However, when compared with EP group, combination. The cell proliferation inhibition was
only the Avastin plus EP could signiÀcantly decrease detected with CCK8 assay, Cell cycle and apoptosis
the migration and invasion activity (EP 35.33 effects detected with Áow cytometry, the expression
EP+Avastin 31.67 P<0.05). The expression of VEGF of EGFR, p-EGFR, ERK, p-ERK, AKT and p-AKT
were signiÀcantly decreased in both single-agent and detected with Western-blot.
angiogenic agent plus EP groups (P<0.05). Results: The expression levels of ERs in A549
Conclusion: There is a signiÀcant synergic cells were highest among these cell lines. In
inhibitory effect of antiangiogenic agents plus EP A549 cell line, ER-Ơ was mainly localized in the
regimen on SCLC cell line NCI-H446. Angiogenic cytoplasma, whereas ER-ơ was mainly localized
drugs’ potent single-agent activity and potential in the cytoplasma and to a lesser degree in the
synergy with standard EP regimen will allow for the nucleoli. The single agent of Anastrozole or GeÀtinib
inhibited the proliferation of A549 cells in a time- circular double-stranded DNA molecule. The 6 early
and dose-dependent manner. The proliferation open reading frames (ORF) include E1, E2, E4, E5,
inhibition rates of A549 cells treated with E6, and E7. The high-risk HPV E6 and E7 ORF
Anastrozole for 24h,48h,72h were (23.32±0.97)%, encode the viral oncoproteins that are invariably
(31.81±1.30)%, (35.88±0.78)% respectively,while expressed in HPV-positive human cancers. E6 and
the proliferation inhibition rates of A549 cells treated E7 oncoproteins, mainly act oncogenic by decreasing
with GeÀtinib for 24h,48h,72h were (21.32±1.57)%, tumor suppression pathways, and unpublished data
(34.44±0.47)%, (39.56±0.45)% respectively.The have shown similar expression of both on HPV
combination of two drugs increased the proliferation related malignancies. Previously, we successfully
inhibition rates for 24h,48h,72h to (37.66±1.02)%, generated E7 fusion proteins of HPV16 and 18. This
(63.41±2.02)%, (70.50±0.86)%respectively, which study explores the presence of antibodies (IgG) in
was closely associated with elevation of the G0/ serum against recombinant E7 for HPV 16,18, in 100
G1 phase fraction(P<0.05). Apoptosis rates of A549 patients with NSCLC and assesses correlation with
cells treated with Anastrozole, GeÀtinib alone or in clinical NSCLC characteristics.
combination were (10.72±1.12)%, (17.40±1.28)%, Methods: 100 deidentiÀed serum samples of
(23.02±2.32)% respectively (P<0.05). The synthetic NSCLC patients were randomly obtained from the
effect of the combination therapy was accompanied institutional biorepository . Clinical data included
by reduction of p-EGFR,p-ERK and p-AKT gender, age, smoking history, histology. E7 genes
expression compared with individual treatment. of HPV16 or 18 were cloned into prokaryotic
Conclusion: The results of this vitro study suggest expression vectors, pMal C2 (New England
the combination of Anastrozole and GeÀtinib BioLabs.) or pQE30 vector (Qiagen) by PCR
compared with either drug alone can maximally cloning technology. The E7 proteins were expressed
inhibit cell proliferation, induce apoptosis, and affect in E.coli, and puriÀed as recommended by the
downstream signaling pathways. Our study supports manufacturers (NEB and Qiagen, respectively).
functional interaction between the ER and the EGFR Direct ELISA method was used to measure IgG
pathways in lung cancer and provides a clinically antibodies against E7 of HPV16 and 18. PuriÀed
exploitable strategy for non-small cell lung cancer MBP proteins were used as control negative. Positive
patients . control human sera, which have been previously
Keywords: GeÀtinib, NSCLC, EGFR/ER pathway, tested as positive, for these HPV oncoproteins, was
Anastrozole employed for each experiment.
Results: Cases were age 42-86 and 53% males.
A revised/updated abstract may be included in 23% had a history of another cancer. 88% had a
the Late Breaking Abstract Supplement, available history of smoking, 7% have never smoked, and
at the 14th World Conference on Lung Cancer. 5% the history of smoking was unknown. Of the
100 samples 43% were adenocarcinoma (AC), 39%
squamous cell carcinoma (SCC), 10% NSCLC not
Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15 otherwise speciÀed (NOS), 4% large cell carcinoma,
2% neuroendocrine type (NEC). Analyzing the data
P1.044 DETECTION OF IGG AGAINST utilizing two standard deviations of the mean as a
E7 OF HPV 16,18 IN NON-SMALL CELL reference. IgG serology for HPV/E7 was positive
LUNG CANCER in 13%. HPV 16 in 5, HPV 18 in 7 and positive
Raul E. Storey, Joh Joongho, Alfred B. Jenson, Shin- for HPV 16 and 18 in 1 case. Of the 5 positive
Je Ghim, Goetz Kloecker for HPV16, 2 were AC, 2 SCC, 1 NOS. For the 7
Hematology Oncology, James G. Brown Cancer HPV18 positives, 5 were AC, 2 SCC. The only case
Center, University Of Louisville/United States Of with both types of HPV, was AC.
America Conclusion: This is the Àrst study detecting the
presence of antibodies against E7 for HPV 16/18
Background: 10-20 % of non-small cell lung in serum. The 13% is in accordance with previous
cancers (NSCLC) occur in never smokers. Human studies detecting HPV in NSCLC in a similar
papilloma virus (HPV) has been identiÀed in 20- proportion. The fact that an immune response to
25% of NSCLC. HPV’s role in the carcinogenesis HPV’s oncogene E7 is found in NSCLC patients
of NSCLC is unclear. The genome of HPV is a raises the question of HPV’s role in NSCLC
carcinogenesis. cell survival was reduced and the mean number of

Keywords: HPV, Lung cancer ƢH2AX foci increased. DNA Topoisomerase IIƠ
and POLB were co-immunoprecipitated from cells
treated with Etoposide.
Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15 Conclusion: In a cell line model of in vivo acquired
Etoposide chemoresistance DNA Polymerase ơ
P1.045 DNA POLYMERASE ȕ PROTECTS prevents Etoposide-induced apoptosis by preventing
SMALL CELL LUNG CANCER the generation of double strand DNA breaks through
CELLS FROM ETOPOSIDE INDUCED promotion of the repair of excess single strand DNA
APOPTOSIS breaks.
Malcolm H. Lawson1, Natalie M. Cummings2, Doris Keywords: etoposide, chemoresistance, Small cell
M. Rassl3, Roslin Russell1, James D. Brenton1, lung cancer, DNA Polymerase beta
Robert C. Rintoul4, Gillian Murphy1
1
Li Ka Shing Centre, Cruk Cambridge Research
Institute/United Kingdom, 2Thoracic Oncology, Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15
Papworth Hospital/United Kingdom, 3Pathology,
Papworth Hospital/United Kingdom, 4Department P1.046 OPTIMISING REGULATORY
Of Thoracic Oncology, Papworth Hospital/United T CELL (TREG) DEPLETION IN
Kingdom COMBINATION WITH CHEMOTHERAPY
FOR ENHANCED ANTI-TUMOUR
Background: Small Cell Lung Cancer (SCLC) IMMUNITY
typically responds well to Àrst line chemotherapy Alison M. Mcdonnell, Bruce W.S. Robinson,
with Etoposide and a Platinum containing agent. Michael Millward, Anna K. Nowak, Richard A. Lake
However survival is poor due to rapid relapse School Of Medicine And Pharmacology (m503), The
with chemoresistant disease. DNA Polymerase University Of Western Australia/Australia
ơ (POLB) has been implicated in single strand
DNA break repair caused by Temozolamide and Background: Cytotoxic chemotherapy is widely
in the repair of DNA adducts caused by platinum used to palliate malignant pleural mesothelioma
containing chemotherapeutics. POLB was identiÀed (MM) and non small cell lung cancer (NSCLC).
as a potential Etoposide chemoresistance factor by While originally considered detrimental to the
cDNA microarray using a unique series of cell lines immune system, there is now abundant preclinical
derived from a single patient during the course of her data showing that chemotherapy can enhance anti-
treatment. This work was planned to investigate the cancer immunotherapy. Tregs are immunosuppressive
functional role of POLB in Etoposide resistance in CD4+ T cells thought to inhibit anti-tumour immune
SCLC. responses; murine data suggests that Treg eradication
Methods: POLB was cloned and transiently may augment existing anti-tumour immunity.
expressed in the cell lines which were then treated Cyclophosphamide (CTX) is immunostimulatory
with Etoposide and assayed for cell survival using and at low doses selectively depletes Tregs in mice
a chemoluminescent method. The speciÀc POLB and humans. The primary objective of this study is to
inhibitor Pamoic Acid was used to determine if identify an optimum dose and schedule of iterative
reducing POLB activity altered cell survival after low dose oral CTX for Treg depletion in the context
Etoposide treatment. Imaging Áow cytometry was of pemetrexed-based chemotherapy, and to determine
used to investigate the role of POLB in preventing how treatment affects the function and phenotype of
Etoposide-induced DNA double strand breaks. the cellular immune response.
Results: Protein expression of POLB was highest Methods: This single centre phase 1b study enrolled
in the cell line that was most resistant to Etoposide patients with advanced MM or NSCLC planned for
compared to the line most sensitive to Etoposide. pemetrexed based chemotherapy. Patients received
When POLB was transiently expressed in the pemetrexed 500 mg/m2 ± cisplatin 75 mg/m2 or
cell line most sensitive to Etoposide cell survival carboplatin AUC 4-6 on a standard 21 day schedule,
after Etoposide treatment was increased. When and from the second cycle received escalating doses
the most Etoposide resistant cells were pre-treated of oral CTX taken every day for days 1-14 of each
with Pamoic Acid prior to Etoposide treatment, cycle, with an initial dose of 50 mg daily. CTX
dose was increased in subsequent cycles until Tregs Respiratory And Pulmonary Circulation, Beijing
comprised <4% of the CD4+ T cell population. Weekly Institute Of Respiratory Medicine, Beijing Chao-
peripheral blood samples were collected and the yang Hospital/China, 2Beijing Key Laboratory Of
proportion of CD25+CD127loFoxp3+ Tregs in whole Respiratory And Pulmonary Circulation, Beijing
blood determined by Áow cytometry in real time. Institute Of Respiratory Medicine, Beijing Chao-
Peripheral blood mononuclear cells (PBMC) were yang Hospital, Department Of Physiology, Capital
cryogenically stored for subsequent analysis. Toxicity Medical University/China
and radiological response were assessed.
Results: To date, 12 patients with MM (10/12) Background: Lung cancer is one of the leading
or NSCLC (2/12) have completed treatment. causes of cancer related deaths worldwide,
Preliminary analyses demonstrate the proportion of representing about 29% of all such cases while fewer
CD25+CD127loFoxp3+ Tregs is stable during the Àrst than 15% of patients are living after 5 years.Non-small
cycle of standard care chemotherapy, with a mean cell lung cancer (NSCLC) accounts for approximately
baseline Tregs 7.70% ± 1.60% of all CD4+ T cells. 85% of all lung cancer cases. The most promising
Following treatment with CTX, the proportion of therapy for NSCLC is complete lung resection.
peripheral blood Tregs decreased, with optimal Treg However, the survival rate after complete lung
depletion achieved during treatment with alternating resection for NSCLC is far from satisfactory and most
50/100 mg per day, then increased back to/and above patients are offered chemotherapy as an alternative,
baseline during the treatment break. The Treg nadir in particular cisplatin (cis-diamminedichloroplatinum
was 5.90% ± 1.51%, and was achieved on cycle 3 II) based chemotherapy.4 Cisplatin has been used
day 15. Increasing doses up to alternating 100/150 clinically for approximately 30 years and is effective
mg daily did not result in improved Treg depletion. against a variety of cancers, including testicular,
Analysis of PBMC T cell populations indicates that ovarian, head and neck, cervical, and NSCLC. It is
cell proliferation (Ki67) and activation (inducible co- primarily effective through formation of adducts with
stimulator; ICOS) peak and trough with each cycle DNA, causing induction of apoptosis.5 However,
of chemotherapy, declining during treatment and the efÀcacy of chemotherapy is limited due to the
increasing during the treatment break. Combining CTX development of multidrug resistance (MDR). Despite
with routine cytotoxic chemotherapy is feasible with no a recent increase in the understanding of the signaling
additional haematological or other toxicities. pathways activated by cisplatin and the mechanisms
Conclusion: The addition of CTX to pemetrexed based contributing to resistance, cisplatin resistance remains
chemotherapy is safe and feasible, but depletes Tregs a major problem that severely limits the usefulness
during CTX administration only. Doses above alternate of this chemotherapeutic agent. Thus, elucidation of
days 50/100 mg do not improve depletion. The next the mechanisms will lead to the development of more
patient cohort will receive continuous oral CTX to effective methods to combat resistance of cisplatin for
establish if this schedule results in more continuous or lung cancer.
more profound Treg depletion. Additional work will Recently, multiple studies have pointed to the
investigate the effect of this chemo-immunotherapy involvement of plasma membrane ion channels
protocol on tumour-speciÀc cellular immunity. in a cell’s response to chemotherapy. Okada et al.
Keywords: Chemo-immunotherapy, Regulatory T reported that pretreatment with cisplatin enhanced the
cells, Thoracic malignancy, Tumour Immunology activity of volume-sensitive Cl- channels in human
epidermoid cancer KB cells; cisplatin-resistant KCP-
4 cells derived from KB cells, on the other hand,
Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15 lacked functional expression of these channels.6
Our previous study also found that activation of
P1.047 MALFUNCTION OF VOLUME- volume sensitive Cl- channels (VSOR) is involved
SENSITIVE CL- CHANNELS IS in carboplatin-induced apoptosis in A549 cells and
INVOLVED IN CISPLATIN RESISTANCE that blockage of VSOR Cl- channels can eliminate
IN HUMAN LUNG ADENOCARCINOMA chemotherapeutic agent induced A549 cell apoptosis.
CELLS These results, along with the Ànding that VSOR
Xian J. Min1, Hui Li1, Jun Wang2 Cl- current activation is essential to the progression
1
Department Of Thoracic Surgery, Beijing of apoptosis in various cell lines, suggest that the
Chao-yang Hospital, Beijing Key Laboratory Of alteration in VSOR Cl- channel functional expression
might contribute to cisplatin resistance in A549 cells. Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15
Methods: Cisplatin-induced the process of apoptotic
volume decrease (AVD) was measured using P1.048 THE FUNCTIONAL ROLE
an inverted microscope with a high-resolution OF EPITHELIAL CELL ADHESION
electronic camera and the cell images were captured MOLECULE (EPCAM) IN THE NON-
and analyzed with a medical digital image analysis SMALL CELL LUNG CANCER CELL
system. Whole cell patch clamp technology was LINES.
applied to record Volume-Sensitive Cl- current and Masashi Kondo1, Tetsunari Hase1, Mitsuo Sato1,
the data were acquired using an EPC-10 ampliÀer Yoshida Kenya1, Yoshihiro Takeyama1, Elshazley
and Pulse software, and the sampled data were Momen1, Yoshitaka Sekido2, Adi F. Gazdar3, John D.
analyzed using an original software application Minna4, Yoshinori Hasegawa1
1
called PulseÀt and Origin 6.1. RT-PCR was used to Respiratory Medicine, Nagoya University/Japan,
2
evaluate the expression of the molecular candidates Division Of Molecular Oncology, Aichi Cancer
for VSOR Cl- channel, which include ClC-3, MDR1 Center Research Institute/Japan, 3Hamon Center
and PIcln. Cell viability was performed by cell For Therapeutic Oncology Research, Pathology,
counting and MTT assay and the apoptosis rate was University Of Texas Southwestern Medical Center/
measured by TUNEL Kit. United States Of America, 4Hamon Center For
Results: 1. A549 cells, which serve as a Therapeutic Oncology Research, University Of
model of sensitive to cisplatin, underwent the Texas Southwestern Medical Center/United States Of
process of apoptotic volume decrease (AVD) America
when treated with cisplatin. This AVD process
were blocked by chloride channel blockers, Background: A transmembrane glycoprotein,
4,4’-diisothiocyanostilbene-2,2’- disulfonic acid epithelial cell adhesion molecule (EpCAM), was the
(DIDS). But in A549/CDDP cells, which serve as Àrst tumor-associated antigen indentiÀed by means
a model of cisplatin-resistance, AVD processes of monoclonal antibodies. Subsequently, it was found
were nearly absent. 2. Cisplatin treatment activated to be frequently over-expressed in a great variety of
a Cl- current in A549 cells, which shows similar human cancers, including lung, esophagus, gastric,
properties to hypotonicity-induced volume-sensitive, breast, colorectal, and hepatocellular carcinomas and
outward rectifying (VSOR) Cl- current in A549 cells, its contribution to increased proliferation through
however, VSOR Cl- currents were nearly absent in up-regulating cell cycle accelerators such as cyclins
the parallel A549/CDDP cells. 3. The expression of A and E is well demonstrated in breast and gastric
MDR1, which is one of the molecular candidates for cancers. Nevertheless, very little is known about its
VSOR Cl- channel also obviously decreased in A549/ role in the survival of cancer cells. In addition, the
CDDP cells. 4. Pretreatment A549/CDDP cells with functional role of EpCAM in the pathogenesis of
trichomycin A (TSA), a drug which inhibits histone lung cancer remains to be explored.
deacetylases could partially restore VSOR Cl- current Methods: 18 human non-small cell lung cancer
but not the expression of MDR1. 5. Treatment of cell lines and an immortalized normal human
the cells with both cisplatin and TSA resulted in bronchial epithelial cell lines (HBEC4) were used.
a decrease in cell viability and an increase in cell The expressions of EpCAM were measured by
apoptosis rate. quantitative real-time PCR (qRT-PCR), Western
Conclusion: Malfunction of volume sensitive blot analysis and FACS. RNA interference (RNAi)-
chloride channels contributes to cisplatin resistance mediated gene silencing for EpCAM was performed
in human lung adenocarcinoma cells in several non-small cell lung cancer cell lines and
Keywords: volume sensitive chloride HBEC4. Cell proliferation was measured by WST-1
channels(VSOR), apoptotic volume decrease (AVD), and clonogenic growth was measured by liquid and
cisplatin-resistance, lung adenocarcinoma cells soft agar colony formation assays. Apoptosis was
evaluated by Annexin V/7-AAD staining. FACS
A revised/updated abstract may be included in with PI staining was done to examine apoptosis and
the Late Breaking Abstract Supplement, available cell cycle. The expression of p27 was evaluated by
at the 14th World Conference on Lung Cancer. Western blot analysis. In vitro invasion assay was
done by using transwell chambers layered with
matrigel.
Results: EpCAM was expressed at highly variable Methods: Mice(Female BALB/c mice, 8-10
levels by lung cancer cells lines. EGFR mutant weeks of age) were divided into four experimental
cell lines expressed EpCAM at higher levels than groups. (control;C, tumor;T, tumor injecction with
EGFR wild-type lines. The knockdown of EpCAM essential oil inhalation;T and E, tumor injection
suppressed proliferation and clonogenic growth and then essential oil with 1week interval; T and
of two EpCAM-expressing lung cancer cell lines then E) Lewis lung cancer cells were injected at
(H3255 and H358) in both anchorage-dependent and back subcutaneously in T, T and E and T and then
-independent conditions, but did not affect cell cycle E group, respectively. 1% Chamaecyparis Obtusa
proÀling in either cell line. EpCAM knockdown Essential oil was dissolved in PBS and administered
suppressed the invasiveness of highly invasive by nebulizer (1% or 2.5mg/ml, respectably) Àve
H358 cells but not poorly invasive H3255 cells. The times to each animal at 24-hour intervals for 5 days
EpCAM knockdown induced massive apoptosis in T and E group and T and then E group. The extent
in both cell lines as well as in another EpCAM- of tumor growth was measured three per week using
expressing lung cancer cell line (HCC2279), but sterile metric calipers.
to a much lesser extent in HBEC4, suggesting that Results: Tumor bearing(TB) mice showed
targeting EpCAM in lung cancer may have a high splenomegaly and essential oil inhalation decreased
therapeutic index. In addition, EpCAM knockdown splenomegaly of TB-mice. Relatively CD4/CD8
partially restored contact inhibition in a contact ratio was decreased in spleen by essential inhalation.
inhibition-resistant cell line HCC827, accompanying Foxp3-positive Treg cells in spleen were highly
p27Kip1 up-regulation. expressed in C and T group comparing with T and
Conclusion: These results demonstrate that EpCAM E, T and then E group but, tumor inÀltrating Foxp3-
contributes substantially to the pathogenesis of lung positive Treg cells, COX-2, IL-17a and IL-10 in
cancer, especially cancer cell survival, and that the tumor were decreased in T and E, T and then E
development of an EpCAM-targeted therapy for lung group. Tumor growth rate was low in T and E, T and
cancer may have promise. then E group.
Keywords: NSCLC, EpCAM Conclusion: Our results indicate that Chamaecyparis
Obtusa Essential oil has a promising anticancer
activity and anti-inÁammatory properties as an
Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15 immune modulating agent.
Keywords: Chamaecyparis Obtusa, Lewis Lung
P1.049 CHAMAECYPARIS OBTUSA Carcinoma, immune modulating agent
ESSENTIAL OILL MODULATES THE
TREG INTRA-TUMORAL INFILTRATED
CELL AND INHIBITS LEWIS LUNG Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15
CARCINOMA GROWTH IN VIVO
Jeong Eun Lee1, Sun Young Kim2, Sun Young Jung2, P1.050 IL-23 EXPRESSION AND
Seung Pyung Lim3, Ju Ock Kim2, Hee Sun Park2 REGULATION IN NSCLC
1
Internal Medicine, Chungnam National University Kenneth J. O’Byrne, Jennifer Leonard, Lisa
Hospital/Korea, 2Internal Medicine, Chungnam Kilmartin, Steven G. Gray
National University/Korea, 3Cardiothoracic Surgery, Clinical Medicine, Trinity College Dublin/st James’
Chungnam National University/Korea Hospital/Ireland
Background: Chamaecyparis Obtusa Essential oil are Background: IL-23 is a heterodimeric

volatile antimicrobial organic compounds that have proinÁammatory cytokine consisting of a p40 subunit
multiple biological properties, such as antifungal, (IL12B), covalently linked to a p19 subunit (IL23A).
insecticidal, and anti-inÁammatory activities. A Critically, IL-23 has been shown to promote tumor
correlation has been shown between survival and the incidence and tumor growth. In addition, IL-23
frequency of tumor-inÀltrating Foxp3-positive Treg stimulates neutrophil and macrophage inÀltration,
cells in cancer patients. The aim of this study was to and also promotes angiogenesis and expression
study the anti-tumor activities of the essential oils of of inÁammatory mediators within the tumor
C. obtuse in vivo via tumor growth and inÀltration of microenvironment. It is thought that IL-23 redirects
Foxp3-positive Treg cells in tumor. the adaptive cytotoxic effector response away from
anti-tumor immunity towards proinÁammatory and Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15
proangiogenic effector pathways that nourish the
tumor. Consequently, IL-23 enables the persistence P1.051 ANTICANCER EFFECT AND
of the recognized tumor cells, accompanied by APOPTOSIS INDUCTION OF GAMBOGIC
tumor-associated inÁammation. We hypothesized ACID IN HUMAN LUNG CANCER LINE
that IL-23 expression is important in the A549
pathogenesis of NSCLC and have examined its Dong Jiang1, Shiying Zheng2, Hong Li3
1
expression and role in NSCLC. Department Of Cardio-thoracic Surgery, The First
Methods: IL-23A mRNA expression was examined AfÀliated Hospital Of Soochow University/China,
2
using RT-PCR in a series of resected fresh frozen .department Of Cardio-thoracic Surgery, The First
NSCLC tumors and matched normal tissue samples, AfÀliated Hospital Of Soochow University/China,
3
and in a panel of NSCLC cell lines including Department Of Geriatrics, The First AfÀliated
normal bronchial epithelial cells. The effects of Hospital Of Soochow University/China
epigenetic targeting on the regulation of IL-23
expression was examined in a NSCLC cell line Background: To investigate the anticancer effect of
using histone deacetylase inhibitors (HDACi) and a traditional Chinese medicine gambogic acid (GA)
DNA methyltransferase inhibitors (DNMTi) by RT- in human lung cancer line A549 and further study the
PCR and chromatin immunoprecipitation (ChIP). mechanism of apoptosis induction of GA.
IL-23 expression in response to treatment with the Methods: Low differential human lung cancer line
antimetabolite chemotherapeutic agent gemcitabine A549 were treated with GA at different doses and
was also studied. Finally, the effect of recombinant different times, the inhibitory rates were detected by
IL-23 protein on NSCLC cell line cellular MTT assay. Apoptosis induced by GA in A549 cells
proliferation was examined. was observed by Annexin-V/PI doubling staining
Results: IL-23A was overexpressed in a subset Áow cytometry assay. And T/C (%) was chosen to
of NSCLC tumors, and only very low basal detect the inhibition of GA on human lung cancer
levels could be detected in a panel of NSCLC line A549 nude mice xenografts. Apoptosis on
cell lines. Treatments of cell lines with the DNA nude mice xenografts was observed by Annexin-V/
methyltransferase inhibitor 5-aza-2-deoxycytidine PI doubling staining Áow cytometry assay and
induced IL-23. The HDAC inhibitors (Trichostatin DNA fragmentation assay. To further determine the
A, Phenylbutyrate and SAHA) also induced IL- molecular mechanism of apoptosis induced by GA,
23A gene expression. ChIP analysis revealed direct the changes on the expression of bcl-2 and bax genes
chromatin remodeling at the IL23A promoter in were detected by RT-PCR.
response to HDACi. Cells treated with gemcitabine Results: After incubation with GA, low differential
were found to have elevated IL-23A expression. human lung cancer line A549 was dramatically
The cellular proliferation of an NSCLC cell line was inhibited in a dose-dependent manner. After these
increased in response to treatments with recombinant cells were exposed to GA for 24, 48 and 72 h,
IL-23. the IC50 value was 1.02±0.05, 1.41±0.20 and
Conclusion: Based on our results IL-23A is 1.14±0.19 ƫmol/L, respectively. Apoptosis in A549
expressed in a subset of primary NSCLC tumors. cells induced by GA was observed by Annexin-V/
Expression of IL-23A in NSCLC is dynamically PI doubling staining Áow cytometry assay. The
regulated by epigenetic mechanisms. The apoptotic population of A549 cells was about
chemotherapy drug gemcitabine enhanced IL23A 12.96% and 24.58%, respectively, when cells were
expression, while recombinant IL-23 stimulated incubated with 1.2 ƫmol/L GA for 48 and 72 h. T/C
NSCLC cell line proliferation. These results may (%) of human lung cancer line A549 nude mice
therefore have important implications for treating xenografts was 44.3, when the nude mice were
patients with epigenetic targeting therapies or treated with GA (8 mg/kg). Meanwhile, apoptosis
gemcitabine. induced by GA was observed in human lung cancer
Keywords: pro-inÁammatory, epigenetics, anti- line A549 nude mice xenografts. The increase of
metabolite, Cytokine bax gene and the decrease of bc1-2 gene expressions
were found by RT-PCR.
Conclusion: The inhibition of GA on human
lung cancer line A549 was conÀrmed. This effect
connects with the inducing apoptosis in A549 cells GOLM1 gene expression and lung adenocarcinoma
and the molecular mechanism might be related to progression.
the reduction of expression of apoptosis-regulated Methods: We analyzed 174 cases of surgically
gene bcl-2, and the improvement of the expression resected lung adenocarcinoma with tumors less than
of apoptosis-regulated gene bax. The result was also 2 cm in diameter. The mean age of the patients was
conÀrmed in vivo. 65.18 years (SD 8.94). Written informed consent
Keywords: Gambogic acid, apoptosis, human lung was obtained from all patients. We performed
cancer line A549, bcl-2/ bax immunohistochemical analysis of GOLM1 and
the Golgi marker protein Giantin. The staining
A revised/updated abstract may be included in intensity of GOLM1 was judged as high and low,
the Late Breaking Abstract Supplement, available relative to that of the normal bronchial epithelium.
at the 14th World Conference on Lung Cancer. We then carried out a morphometric analysis
of immunohistochemical staining. A BZ-9000
microscope system with BZ-II Analyzer software
Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15 (KEYENCE, Japan) was used for the morphometric
analysis and measurement of GOLM1-positive
P1.052 ABNORMAL GOLM1 GENE signals in lung cancer cells. Furthermore, we
EXPRESSION IN ADENOCARCINOMA examined the lung cancer cells by electron
OF THE LUNG microscopy.
Tsutomu Yoshida1, Yuko Minami1, Aya Shiba-Ishii1, Results: Of the 174 cases, 153 were at
Shingo Sakashita1, Keisei Tachibana2, Yoshimasa pathological stage I while 21 were at stage II or III.
Nakazato3, Tomoyuki Goya2, Masayuki Noguchi1 Immunohistochemical tests showed that, in normal
1
Department Of Pathology, Institute Of lung tissues, GOLM1 staining appeared as coarse
Basic Medical Sciences, Graduate School Of uniform signals around the nuclei of bronchial
Comprehensive Human Sciences, University Of epithelial cells. In lung cancer cells, on the other
Tsukuba/Japan, 2Department Of Surgery, School Of hand, these signals were small but irregularly
Medicine, Kyorin University/Japan, 3Division Of sized. GOLM1-positive signals in cancer cells were
Diagnostic Pathology, Gunma Prefectural Cancer distributed similarly to the Giantin-positive signals.
Center/Japan High GOLM1 expression was evident in 135 cases,
and low GOLM1 expression in 39. The mean size
Background: Noguchi type C lung adenocarcinoma of the GOLM1-positive signals in cancer cells was
is an early invasive adenocarcinoma, some cases 2.05 ƫm2 (SD 1.23). The data obtained through
of which show an extremely favorable outcome. our morphometric analysis were then compared
Such cases are considered to be minimally with the groupings of the Noguchi classiÀcation.
invasive adenocarcinoma. Although various sets GOLM1-positive signals had a signiÀcantly smaller
of histological criteria have been proposed for the mean size in type A tumors than in type B and C
evaluation of minimally invasive adenocarcinoma, tumors. In addition, GOLM1-positive signals had a
none have yet been widely accepted. Previously, we signiÀcantly larger mean size in non-lepidic tumors
compared the gene expression proÀles of Noguchi (types D, E, and F) than in lepidic tumors (types A,
Type A lung adenocarcinoma (adenocarcinoma in B, and C). Electron microscopy revealed signiÀcant
situ) with those of Type C lung adenocarcinoma development of the ER-Golgi in cases with high
associated with lymph node metastasis or a fatal GOLM1 expression. Cases with low GOLM1
outcome, and screened the differentially expressed expression tended to have a better outcome than
genes using a cDNA microarray (Shiba-Ishii et cases with high GOLM1 expression.
al., Int J Cancer 2011). Among the genes showing Conclusion: GOLM1 expression pattern may affect
signiÀcantly higher expression in type C than in type the prognosis of lung cancer. SigniÀcant variation
A, we focused on GOLM1, which encodes a 73-kDa of GOLM1 expression in lung cancer cells may be
human Golgi protein. Up-regulation of GOLM1 associated with morphological variation in the Golgi
has been observed in certain other cancers such as apparatus.
hepatocellular carcinoma, prostate carcinoma, and Keywords: cDNA microarray, GOLM1,
renal cell carcinoma. The purpose of the present Adenocarcinoma, Noguchi clasiÀcation
study was to investigate the relationship between
Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15 was conÀrmed as cells lacking Ephrin B3 expression
showed decreased clonogenic survival potential,
P1.053 ROLE OF AN EPHA2/EPHRIN alone and when combined with RT. Inhibition of
B3 SIGNALLING CIRCUIT IN Ephrin B3 expression sensitized NSCLC cells to RT
REGULATION OF NSCLC RESPONSE TO by increased senescence and apoptotic signalling.
RADIOTHERAPY. We also observed altered activation of EphA2 and
Ghazal Efazat1, Sara Ståhl1, Vitaliy Kaminskyy2, Ephrin B3 in response to RT and conÀrmed a role
Claudia Selck1, Petra Hååg1, Rolf Lewensohn1, Boris for Ephrin B3 in EphA2 activation. Knockdown
Zhivotovsky2, Kristina Viktorsson1 of Ephrin B3 in combination with RT altered Eph
1
Oncology/pathology, Karolinska Institutet/Sweden, downstream targets such as Akt and p38MAPK.
2
Enviromental Medicine, Karolinska Institutet/ Analysis of EphA2 mRNA expression revealed
Sweden its increase in NSCLC compared to SCLC with
a tendency of higher expression in radioresistant
Background: Lung cancer (LC) is the leading compared to radiosensitive cell lines. Moreover,
cause of cancer deaths in the world. The current inhibiting EphA2 expression resulted in reduced cell
treatment regimens include a combination of chemo- proliferation and induction of a senescent phenotype,
and radiotherapy (CT and RT) and for some cases similar to downregulation of Ephrin B3 expression in
targeted therapies against EGFR/IGFR growth factor NSCLC cells.
(GF) receptor signalling circuits. Ephrin ligands Conclusion: Our data imply that Ephrin B3,
and their receptors Ephs, are other GF signalling Ephrin A1 and EphA2 are putative molecules
molecules reported to inÁuence proliferation and which inÁuence NSCLC proliferation and RT
migration of tumour cells. Their function is also responsiveness. The RT sensitizing effect of Ephrin
deregulated in various tumors compared to normal B3 knockdown and the reported Eph mutations
tissue. Moreover, several mutations are reported in NSCLC suggest Ephrins and Ephs to be novel
in different Ephs both in the ligand binding and molecules for targeted therapy approach to combat
kinase domain placing Ephs among the top ten most RT resistance in LC.
frequently mutated genes in NSCLC. Using global Keyword: Ephrin, Eph, radiotherapy, senescence,
gene array analysis we recently identiÀed Ephrin B3 PathScan® Antibody Array
as a potential RT sensitizing target in NSCLC cells.
The aim of these studies was to further explore the
potential of Ephrins and Ephs as novel molecules Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15
with RT sensitizing capacity in LC.
Methods: A panel of SCLC and NSCLC cell lines P1.054 EGFR MUTATION ASSESSMENT
with different RT sensitivities was used. RNA and FROM FIXED AND FRESH
protein expression of Ephrin B3, Ephrin A1 and CYTOLOGICAL MATERIAL IN NON-
EphA2 were analysed by real-time quantitative SMALL CELL LUNG CANCER
PCR (RT-Q-PCR) and western blotting (WB). Small Anna Szumera-Cieckiewicz1, Andrzej Tysarowski2,
interfering RNA (siRNA) was used to knock down Michal Wćgrodzki1, Dariusz M. Kowalski3, Maciej
Ephrin B3 and EphA2. RT response was examined Glogowski3, Janusz A. Siedlecki2, Wlodzimierz T.
by clonogenic survival and apoptotic assays. Olszewski1
PathScan® Antibody Array was used to determine 1
Department Of Pathology, Maria Skãodowska-curie
activation of Ephs and their downstream targets prior Memorial Cancer Center And Institute Of Oncology/
and post RT in LC cells with or without Ephrin B3 or Poland, 2Department Of Molecular Biology, Maria
EphA2 protein expression. Skãodowska-curie Memorial Cancer Center And
Results: Ephrin B3, EphA2 and Ephrin A1 Institute Of Oncology/Poland, 3Medical Oncology,
expressions were analyzed in the SCLC and NSCLC The Maria Sklodowska-curie Institute Of Oncology/
cell line panel using RT-Q-PCR and WB. We found Poland
higher expression of Ephrin B3 in radioresistant
(SF2>0.3) compared to radiosensitive (SF2<0.3) Background: Recent progress in lung cancer
NSCLC cell lines with a correlation of 0.6. No biology has led to the development of small-
correlation was observed in SCLC cells. A role for molecule inhibitors of target proteins involved
Ephrin B3 in NSCLC proliferation and RT response in proliferation, apoptosis and angiogenesis. The
epidermal growth factor (EGFR) super family Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15
was identiÀed as a potential therapeutic target
in non-small-cell lung cancer (NSCLC) and P1.055 CONSISTENT LOW DEGREE
several EGFR inhibitors have been synthesized ANTAGONISM OF COMBINED
including geÀtinib and erlotinib. Concurrently, EPIDERMAL GROWTH FACTOR
studies on deÀning predictive factors to the anti- RECEPTOR-TYROSINE KINASE
EGFR therapy responsiveness have started. Most INHIBITOR (EGFR-TKI) AND
of the patients with advanced and non-resectable INDIVIDUAL CHEMOTHERAPEUTIC
NSCLC can be diagnosed only on the examination AGENTS IN NON-SMALL CELL LUNG
of cytology specimens. Thus, in order to apply CANCER (NSCLC) CELLS HARBORING
the EGFR mutation strategy to all patients, a new SENSITIZING-EGFR MUTATIONS
method that requires only a small number of cells Chun-Ming Tsai, K.-T. Chang, Chao-Hua Chiu,
is necessary. The aim of the study was to evaluate Shih-Yin Hsiao
the EGFR mutations in two types of material – Division Of Thoracic Oncology/department Of Chest
fresh and Àxed cytology specimens – obtained by Medicine, Taipei Veterans General Hospital/Taiwan
trans-thoracic, computed tomography supported
biopsy and brush cytology material acquired during Background: NSCLC cells harboring sensitizing-
bronchoÀberoscopy. EGFR mutations are supposed to be more sensitive
Methods: 89 patients with cytologically conÀrmed than EGFR wild type cells to the treatment of
NSCLC were entered into the study. Each specimen combined EGFR-TKI and chemotherapy. We tested
contained at least 50% of neoplasmatic cells. The this theory in a panel of NSCLC cell lines.
Àxed material comprised 78 (87.6%) and fresh - 11 Methods: Using the MTT assay and the classical
(12.4%). DNA was extracted from both types of isobole method, we examined the combination
material and the EGFR mutation was analyzed in effects of six geÀtinib (G)-containing doublets,
exons 18, 19 20 and 21 using the direct sequencing namely, G/C (cisplatin), G/Gem (gemcitabine), G/
method. Pem (pemetrexed), G/P (paclitaxel), G/D (docetaxel)
Results: The mean age of patients was 63.3 and G/V (vinorelbine) in a panel of 15 (three
years (range 30 – 82) with males predominance harboring sensitizing-EGFR mutations) chemonaive
(50 males vs. 39 females). The histological types NSCLC cell lines, in a concomitant administration
included: adenocarcinoma 60 (67.4%), non-small schedule.
cell carcinoma non-otherwise speciÀed 17 (19.1%), Results: In the whole group of 15 cell lines, overall
squamous cell carcinoma 9 (10.1%) and large cell results showed marked antagonism (Ant) of G/C,
carcinoma 3 (3.4%). Both types of material were additivism (Add) of G/Gem, marginal synergism of
equally sufÀcient to evaluate EGFR mutations. The G/P, marked synergism (Syn) of G/Pem, G/D and G/V,
ratio of molecularly non-diagnostic material due with the mean values of combination index (mCIs)
to DNA degradation or too scant DNA probe was were 1.184 (95% conÀdence interval: 1.12-1.24,
5.6% (5 cases). In 10 (11.2%) cases EGFR somatic P=0.001), 1.027 (0.948-1.107, P=0.683), 0.911(0.833-
mutations was conÀrmed. 0.989, P=0.078), 0.814 (0.7-0.92, P=0.011), 0.870
Conclusion: This study demonstrates that EGFR (0.78-0.96, P=0.017), and 0.899 (0.816-0.982,
mutation status can be analyzed from fresh samples P=0.041), respectively. The mCIs of G/C, G/Gem, G/
as well as regained material from cytological smears. Pem, G/P, G/D and G/V of the 3 sensitizing mutants
The classical cytology may become a useful tool to were 1.116 (Ant), 1.110 (Ant), 0.993 (Add), 1.077
provide molecular biological information, essential (Ant), 1.067 (Ant), and 1.082 (Ant), respectively. In
for the targeted treatment of advanced and recurrent contrast, the mCIs of the other 12 cell lines were 1.201
lung cancer. (Ant), 1.007 (Add), 0.769 (Syn), 0.869 (Syn), 0.820
Keywords: Lung cancer, EGFR mutation, cytology (Syn), and 0.853 (Syn), respectively. The combination
effects of geÀtinib and single chemotherapeutic agents
that act through a variety of anti-cancer mechanisms
showed consistent low degree antagonism (G/Pem,
additivism) in the sensitizing-EGFR mutants, while
the combination effects could be marked antagonism
(G/C), additivism (G/Gem), or obvious synergism (G/
Pem, G/P, G/D and G/V) in cells with no sensitizing Methods: Total RNA was extracted from resected
mutations. lung adenocarcinomas (from Hong Kong, Univ of
Conclusion: We hypothesized that the geÀtinib Michigan, and MSKCC, NY) followed by reverse
hypersensitivity and associated oncogenic transcription and hybridization onto Affymetrix
shock might lead to a broad spectrum of chemo- GeneChips HG U133A-B and Plus 2. Captured gene
refractoriness in the sensitizing-EGFR mutants expression signals were analyzed by SigniÀcance
when concomitantly treated with EGFR-TKI plus Analysis of Microarray (SAM) and class prediction
individual chemotherapeutics. analysis with Support Vector Machine (SVM) to
Keywords: geÀtinib, drug combination, sensitizing- identify the discriminatory gene expression signature
EGFR mutations with respect to the presence of different types of
EGFR gene mutations at exons 18 – 21. DNA
extracted was PCR-ampliÀed and directly sequenced
Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15 to read for EGFR gene mutations at exons 18 – 21.
Results: 96 lung adenocarcinomas were included
P1.056 EXPRESSION OF LATS2 AND (M:F = 28:68, smokers: non-smokers = 54: 42,
STK17B DISTINGUISHES EPIDERMAL pTNM Stages I/II/III/IV = 55/19/20/2, Chinese:
GROWTH FACTOR RECEPTOR (EGFR) Caucasian = 49: 47). EGFR mutations were present
GENE MUTATIONS IN EXONS 19 AND in 52 tumors (2 with point mutations at exon 18,
21 FROM THOSE IN 18 AND 20 IN LUNG 25 with in-frame deletion and 1 with silent L760L
ADENOCARCINOMAS mutation at exon 19, 5 with insertion at exon 20,
David C. Lam1, Luc Girard2, David G. Beer3, 18 with L858R and 1 with L861Q mutations at
Mark G. Kris4, Marc Ladanyi5, William L. Gerald exon 21). The most discriminatory gene expression
(deceased)4, Alan D. Sihoe6, Lik-Cheung Cheng6, differences between tumors with EGFR gene
Maria P. Wong7, Lap Ping Chung7, Mary Ip1, Wah mutations at exons 18 and 20 compared to those
Kit Lam1, Adi F. Gazdar2, Ignacio I. Wistuba8, John with mutations at exons 19 and 21 were the large
D. Minna9 tumor suppressor homolog 2 (LATS2) and the
1
Medicine, University Of Hong Kong/Hong Kong, serine/threonine kinase 17b (STK17B), with known
2
Hamon Center For Therapeutic Oncology Research, regulatory function in apoptosis.
University Of Texas Southwestern Medical Center/ Conclusion: We conclude, there are deÀned
United States Of America, 3Medicine, Univeristy discriminatory gene expression differences between
Of Michigan/United States Of America, 4Medicine/ tumors with more sensitive EGFR mutations at
thoracic Oncology Service, Memorial Sloan- exons 19 and 21 compared to tumors with lesser
kettering Cancer Center/United States Of America, sensitive EGFR mutations at exons 18 and 20.
5
Pathology, Memorial Sloan-kettering Cancer Center/ Further investigation into the biological roles of
United States Of America, 6Cardiothoracic Surgery, these discriminatory genes could allow for further
University Of Hong Kong/Hong Kong, 7Pathology, understanding of the mechanisms of differential
University Of Hong Kong/Hong Kong, 8Pathology, sensitivity to treatment of different EGFR gene
The University Of Texas MD Anderson Cancer mutation in lung adenocarcinomas
Center/United States Of America, 9Hamon Center For
Therapeutic Oncology Research, Internal Medicine,
Pharmacology, University Of Texas Southwestern Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15
Medical Center/United States Of America
P1.057 DIFFERENTIAL SIGNALING
Background: Lung adenocarcinomas bearing EGFR CONTROL OF CAP-DEPENDENT
gene mutations at exons 19 and 21 are associated TRANSLATION: NOVEL TARGETED
with better clinical response to treatment with THERAPY FOR SMALL CELL LUNG
EGFR-tyrosine kinase inhibitors than tumors with CANCER
EGFR mutations at exons 18 and 20. The aim of Tanawat Jirakulaporn1, Marian G. Kratzke2, Blake A.
this study was to explore the discriminatory gene Jacobson3, Manish R. Patel3, Robert A. Kratzke3
1
expression signatures between tumors bearing Department Of Biochemistry, Faculty Of Medicine
different types of EGFR gene mutations at exons Siriraj Hospital/Thailand, 2Research Service,
18 – 21. Minneapolis Veterans Affairs Medical Center/
United States Of America, 3Department Of Medicine, translation was conÀrmed by an increased eIF4G/
University Of Minnesota/United States Of America eIF4E ratio in the cap-afÀnity assays. Inhibition
of the cap-dependent translation by DA-4EBP1
Background: Molecular targeted therapy, such as overexpression in these four SCLC cell lines
tyrosine kinase inhibitor and mTOR inhibitor, failed resulted in a marked decrease in cell proliferation as
to demonstrate any clinical beneÀt in unselected, quantitatively measured by CCK-8 assays.
previously treated small cell lung cancer (SCLC) Conclusion: The differential upstream signaling
patients. The possible explanation is that they activation (c-Met, Akt, MAPK and JNK pathways)
were tested in unselected fashion and SCLC is a found in SCLC cell lines may eventually converge
heterogenous disease involving different signaling their signals to upregulate the cap-dependent
pathways in each individual patient. It would be translation process. Inhibition of the cap-mediated
necessary to learn more about cell signaling network translation reduced cell proliferation in all tested
in SCLC in order to identify a common link of these SCLC cell lines; therefore, this cap-dependent
various signals that could be a potential target for translation process could be the common link served
SCLC treatment. Akt/mTOR pathway is well-known as a novel potential target for SCLC therapy.
to positively control cap-dependent translation by Keywords: signaling, cap-dependent translation,
inducing 4EBP1 phosphorylation. MAPK and c-Met targeted therapy, Small cell lung cancer
signaling can cross-talk and transduce their signals to
the Akt/mTOR pathway to stimulate cap-dependent
translation. JNK activation was recently proposed Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15
by our group to positively regulate cap-dependent
translation by phosphorylating 4EBP1 (Patel et P1.058 ANALYSIS OF KRAS MUTATIONS
al (2007) J. Thorac. Oncol. 2(9), 789-95). This IN NON-SMALL CELL LUNG CANCER
differential upstream signaling activation (c-Met, (NSCLC) BRAZILIAN PATIENTS
Akt, MAPK and JNK pathways) can converge their Patrícia G.P. Couto1, Luciana Bastos-rodrigues2,
signals to upregulate the cap-dependent translation Cristina Sabato2, Fernanda Guieiro2, Alyne Vilhena3,
process that may serve as the common link in the Nilson F. Amaral3, Luiz De Marco2
1
SCLC carcinogenesis. Surgery, Universidade Federal De Minas Gerais
Methods: We conducted a series of immunoblotting Ufmg/Brazil, 2Surgery, Universidade Federal De
assays to determine c-Met, Akt, MAPK and JNK Minas Gerais/Brazil, 3Hospital Julia Kubitscheck/
activation in several SCLC cell lines derived Brazil
from different patients. Phospho-4EBP1 and
eIF4E expression were also assessed by Western Background: Lung cancer is the leading global
blot analysis. Cap-afÀnity assays to assess the cause of cancer-related mortality. To improve
activation of cap-mediated translation process were the survival rate of lung cancer patients, a better
performed in the SCLC cell lines and in human understanding of tumor biology is required as well
bronchial epithelial cells as a control. To determine as the subsequent development of new therapeutic
if cap-dependent translation is essential to SCLC strategies. The RAS family has been implicated
proliferation, dominant-active 4EBP1 (DA-4EBP1) in the development of human malignancies. The
mutant, which constitutively binds to eIF4E and KRAS oncogene resides on chromosome 12p12 and
blocks cap-dependent translation, was overexpressed encodes a protein (p21RAS) involved in the MAP-
in the SCLC cell lines and subsequently cell kinase signal transduction pathway modulating
proliferation was measured by Cell Counting Kit-8 cellular proliferation and differentiation. KRAS
(CCK-8). mutations, mainly codons 12, 13 and 61 (exons two
Results: Immunoblotting assays demonstrated and three) are present in roughly 25% of NSCLC
that c-Met, Akt, ERK1 and JNK activation was tumors but the overall impact of these mutations on
preferentially observed in H69, H1092, H146 and clinical outcome in NSCLC remains unclear.
N417 SCLC cell line, respectively. Interestingly, Methods: To determine the presence of KRAS
4EBP1 phosphorylation and eIF4E expression were mutations in a Brazilian population, we studied 50
increased in all four cell lines, suggesting that cap- patients with NSCLC. The target regions of KRAS
dependent translation is commonly upregulated in gene’s exons 2 and 3 were ampliÀed using speciÀc
SCLC. Indeed, the upregulation of the cap-mediated primers, puriÀed and sequenced. We also ascertained
the ancestry of patients using 40 ancestry informative most common symptom is dyspnea, followed by
indels. cough and chest pain. The predominant histologic
Results: In our sample, no KRAS mutations were Cancer non-small cells (91.6%) in relation to snuff
found and ancestry analysis showed a higher African most frequent histological type is the undifferentiated
component among cancer patients than controls. carcinoma. The predominant stage IIIB / IV, going
Conclusion: To our knowledge our study is the mostly with a ECOG2. As for treatment: surgery
Àrst to examine the association between KRAS were only 10 patients. Chemotherapy or radiotherapy
mutations and NSCLC in the Brazilian population. performed exclusively for 26.7% and 8.3%
The lack of mutations can be explained by the fact respectively, the combination of both 14%, 27.4%
that adenocarcinoma, the cancer subtype mainly refused treatment, received exclusive palliative care
associated with KRAS mutations, is less prevalent 10.1% and 12.9% died before deciding a treatment.
in our sample (24%) than other subtypes. These Of the 113 patients who received chemotherapy,
Àndings suggest that genes other than KRAS are 100% used platinum, with more than 50% response
related to NSCLC. Therefore, it is necessary to in only 21.2%. Radiotherapy was performed to
investigate possible molecular alterations in other 62 patients where the emergency was 51.2%.
tumor-related genes. A signiÀcant number of patients discontinued
Keywords: INDELS, NSCLC,, Kras treatment, with no record of its evolution.
Conclusion: The consultation late and advanced
A revised/updated abstract may be included in stages, and the lack of adherence to treatment by the
the Late Breaking Abstract Supplement, available patient and sometimes their environment, not allow
at the 14th World Conference on Lung Cancer. us to offer better quality of life to them, being at our
disposal only palliative measures.
Keywords: Lung Cancer, Snuff, Chemotherapy.
P1.059 PROFILE OF PATIENTS WITH the Late Breaking Abstract Supplement, available
LUNG CANCER: REVIEW OF NATIONAL at the 14th World Conference on Lung Cancer.
CANCER INSTITUTE OF PARAGUAY.
PERIOD FROM 2004 TO 2008.
Miguel A. Aguero Pino, Cinthia Gauna Colas, Maria Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15
Rita Pereira
Medical Oncology, Instituto Nacional Del Cancer/ P1.060 INCREASED TUMOR
Paraguay EXPRESSION OF ESTROGEN
RECEPTOR ALPHA (ERĮ) MRNA
Background: Objective: To demonstrate the proÀle CORRELATES WITH POOR PROGNOSIS
is presented to the consultation and the development IN RESECTED NON SMALL CELL LUNG
of a patient with lung cancer in our department, as CANCER (NSCLC)
well as diagnostic and therapeutic limitations. Sergio Carrera Revilla1, Unai Aresti Goiriena1,
Methods: A retrospective analysis of records BegoÑa Calvo Martinez1, Itziar Rubio Etxebarria1,
of patients seen at the National Cancer Institute Juan Jose Vilanova Rodriguez2, Aitziber Buque1,
between the period January 2004 to December Rafael Zalacain Jorge3, Alberto MuÑoz Llarena1,
2008. Inclusion criteria: Patients with histologically Juan Manuel Mañé Martínez1, Joaquin Pac Ferrer4,
conÀrmed attending their Àrst consultation in the Guillermo Lopez Vivanco1
1
independent set period of treatment. Data Collection: Medical Oncology, Cruces Hospital/Spain,
2
We analyzed the sex, age, origin, occupation, risk Anatomical Pathology, Cruces Hospital/Spain,
3
factors, reason for visit, ECOG, histology, stage and Neumology, Cruces Hospital/Spain, 4Thoracic
treatment performed in 277 patients Surgery, Cruces Hospital/Spain
Results: Of 277 patients studied are predominantly
male (86.6%) from mostly rural area. The mean age Background: Although several studies have shown
was 59.6 years. Risk factors are smoking 68.5%, the presence of estrogen receptors (ERs) in lung
41.1% alcohol, environmental exposures have 54.8% tumors, a considerable number of reports have
and family history of cancer only 9% have such. The published inconsistent conclusions about their
1
activity and importance. The biological role of ERƠ, Medical Oncology, Hospital Clinic, University
ERơ and aromatase in the development of NSCLC is Of Barcelona (ub)/Spain, 2Physiological Sciences,
unclear and there is little consensus on whether their Unit Biophysics And Bioengineering, University Of
expression constitutes a prognostic factor. The aim of Barcelona (ub)/Spain, 3Thoracic Surgery, Hospital
this study was to investigate the prognostic value of Clinic, University Of Barcelona (ub)/Spain
ER and aromatase in resected NSCLC.
Methods: Lung tumor samples and normal lung Background: Squamous cell lung cancer (SCC) is
tissue samples were analyzed for the expression of the second commonest type of non-small cell lung
ERƠ, ERơ and aromatase. Reverse transcription- cancer, which is the leading cause of cancer death
polymerase chain reaction (RT-PCR) analysis was in western countries. Because tumor associated
performed for the detection of ER and aromatase Àbroblasts (TAFs) have been involved in tumor
expression using RNA from lung cancer tissues initiation, growth, invasion, angiogenesis and
immediately submerged in RNA Later (Qiagen) after metastasis in a variety of solid tumors including
surgery, and then maintained one night at 4ºC, and lung cancer, there is growing interest in developing
stored at -80ºC until RNA extraction. We included speciÀc therapies against TAFs dependent tumor-
96 consecutive patients (81 male/15 female) with progression effects. While our understanding of the
resected NSCLC; 51% were adenocarcinoma, mechanisms underlying these tumor-progression
43% squamous and 6% others. The pathological effects is still scarce, recent studies in breast cancer
stages were as follows: 43% stage I, 33% stage support the hypothesis that loss of caveolin-1
II, 22% stage III and 2% stage IV. Neoadjuvant (cav1) expression is necessary to transform normal
chemotherapy was not allowed. Àbroblasts into tumor-promoting TAFs. However,
Results: The mean expression of ERƠ in normal lung this hypothesis has not been examined in lung
tissues was signiÀcantly higher than in lung tumor cancer so far.
samples (0.1554 vs. 0.1182 p < 0.0001). No statistically Methods: We examined the expression of cav1
signiÀcant differences in ERơ and aromatase and alpha-smooth muscle actin (a-sma), a common
expression were found between normal lung samples marker for activated Àbroblasts or myoÀbroblasts,
and lung tumor samples. Tumoral expression of ERơ in primary human lung Àbroblasts isolated from
inversely correlated with cigarette consumption (pack/ either tumor-free regions - non-cancer associated
years) in those identiÀed as current smokers(ANOVA, Àbroblasts (NTAFs)- or squamous tumor tissue
p =0.004). Furthermore, patients with highest values of (TAFs). Fibroblast proliferation was assessed by
tumoral ERƠ mRNA had better overall survival than MTT assay. Cell morphology was examined by
those with lowest values (25th percentile = 83 weeks vs. phase contrast microscopy.
75th percentile = 104 weeks; p= 0.025). Results: Cultured TAFs from SCC tissue exhibited
Conclusion: We report a signiÀcant association abnormal proliferation and differentiation patterns
between quantitative expression of mRNA ERƠ and compared to patient’s matched NTAFs. TAFs
overall survival in tumor tissue samples of resected exhibit increased spreading, reduced proliferation
NSCLC. Our results could be useful for selecting and increased a-sma expression (all markers
resected NSCLC with poor prognosis. A better of Àbroblast activation) compared to NTAFs.
understanding of estrogen action in lung cancer Downregulation of cav1 in TAFs occurred only in
could provide the basis for future targeted therapies. a subset of patients, whereas activation of TAFs
Keywords: aromatase, survival, Lung cancer, was observed in all patients suggesting the presence
estrogen receptors of cav1-independent mechanisms of Àbroblast
activation.
Conclusion: Our Àndings reveal that the tumor
Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15 microenvironment of SCC is enriched in activated
Àbroblasts, and suggest that unlike breast cancer,
P1.061 CAVEOLIN-1-INDEPENDENT loss of cav1 is common but not essential for SCC
FIBROBLAST ACTIVATION IN Àbroblast activation.
SQUAMOUS CELL LUNG CANCER (SCC) Keywords: caveolin-1 (cav1), tumor associated
Marta Puig1, Alicia Gimenez2, Abel Gomez-Caro3, Àbroblasts (TAFs), squamous cell lung cancer
Roberto Lugo2, Roland Galgoczy2, Pere Gascon1, (SCC)
Jordi Alcaraz2, Noemi Reguart1
Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15 measured by BLI (P<0.0001, all groups vs PBS).
The mean BLI signal in hind limbs of mice treated
P1.062 INHIBITION OF LUNG CANCER- with OPG-Fc or docetaxel (35 mg/kg) alone
INDUCED OSTEOLYTIC LESIONS AND decreased 6.7-fold and 28.9-fold versus controls,
SKELETAL TUMOR BURDEN WITH respectively. Combined treatment with OPG-Fc and
THE RANKL INHIBITOR OPG-FC AND docetaxel (35 mg/kg) resulted in a 322-fold decrease
DOCETAXEL IN A MURINE MODEL OF in hind limb BLI, 10-fold greater than with docetaxel
METASTATIC NON-SMALL CELL LUNG alone, and signiÀcantly reduced tumor progression
CANCER when compared to treatment with docetaxel alone
Robert Miller, Jon Jones, Mark Tometsko, Michelle (P=0.0003). Similar results also were observed with
Blake, William Dougall the 50 mg/kg dose of docetaxel in combination with
Hematology/oncology Research, Amgen Inc./United OPG-Fc. Docetaxel alone reduced skeletal tumor
States Of America burden in the hind limb and decreased development
of osteolytic lesions. However, in all groups treated
Background: Bone metastases occur in up to with OPG-Fc osteolytic lesions were completely
40% of patients with lung cancer. Tumor cells prevented. In the combination treatment groups,
interact with the bone microenvironment to induce skeletal tumor burden was reduced below the level of
osteoclastogenesis via RANK ligand (RANKL), the detection.
essential mediator of osteoclast formation, function, Conclusion: These results clearly demonstrate that
and survival. The resulting bone destruction and RANKL is a required factor for development of
release of growth factors have the potential to tumor-induced osteolytic lesions caused by a non-
promote tumor growth and survival within bone. small cell lung cancer cell line in vivo. RANKL
In animal models of breast or prostate cancer bone inhibition reduced skeletal tumor burden, presumably
metastasis, inhibition of RANKL blocks tumor- by blocking tumor-induced osteoclastogenesis and
induced osteolysis and prevents increase in skeletal the resultant production of growth factors from
tumor burden. Docetaxel, a well-established the bone microenvironment. RANKL inhibition
chemotherapy approved for the treatment of with OPG-Fc also provided an additive beneÀt to
metastatic lung cancer, arrests the cell cycle and docetaxel treatment by augmenting the reduction
induces apoptosis of tumor cells. In this study we of tumor burden. The results support the clinical
used the RANKL inhibitor OPG-Fc in combination evaluation of these combined treatments for the
with docetaxel to assess the effects of combining reduction of skeletal tumor burden in lung cancer
an anti-resorptive therapy with a chemotherapeutic patients.
agent on tumor-induced osteolysis and skeletal tumor Keywords: RANK Ligand, OPG-Fc, Docetaxel,
burden in a murine model of non-small cell lung bone metastases
cancer bone metastasis.
Methods: Human non-small cell lung carcinoma cell
line NCI-H1299 was engineered to express ÀreÁy Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15
luciferase to allow for non-invasive assessment of
tumor burden using bioluminescent imaging (BLI). P1.063 NOVEL FACS-BASED
Tumor cells were injected into the left cardiac CHARACTERISATION OF
ventricle of mice. BLI and radiography were used to INFLAMMATORY LUNG PHENOTYPES
conÀrm that the lung cancer cell established tumors IN PATIENTS WITH LUNG CANCER
and progressed to bone. Beginning 5 days after Mubing Duan1, Catherine Li2, Daniel Steinfort3,
tumor challenge, mice were treated therapeutically Louis Irving3, Gary Anderson4, Magaret Hibbs1
1
with either OPG-Fc (SC, 3 mg/kg, 3x/week) or Immunology, Monash University/Australia,
2
two cycles of docetaxel (IP, 35 or 50 mg/kg 1x/ Ludwig Institute (parkville)/Australia, 3Respiratory
week) alone, or in combination. Tumor progression Medicine, Royal Melbourne Hospital/Australia,
4
was monitored twice weekly by BLI and osteolytic Pharmacology, University Of Melbourne/Australia
changes by radiography.
Results: Both OPG-Fc and docetaxel, alone or in Background: In recent years, there has been a
combination, signiÀcantly reduced NCI-H1299 growing awareness of the link between chronic
tumor progression in the hind limbs of mice as inÁammation and cancer. Chronic inÁammation is
1
now postulated to promote tumourigenesis through Internal Medicine, Wonkwang University Hospital/
i) the establishment of a stromal microenvironment Korea, 2Pathology, Wonkwang University Hospital/
favouring tumour growth and progression by Korea, 3Radiation Oncology,, Wonkwang University
tumour associated macrophages (TAMs), and Hospital/Korea, 4Thoracic Surgery, Wonkwang
ii) circulating myeloid derived suppressor cells University Hospital/Korea, 5Radiology, Wonkwang
which suppress anti-tumour immune surveillance University Hospital/Korea
mediated by cytotoxic T lymphocytes. The role
of these two features in the development and Background: Most of lung cancer patients had
progression of primary lung carcinoma, however, received the systemic chemotherapy because they
remains relatively unknown. This is chieÁy due to a had diagnosed the advanced stage at presentation.
difÀculty in studying lung macrophage phenotypes, Cislplatin-based chemotherapy is main regimen for
whose highly autoÁuorescent properties hamper advanced lung cancer. But serious adverse reaction
their characterisation by Áuorescence-activated cell (SAE) had occurred after chemotherapy. This is main
sorting (FACS). reason for chemotherapy withdrawal. If we will use
Methods: We have recently developed a novel the reduced dose of cispaltin, cisplatin-based the
approach of characterising inÁammatory lung chemotheray will be continued. To Àgure out whether
macrophages in mice using FACS. the effect of low dose of cisplatin will be synergistically
Results: This work has allowed us to proÀle alveolar enhance by autophagy inhibiton, even though the
macrophages in animal models of acute and chronic reduced dose of cisplatin less effect for treatment
lung inÁammation, and identify a pathological Mac- response, We investigated that role of autophagy
1+ alveolar macrophage subpopulation associated by 3-methyladenine, class III PI3kinase inhibitor in
with the development of type II alveolar epithelial cisplatin-treated lung cancer cells.
cell hyperproliferation and lung Àbrosis. We are now Methods: Lung cancer cells were incubated with
translating this approach to the characterisation of normal media and treated the 5uM (LD20) and
alveolar macrophage phenotypes associated with 20uM(LD50) of cislpaltin according to time dependent.
human lung cancer lesions. Here, we report both We examined the sensitivity to low or high doses of
its feasibility and the inÁammatory BAL proÀle cisplatin treatment using the MTT cell viability assay
of patients with lung cancer ± chronic obstructive and compared apoptosis and autophagy by nuclear
pulmonary disorder (COPD) versus sarcoidosis. stianing, apoptotic or autophagic related proteins or
Conclusion: Using our FACS-based approach to autophagic vacuoles. autophagy is also displayed the
characterise patient inÁammatory lung phenotypes development of acidic vascular organelles by acridine
may help determine whether discreet macrophage orange and the Áuorescent expression of GFP-LC3
subpopulations are associated with lung cancer protein in the GFP-LC3 transfected cells.
(patient prognosis, tumour subtype and staging) and Results: Low dose of cisplatin-treated lung cancer
if chronic inÁammatory macrophage gene signatures cells is relatively less sensitive to cell death rather
discriminate early-stage disease from locally than high dose treated cells in a time-dependent
advanced disease. manners. We didnot Ànd out the nuclear fragmentation
Keywords: alveolar macrophages, Áow cytometry, in lower dose even though detected its in high dose.
chronic inÁammation PARP cleavages also were not detected in low dose
of cisplatin exception 24H. We observed that massive
A revised/updated abstract may be included in vacuolization in the cytoplasm were seen at lower
the Late Breaking Abstract Supplement, available dose treated cells. Acridine orange stain-positive cells
at the 14th World Conference on Lung Cancer. also were increased according to time dependent.
We Àgured out that the autophagosome-incorporated
LC3 II protein expression more increased in low dose
Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15 treated cells (24H to 48H) in spite of no detection
of LC3 II in high dose treated cells. The expression
P1.064 AUTOPHAGY INDUCES of GFP-LC3 were increased in 5uM treated cells by
CYTOPROTECTION IN CISPLATIN- time-dependent manner. When 3-methyladenine,
TREATED LUNG CANCER CELLS class III PI3kinase inhibitor, was pretreated in 5uM
Sei-Hoon Yang1, Hyang Jeong Jo2, Sun Rock Moon3, cisplatin-treated lung cancer cells, cell survival
Soon Ho Choi4, Sung Hoon Park5 signiÀcantly were decreased.
Conclusion: Autophagy induces cytoprotection in contrast, the percentage of a-sma positive Àbroblasts
lower dose of cisplatin-treated lung cancer cells. rose from 10 to 25% upon treatment with TGF-b1,
whereas it remained below 1% in NSCLC cell lines.
Likewise, expression of Àbrillar collagens was more
Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15 than 3 orders of magnitude larger in Àbroblasts than
in NSCLC cells. Interestingly, TGF-b1 efÀciently
P1.065 EPITHELIAL CONTRIBUTION TO stiffened all vimentin positive NSCLC cells, whereas
THE MYOFIBROBLASTIC PHENOTYPE it only stiffened ~50% of Àbroblasts and non
IN NON SMALL CELL LUNG CANCER vimentin positive NSCLC cells.
VIA EPITHELIAL TO MESENCHYMAL Conclusion: Our data indicate that EMT, as
TRANSFORMATION induced by treatment with TGF-b1 for 3 days,
Jordi Galgoczy1, Marta Puig2, Roberto Lugo1, is not sufÀcient to render NSCLC cells with a
Alicia Gimenez1, Marta Gabasa3, Antoni Xaubet3, myoÀbroblast-like phenotype. These results suggest
Daniel Navajas1, Noemi Reguart2, Jordi Alcaraz that either cancer cells undergoing EMT do not
Casademunt1 contribute to the abnormal increase of myoÀbroblasts
1
Unit Of Biophysics And Bioengineering, University in NSCLC, or that higher doses of TGF-b1 or other
Of Barcelona/Spain, 2Medical Oncology, Hospital factors are required to efÀciently transdifferentiate
Clinic Barcelona/Spain, 3Idibaps/Spain carcinoma cells into myoÀbroblasts. Furthermore,
these Àndings strongly suggest that TGF-b1 is a key
Background: A hallmark of most solid tumors in effector molecule in altering the normal balance of
the lung and other organs is a reactive stroma rich forces in NSCLC.
in alpha-smooth muscle actin (a-sma) positive cells Keywords: Tumor Microenvironment, Epithelial-to-
and Àbrillar collagens. A-sma positive cells are mesenchymal transformation, myoÀbroblast
indicative of activated Àbroblasts or myoÀbroblasts.
In normal conditions, myoÀbroblasts appear at the
Ànal stages of wound healing and are regarded as Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15
essential contributors to tissue repair. In tumors,
myoÀbroblasts provide biochemical and mechanical P1.066 EVALUATION OF INCREASED
cues that support tumor progression. Although it SENSITIVITY TO ETOPOSIDE AND
is currently thought that most myoÀbroblasts arise HYPERTHERMIA IN CISPLATIN-
from the activation of resident Àbroblasts, it has been RESISTANT HUMAN LUNG CANCER
suggested that carcinoma cells undergoing epithelial- CELLS
to-mesenchymal transformation (EMT) may also Ichiro Tsujino, Tetsuo Shimizu, Toshio Sugane,
acquire a myoÀbroblast-like phenotype. However Yasushi Ochi, Noriaki Takahashi, Shu Hashimoto
this hypothesis has not been examined yet. Department Of Medicine, Division Of Respiratory
Methods: Human non-small cell lung cancer Medicine, Nihon University School Of Medicine/
(NSCLC) carcinoma cell lines or primary lung Japan
Àbroblasts were cultured for 3 days in serum free
medium with or without the potent Àbroblast Background: In the present study, we sought to
activator TGF-b1. Expression of vimentin and determine whether or not the sensitivity to etoposide
a-sma, which are standard markers for EMT and hyperthermia could be changed and also
and myoÀbroblasts, respectively, was examined evaluated the intracellular alteration in cisplatin-
by immunoÁuorescence. Expression of Àbrillar resistant human lung cancer cells.
collagens was performed by qRT-PCR. The elastic Methods: We examined continuous exposure to
modulus E (indicative of cell stiffness) of single cells etoposide and short time exposure to hyperthermia
was assessed by Atomic Force Microscopy. in PC14, H69 and the corresponding cisplatin-
Results: TGF-b1 induced a ~two-fold increase resistant mutant subline of PC14, H69 human lung
in vimentin expression in two of the NSCLC cell cancer cells, respectively. Clonogenic surviving
lines examined (H1975, A549), whereas vimentin assay was employed for the evaluation of cell killing.
levels remain unaltered in the other cell lines (H441, We further analyzed intracellular accumulation of
PC9). Unlike vimentin, TGF-b1 failed to induce a etoposide, intracellular pH for thermosensitivity and
marked increase in a-sma in the NSCLC cell lines. In also intracellular glutathione content.
Results: It was found that cisplatin-resistant lung levels of AURKA gene.

cancer cells showed higher sensitivity to etoposide and Results: AURKA expression was signiÀcantly
intracellular etoposide accumulation, furthermore, also up-modulated in tumor samples compared to
higher thermosensitivity and lower intracellular pH. matched lung tissue (p<0.01, mean log2(FC)
Intracellular glutathione content was found increased in = 1.5). Moreover, AURKA was principally up-
cisplatin-resistant human lung cancer cells. modulated in moderately and poorly differentiated
Conclusion: Cisplatin-resistance increased sensitivity lung cancers (p<0.01), as well as in squamous and
to both etoposide and hyperthermia. It was thought that adenocarcinomas compared to the non-invasive
intracellular acidiÀcation and glutathione higher content bronchioloalveolar histotype (p= 0.029). No
in cisplatin-resistance were related. correlation with survival was observed.
Keywords: Hyperthermia, increased sensitivity, Conclusion: These results indicate for the Àrst time
cisplatin-resistance, etoposide that NSCLC histological subtypes showed a different
degree of AURKA modulation with the highest over-
A revised/updated abstract may be included in expression observed in squamous carcinoma whereas
the Late Breaking Abstract Supplement, available no signiÀcant modulation in bronchioloalveolar
at the 14th World Conference on Lung Cancer. carcinoma was reported. We also showed that
AURKA transcript over-expression was signiÀcantly
associated to tumor de-differentiation.
Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15 Keywords: Non small cell lung carcinoma,
quantitative PCR, immunohistochemistry
P1.067 AURORA KINASE A EXPRESSION
IS ASSOCIATED WITH LUNG CANCER
HISTOLOGICAL-SUBTYPES AND WITH Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15
TUMOR DE-DIFFERENTIATION
Marco Lo Iacono, Valentina Monica, Silvia Saviozzi, P1.068 ENDOPLASMIC RETICULUM
Paolo Ceppi, Enrico Bracco, Mauro Papotti, Giorgio STRESS INDUCERS AND EFFECT OF
Scagliotti CANCER DRUGS
Department Of Clinical And Biological Sciences, S. Saveljeva, Juana M. Barceló
University Of Torino/Italy Neumología, Universitat De Les Illes Balears-iunics
And Hospital Son Espases/Spain
Background: Aurora kinase A (AURKA) is a
member of serine/threonine kinase family. It plays Background: The aim of this research project
an important role in completing mitotic events is to exploit the intrinsic and the drug-induced
such as centrosome separation, bipolar spindle stressed status of the endoplasmic reticulum (ER)
assembly, chromosome segregation and cytokinesis. in lung cancer cells to convert this organelle/cell
Ectopic expression of Aurora A leads to an increase compartment into a target of chemotherapeutic
in centrosome numbers, causes catastrophic loss treatments. In a cell culture based in vitro system
or gain of chromosomes, and results in either cell the exposure of ER stress-inducing drugs combined
death or survival through malignant transformation. with chemotherapeutic lung cancer treatments will
Over-expression of AURKA has been detected in be assessed for the possible presence of synergy
many tumor cells and tissues, such as breast, gastric, in cell death or cell cycle arrest induction. One of
colorectal, bladder, pancreatic, ovarian, prostate and the advantages of this approach is the possibility
lung cancers. The purpose of the present study was of inducing speciÀc lung cancer cell toxicity while
to investigate the expression of AURKA in non small reducing the nuclear toxicity (mutations) of standard
cell lung cancer (NSCLC) specimens and to correlate drugs as well as part, if not practically all, of their
its mRNA or protein expression with patients’ genetically acquired resistance problems.
clinico-pathological features. Methods: Both available established standard cell
Methods: A quantitative real-time PCR and lines and primary cell lines obtained directly from
immunohistochemistry analysis on matched cancer the tumours of lung cancer patients will be exposed
and corresponding normal tissues from surgically to selected treatments. Those treatments will include
resected non-small cell lung cancers (NSCLC) have subsets in which common drugs in lung cancer
been performed aiming to explore the expression therapy are combined with a panel of available ER
stress inducing drugs. Analysis of cell survival will Methods: NSCLC, mesothelioma and prostate
involve the use of cellular and molecular biology cancer cell lines were treated with 5-aza-2-
assays. Markers of ER stress and cell death will deoxycytidine and gemcitabine. Reactivation of
be assessed through RNA and protein levels and epigenetically silenced genes was examined by
electronic microscopy imaging. RT-PCR/qPCR. DNA methyltransferase activity
Results: (To be included upon submission of the in nuclear extracts was measured using a DNA
Late Breaking abstract) methyltransferase assay, and alterations to DNA
Conclusion: (Dependent on the results of this study) methylation status were examined using methylation-
Keywords: ER, ER stress, endoplasmic reticulum, speciÀc PCR (MS-PCR).
lung cancer chemotherapy, toxicity Results: Reactivation of several previously
published epigenetically silenced genes was
A revised/updated abstract may be included in observed for all cell lines tested, including
the Late Breaking Abstract Supplement, available GSTP1 (p<0.05) and IGFBP-3 (p<0.05). Using
at the 14th World Conference on Lung Cancer. a DNA methyltransferase activity assay, DNA
methyltransferase activity was inhibited in nuclear
extracts from cells treated with gemcitabine. Finally,
Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15 using MS-PCR, we show a direct loss of DNA CpG
methylation at the promoter of GSTP-1 in response
P1.069 GEMCITABINE ALTERS DNA to gemcitabine treatment.
CPG METHYLATION AND MAY ACT Conclusion: Gemcitabine is a demethylating
AS A DNA METHYLTRANSFERASE agent having activity equivalent to decitabine
INHIBITOR at concentrations signiÀcantly lower than those
Steven G. Gray1, Anne-Marie Baird1, Fardod achieved in the treatment of patients with solid
O’kelly2, Armelle Meunier2, Donal Hollywood2, tumours. This property may contribute to the
Antoinette Powell2, Kenneth J. O’Byrne3 anticancer activity of gemcitabine.
1
Clinical Medicine, Trinity College Dublin/st James’ Keywords: epigenetics, DNA methyltransferase,
Hospital/Ireland, 2Prostate Molecular Oncology, gemcitabine, inhibitor
Trinity College Dublin/Ireland, 3Oncology (hope), St
James’s Hospital/Ireland
Background: Gemcitabine is indicated in
combination with cisplatin as a Àrst-line therapy P1.070 SPLICING FACTOR HSLU7
for solid tumours including non-small cell lung EXPRESSION IN NON SMALL CELL
cancer (NSCLC), bladder cancer, and mesothelioma LUNG CANCER AND CORRESPONDING
(MPM). Gemcitabine is an analogue of the MORPHOLOGICAL NORMAL LUNG
pyrimidine cytosine and functions as an anti- TISSUE
metabolite. Structurally, however, gemcitabine Marco Lo Iacono, Valentina Monica, Silvia Saviozzi,
has similarities to (Dacogen®), more familiarly Enrico Bracco, Silvia Novello, Mauro Papotti,
known as Decitabine or 5-aza-2’-deoxycytidine, a Giorgio Scagliotti
DNA methyltransferase inhibitor (DNMTi). Based Clinical & Biological Sciences, University Of Turin/
on this structural similarity, we hypothesized that Italy
gemcitabine may also inhibit DNMTs.
Background: Alternative splicing is the biological
process that could generate different transcripts from
a single mRNA precursor with a profound effect
on the functions of the Ànal protein. Recent data
indicate that the majority of human genes undergo
alternative splicing and alterations in this process
could affect essential biologic processes contributing
to develop several diseases, including cancer. The
splicing factor hSlu7 plays an important role in 3’
splice site selection during the second step of splicing
in vitro and has been suggested to affect alternative Background: The modulation of tumor
splicing in vivo. Recently, it was identiÀed that characteristics, including their metastatic
down-modulation of hSLU7 mediated through the potential, by stromal cells within a tumor is well
activation of c-Jun N-terminal kinase 1 (JNK1) established. We were interested to determine
promote splicing of TP73 gene to production of whether tumor cell heterogeneity itself might fulÀll
oncogenic isoform Ƌex2p73. The purpose of the a similar role. Using a mouse model for small
present study was to investigate the expression of cell lung cancer (SCLC), based upon conditional
hSLU7 mRNA in non small cell cancer (NSCLC) deletion of both Trp53 and Rb1 genes in lung
and analyze the correlation between hSLU7 mRNA epithelium, we previously identiÀed two distinct
expression and clinicopathological features. cell populations present within the primary lung
Methods: A real-time PCR analysis on matched tumors: a neuroendocrine (NE) cell component and
cancer and corresponding normal tissues from 86 a non-neuroendocrine (NonNE) cell component.
surgically resected patients has been performed. Interestingly, in a series of subcutaneous graft
Expression levels of hSLU7, POL2 and ESD experiments it was shown that metastasis occurs
(two reference genes) were evaluated via SYBR only following co-injection of both cell lines,
technology with ABI PRISM 7900HT Sequence indicating that crosstalk exists between the two cell
Detection System using speciÀc primers. populations.
Results: The hSLU7 expression in NSCLC Methods: In order to investigate the underlying
was signiÀcantly associated with tumor subtype molecular events occurring between these two
(p<<0.001). When all considered specimens were tumor cell variants that drive metastasis, we
evaluated as a whole, no difference in hSLU7 performed a series of in vitro assays. Moreover,
mRNA expression levels between tumor cells and whole genome microarray analysis of NE cells
matched normal tissue were detected. By contrast, following culture with conditioned medium from
when tumor subtypes were taken into consideration NonNE was performed to identify differentially
we identiÀed that hSLU7 mRNA was signiÀcantly expressed genes.
up-modulated in adenocarcinoma (p<0.01, mean Results: We examined the invasion activity of
log2(FC)=0.79), while was down-modulated in NE cells and found that conditioned medium from
squamous cell carcinoma (p=0.01, mean log2(FC)= NonNE cells enhanced the invasive capacity of NE
-0.73). Moreover, low hSLU7 transcript levels in cells in vitro. Moreover, microarray analysis of NE
tumors were signiÀcantly correlated with adverse cells following culture with conditioned medium
prognosis in NSCLC patients (p= 0.025). from NonNE revealed altered expression of Pea3,
Conclusion: These results indicate that the splicing a member of the ETS transcription factor family.
gene hSLU7 is deregulated in NSCLC and its The invasion activity of NE cells was regulated
modulation could contributes to the molecular by the overexpression of Pea3 and knockdown
differences existing between lung adenocarcinoma of the endogeneously expressed Pea3. We further
and squamous cell carcinoma. Moreover, low hSLU7 identiÀed that Ras-dependent MAPK signaling
mRNA expression in tumors is a putative marker of regulated the invasion activity of NE cells via Pea3
poor prognosis in NSCLC patients. expression.
Keywords: Non small cell lung carcinoma, Conclusion: Our results reveal that tumors can be
quantitative PCR, Splicing Factor heterogeneous in functional ways and the activation
of Pea3 is an essential mediator between the cell
variants for the metastasis of SCLC
Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15 Keyword: tumor heterogeneity, metastasis, small
cell lung cancer, SCLC, Pea3, Etv4
P1.071 THE ROLE OF TUMOR CELL
HETEROGENEITY IN THE METASTASIS A revised/updated abstract may be included in
OF SMALL CELL LUNG CANCER the Late Breaking Abstract Supplement, available
Min Chul Kwon, Joaquim Calbo, Erwin Van at the 14th World Conference on Lung Cancer.
Montfort, Natalie Proost, Anton Berns
Molecular Genetics And Centre For Biomedical
Genetics, Netherlands Cancer Institute/Netherlands
Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15 Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15
P1.072 THE EFFECT OF TTF-1 PROTEIN P1.073 ROLE OF SRC FAMILY KINASES
EXPRESSION ON N2 STATUS IN IN NSCLC: AUTOPHAGY INHIBITORS
PRIMARY ADENOCARCINOMA OF THE POTENTIATE KILLING EFFECTS OF
LUNG DASATINIB
Ozgur Samancilar1, Kenan C. Ceylan1, Ozan Usluer1, Ewa Rupniewska1, Francesco Mauri2, Diane
Seyda O. Kaya1, Ali G. Yener2 Watling1, Olivier Pardo1, Michael Seckl1
1 1
Thoracic Surgery, Dr. Suat Seren Chest Diseases Surgery And Cancer, Imperial College London/
And Thoracic Surgery Training And Research United Kingdom, 2Histopathology, Imperial College
Hospital/Turkey, 2Pathology, Dr. Suat Seren Chest London/United Kingdom
Diseases And Thoracic Surgery Training And
Research Hospital/Turkey Background: Lung cancer is the commonest
cause of cancer mortality, mostly due to the
Background: In this study, the effect of thyroid rapid development of drug resistance and early
transcription factor-1 (TTF-1) protein expression on metastasis. Src family kinases (SFKs) are frequently
N2 status in primary adenocarcinoma of the lung is overexpressed in various cancers and are strongly
investigated. implicated in all hallmarks of tumorigenesis
Methods: The patients operated between January including proliferation, survival and invasiveness.
2009 and December 2010 with a diagnosis Therefore, we sought to evaluate the involvement of
of primary adenocarcinoma of the lung are SFKs in lung cancer biology and assess the possible
retrospectively analyzed and devided into two groups therapeutic beneÀts of their inhibition, either alone or
according to their TTF-1 protein expression. The in combination with other treatments.
relationship between TTF-1 protein expression and Methods: The following NSCLC cell lines were
N2 status is evaluated. used: A549, EKVX, HOP62, HOP92, H226, H23,
Results: There were 73 patients (58 male, 15 H322M, H460, H522, HCC78, HCC95. Proliferation
female) with a mean age of 58,4+10,2 in the study was assessed using crystal violet staining and
group. Sixty-six lobectomies or pneumonectomies Western Blotting (WB) for cyclin D3 and p27; DNA
and mediastinal lymph node dissection, and seven synthesis by EdU proliferation assay; apoptosis by
mediastinoscopies were performed. The positivity caspase 3/7 activity assay, FACS analysis and WB
of the TTF-1 protein expression detected by the for caspases 3/7 and PARP cleavage; autophagy by
immunohistochemical staining of the specimens Áuorescent microscopy using LC3-GFP-expressing
were present in 33 patients (45,2%) and these cells and by WB for LC3.
patients are classiÀed as group A and the rest of the Results: We demonstrate that Src family kinases are
patients as group B. Eleven patients had N2 disease commonly overexpressed and activated in vitro in a
in group A against Àve pateints in group B and the panel of lung cancer cell lines as well as in vivo in
difference between the two groups were statistically lung cancer tissue microarrays, as compared to normal
signiÀcant. lung tissue. Furthermore, this overexpression seems
Conclusion: Patients with primary adenocarcinoma to correlate with poor patient survival. Dasatinib is
of the lung having TTF-1 protein expression are a novel Src/Abl inhibitor which effectively blocks
more tendant to have N2 disease. They might be SFKs activity at nanomolar concentrations. We show
considered as candidates for adjuvant chemotherapy that 10 of 11 NSCLC cell lines tested are sensitive
even without any N1 or N2 disease. to dasatinib treatment. Observed reduction in cell
Keywords: thyroid transcription factor-1, N2 numbers can be mostly attributed to strong inhibition
of DNA synthesis and proliferation. Additionally,
dasatinib treatment induces autophagy and, in some
cell lines, apoptosis. In this context, autophagy
seems to be a pro-survival mechanism as autophagy
inhibitors sensitise NSCLC cells towards dasatinib
treatment through enhanced apoptosis. These results
were conÀrmed by siRNA-mediated depletion of
essential autophagy-related proteins.
Conclusion: Our results suggest that inhibition of Results: miRNA proÀling revealed a number of
Src family kinases alone or in combination with miRNAs to be correlated to RT resistance in NSCLC
autophagy inhibitors, may be a beneÀcial therapeutic and SCLC, respectively. Among those were miR-
strategy in the management of lung cancer patients. 214, miR-1827, miR-625, miR-21, miR-339-5p,
Keywords: Src Family Kinases, NSCLC, Dasatinib, miR-768-3p, miR-532-3p and miR-1301 which were
autophagy up-regulated in RR NSCLC and miR-324-5p, miR-
1227, miR-1249, miR-423-5p and miR-625 which
were up-regulated in RR SCLC cells respectively.
Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15 We focused our analysis on miR-214 and conÀrmed
a higher miR-214 expression in RR NSCLC cells
P1.074 DOWN REGULATION OF MIR- using real time PCR. In order to examine if ablation of
214 SENSITIZES NSCLC CELLS TO miR-214 expression could sensitize for RT, NSCLC
IONIZING RADIATION BY INCREASING cells were transfected with anti-miR-214 antagomir
THE SENESCENCE SIGNALLING and the RT response of these cells was compared to
Hogir Salim1, Nadeem Shahzad Akbar2, Dali mock transfected cells. Clonogenic survival assay
Zong1, Ali Moshfegh1, Kristina Viktorsson1, Rolf as well as proliferation assessment conÀrmed a role
Lewensohn1, Boris Zhivotovsky2 of miR-214 in RT resistance as the cell growth after
1
Oncology-pathology, Karolinska Institutet/Sweden, RT was reduced by about 40% after knock down of
2
Department Of Environmental Medicine, Karolinska miR-214 and irradiated by a dose of 8-Gy. Following
Institutet/Sweden these results we examined if down regulation of miR-
214 altered RT-induced apoptotic signalling in these
Background: MicroRNAs are small single NSCLC cells by evaluating caspase-3 activation as well
stranded endogenous RNA molecules that act as induction of apoptotic morphology. No increase in
as negative regulators of gene expression at the RT-induced apoptosis was observed in NSCLC with
posttranscriptional level and thereby greatly ablated miR-214 expression. However, we found that
inÁuence tumour cell behaviour, i.e. causing down regulation of miR-214 increased RT-induced
differentiation, increasing proliferation and senescence. We then looked for the predicted targets
metastatic capacity and impairing apoptotic of the miR-214 in Targetscan, PicTar and Microcosm
signalling processes. The importance of miRNAs and found about 120 putative target genes which in
in regulating small (SCLC) and non-small cell lung turn regulate several different pathways including
cancer (NSCLC), radiotherapy (RT) resistance is, senescence, ex. P27 and CDK6.
however, unknown. Therefore, we aimed to analyze Conclusion: In conclusion, we demonstrate that
this by performing miRNA expression proÀling of a increased miR-214 expression contributes to RT
panel of SCLC and NSCLC cell lines with different resistant phenotype of NSCLC. Analysis of miR-
degrees of RT resistance. 214 expression in NSCLC patient derived material
Methods: A panel of SCLC and NSCLC cell lines as well as in depth analysis of miR-214 targets in
were used and subdivided into radioresistant (RR), relation to RT resistance is in progress.
having an SF2 value (surviving fraction after 2-Gy
irradiation) 0.3 or radiosensitive (RS) with an SF2
value < 0.3. RNA was extracted from cells by using Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15
Trizol reagent and microRNA expression proÀling was
performed using Affymetrix genechip microRNA array. P1.075 THE ROLE OF EGFR
For validation of identiÀed microRNA expression, real TRAFFICKING IN DRUG RESISTANCE
time PCR was used. Antagomir against the miRNAs OF LUNG CANCER CELLS
were designed and obtained from Dharmacon. A Co60 Chao-Hua Chiu, Yu-Ting Huang, Ting-Chun Huang,
was used for the irradiation which was performed at Chun-Ming Tsai
ambient room temperature. Level of apoptosis was Division Of Thoracic Oncology/department Of Chest
measured using caspase-3 antibody followed by FACS. Medicine, Taipei Veterans General Hospital/Taiwan
Colony formation assay was analyzed by Giemsa-
staining. Beta-galactosidase assay was performed for Background: Epidermal growth factor receptor
analyzing senescence of the cells upon treatment and (EGFR) can transduct signaling for cell proliferation
for protein analysis western blot was applied. and survival and plays important roles in
tumorigenesis and drug resistance. It is thought that among the depositions of crystalline silica in
EGFR undergoes rapid internalization after ligand different lung tissues, nuclear factor NF-ƩB protein
binding and this trafÀcking is simply a mechanism expression caused by oxidative damage and female
for cell to terminate signaling. However, it is now non-small cell lung cancer (NSCLC ) in Xuanwei.
clear that, in fact, internalized EGFR can continue Methods: Transmission electron microscopy
signaling. We hypothesize that chemotherapeutic (TEM), selected area electron diffraction(SAED) and
agents may inÁuence EGFR trafÀcking and play a energy dispersive X-ray analysis (EDS) detect the
role in drug resistance. occurrence of quartz in lung tissues of the following
Methods: Lung cancer cell lines were treated with cases: experimental group , 18 cases of Xuanwei
different kinds of platinum and EGFR trafÀcking was female lung cancer patients; control group A, 15
evaluated by subcellular fractionation and Western cases of Xuanwei male lung cancer patients; 16
blotting and confocal microscopy. MTT assay and the cases of Non-xuanwei female lung cancer patients;
classical isobole method were used to examine the control group B, 16 cases of Xuanwei male benign
combination effects of platinum and other inhibitors. pulmonary diseases patients; 15 cases of Xuanwei
Results: In consistent with previous studies, cisplatin female benign pulmonary diseases patients; 15 cases
could result in EGFR internalization and nuclear of Non-xuanwei female benign pulmonary diseases
translocation in a p38-dependent manner. Interestingly, patients. Observing average particle size of quartz
two other clinically-used platinum, carboplatin and and local pathology in each group, the occurrence
oxaliplatin, also activated p38 and induced EGFR rates of quartz in different lung tissues as count data,
internalization and nuclear translocation. However, a using SPSS statistical software (R×C Ƶ2 test, if more
non-toxic platinum, transplatin, could not effectively groups would be a difference, then adjusting the test
activate p38 and did not induce EGFR internalization. level compared to 2-sided) for statistical analysis.
We further demonstrated that, in response to cisplatin Results: 1. the smallest particle size of quartz is
treatment, p38 induced S1046/7 phosphorylation of 10.0nm × 12.5nm, the maximum size of quartz
EGFR. Lastly, combination of cisplatin and EGFR- is 1578.94nm × 2500nm, average particle size
TKI did not show a synergistic effect; instead, an is distributed around 200nm ~ 450nm; quartz
antagonistic effect was noted. These data will be (<120nm) were often under the nuclear membrane or
updated and further study results will be presented in on the border of nuclear membrane and cytoplasmic
the Conference. in interstitial lung cells and alveolar type cells,
Conclusion: Cytotoxic platinum could induce EGFR with accumulation of sand-like polycrystalline
internalization and nuclear translocation which compounds; The larger particles (>120nm) presented
might contribute to chemoresistance. It is possible to in alveolar, interstitial, or occasionally in the
overcome drug resistance by targeting the aberrant cytoplasm, there were a large number of collagen
EGFR trafÀcking. Àbers, Àbrosis in local occurrences. 2. For Xuanwei
Keywords: EGFR trafÀcking, platinum, Non-small NSCLC groups, the occurrence rates of crystalline
cell lung cancer silica in cancer tissues, adjacent tissues and normal
lung tissues showed no signiÀcant difference
(P>0.05); 3. The lung tissues of Xuanwei female and
Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15 male NSCLC were no difference in occurrence rate
for crystalline silica; but both of them were above
P1.076 THE RELATIONSHIP BETWEEN non-xuanwei female NSCLC lung tissures(P <0.01).
NUCLEAR FACTOR NF-țB EXPRESSION 5. In benign lesions, there were the same overall
BY QUARTZ PEROXIDATION AND distribution for the occurrence rates of crystalline
XUANWEI FEMALE NON-SMALL CELL silica, but they were signiÀcantly lower than
LUNG CANCER Xuanwei female NSCLC (P <0.01).
Yunchao Huang, Mengjiao Quab Conclusion: 1. quartz has different degrees of
Thoracic And Cardiovascular Surgery, Yunnan deposition in the lung tissues of each group, the
Tumor Hospital/China deposition in Xuanwei NSCLC was signiÀcantly
higher than in patients of Non-xuanwei NSCLC
Background: Yunnan Xuanwei county is one of the and lung benign lesions, suggesting that quartz in
highest cancer incidence of lung cancer in the world. Xuanwei lung cancer, especially Xuanwei female
To study the relationship and biological signiÀcance NSCLC plays an important role for the incidence of
lung cancer. 2. The high expression of NF-kB protein with BRCA1 expression level in a panel of 6
in cancer tissues, the high expression of NF-kB mesothelioma cell lines. We then investigated the
protein in adjacent tissues and normal lung tissues effect BRCA1 silencing on vinorelbine sensitivity.
in Xuanwei female NSCLC that was signiÀcantly The downregulation blocked caspase-3 activation,
higher than other group could be further studied PARP cleavage and the percentage of subG1 cell
as a diagnostic marker for lung cancer in Xuanwei population. Moreover, when cells were selected
and a possible target for treatment. 3. The smaller for resistance to vinorelbine, this was associated
the crystal size was, the stronger the cytotoxicity with a reduction in BRCA1 expression compared
of quartz was, leading to NF-kB protein highly to parental cells. BRCA1 mRNA expression was
expressed, which provides an important clue for not altered as shown by gene expression analysis,
further study of the pathogenesis of Xuanwei suggesting a post-transcriptional regulation
NSCLC. mechanism. Data obtained in BAX/BAK double
Keywords: Non-small cell lung cancer, quartz, NF- negative cells show that vinorelbine mediates
ƩB, Xuan Wei county toxicity irrespective of a functional mitochondrial
apoptosis pathway, however caspase 8 can be
activated in these cells; furthermore silencing
Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15 of Caspase8 induced resistance to apoptosis by
vinorelbine. We are addressing the prevalence of
P1.077 BRCA1 REGULATES APOPTOSIS BRCA1 negativity in primary mesotheliomas to
INDUCED BY VINORELBINE IN delineate its potential as a predictive biomarker.
MALIGNANT MESOTHELIOMA Conclusion: Our data highlight the BRCA1 as
Sara Busacca1, Ian Paul1, Niall Mctavish1, Keith M. a candidate predictive biomarker for vinorelbine
Kerr2, Michael Sheaff3, Jennifer E. Quinn1, Dean A. induced apoptosis suggesting a potential utility in
Fennell1 personalising therapy with this agent.
1
Centre For Cancer Research And Cell Biology, Keywords: Malignant mesothelioma, BRCA1,
Queen’s University Of Belfast/United Kingdom, Vinorelbine, chemoresistance
2
Department Of Pathology, Aberdeen Royal
InÀrmary/United Kingdom, 3Department Of
Pathology, Barts And The London Nhs Trust/United Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15
Kingdom
P1.078 THE EMT REGULATOR SLUG
Background: Malignant mesothelioma is an CONTROLS THE DNA REPLICATION
aggressive tumor refractory to current therapies and AND GENOMIC INSTABILITY
this may be due to intrinsic apoptosis resistance. Wen-Lung Wang1, Shih-Han Kao2, Shu-Ping Wang3,
Vinorelbine has been shown to exhibit useful clinical Szu-Hua Pan3, Tse-Ming Hong4, Pan Chyr Yang5
1
activity in phase II trials and showed a trend to Graduate Institute Of Life Sciences, National
improved survival as front-line monotherapy in the Defense Medical Center/Taiwan, 2Institute Of
MS01 phase III study. BRCA1 has been reported Molecular Medicine, Nation Taiwan University
to regulate sensitivity to microtubule poisons; College Of Medicine/Taiwan, 3Institute Of
however its involvement in regulating apoptosis in Biomedical Sciences, Academia Sinica/Taiwan,
4
Mesothelioma has not been investigated. We have Graduate Institute Of Clinical Medicine, National
hypothesised that loss of BRCA1 confers resistance Cheng Kong University/Taiwan, 5Department Of
to vinorelbine induced apoptosis. Internal Medicine, National Taiwan University
Methods: Dose-response curves were generated by College Of Medicine/Taiwan
vialight assay and caspase 3/7 activity determined by
a luminescence assay. Three resistant cell lines were Background: The well-characterized function
generated by increasing exposure to vinorelbine. of the transcription factor, Slug, is to promote
Cells were transfected with 10nM non-targeting EMT and tumor invasion/metastasis by down-
siRNA or BRCA1 /Caspase8 siRNA. The percentage regulating E-cadherin expression. In addition,
of apoptotic cell population was determined by PI Slug also functions in cell cycle but the underlying
staining and measurement of hypodiploidy. mechanisms are still unclear. We thus infer that the
Results: Vinorelbine induced cytotoxicity correlated EMT regulator, Slug, affects the normal cell cycle
control. In this study, we investigate how Slug demonstrated clinical beneÀt, outcomes remain
proteins are regulated and the signiÀcance of Slug poor with overall Àve-year survival rates of <15%.
during the S phase. Angiogenesis is critical for the growth, progression
Methods: Cells synchronized with nocodazole and metastasis of solid tumours, including NSCLC.
or double thymidine were released into drug-free The biological effects of VEGF are mediated via
medium for the indicated time, following by the binding to the classical VEGF receptors, VEGFR-1
Western blot and FACS analysis. The Slug mRNA and VEGFR-2 that have shown to be important
expression was detected by qRT-PCR. Next, the half- for angiogenesis, while VEGFR-3 plays a role in
life of protein was performed by the cycloheximide lymphangiogenesis. In addition, VEGF also binds
inhibition assay. The phosphorylation of Slug by to the non-tyrosine kinase receptors, the Neuropilins
Cdk2/cyclin E was detected by the in vitro kinase (NP1 and NP2), and stimulates cell signalling
assay . Further, DNA synthesis on the S phase was transduction in conjunction with VEGFR-2.
conÀrmed by the [3H]-thymidine incorporation assay Downstream signalling, triggered by ligand-receptor
and 32P-orthophosphate labeling. Finally, genomic binding, leads to endothelial cell proliferation and
instability was analyzed by cytokinesis-block migration, increased permeability of blood vessels,
micronucleus cytome assay and array cGH. and changes in the tumour microenvironment. The
Results: We found that the endogenous Slug VEGF pathway has therefore become an important
protein levels in CL1-5 lung cancer and U2OS therapeutic target. In Phase III trials, blocking
osteosarcoma cells were Áuctuated during the cell VEGF using the humanised VEGF monoclonal
cycle progression, which obviously decreased at antibody, Bevacizumab (Avastin®), has yielded
two stages: G1/S transition and from M phase to improved progression-free and overall survival in
early G1 phase. Downregulation of Slug protein NSCLC patients when combined with standard
at these phases was possibly attributed to protein chemotherapy, demonstrating the use of VEGF as
destabilization mediated by the ubiquitin-proteasome a target for therapy. The precise mode of action
degradation system. During the G1/S transition, of removing VEGF from the circulation however,
Cdk2 interacted with and phosphorylated Slug. remains uncertain. In this study, we examined the
Furthermore, overexpression of Cdk2 and cyclin E mechanisms of VEGF-mediated survival in non-
facilitated Slug degradation. In contrast, knockdown small cell lung cancer cells.
of Cdk2 and cyclin E increased the Slug protein Methods: A panel of NSCLC cells (H460, H647,
accumulation. We then found that overexpression of A549 and SKMES-1) were screened for expression
Slug markedly reduced DNA replication, increased of VEGF and its receptors, VEGFR-1, VEGFR-2
micronuclei formation and genomic instability. and the Neuropilins (NP1 and NP2) at the mRNA
Conclusion: This study indicates that Cdk2/cyclin and protein levels. The survival effects of VEGF
E regulates the Slug protein stability to control Slug were examined using a pharmacological (VEGF
within normal protein levels and it may be critical antibodies) and genetic (siRNA) approach. The
for the regulation of DNA replication. effect of recombinant VEGF (100ng/ml), and its
Keywords: Cell cycle, Slug, DNA replication, Cdk2/ blockade using neutralising antibodies (1g/ml)
cyclin E on lung tumour cell proliferation was examined
using the BrdU assay. Cell cycle was assessed by
propidium iodide staining following neutralisation
Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15 of VEGF and analysed by FACS. Phosphorylation
of the PI3-K and MAPK signalling proteins, Akt and
P1.079 VEGF IS AN AUTOCRINE Erk1/2, respectively, was examined by High Content
SURVIVAL FACTOR IN NON-SMALL Screening (HCS) analysis and confocal microscopy.
CELL LUNG CANCER The effects of silencing VEGF (100nM siVEGF)
Martin P. Barr, Kathy A. Gately, Kenneth J. O’Byrne on cell proliferation/survival and pAkt expression
Clinical Medicine, St. James’ Hospital/trinity were assessed using BrdU and Western blot analysis,
College Dublin/Ireland respectively.
Results: VEGF increased proliferation of NSCLC
Background: Lung cancer is the leading cause cells (H647, A549 and SKMES-1) expressing
of cancer mortality worldwide, where NSCLC VEGFR-2 and Neuropilin receptors. VEGF blockade
accounts for 85-90% of all lung cancers. Despite inhibited VEGF-mediated proliferation and induced
growth arrest in the G0/G1 phase of the cell cycle. inhibition of these receptors in lung cancer cell lines.
Phosphorylation of Akt and Erk1/2 proteins was Methods: T-type calcium channel expression and its
signiÀcantly upregulated in response to VEGF, while role in cell proliferation were examined in non-small
antibodies to VEGF inhibited this effect. VEGF cell lung cancer. In vitro studies were conducted
gene silencing inhibited the survival of A549 and using H23 adenocarcinoma, H460 carcinoma, H522
SKMES-1 cells and reduced pAkt protein expression adenocarcinoma and H1299 carcinoma cell lines.
in both cell lines. Initial investigation involved Western blot analysis
Conclusion: Tumour angiogenesis is mediated with antibodies for all three isoforms in all lines. To
by VEGF and its receptors in many tumour types. determine if the expressed proteins were functional
While a number of anti-angiogenic small molecule voltage clamp studies were conducted to detect the
tyrosine kinase inhibitors and monoclonal antibodies unique t-current generated by the channels. The
against VEGF and its receptors have been developed effects of the channels in NSCLC proliferation were
and tested in clinical trials, our data support the examined using Mibefradil, a putative t-type calcium
hypothesis that VEGF is a survival factor for channel antagonist. Mibefradil was introduced in
NSCLC cells, acting primarily via VEGFR-2 and vitro and cell proliferation assays were performed
the Neuropilin receptors. Targeting the VEGF pre and post treatment. Voltage clamp studies
survival pathway in NSCLC may potentially be more were again performed to ensure the channels were
effective in the development of anti-cancer therapies blocked. Finally, ex-vivo studies are underway
than anti-angiogenics. utilizing immunohistochemistry in conjunction with
Keywords: VEGF, NSCLC, cell survival the Glans-Look Lung Cancer Database.
Results: Several of the NSCLC lines expressed
one or more of the t-type calcium channel isoforms.
Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15 Using densitometry to analyze the Western blot
results, H460 seems to express Ca(v)3.1 signiÀcantly
P1.080 T-TYPE CALCIUM CHANNEL more than the other cell lines, while H522 has a
EXPRESSION IN NON SMALL CELL greater expression of Ca(v)3.2 when compared to
LUNG CANCER H23, H460 and H1299. Preliminary in vitro results
Allison Childers1, Gerald Zamponi2, Huong Muzik3, suggest that t-type calcium channel blockers can
Shannon Otsuka1, Dafydd G. Bebb3 inÁuence the viability of these cell lines in vitro.
1
Medicine, University Of Calgary/tom Baker Cancer Conclusion: T-type calcium channels are expressed
Centre/Canada, 2Physiology And Pharmacology, with differing levels within the NSCLC cell lines
University Of Calgary/Canada, 3Department Of studied. Based on the t-type antagonist results,
Medical Oncology, Tom Baker Cancer Centre/ t-type calcium channels may have an inÁuence on
Canada the proliferative abilities of NSCLC and continued
study is warranted. Further inquiry into the clinical
Background: Calcium signaling is ubiquitous signiÀcance of t-type channel expression in NSCLC
throughout the cell cycle and is known to directly, patients is currently underway using the Glans-Look
and indirectly, regulate cell proliferation via Lung Cancer Database, in which expression of the
numerous channels and pathways. A newly emerging channels in resected tumors are correlated with
therapeutic target in cancer treatment is the t-type patient outcome. Full results will be presented.
calcium channel. These channels are low-voltage Keywords: t-type calcium channel, Non small cell
activated and exist in three isoforms Ca(v)3.1, lung cancer
Ca(v)3.2, and Ca(v)3.3, differing by their a1
subunits, a1G, a1H and a1I respectively. Typically
these channels are only expressed in epithelia during Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15
development, and usually only found at other stages
in abnormal conditions. T-type calcium channels P1.081 CIGARETTE SMOKE ENHANCES
have been implicated in breast and prostate cancer THE MALIGNANT PHENOTYPE OF
as a facilitator of cell proliferation, although the LUNG CANCER CELLS VIA INDUCTION
mechanism is not well understood. Their role in lung OF THE PUTATIVE STEM CELL
cancer has not been thoroughly investigated. We MARKER ABCG2
set out to assess the expression level and effect of David S. Schrump1, Mary Zhang1, Aarti Mathur1,
Mahadev Rao1, Sichaun Xi1, Yuwei Zhang1, Julie A. response elements as well as SP-1 recognition
Hong1, Clinton Kemp1, R taylor Ripley1, Fang Liu1, sequences within the ABCG2 promoter. CSC-
Gordon Weigand2, Itzak Avital2 mediated induction of ABCG2 coincided with
1
Thoracic Oncology, National Cancer Institute/ recruitment of aryl hydrocarbon receptor (AHR)
United States Of America, 2Gastrointestinal And and SP-1, as well as increased levels of RNA pol II
Hepatobiliary, National Cancer Institute/United and H3K9Ac within the ABCG2 promoter. Under
States Of America exposure conditions potentially achievable in clinical
settings, mithramycin A decreased AHR and SP-1
Background: Limited information is available levels within the ABCG2 promoter, and markedly
regarding epigenetic mechanisms by which cigarette down-regulated ABCG2 expression in lung cancer
smoke mediates initiation and progression of lung cells.
cancers, and how smoking status at diagnosis affects Conclusion: Cigarette smoke enhances the
outcome of patients with these malignancies. malignant phenotype of lung cancer cells, in part,
Methods: Lung cancer cells as well as small airway via induction of ABCG2. These Àndings provide
epithelial cells (SAEC) were cultured in normal a mechanistic link between cigarette smoking and
media (NM) with or without cigarette smoke adverse outcome of lung cancer patients, and suggest
condensate (CSC) under clinically relevant exposure that mithramycin infusions may be a novel strategy
conditions. Microarray, quantitative RT-PCR to target lung cancer stem cells.
and immunoblot experiments were performed to
examine ABCG2 expression levels. Flow cytometry A revised/updated abstract may be included in
techniques were used to assess side population the Late Breaking Abstract Supplement, available
(SP) in lung cancer cells exposed to NM or CSC. at the 14th World Conference on Lung Cancer.
Transfection experiments using shRNA or cDNA
were used to stably knock-down, or constitutively
express ABCG2 in lung cancer cells. MTT, scratch, Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15
soft agar and murine xenograft experiments were
performed to assess proliferation, migration, P1.082 PROANGIOGENESIS FACTORS
clonogencity and tumorgenicity of lung cancer cells AND CELL PHENOTYPING IN THE
following manipulation of ABCG2 expression. ETHIOLOGY AND DIAGNOSIS OF
Transient transfection assays with promoter- MALIGNANT PLEURAL EFFUSIONS
reporter constructs, pyrosequencing, and chromatin Elizabeth Lieser1, Michael Bradshaw2, Gary
immunoprecipitation (ChIP) techniques were used Croghan1, John Mullon2, K robert Shen2, Francis
to examine ABCG2 expression, chromatin structure, Nichols2
1
and transcription factor occupancy within the Oncology, Mayo Clinic/United States Of America,
2
ABCG2 promoter. College Of Medicine, Mayo Clinic/United States Of
Results: Five day CSC exposure signiÀcantly America
up-regulated ABCG2 (a xenobiotic pump highly
expressed in cancer stem cells), in cultured lung Background: Malignant pleural effusions (PEs)
cancer lines as well as SAEC. CSC increased the are a signiÀcant source of cancer morbidity and
pluripotent side population (SP) of lung cancer cells; mortality, and are associated with a median survival
interestingly, ABCG2 up-regulation was observed in of 5 months. Treatments, including pleural catheters,
SP as well as non-SP cells following CSC exposure. pleurodesis, and thoracentesis, which provide some
Knock-down of ABCG2 inhibited proliferation, degree of symptomatic relief, do not address the
migration, and clonogenicity of A549 lung cancer underlying pathobiology. Our prior data shows that
cells endogenously expressing high levels of many malignant PEs contain high levels of VEGF.
ABCG2. In contrast, constitutive over-expression The purpose of this study was to compare levels of
of ABCG2 signiÀcantly enhanced proliferation, VEGF and other markers of angiogenesis in lung
migration, clonogenicity, and tumorigenicity of adenocarcinoma-induced malignant PEs relative to
Calu-6 lung cancer cells endogenously expressing non-malignant PEs.
low levels of ABCG2. CSC-mediated induction Methods: PE samples from nine patients were
of ABCG2 was unrelated to ABCG2 promoter collected and evaluated by ELISA for VEGF
demethylation, but was attributable to xenobiotic (R&D, Minneapolis, MN). An angiogenesis protein
1
array was completed in order to perform a semi- Biochemistry & Molecular Biology, University Of
quantitative comparison of peptide expression in Calgary/Canada, 2Department Of Medical Oncology,
malignant and non-malignant effusions (R&D, Tom Baker Cancer Centre/Canada, 3Medicine,
Minneapolis, MN). Cells were isolated from PE University Of Calgary/tom Baker Cancer Centre/
Áuid and phenotyped using Áuorescent cell sorting Canada
(FACS).
Results: Five lung adenocarcinoma-derived Background: Lung cancer continues to cause
malignant PEs and four non-malignant PEs were signiÀcant morbidity and mortality and the need for
assayed for levels of VEGF. Malignant PEs were newer, gentler therapeutic interventions remains.
found to have 280-fold higher VEGF levels It is reported that 40-60% of non small cell lung
compared to non-malignant by ELISA. The semi- cancer (NSCLC) tumors over-express Bcl-2.
quantitative protein array demonstrated elevated The attenuation of apoptosis by bcl-2 is thought
levels of Leptin, CXCL4 and FGF-7, and decreased to contribute to tumor malignancy and increase
levels of IL-8, MCP-1 and IL-1ơ in malignant PEs. resistance to some cytotoxic agents. GX15-070 is a
FACS analysis of malignant cells showed effusions small molecular inhibitor of the BH3 binding groove
express low levels cytotoxic T-cells (CD3.8) and of Bcl-2 that has shown promise in the treatment of
high levels of dendritic cells (CD11c), monocytes several malignancies in Phase I and II clinic trials.
(CD14) and tumor cells (EpCAM) compared to We have previously shown that anti-sense based anti-
benign PEs. No signiÀcant difference was noted Bcl-2 strategies when combined with vinorelbine
between natural killer (CD16.56) and helper T-cell increase survival in an orthotopic xenograft murine
(CD3.4) populations. Fluid from adenocarcinomas model. We set out to assess the utility of this agent
demonstrated an 8 fold increase of mesothelial cells alone and in combination on a series of NSCLC cell
when compared to non-malignant PEs. lines in-vitro.
Conclusion: Our research demonstrates that Methods: Five NSCLC cell-lines (A549, H23,
malignant effusions possess increased expression H226, H522, H460, H1299) previously characterized
of VEGF-A and other proangiogenic factors may in detail representing three histological subtypes
lead to increased vascular permeability, blood (squamouos, adeno and large cell) were used. Bcl-2
vessel formation and tumor cell implantation. expression was assessed by Western blot techniques.
Levels of other VEGF species, chemokines and Cells were grown in standard media and exposed to
proinÁammatory proteins, did not show signiÀcant a range of concentrations of GX15-070. The dose-
differences between benign and malignant effusions. response curve was assessed by measuring viability
There is a strong indication that mesothelial cells at 24 and 48 hours using the MTT assay. When
play an important role in malignant effusions, but used in combination with other cytotoxic agents,
that function remains indeterminate. Treatment Calcusyn, a mathematical software was used to
with an anti-angiogenesis therapy, such as a calculate the optimum range of drug ratio with the
VEGF inhibitor, may improve the quality of life highest drug synergy.
and prognosis for patients with malignant pleural Results: Each of the NSCLC cell lines grew well
effusions. in-vitro. Each cell line expresses Bcl-2 protein. At 48
Keywords: malignant pleural effusions, hours incubation each cell line exhibited resistance
proangiogenesis factors to GX15-070 at all concentrations tested. Only a
minor reduction in viability was seen at the highest
concentration. There was no difference according
Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15 to histological subtype. However, an increased in
sensitivity was observed when 25uM of GX15-070
P1.083 SUSCEPTIBILITY OF NON SMALL was used in combination with 5M of Vinorelbine,
CELL LUNG CANCER CELL (NSCLC) as compared to treatments when individual drugs
LINES TO TARGETING BCL-2 USING were used.
THE SMALL MOLECULAR INHIBITOR, Conclusion: Although our results demonstrate
GX15-070, ALONE AND IN COMBINATION GX15-070 to be less effective on NSCLC cell lines
WITH CYTOTOXIC AGENTS. as a single agent, an increase in sensitivity was
Poh Soo Lee1, Huong Muzik2, Shannon Otsuka3, observed when it was used in combination with
Dafydd G. Bebb3 Vinorelbine. Using this synergistic combination, a
lower dose of Vinorelbine could be used to achieve a expression in lung cancer cells were used to verify
similar reduction in viability to that achieved with a the role of KIF14 in tumor progression in several
much higher vinoerlbine conentraion. This suggests experiments including cell proliferation, anchor-
GX15-070 to be a plausible candidate that could be independent growth, migration, invasion and tumor
used to boost the effect of current chemotherapeutic growth. The expression patterns of KIF14 mRNA
drugs. With a lower drug dosage, this will in turn and protein in non-small-cell lung cancer (NSCLC)
reduce the side effects experienced by patients, yet patients were investigated by real-time reverse
improving clinical outcome. Work assessing the transcription polymerase chain reaction (RT-PCR)
utility of combining this agent with other cytotoxic and immunohistochemistry (IHC), respectively in
agents in-vivo is currently ongoing and will be an independent cohort and evaluated the correlation
presented. with patients’ clinical outcomes.
Keywords: Bcl2, small molecular inhibitor, Non Results: Overexpression of KIF14 in non-small-
small cell lung cancer cell lung carcinoma CL1-5 cell lines did not affect
the proliferation remarkably but decreased colony
formation in soft agar and the tumor size of
Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15 transplantation in mice. We also observed that the
expression of KIF14 reduces the abilities of cell
P1.084 MOTOR PROTEIN KIF14 AS migration and invasion in vitro. Furthermore, the
A TUMOR SUPPRESSOR IN LUNG results of real-time RT-PCR and IHC are both shown
CANCER that low level expression of KIF14 signiÀcantly
Pei-Fang Hung1, Szu-Hua Pan2, Yih-Leong Chang3, decreased overall survival (P=0.0128 and P<0.0001
Chen-Tu Wu3, Tse-Ming Hong4, Pan Chyr Yang5 respectively, log-rank test).
1
Graduate Institute Of Life Sciences, National Conclusion: KIF14 may consider a tumor
Defense Medical Center/Taiwan, 2Institute Of suppressor and biomarker of lung cancer risk.
Biomedical Sciences, Academia Sinica/Taiwan, Keyword: KIF14
3
Department Of Pathology And Graduate Institute
Of Pathology, College Of Medicine, National
Taiwan University/Taiwan, 4Institute Of Clinical Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15
Medicine, National Cheng Kung University/Taiwan,
5
Department Of Internal Medicine, National Taiwan P1.085 UNRAVELING SUCCESSIVE
University College Of Medicine/Taiwan MOLECULAR EVENTS IN LUNG
CARCINOGENESIS: A CASE REPORT
Background: Intracellular transport is essential for Robert A. Van Boerdonk1, Thomas G. Sutedja2,
the morphology and function of the cell. The kinesin Peter J. Snijders1, Frederik B. Thunnissen1, Sylvia
superfamily proteins (KIFs) have been identiÀed Duin1, Bauke Ylstra1, Gerrit A. Meijer1, Johannes
as motor proteins which can transport organelles, M. Daniels2, Pieter E. Postmus2, Egbert F. Smit2,
proteins and mRNAs in an ATP- and microtubule- Daniëlle A. Heideman1
1
dependent manner. They perform diverse functions Pathology, Vu University Medical Center/
in cell, including membrane motility, chromosome Netherlands, 2Pulmonary Diseases, Vu University
segregation, microtubule dynamics, ciliogenesis Medical Center/Netherlands
and intracellular signaling. Recently, several studied
showed that KIFs also involve in cancer progression Background: Lung cancer is believed to arise
such as KIF1B in oligodenrogliomas, KIF11 in via sequential accumulation of genetic changes.
B-cell leukemia, KIF18A in colon cancer and so on. The current study was set out to evaluate the
KIF14 which belongs to Kinesin-3 family has been genetic changes present in normal lung tissues and
isolated from human immature myeloid cell and is preneoplastic lesions adjacent to the tumours in
involved in the organization of central spindle. Until subjects with lung squamous cell carcinoma (SqCC)
now, little is known about its’ function. to identify the earliest genetic changes that may
Methods: Loss of heterozygosity (LOH) was used be responsible for tumour development in these
to analyze the region of chromosome 1q near the subjects.
loci of KIF14 in lung adenocarcinoma patients. Methods: Post surgical resection, multiple cross-
Overexpressing and knocking down KIF14 sections of the bronchial tree of a subject with SqCC
were dissected. Each cross-section was evaluated by that this miRNA has target sites in the 3’UTR of
histopathology. Genomic DNA was isolated from the Zic1 mRNA. The aim of the current study was
laser-capture micro-dissected normal lung tissue, to investigate the functional signiÀcance of Zic1
premalignant lesions and SqCC, and subjected silencing and hsa-miR-23a over-expression in MM.
to array comparative genomic hybridization Methods: We analysed the mRNA expression
(arrayCGH) analysis (4x44K Agilent). level of Zic1 in MM cell lines (H2052, H452, H28,
Results: Preliminary evaluation indicates the H226 and MSTO), normal mesothelial line Met-
presence of tumour-adjacent, histomorphologically 5A, and human mesothelial cells from pericardial
premalignant changes of various grades. At this Áuid (HMCs) using RT-PCR. The DNA methylation
moment, starting with tumour distant normal status of Zic1 in MM cell lines was conÀrmed using
epithelium the DNA copy number proÀles of the MSP and the COBRA assay. DNA methylation of
tumour adjacent cross-sections are being determined Zic1 in MM tumours was assessed with MSP. The
in order to unravel molecular events associated with expression level of hsa-miR-23a was measured in
histomorphological progression. MM cell lines and primary MM specimens using
Conclusion: It is expected that data and statistical a TaqMan assay. To investigate the functional
analyses will be Ànished by May 2011. signiÀcance of Zic1 silencing, Zic1 was re-expressed
Keywords: lung carcinogenesis, molecular events, in MM cell lines and the effects on cell cycle,
Array comparative genomic hybridization proliferation, migration and colony formation were
assessed. The relationship between hsa-miR-23a and
A revised/updated abstract may be included in Zic1 expression was investigated by the use of an
the Late Breaking Abstract Supplement, available antagonist of hsa-miR-23a.
at the 14th World Conference on Lung Cancer. Results: RT-PCR analysis indicated high levels of
mRNA expression of Zic1 in Met-5A and HMCs.
In contrast, Zic1 was not expressed or was down-
Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15 regulated in MM cell lines. Following treatment
with 5’Aza, expression of Zic1 was signiÀcantly
P1.086 FUNCTIONAL SIGNIFICANCE up-regulated in all mesothelioma lines but was
OF ZIC1 AND HSA-MIR-23A OVER- unchanged in Met-5A and HMCs. Zic1 COBRA and
EXPRESSION IN MALIGNANT MSP analysis correlated with mRNA expression,
MESOTHELIOMA suggesting Zic1 is silenced in MM through DNA
Yuen Yee Cheng1, Michaela B. Kirschner1, hypermethylation. Enforced Zic1 expression
Hongchuan Jin2, Francis K.L. Chan3, Nico Van inhibited cell migration and colony formation in H28
Zandwijk1, Glen Reid1 cells. Hsa-miR-23a overexpression in MM and is
1
Asbestos Diseases Research Institute, The closely linked to Zic1gene expression.
University Of Sydney/Australia, 2Biomedical Conclusion: Our results show that Zic1 behaves
Research Center, Zhejiang University/China, in MM cell culture as a functional tumour
3
Medicine, The Chinese University Of Hong Kong/ suppressor that is silenced by a combination of
Hong Kong hypermethylation and hsa-miR-23a-mediated
inhibition. hsa-miR-23a is a potential therapeutic
Background: Epigenetic inactivation of tumour target deserving further studies.
suppressor genes through DNA hypermethylation Keyword: Zic1, microRNA, Mesothelioma
plays a crucial role in the progression of malignant
mesothelioma (MM). Our previous work indicated
that Zic1 silencing in MM lines is only partially Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15
explained through DNA hypermethylation. Zic1
is essential for the regulation of proliferation and P1.087 EPIGENETIC INACTIVATION
differentiation of the neural crest and subsequent OF THE SFRP FAMILY BY DNA
cerebellar development. It is also a tumour METHYLATION IN MALIGNANT
suppressor gene down-regulated through promoter MESOTHELIOMA
hypermethylation in gastric cancer. Interestingly, Yuen yee Cheng1, Chris Mclaughlin2, Hongchuan
miRNA microarray analysis revealed that hsa- Jin3, Francis K.L. Chan4, Michaela B. Kirschner1,
miR-23a is over-expressed in MM cell lines, and Tony George2, Nico Van Zandwijk1, Glen Reid1
1
Asbestos Diseases Research Institute, The (16/17) primary clinical MM samples, respectively.
University Of Sydney/Australia, 2The University Conclusion: Our results indicate that SFRP2 and
Of Technology And Science/Australia, 3Biomedical SFRP5 genes are silenced by DNA methylation
Research Center, Zhejiang University/China, and reactivated by the DNA demethylating agent
4
Medicine, The Chinese University Of Hong Kong/ 5’Aza. Methylation of SFRP2 and 5 promoters was
Hong Kong observed in a majority of MM tumour specimens,
suggesting that epigenetic inactivation of SFRP gene
Background: The etiology of Malignant family plays a pivotal role in MM development.
Mesothelioma (MM) is closely linked with asbestos Keyword: SFRP, Tumour suppressor, mesothelioma
exposure. Asbestos is capable of inducing chronic
inÁammation with the potential to contribute to
epigenetic silencing of tumour suppressor genes. Poster Session 1 – Cancer Biology Monday, 4 July 2011 12:15-14:15
Epigenetic silencing of the Wnt pathway, well
characterized in the progression of colon cancer, is P1.088 GENDER RELATED
associated with chronic inÁammation. The SFRP GENOMIC DIFFERENCES IN LUNG
gene family acts as antagonist to the Wnt pathway ADENOCARCINOMA
and expression of SFRPs is silenced in colon, gastric, Greg L. Stewart1, Kelsie Thu1, Emily A. Vucic1,
breast, ovarian and lung cancers, with some members Jennifer Y. Kennett1, Larissa A. Pikor1, Raj Chari2,
silenced in mesothelioma. The Wnt pathway has Wan Lam1, Stephen Lam1
1
been found activated in MM. There is evidence that Integrative Oncology, British Columbia Cancer
inÁammation can lead to epigenetic silencing of Research Centre/Canada, 2Genetics, Harvard
members of the SFRP family. In this study, we aimed Medical School/United States Of America
to investigate the relationship between gene silencing
and DNA methylation of the SFRP gene family in Background: Gender disparities related to
MM. incidence, clinical presentation, mortality and
Methods: We investigated SFRP expression in MM therapeutic response in non small cell lung cancer
cell lines, mesothelial cell line Met5A and primary (NSCLC) are becoming increasingly apparent.
human mesothelial cell cultures from pericardial It is unclear whether environmental, behavioral,
Áuid (HMCs). The effect of the demethylating agent hormonal, genetic, or biological factors, including
5’Azacitidine (5 days, 2mM) on SFRP expression nicotine clearance, can fully explain such disparities.
was also determined. Expression of SFRP mRNA For example, women on hormone replacement
was measured by conventional RT-PCR, and DNA therapy have an increased risk of NSCLC, but
methylation analysis using methylation-speciÀc PCR these changes cannot explain observed clinical
(MSP) and COBRA. MSP was used to study the disparities. Recent Àndings in never smokers with
DNA methylation status of SFRPs in MM tumour adenocarcinoma, have shown females display a
specimens. higher rate of EGFR mutation than males. It is
Results: SFRP2 and SFRP5 expression was absent possible that other gender based genetic differences
in 3 and 4 out of 5 MM lines, respectively. And play a role in susceptibility to lung cancer in
high levels were detected in Met-5A and HMCs. In smokers. We hypothesize that lung tumor genomes
contrast SFRP1 and SFRP4 were highly expressed of males and females smokers harbor differences
and unmethylated in all MM lines. As previously at the molecular level that may underlie the gender
reported SFRP2 and 5 were down-regulated in the based disparities observed in adenocarcinoma.
lung cancer line A549 and we showed corresponding Methods: Global gene dosage proÀles for 48 lung
results as others. Following treatment with 5’Aza, adenocarcinoma from 16 males and 32 females
expression of SFRP2 and SFRP5 was signiÀcantly (all current smokers) were generated by array
up-regulated in all 5 MM lines but unchanged in comparative genomic hybridization. A Fisher’s test
Met-5A and HMCs. COBRA analysis of SFRP2 was used to identify genomic regions differentially
and SFRP5 correlated with presence of mRNA altered between males and females. The identiÀed
expression. MSP analysis of the DNA methylation candidate regions from our discovery set were
status of SFRP2 and SFRP5 in cell lines revealed validated in an external cohort comprised of male
methylation in non-expressing cell lines. SFRP2 and (n=29) and female (n=37) current smokers with lung
SFRP5 were methylated in 65% (11/17) and 94% adenocarcinoma from the database of Genotypes and
Phenotypes (dbGaP). non-small cell lung cancer (NSCLC), and on the

Results: We found 7 distinct differentially clinical severity of NSCLC in 52 NSCLC patients
altered regions between male and female lung and 60 control subjects were examined. A hospital-
adenocarcinoma, that overlapped between our based case-control study was undertaken in Ankara
discovery and external datasets, which encompassed University Hospital. PON 1 L55M 55 and Q192R
200 genes in these chromosomal regions: chr14 192 genotypes were determined by PCR, RFLP and
q12-q21.3, chr17 q21.33-q22, chr8 q11.22-q12.1, agarose gel electrophoresis techniques.
chr8 q22.1-q22.2, chr8 q22.2-q24.13, chr8 q24.3, Results: The analysis showed genotype distributions
chr3 q26.1. Using Ingenuity Pathways Analysis we and allele frequencies for PON 1 Q192R
identiÀed several pathways and biological functions polymorphism were not signiÀcantly different
affected by genes located in these regions. Many between controls and NSCLC patient group (
of these genes are known oncogenes previously p>0.05), but in genotype and allele distribution
shown to be involved in NSCLC and inÁammatory of PON 1 L55M polymorphism, there was
pathways such as PI3/AKT and IL6 while others signiÀcantly difference among groups (p<0.05).
are new. These Àndings imply that these seven Genotype distributions for both polymorphisms
differentially altered regions and the genes they were not signiÀcantly different between subgroups
encompass may play a signiÀcant role in gender of squamous cell carcinoma and adenocarcinoma
differences observed in NSCLC. type. There was a statistically signiÀcant difference
Conclusion: Our study suggests there are gender of NSCLC risk in mutant genotypes, especially for
speciÀc genetic disparities in NSCLC at the gene current smokers and heavy smokers. Moreover,
dosage level, and provides rationale for further mutant genotypes present signiÀcantly lower risk of
investigation in larger cohorts. On-going studies that developing cancer in stage IV for NSCLC.
include analyses of different genomic dimensions Conclusion: Our results suggest that both of PON1
such as gene expression and DNA methylation, may polymorphisms appear to be common genetic traits
lead to additional information on gender differences that are associated with a decreased risk and severity
in NSCLC, potentially leading to improvements in for NSCLC. The effect is especially strong for heavy
prevention, diagnosis, and treatment. smokers.
Keywords: Current Smokers, gender, Non small cell Keywords: Paraoxonase I gene, SNP, Non small cell
lung cancer, Genomics lung cancer, Heavy smoker

Poster Session 1 – Novel Cancer Monday, 4 July 2011 12:15-14:15 the Late Breaking Abstract Supplement, available
P1.089 A STUDY OF PARAOXONASE I
GENE POLYMORPHISMS WITH THE
RISK AND SEVERITY OF NON-SMALL Poster Session 1 – Novel Cancer Monday, 4 July 2011 12:15-14:15
CELL LUNG CANCER (NSCLC) IN
TURKISH PATIENTS P1.090 THE FUNCTION OF STAT3
Fadhil Ahsan1, Asuman Sunguroglu2 SIGNALING PATHWAY DURING
1
Internal Medicine, University Of Indonesia/ LEPTIN PROMOTING HUMAN
Indonesia, 2Medical Biology, Ankara University/ LUNG ADENOCARCINOMA CELLS’
Turkey PROLIFERATION PROCESS
Yanbei Zhang, Bidan Hu
Background: Paraoxonase 1 is a high-density Department Of Geriatric Pulmonary, The First
lipoprotein (HDL)-associated enzyme that was AfÀliated Hospital Of Anhui Medical University/
thought to against lung cancer (LC) because it may China
has a role in protecting from oxidative stress in
the lung and circulation. PON 1 has two genetic Background: lung cancer is one of the most
polymorphisms in coding region; L55M and Q192R. prevalent malignancies in the whole world, and now
Methods: In the present study, distribution of it has been on the top of deaths caused by cancer.
PON 1 L55M and Q192R polymorphisms and There are about 600 thousand people died of cancer,
the effect of these polymorphisms on the risk of and the number was increasing every year. The
incidence rate of female patients especially got an and pathological process of lung. For example, it
increasingly trend. China is also a country which is involved in fetal lung maturity and play a role in
has a high incidence of lung cancer. Therefore, the physiological function in the maintenance of adult
reacerch of correlation of lung cancer has been normal lung epithelial cells. It also found that leptin
taken to attention. According to pathohistology, can promote the proliferationof SQ-5 lung squamous
lung cancer is devided into two category. One is cell carcinoma cell line. Therefore, leptin is closely
small cell lung cancer (SCLC), another is non- related to the development of the occurrence of lung
small cell lung cancer(NSCLC). Non-small cell cancer. Currently, however, it is still unclear the
lung cancer(NSCLC) comprises about 75-80% of concrete mechanism of leptin in the development
all lung cancers and represents a heterogeneous of lung cancer. Another study showed that leptin
group of cancers, consisting mainly of squamous signal transduction pathways have relationships
cell carcinoma, adenocarcinoma, adenosqamous with the activity of JAKs / STATs family. Animal
carcinoma and large cell carcinoma subtypes. In tests also suggested that the hypothalamus of leptin
the tumor process, abnormality of the cell signal signal transduction mainly involves JAK2/STAT3.
transduction and loss of balance of cell proliferation Ob-R ligand binds to Ob-Rb and phosphorylate
and apoptosis have been proven to be the two tyrosine residue in cells, and then activates JAK2 by
key elements. These two aspects are inseparable transphosphorylation. A connection site with single
with lung cancer occurrence and development of STAT3 is formed through phosphorylation of Ob-Rb.
mechanisms. Leptin is a N terminal signal peptide STATs are a group of cytoplasmic proteins. Its role as
with 21 amino acid peptide which is coded by a signal transductor and transcription factor involved
obese gene (OB) and mainly secreted by adipose in the reaction to cytokines and growth factors in
tissue. Its main function is to regulate the body’s normal cells. STAT3 is a potential cytoplasmic
energy metabolism and fat synthesis. Serum leptin transcription factor in STATs family. Once STAT3
levels were directly correlated with patient’s body attachs its receptors, in the No. 705 carboxy-terminal
weight, suggesting that leptin is closely related tyrosine phosphorylation site (Y705) has been
with the feeding. Leptin also has many important phosphorylated by JAK2, and the STAT3 transforms
physiological functions, including ampliÀcation into p-STAT3. Through the role of SH2 region
of inÁammation and immune function. However, STAT3 forms the homodimer or heterodimer, and
further studies have shown that leptin can stimulate transfers into the nucleus. nteracted with a speciÀc
the proliferation of tumor cells, inhibit tumor cell gene promoter region of the DNA components or
apoptosis and can increase the invasiveness of other transcription factors or ancillary proteins, the
tumor cells and to promote the formation of new homodimer or heterodimer regulate the downstream
blood vessels within the tumor, Therefore, in tumor target genes, Such as: bcl-2 transcription, which
occurrence and development of leptin plays a role can cause growth disorders, promote cell malignant
can not be ignored. The current study conÀrmed transformation and tumorigenesis.
that leptin over expressed in various tumor tissues Methods: The immunohistochemical SP method
and cells, and was closely linked with tumor was used to examine the protein expressions of
occurrence and development. Leptin can only leptin, STAT3, p-STAT3, Bcl-2 in 52 cases of non-
perform its biological function through combining small cell lung cancer and 34 cases of paracancerous
with its receptor (Ob-R) on different target organs. normal lung tissues. Their correlations with
The long leptin receptor (Ob-Rb) of its receptors clinical stage, and lymph node metastasis of lung
is the only complete intracellular domain and has cancer were statistically analyzed. MTT assay was
intracellular tyrosine residues of the Ob-R forms, used to determine the effect of leptin on the cell
which have a signal transduction function. Many proliferation. Flow cytometry was used to detect
clinical trials conÀrm that functional leptin and the growth rate of A549 cells treated by different
leptin receptor (OB-Rb) have high expressions in concentration of leptin. Immunocytochemistry
endometrial cancer, stomach cancer, breast cancer, staining were used to evaluate the protein expression
prostate cancer and a variety of tumor tissue and of STAT3, p-STAT3 and Bcl-2 in human lung
tumor cell lines. Meanwhile, we found expression of adenocarcinoma A549 cells.
OB-Rb in human lung tissues, which indicated that Results: The positive staining rates of leptin, STAT3,
the lung is the target organ of leptin. As a cytokine, p-STAT3 and Bcl-2 protein in NSCLC tissues were
leptin have functions both in physiological process signiÀcantly higher than Para cancerous normal lung
tissues. The expression of STAT3 and p-STAT3 had Background: Transforming growth factor-alpha
close relationships with TNM stage of lung cancer and (TGF-alpha) and transforming growth factor-beta
Lymph node metastasis (P 0.05). The expression of (TGF-beta) are two pivotal cytokines regulating
STAT3 was positively correlated with the expression positive and negative proliferation, respectively,
of p-STAT3(P 0.05), and the expression of p-STAT3 of tracheobronchial epithelial cells during normal
was positively correlated with the expression development as well as cancer progression. Though
of Bcl-2 (P 0.05). The expressions of STAT3, Cited2, a novel cytokine inducible modulator,
p-STAT3 and Bcl-2 were detected in the human lung regulates mouse fetal lung development and possess
adenocarcinoma A549 cells, which were gradually transforming ability, the role of Cited2 in lung
increased accompaning time and concentration tumorigenesis is still elusive.
increasing. And The expressions of STAT3, p-STAT3 Methods: Immunohistochemical analysis was
and Bcl-2 were signiÀcantly increased in 100ng/ performed to analyze the Cited2 expression in 45
ml leptin treated group. Leptin can stimulate the lung adenocarcinoma cases. TGF-alpha and TGF-beta
proliferation of A549 cells, especially when leptin mediated Cited2 expressions were also determined in
was 100 ng/ml after 24-hour treatment. Moreover, the lung cancer cells by Q-PCR and immunoblotting.
ratio of cells in G2/M cell cycle in those treated with Results: We observed that Cited2 correlates with
100 ng/ml leptin was signiÀcant higher than in 0ng/ tumor staging in human adenocarcinoma, suggesting
ml,10ng/ml leptin treated group. the involvement of Cited2 in lung tumorigenesis.
Conclusion: (1) The high expression of leptin, STAT3, We discovered that Cited2 is induced by TGF-alpha
p-STAT3 may play an important role in the progression via c-Myc and further activates TGF-alpha/EGFR
and development of human NSCLC which may be signaling in a positive feedback manner. Moreover,
useful in the assessment of the malignant processing Cited2 acts collaboratively with c-Myc to induce
and biological behavior of the malignant tumor. (2) E2F3a and G1/S cell cycle transition. Whereas TGF-
The activation of STAT3 is possibly mediated by over- beta inhibits growth of lung cancer cells, it decreases
expression of anti-apoptosis gene bcl-2 in the lung Cited2 level but induces p21CIP1 expression. Cited2
cancer cells which make continued proliferation of lung inhibits cellular senescence through binding to
cancer cells. It plays an important role in malignant p21CIP1 promoter, potentiating c-Myc-mediated
transformation and evolution of lung cancer cells. (3) suppression of p21CIP1. Overexpression of Cited2
Leptin may promote the proliferation of A549 cells by enhances tumor growth in nude mice; furthermore,
activating STAT3 signaling pathway and inducing the knockdown of Cited2 causes tumor shrinkage and
over expression of bcl-2. increases overall survival rates of host mice. Clinical
Keywords: Non-small cell lung cancer, leptin, JAK/ data analysis showed that Cited2 is highly expressed
STAT3 signal pathway, Bcl-2 in human lung adenocarcinoma and correlated with
c-Myc expression.
A revised/updated abstract may be included in Conclusion: These data demonstrate that Cited2
the Late Breaking Abstract Supplement, available plays an emerging role in cytokine induced
at the 14th World Conference on Lung Cancer. proliferation and senescence of lung cancer,
with potential applications as a novel prognostic
biomarker and therapeutic target in lung cancer.
Poster Session 1 – Novel Cancer Monday, 4 July 2011 12:15-14:15 Keywords: Cited2, c-Myc, proliferation, senescence
P1.091 THE EMERGING ROLE OF

CITED2 IN CYTOKINE MEDIATED Poster Session 1 – Novel Cancer Monday, 4 July 2011 12:15-14:15
PROLIFERATION AND SENESCENCE OF
LUNG CANCER P1.092 COMPREHENSIVE EVALUATION
Yu-Ting Chou1, Cheng-Han Hsieh1, Chiung-Fang Hsu1, OF THE RESPONDED GENES BY THE
Yu-Rong Kao1, Yi-Shing Shieh2, Cheng-Wen Wu3 ADMINISTRATION OF ANTI-TUMOR
1
Institute Of Biomedical Sciences, Academia DRUG, S-1 USING LOW DENSITY ARRAY.
Sinica/Taiwan, 2Department Of Oral Diagnosis & Hisashi Matsuoka1, Kazuya Kondo1, Hiromitsu
Pathology,, Tri-service General Hospital/Taiwan, Takizawa2, Haruhiko Fujino1, Koh Uyama2, Hiroaki
3
Microbiology And Immunology, National Yang-ming Toba2, Koichiro Kenzaki2, Shoji Sakiyama2, Akira
University/Taiwan Tangoku2
1
Department Of Oncological Medical Services,, have positive correlation with TGI .
Institute Of Health Biosciences, The University Of Conclusion: In orthotopically implanted SCID
Tokushima Graduate School/Japan, 2Department mice model of the lung cancer 4 cell lines, the
Of Thoracic, Endocrine And Oncological Surgery, expression of PRSS3, ABCC4, TXN, SHMT1 and
Institute Of Health Biosciences, The University Of CMPK genes were signiÀcantly prompted by the
Tokushima Graduate School/Japan administration of S-1, and the expression of LMO7
and FOLH1 genes were signiÀcantly suppressed.
Background: There were several studies which have However, the extent of variation of gene expressions
comprehensively examined genes which predict except FOLH1 was low (1.5-2.0). There were not a
the response of cancer cells to chemotherapies, signiÀcant variation of TS (thymidylate synthase),
including 5-FU using in vitro cancer cell lines DPD (dihydropyrimidine dehydrogenase), TP
and xenograft subcutaneous implantation models. (thymidine phosphorylase) and OPRT (orotate
In 1889, Paget proposed the original “seed and phosphoribosyltransferase) gene expressions which
soil” theory that organ-site-speciÀc implantation were reported to be related to chemosensitivity of
of tumor cells is essential for optimal growth and 5-FU by several previous studies. Resistant tumor
progression of tumors in vivo. Fidler established group (A549) and moderately effective group (Lu99,
an orthotopic implantation metastatic model using Lu130, LC6) were classiÀed by tumor growth
tumor cell suspensions which were inoculated into inhibition rate (TGI) for S-1. The expression of
the corresponding organ of nude mice. ATo identify ABCC1, 2and TST genes have negative correlation
genes that might be associated with chemosensitivity with TGI. The expression of TK1 and ERCC2 genes
of the anti-tumor drug S-1, we used a low density have positive correlation with TGI .
array representing 93 genes to analyze expression Keywords: S-1, orthotopically implanted SCID
proÀles in 4 orthotopically implanted lung cancers mice, low density array
derived from human lung cancer cell lines.
Methods: The mice were orthotopically implanted 4
cell lines( A549,LC6,Lu99,Lu130) . After 6 weeks, Poster Session 1 – Novel Cancer Monday, 4 July 2011 12:15-14:15
we administered S-1 (10mg/kg) to SCID mice for
3 weeks. Then mice were sacriÀced and tumors P1.093 ANALYSIS OF INTRA-TUMOR
were resected. We extracted RNA from tumors and HETEROGENEITY OF EGFR
examined the expression of 96 genes related to 5-FU MUTATIONS IN MIXED-TYPE LUNG
using low density array. ADENOCARCINOMA
Results: In A549, the tumor weight was Nanae Tomonaga1, Yoichi Nakamura1, Hiroyuki
0.020g±0.011g in control group and 0.019±0.008g Yamaguchi1, Takaya Ikeda1, Kosuke Mizoguchi1,
in S-1 group. TGI (%)[=(1-Average tumor weight Kohei Motoshima1, Katsumi Nakatomi1, Tetsuya
of S-1 dosed group/ Average tumor weight of Iida1, Tomayoshi Hayashi2, Takeshi Nagayasu3,
Control group)*100] was 3.6. The expression of Kazuhiro Tsukamoto4, Shigeru Kohno1
1
TXN, SHMT1 and CMPK genes were signiÀcantly Second Department Of Internal Medicine,
prompted by the administration of S-1. In LC6, the Nagasaki University Hospital/Japan, 2Department
tumor weight was 0.029g±0.017g in control group Of Pathology, Nagasaki University Hospital/
and 0.020±0.011g in S-1 group. TGI was 32.1. Japan, 3Division Of Surgical Oncology, Nagasaki
The expression of LMO7 and FOLH1 genes were University Hospital/Japan, 4Department Of
signiÀcantly suppressed by the administration of Pharmacotherapeutics, Nagasaki University
S-1. In Lu99, the tumor weight was 0.14g±0.11g Graduate School Of Biomedical Science/Japan
in control group and 0.092±0.048g in S-1 group.
TGI was 34.6. The expression of PRSS3 and Background: Epidermal growth factor receptor
ABCC4 genes were signiÀcantly prompted by (EGFR) mutations are predictive of the success of
the administration of S-1. In Lu130, the tumor EGFR tyrosine kinase inhibitor (TKI) treatment in
weight was 0.024g±0.016g in control group and patients with advanced non-small-cell lung cancer
0.015±0.008g in S-1 group. TGI was 37.5. No (NSCLC). As with other solid tumors, lung cancer is
gene had signiÀcant difference. The expression of thought to be the result of an accumulation of genetic
ABCC1, 2 and TST genes have negative correlation alterations following exposure to carcinogens.
with TGI. The expression of TK1 and ERCC2 genes Here, we aim to clarify the relationship between the
multistep carcinogenesis and the accumulation of Institute Of Development, Aging And Cancer, Tohoku
EGFR mutations. University/Japan
Methods: We analyzed intra-tumor heterogeneity
of EGFR mutations in 38 patients with resected Background: Survivin is a member of Inhibitor of
mixed type lung adenocarcinoma in accordance Apoptosis (IAP) family and plays signiÀcant role
with the distribution of histological subtypes. Each of tumorigenesis and proliferation of Non-small
part of each specimen was classiÀed into its lung cell lung cancer (NSCLC). Survivin has at least Àve
adenocarcinoma subtype, papillary, acinar or BAC, kinds of spliced variants, but the details of their role
by a pathologist. Then, formalin-Àxed, parafÀn- have been unclear. We presented that Survivin-2B
embedded surgical specimens were microdissected expression had correlated with good prognosis, and
in accordance with the pathological subtypes using Survivin-3B expression had correlated with poor
a Leica application solutions laser micro dissection prognosis. Thus, we have studied the relationship
(AS LMD) system. We extracted genomic DNA between survivin spliced variants and cell viability
from tumor cells obtained from each microdissected of non small cell lung cancer.
specimen. The mutations of EGFR, deletions in exon Methods: To knockdown survivin variants
19 and point mutation of L858R in exon 21, expression, small interfering RNAs targeting against
were analyzed using mutant-enriched polymerase survivin variants was synthesized. and transfected
chain reaction (PCR) to increase the sensitivity of into NSCLC cell lines. The down regulation of
these mutations. Finally, we evaluated the clinical survivin spliced variants expression at mRNA
features of the patients harboring intra-tumor levels were detected by RT-PCR. Cell proliferation
heterogeneity of EGFR mutations. inhibition rates were determined by MTT assay.
Results: We detected intra-tumor heterogeneity of Results: Both non-speciÀc and speciÀc siRNA to
EGFR mutations in 9 of 38 tumors. survivin and its variants could efÀciently suppress
EGFR mutations were more common in the BAC mRNA levels of survivin and its variants. The
subtype than the papillary and acinar subtypes, non-speciÀc siRNA could efÀciently inhibit cell
although this difference was not statistically proliferation but the speciÀc siRNA could not.
signiÀcant. Conclusion: The use of survivin siRNA deserves
However, we found a statistically signiÀcant further investigation to cancer therapy but survivin
correlation between intra-tumor heterogeneity of variant speciÀc siRNA may be useless.
EGFR mutations and smoking history (P<0.043). Keywords: survivin, NSCLC
Conclusion: Intra-tumor heterogeneity of EGFR
mutations correlates with the distribution of A revised/updated abstract may be included in
histological subtype in mixed-type adenocarcinoma, the Late Breaking Abstract Supplement, available
and is associated with smoking history. at the 14th World Conference on Lung Cancer.
Keywords: Non-small cell lung cancer, EGFR, intra-
tumor heterogeneity
Poster Session 1 – Novel Cancer Monday, 4 July 2011 12:15-14:15
Poster Session 1 – Novel Cancer Monday, 4 July 2011 12:15-14:15 P1.095 FOXF1 OVEREXPRESSION
IN NSCLC CORRELATES WITH
P1.094 SURVIVIN SPLICED VARIANTS ACTIVATION OF THE HEDGEHOG (HH)
AND CELL VIABILITY OF NON SMALL SIGNALING PATHWAY
CELL LUNG CANCER. Ioannis Gialmanidis1, E. Klironomakis1, Georgios
Fumihiko Hoshi1, Chiaki Endo2, Akira Sakurada2, Mathioudakis2, Ioannis Sarantitis1, Nikolia
Hirotsugu Notsuda3, Yoshinori Okada3, Yui Sotiropoulou1, Vasiliki Bravou1, Helen Papadaki1
Watanabe2, Shunsuke Eba3, Tatsuaki Watanabe2, 1
Anatomy Medicine School, University Of Patras/
Masaki Kawamura3, Yasuki Saito1, Toru Hasumi1, Greece, 2General Hospital Of Nikea/Greece
Takashi Kondo2
1
Thoracic Surgery, Sendai Medical Center/ Background: The Hedgehog (Hh) signaling
Japan, 2Department Of Thoracic Surgery, Institute pathway is crucial for normal development while
Of Development, Aging, And Cancer, Tohoku activation of the pathway in adult tissues is
University/Japan, 3Department Of Thoracic Surgery, associated with the development of different types of
cancer. Recent studies have shown that members of Of Development, Aging, And Cancer, Tohoku
Forkhead Box (Fox) family of transcription factors University/Japan, 2Department Of Thoracic Surgery,
are targets of Hh pathway. We have previously Institute Of Development, Aging And Cancer, Tohoku
shown that Hh signaling pathway is activated in University/Japan, 3Thoracic Surgery, Sendai Medical
NSCLC and correlates with histologic subtype, Center/Japan
prognostic parameters of the tumors as well as
with the increased expression of FoxM1. The aim Background: p190-A RhoGAP(Grlf1) is a 172-kDa
here was to determine the expression pattern of the protein that is encorded by GRLF1 gene which locates
fox gene FoxF1 in relation to the Hh pathway in on 19q13.3. In some cancer cell lines, Grlf1 is reported
NSCLC. to be one of negative regulators of RhoA and inhibit
Methods: A total of 80 NSCLC (35 cell migration and invasion. This suggests that Grlf1
adenocarcinomas, 22 squamous cell carcinomas, protein plays potential tumor suppressor roles. On the
17 large cell carcinomas, 3 adenosquamous other hand, EGF – induced Grlf1 phosphorylation has
and 3 bronchioloalveolar carcinomas) were been reported to be essential in Ras activation and cell
immunohistochemically analyzed with anti-FoxF1 proliferation. Recent large scale screening using mass
antibody on parafÀn tissue sections. Correlations spectrometry indicated that Grlf1 is involved in EGFR
with Hh signaling components Shh, Ptch1 and Gli1 pathways in lung adenocarcinoma cells. To clarify
as well as FoxM1 and clinicopathological data were the role of Grlf1in lung adenocarcinoma cells is an
evaluated. important issue.
Results: FoxF1 expression was positive in 77.5% Methods: We used 4 lung adenocarcinoma cell lines,
of tumors while was absent in adjacent non-tumoral A549 (Ras mutation and WT EGFR), 11-18 (L858R
lung tissue. Cytoplasmic expression of FoxF1 was mutation EGFR), PC-14 (Exon19 deletion EGFR),
correlated with Hh pathway activation (expression and H1975 (L858R and T790M mutation EGFR)
of both Ptch1 and Gli1 in the tumor) (p=0.047). respectively. Immunoprecipitation technique was used
There was also a statistical signiÀcant correlation to detect the phosphorylation of p190-A RhoGAP.
of lymph node metastasis and FoxF1 nuclear Effects of Grlf1 siRNA knockdown in 4 cell lines were
expression (p=0.044). Statistical analysis also analyzed by RT-PCR and MTS assay in Grlf1 mRNA
revealed a signiÀcant correlation between nuclear expression and cell proliferation. We studied relative
FoxF1 expression and histological type of the tumor expression level of Grlf1 mRNA in lung tissue from 67
(p=0.005), higher expression in squamous cell human samples (67 tumor and 67 normal) by RT-PCR.
carcinomas. Results: Phosphorylation of Grlf1 was induced in
Conclusion: Overexpression of the Fox transcription 4 cell lines by EGF stimulation. Phosphorylation
factor FoxF1 is implicated in lung cancer of Grlf1 was inhibited by administration of EGFR-
pathogenesis and correlates with activation of the Hh TKI (geÀtinib) 11-18 and PC-14, but not in A549
pathway.FoxF1 seems to play an important role in and H1975. The proliferation of A549, 11-18, PC-
the development of squamous cell carcinomas and 14 and H1975 cells was inhibited by Grlf1 siRNA
also controls the potential of lymph node metastasis. knockdown, while no obvious inhibition was
Keywords: FoxF1, Hedgehog, NSCLC, Shh observed in normal human bronchial epithelial cells.
mRNA expression level of Grlf1 was conÀrmed by
RT-PCR in set of 67 human lung tissue samples.
Poster Session 1 – Novel Cancer Monday, 4 July 2011 12:15-14:15 Conclusion: p190-A RhoGAP is involved in
epidermal growth factor receptor pathways and
P1.096 PHOSPHORYLATION OF activates cell proliferation in lung adenocarcinoma.
P190-A RHOGAP IS INVOLVED IN Overexpression of Grlf1 mRNA was detected
EPIDERMAL GROWTH FACTOR from some human lung cancer samples. Further
RECEPTOR PATHWAYS IN LUNG conÀrmation for the role of Grlf1 in lung
ADENOCARCINOMA CELLS. adenocarcinoma seems to be important.
Akira Sakurada1, Hirotsugu Notsuda2, Chiaki Keywords: p190-A RhoGAP, EGFR, proliferation
Endo1, Fumihiko Hoshi3, Shunsuke Eba2, Tatsuaki
Watanabe1, Yui Watanabe1, Yoshinori Okada2, A revised/updated abstract may be included in
Takashi Kondo1 the Late Breaking Abstract Supplement, available
1
Department Of Thoracic Surgery, Institute at the 14th World Conference on Lung Cancer.
Poster Session 1 – Novel Cancer Monday, 4 July 2011 12:15-14:15 concentrations of 17AAG prior to gamma-irradiation
(3-5 Gy) sharply enhanced the apoptotic death in
P1.097 INHIBITION OF HEAT SHOCK both the treated lung cancer cell lines and decreased
PROTEIN 90 ACTIVITY IN HUMAN their clonogenic ability, whereas without 17AAG
LUNG CANCER CELLS ENABLES TO analogous treatments induced the considerably
SENSITIZE THEM TO RADIOTHERAPY less cytotoxicity and only a slight decrease in the
Alexander Kabakov, Vladimir Kudryavtsev clonogenicity. This 17AAG-conferred sensitization
Department Of Radiation Biochemistry, Medical seemed to be due to down-regulation and/or
Radiology Research Center/Russian Federation inactivation of pro-survival proteins (e.g. Akt, Bcl-
2, survivin, XIAP) and activation of pro-apoptotic
Background: Human lung carcinomas are often proteins (e.g. Bad, GSK-3). In contrast to the
resistant to radiotherapy; therefore, development described responses of the lung cancer cells, 17AAG
of approaches to their radiosensitization is of affected neither apoptosis nor clonogenicity in the
paramount importance. On the other hand, such normal lung-derived Àbroblast cultures irradiated
radiosensitization must be selective toward the at the same doses. Besides the enhancement of
tumor cells without aggravating radiation damage killing of the irradiated lung cancer cells, 50-100 nM
to adjacent normal tissues. Here we explored how 17AAG considerably reduced their angiogenicity
17-N-allilamino-17-demethoxygeldanamycin that was revealed on down-regulation of the HIF-
(17AAG), known as a pharmacological inhibitor 1alpha and VEGF expression levels, and on the
of the heat shock protein 90 (Hsp90) chaperone impaired stimulation of EC proliferation by adding
activity, affects responses of human lung cancer lung carcinoma cell culture-conditioned medium.
cells and human normal lung cells to ionizing Conclusion: Clinically achievable (nanomolar)
radiation exposure. Our study was mainly aimed at concentrations of 17AAG allow to selectively
comparison of the effects of 17AAG on human lung enhance the cytotoxicity of radiotherapy toward
carcinoma cells and normal lung cells subjected the lung carcinoma cells and to suppress the lung
to radiation exposure modeling the action of cancer-associated angiogenesis. So, pharmacological
radiotherapy. inhibition of Hsp90 may become a beneÀcial tool in
Methods: In vitro cultured human lung carcinoma Àght against lung cancer.
cell lines SQ-5 and A549, and human normal Keywords: radiosensitization, Radiotherapy, lung
lung-derived Àbroblasts were exposed to clinically carcinoma, radioprotective response
relevant doses (3-5 Gy) of gamma-photon
irradiation, while some samples were co-treated
with 10-500 nM 17AAG. Inhibition of the Poster Session 1 – Novel Cancer Monday, 4 July 2011 12:15-14:15
intracellular Hsp90 chaperone activity was detected
on a delay in the Hsp90-dependent reactivation of P1.098 INVOLVEMENT OF
thermally denatured luciferase in the heat-stressed CASPASE-3 ACTIVITY AND
transfectants. The cell death/survival was assessed SURVIVIN DOWNREGULATION IN
in TUNEL, annexin V-staining and clonogenic CINOBUFOCINI-INDUCED APOPTOSIS
assays. The expression levels of cell death/survival- IN A 549 CELLS
and angiogenesis-related proteins were probed by Shiying Zheng1, Dong Jiang1, Hong Li2
1
Western blot analyses. The angiogenic potential of Department Of Cardio-thoracic Surgery, The First
lung cancer cells was tested in cell-proliferation AfÀliated Hospital Of Soochow University/China,
2
assays with cultured human vascular endothelial Department Of Geriatrics, The First AfÀliated
cells (EC). Hospital Of Soochow University/China
Results: In both the lung cancer cell cultures (SQ-5
and A549), very low (40-150 nM) concentrations Background: Cinobufocini injection is a preparation
of 17AAG inhibited the chaperone function of containing water-soluble components of the toad
Hsp90 and down-regulated the protein levels skin. The aim of the present study was to investigate
of Bcl-2, survivin, HIF-1alpha and Akt; also, the apoptosis of human lung adenocarcinoma cell
the phosphorylation of Akt and its down-stream line A 549 induced by cinobufocini.
targets such as Bad, XIAP or GSK-3 became Methods: A 549 or HLF-1(human lung Àbroblast)
markedly suppressed. Pretreatments with the same cells were treated with cinobufocini at different
concentrations for 24 and 48 h, respectively. The lung adenocarcinoma cells.

proliferation of cells was detected with the 3-(4, Methods: The identiÀcation of methylation-
5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium silenced genes is offering new insights into tumor
bromide (MTT) assay. Morphology of cells was development and may reveal the potential for
carried out with scanning electronic microscopy inhibiting DNA methylation as a cancer treatment.
(SEM) and Hoechst 33258 staining. The apoptosis In this regard, a number of strategies have been
rate was examined by Áow cytometry. The used to uncover methylation-regulated genes,
expression of survivin was examined with RT-PCR including candidate gene analysis, representational
and Western blot assay. The caspase-3 and caspase-7 difference analysis, restriction landmark genome
activities were detected with caspase colorimetric scanning, methylation-sensitive, arbitrarily primed
protease assay. PCR, and methylated DNA-binding protein afÀnity
Results: We found that cinobufocini signiÀcantly chromatography. Another strategy, gene expression
inhibited tumor growth of A 549 cells in a dose- microarrays, is particularly suited for identifying
and time-dependent manner without damaging candidate, methylation-silenced genes and for
non-cancerous cells (HLF-1) and induced granular assessing the downstream, cellular consequences
apoptotic bodies of A 549 cells. Next, cinobufocini of reactivating these genes. Microarray technology
increased the percentage of cells in G1 phase and permits the systematic examination of thousands
decreased the percentage of cells in S phase in A 549 of gene expression changes simultaneously and
cells. Furthermore, cinobufocini downregulated the has been used to follow the transcriptional changes
expression of survivin mRNA and protein. Finally, that accompany disease development and cellular
cinobufocini upregulated caspase-3 activity. responses to environmental stimuli.
Conclusion: We concluded that cinobufocini induces Results: we found that 5-Aza-CdR treatment
apoptosis of A 549 cells, which is associated with sensitized A549 cells to growth inhibition by
the decreasing expression of survivin mRNA and exogenous IFN-Ơ2a, indicating that 5-Aza-CdR
protein, increasing caspase-3 activity of A 549 cells. should be investigated as a potentiator of IFN
Keywords: apoptosis, survivin, caspase-3, A 549 cel responsiveness in certain IFN-resistant tumors.
DNA cytosine methyltransferase I (DNA MeTase)
A revised/updated abstract may be included in recognizes hemimethylated CpG dinucleotides
the Late Breaking Abstract Supplement, available in mammalian DNA and catalyzes the transfer
at the 14th World Conference on Lung Cancer. of methyl groups to cytosine residues in newly
synthesized DNA. The methylation of cytosines
within CpG islands located in core promoter regions
Poster Session 1 – Novel Cancer Monday, 4 July 2011 12:15-14:15 can negatively regulate the transcription of the
adjacent genes. The basis for this negative regulation
P1.099 INHIBITION OF DNA may involve recruitment of histone deacetylases to
METHYLTRANSFERASE STIMULATES methylated CpG islands. Holliday Àrst suggested a
THE EXPRESSION OF SIGNAL relationship between abnormal DNA methylation
TRANSDUCER AND ACTIVATOR OF and cancer. Subsequently, a number of methylation-
TRANSCRIPTION 1, 2, AND 3 GENES IN silenced tumor suppressor genes, including
LUNG CANCER CELLS p16Ink4a, retinoblastoma, estrogen receptor,
Shiying Zheng1, Dong Jiang1, Hong Li2 hMLH1, and E-cadherin, have been identiÀed in
1
Department Of Cardio-thoracic Surgery, The First cancer cells in vitro and in vivo. It is becoming clear
AfÀliated Hospital Of Soochow University/China, that epigenetic processes constitute a signiÀcant
2
Department Of Geriatrics, The First AfÀliated factor in the formation of cancer. In this regard, DNA
Hospital Of Soochow University/China methylation abnormalities have been implicated
in colon cancers in both mouse and human tumor
Background: Inhibitors of DNA methyltransferase, model systems. 5-Aza-2v-deoxycytidine (5-Aza-
typiÀed by 5-aza-2v-deoxycytidine (5-Aza-CdR), CdR) inhibits DNA methylation and often is used in
induce the expression of genes transcriptionally vitro to induce the reexpression of genes putatively
down-regulated by de novo methylation in tumor silenced by promoter methylation. 5-Aza-CdR is
cells. We utilized gene expression microarrays to substituted for cytosine during replication and is
examine the effects of 5-Aza-CdR treatment in A549 recognized by DNA MeTase. Attempted transfer of
methyl groups to 5-Aza-CdR, however, covalently hypomethylation induced the re-activation of tumor
traps the enzyme to newly synthesized DNA. This suppressor genes that were silenced by methylation-
sequestration ultimately depletes cellular stores of mediated mechanisms, could inhibit proliferation and
DNA MeTase and results in widespread genomic induce differentiation of tumor. Histone deacetylase
hypomethylation. Clinical trials have demonstrated (HDAC) inhibitor, sodium phenylbutyrate (SPB), has
promise in the use of 5-Aza-CdR (decitabine) for multiple effects on tumor cells that include inhibition
treating leukemia, and current trials are evaluating of proliferation, induction of differentiation and
5-Aza-CdR in the treatment of lung and prostate induction or repression of gene expression. The
cancers. It is plausible that the antitumor activity aims of this research were as follows:(l)To compare
of 5-Aza-CdR results from the induction of the proliferation inhibition and apoptosis effect of
methylation-regulated tumor-suppressive pathways. 5-aza-C or SPB used alone or in combination.(2)To
Conclusion: This analysis revealed the induction of evaluate the synergistic effect of 5-aza-C and SPB.
a set of genes that implicated IFN signaling in the (3)To analyze the inÁuence of 5-aza-C and SPB on
A549 cellular response to 5-Aza-CdR. Subsequent the expression of DNMTl,DNMT3a and HDAC
investigations revealed that the induction of this gene when they were used alone or in combination.(4)
set correlates with the induction of signal transducer To evaluate the effect of 5-aza-C and SPB on re-
and activator of transcription (STAT) 1, 2, and 3 activation of genes that are silenced by epigenetics
genes and their activation by endogenous IFN-Ơ. mechanisms.
These observations implicate the induction of the Methods: (1) The antiproliferation and apoptosis
IFN-response pathway as a major cellular response effect were assayed by ordinary microscopy,
to 5-Aza-CdR and suggests that the expression transmission electron microscopy, Áow cytometry
of STATs 1, 2, and 3 can be regulated by DNA and DNA fragment. (2) The synergistic effect
methylation. Consistent with STAT’s limiting cell of 5-aza-C and SPB were observedby 5-aza-C
responsiveness to IFN. combination with SPB or 5-aza-C (or SPB)
Keywords: DNA methylation, A549 lung combination with nolatrexed, a thymidylate synthase
adenocarcinoma cells, 5-aza-2v-deoxycytidine inhibitor, in vivro. (3)The inÁuence of 5-aza-C and
(5-Aza-CdR) SPB used alone or in combination on the expression
of DNMT1, DNMT3a and HDAC was measured by
A revised/updated abstract may be included in RT-PCR. (4) Used microarray to evaluate the effect
the Late Breaking Abstract Supplement, available of 5-aza-C and SPB on re-activation of genes that are
at the 14th World Conference on Lung Cancer. silenced by epigenetics mechanisms.
Results: (1) 5-aza-C used alone or SPB used
alone or both used in combination all have
Poster Session 1 – Novel Cancer Monday, 4 July 2011 12:15-14:15 antiproliferation, differentiation and apoptosis
effect when showed by ordinary microscopy and
P1.100 ANTITUMOR EFFECT BASED Áow cytometry.Both 5-aza-C used alone and two
ON THE INTERACTION OF DNA drugs used in combination caused nucleus change
METHYLTRANSFERASE INHIBITOR and DNA fragment when showed by transmission
AND HISTONE DEACETYLASE electron microscopy and Áow cytometry, but these
INHIBITOR did not show in case of SPB used alone. (2)Results
Shiying Zheng1, Dong Jiang1, Hong Li2 showed both 5-aza-C and SPB have markedly
1
Department Of Cardio-thoracic Surgery, The First synergistic effect. (3) DNMT1, DNMT3a and HDAC
AfÀliated Hospital Of Soochow University/China, were inhibited 59.3%, 38.6% and 7.4% respectively
2
Department Of Geriatrics, The First AfÀliated when 5-aza-C used alone; they were inhibited 7.6%,
Hospital Of Soochow University/China 4.6% and 60.3% respectively when SPB used alone;
and they were inhibited 78.9%, 75.0% and 84.4%
Background: Both aberrant DNA methylation and respectively When two drugs used in combination.
altered histone acetylation are two key mechanisms (4) Four genes were down-regulated when 5-aza-C
in epigenetics, which play an important role in used alone, while fourteen genes were activated at
the development and progression of cancer. DNA the same time. Two genes were down-regulated by
methyltransferase (DNMT) inhibitor, 5-aza-cytidine SPB used alone while elevated fourteen genes.When
(5-aza-C), was widely studied because DNA two drugs combination, twelve genes were inhibited,
and forty-six genes were activated. is forming.According to the results of observation

Conclusion: (1) Both 5-aza-C and SPB have in normal cells,TGF-ơ1 can regulate Fas/FasL.Fas/
favorable anti antiproliferation and apoptosis FasL system is a very important apopatosis pathway.
effect. (2) Both 5-aza-C and SPB have markedly In normal cells,TGF-ơ1 can upregulat Fas,so that
synergistic effect, inhibitors of DNMT and HDAC caspases in Fas/FasL pathway are activated to
may have well foreground in drugs combination induce cell apoptosis.Moreover,caspases can be
and overcome muti-drugs resistance. (3)Aberrant activated by combination of Fas with FasL.So
epigenetics inactivated many genes which suppress TGF-ơ1 can be regarded as an important factor that
tumorigenesis, inhibitors of DNMT and HDAC induces apoptosis and plays the role of abnormal
can reverse this morbidity. (4) The combination of cell clearance.But the relationship between TGF-ơ1
HDAC and DNMT inhibition is very effective (and and cancer cell apoptosis is not very clear yet.The
synergistic) in inducing apoptosis, differentiation and experimental report on it is very scarce.
cell growth arrest, this suggested that methylation Methods: In order to study the relationship of
and deacetylation are coupled with each other. TGF-ơ1 and cancer apoptosis,the experiment
Keywords: DNA methyltransferase inhibitor, 5-aza- develops according to three steps:step1,siRNA target
cytidine, Histone deacetylase inhibitor, sodium sequences were analysed and synthesized by siRNA
phenylbutyrate design software plus Angela siRNA principle.Then
siRNA vehicle was reformed by the inserting of
A revised/updated abstract may be included in siRNA target sequences to PAVU6+27.Expressing
the Late Breaking Abstract Supplement, available Level of TGF-ơ1 was analysed with indirect
at the 14th World Conference on Lung Cancer. immunoÁuorescence and western blotting after
siRNA vehicles were transfected into A549 cells.
Step2,the expression level of Fas/FasL and activity
Poster Session 1 – Novel Cancer Monday, 4 July 2011 12:15-14:15 of caspase-3/caspase-8 was detected in A549 cells
that had been transfected with pOligo1216 or pOligo
P1.101 EXPERIMENTAL STUDY ON THE Control.Then the expression level of Fas/FasL and
APOPTOSIS REGULATION OF TGF-ȕ1 IN activity of caspase-3/caspase-8 was detected in A549
HUMAN LUNG ADENOCARCINOMA cells that had been transfected with TGF-ơ1 protein.
Shiying Zheng1, Dong Jiang1, Hong Li2 In this way the relationship between TGF-ơ1 and
1
Department Of Cardio-thoracic Surgery, The First Fas/FasL system can be found out.Step3,accoridng
AfÀliated Hospital Of Soochow University/China, to the methods of Saitoh and Crowley,HLA-ABDR
2
Department Of Geriatrics, The First AfÀliated genes in A549 and Calu-6 cells were detected and
Hospital Of Soochow University/China then HLA-A2+A549 cells had been founded.The
foundation of tumor speciÀc CTL was preliminarily
Background: TGF-ơ1 belongs to super family studied and explored with MLTC.
of growth factor and its biological effect is very Results: 1.SiRNA effects are different.The effects
common including regulation of cell proliferation of pOligo1858 are the lowest as it meets with 2
and differentiation,regulation of embryonic Angela’s principles.While the effects of pOligo1216
development,enhancement of ECM formation and are the highest as it meets with 7 Angela’s principles.
suppression of immune-system.TGF-ơ1 is highly Lung adenocarcinoma strain in which TGF-ơ1 has
expressed in many malignant tumor cells including been scilenced is obtained.
lung cancer cells and it can be expressed in matrix 2.Expression level of FasL/Fas and activity of
cells around cancer cells.In current opinion,TGF-ơ caspase-3/caspase-8 has no changes after the content
1 suppresses proto-oncogene such as c-myc to of TGF-ơ1 is upregulated or downregulated.
inhibit cell growth cycle of G1 stage to S stage. 3.HLA-ABDR genes in A549 cells are HLA-A30/
But in the middle or later stage of cancer when HLA-B44/-HLA-DR7/HLA- DR53.While HLA-
the tumor inÀltrating blood vessels has been ABDR genes in Calu-6 cells are HLA-A01/-HLA-
forming,TGF-ơ1 can make tumor cells be of much B08/-HLA-DR17/HLA-DR52.Both A549 cells and
maliganancy by stimulation of tumor inÀltrating Calu-6 cells lose their HLA gene but retain HLA-
blood vessls,by enhancement of cell migration and gene.
by immune suppressing.So the microenvironment 4.A549 cell line in which HLA-A2 gene is stably
of growth,inÀltration and metastasis for cancer cells expressed is obtained with the transfection of
pcDNA3.1D/V5. Background: Lack of surface Fas expression

5.The proliferation trend of PBL from 4 healthy is a main route for apoptotic resistance which is
donators is obvious and it is consistent with the considered an important mechanism of tumorigenesis
morphology features of tumor speciÀc CTL. and tumor progression.
Four groups T lymphocytes are induced with the Methods: Fas and FasL expressions in 110 non-
stimulation of tumor cells.The proliferation is 10- small cell lung carcinomas (NSCLCs) were
20 times after 5 days MLTC from such above PBL investigated to evaluate their roles in pulmonary
that is consistent with proliferation features of carcinogenesis and to examine the clinico-
tumor speciÀc CTL.But there are some disparities pathologic signiÀcance of Fas expression with its
according to kill test,antibody blocking and the test relationship with p53 and bcl-2 overexpressions.
of caspase activity on tumor speciÀc CTL.We make a Results: Immuno- histochemical analysis using
presumption that stimulation times are not enough so tissue microarray demonstrated that a large
that the CTL is too little or the activity of CTL is so proportion of NSCLC patients (60%) showed lack
weak that tumor cells can not be killed. of membranous Fas expression. The Fas- negative
Conclusion: 1.TGF-ơ1 is highly expressed in human cases revealed the signiÀcantly lower survival rate
lung adenocarcinoma that indicates it plays an than Fas-positive ones. Also, the loss of Fas receptor
important role in the biological behavior. expression was found more frequently in advanced
2.SiRNA efÀciency can be improved according stage and higher nodal status. FasL protein was
to Angela’s principle when the siRNA targets are increased in most NSCLCs (89%) compared to
screening.While the method of none-degeneration normal lungs. p53 and bcl-2 overexpressions showed
polypropylene gel can be widely applicated in the no association with Fas expression.
screening of siRNA recombinant plasmid. Conclusion: reduced membranous Fas expression
3.In A549 cells TGF-ơ1 losing the function of as a mechanism of apoptotic resistance is considered
apoptosis inducing and the decreasing of TơR and to play an important part of the pulmonary
mutation plays an important role possibly. carcinogenesis, which may predict poor survival
4.HLA genes are losing and HLA-genes retain.It and have a bad prognostic inÁuence. Increased FasL
may be another important mechanism of immune expression is thought to be a basis for the immune
tolerance and immnue evading for tumor.. evasion in NSCLCs. The rare bcl-2 overexpression
5.Some experience and experimental data are suggests that this anti- apoptotic protein is unlikely
obtained from the initial study on foudation of tumor to play a role in the apoptotic resistance of NSCLCs
speciÀc CTL with HLA-A2+adenocarcinma.That is Keywords: FasL protein, Non-Small- Cell Lung,
very helpful for the optimization of CTL model to Carcinogenesis, Non-small Cell Lung Carcinoma
study immune evading and tolerence in tumor cells
Keywords: Fas/FasL, lung adenocarcinoma, A revised/updated abstract may be included in
TGF-ơ1, RNA interference the Late Breaking Abstract Supplement, available
at the 14th World Conference on Lung Cancer. Poster Session 1 – Novel Cancer Monday, 4 July 2011 12:15-14:15
P1.103 PHARMACOLOGIC INHIBITION

Poster Session 1 – Novel Cancer Monday, 4 July 2011 12:15-14:15 OF SULF-2 IN LUNG CANCER CELLS
REVERTS TRANSFORMED PHENOTYPE
P1.102 RELATIONSHIP OF FAS、FASL Steven D. Rosen1, Hassan Lemjabbar-Alaoui2
、P53 AND BCL-2 EXPRESSIONS IN 1
Anatomy, University Of California, San Francisco/
HUMAN NON-SMALL CELL LUNG United States Of America, 2Thoracic Oncology
CARCINOMAS Laboratory, Department Of Surgery, Comprehensive
Yin Li1, Shiying Zheng2, Dong Jiang2 Cancer Center, University Of California, San
1
Department Of Thoracic Surgery, The Tumor Francisco/United States Of America
Hospital Of Henan ,zhengzhou/China, 2Department
Of Cardio-thoracic Surgery, The First AfÀliated Background: Heparan sulfate proteoglycans
Hospital Of Soochow University/China (HSPGs) bind to multiple growth factors/
morphogens and regulate their signaling. (NSCLC) cell lines and in actual NSCLC tumors from
6-O-sulfation (6-O-S) of glucosamine within patients. Using RNAi knockdown, we demonstrated
HS-chains is critical for many of these ligand that Sulf-2 promoted the in growth on plastic, growth in
interactions. Sulf-1 and Sulf-2, are extracellular soft agar and cell migration of several Sulf-2+ NSCLC
neutral-pH sulfatases that provide a novel post- lines. In addition, Sulf-2 knockdown in the same cells
synthetic mechanism for regulation of HSPG strongly suppressed xenograft tumor formation in nude
function by removing 6-O-S from intact HS-chains. mice. Previous work (Hossain et al. Glycobiology,
The Sulfs can thereby modulate several signaling 2010) has shown that PI-88 (a heparin mimetic) inhibits
pathways, including the promotion of Wnt signaling. the endosulfatase activity of both Sulfs. In the present
Methods: Cell lines and cell culture: H292, cells studies, we found that overnight culture of a Sulf-2+
were from American Type Culture Collection. P-ST, NSCLC line (H292 cells) with PI-88 resulted in an
which were obtained by exposing primary human increase of 6-O-S on the cell surface, as detected by
bronchial epithelial cells to an aqueous extract of phage-display antibody (not shown). In H292 cells with
cigarette smoke (Lemjabbar-Alaoui et al., 2006). All Sulf-2 knockdown, PI-88 had a minimal effect on the
cells were grown in RPMI-1640 with 10% FBS and epitope. These results indicate that PI-88 inhibits the
penicillin/streptomycin. HSPG sulfation analysis: To endogenous sulfatase activity of Sulf-2 and prevents
determine the effects of Sulf-2 inhibition (Knockdown the loss of 6-O-S from the cell surface. Furthermore
or PI-88) on HSPGs, we used a phage-display PI-88 (3 g/ml) inhibited the growth of H292 cells on
antibody (RB4CD12) (Dennissen et al., 2002) with plastic to the same extent as Sulf-2 knockdown. Similar
an irrelevant antibody as a control. A Cy3-conjugated results were obtained with 4 other Sulf-2 positive
mouse anti-VSV secondary antibody (Sigma) was NSCLC cell lines. However, PI-88 did not affect the
used and cells were analyzed by Áow cytometry. Cell growth of NSCLC cells that lack endogenous Sulf-2. In
growth, proliferation and survival assays: Cell growth addition, PI-88 inhibited the migration of H292 cells in
was determined by Cell Titer Blue cell viability assay the monolayer scratch assay, recapitulating the effect of
(Promega). BrieÁy, 1000 cells were seeded per well Sulf-2 knockdown. Finally, PI-88 markedly decreased
of a 96 well plate. Cultures were maintained in a the growth of H292 cells in soft agar but not that of the
37°C incubator in a humidiÀed atmosphere of 5% same cells with Sulf-2 knockdown
CO2. Medium was removed and replaced with fresh Conclusion: These Àndings establish the principle
medium every 2 days. PI-88 was added on day 0 and that the Sulfs can be inhibited pharmacologically in
replenished at the time of medium change every 2 lung cancer cells. PI-88 is not a selective inhibitor
days. After 6 days of incubation at 37ºC, counts of of the Sulfs in that it binds to heparanase and a
viable cells were determined with the Cell Titer Blue number of growth factors. The experiments above
assay. Monolayer wound healing assays: Cells were control for off-target effects by taking advantage of
grown to conÁuency on 6-well plates. Scratches were Sulf-2 knockdown cells. More selective inhibitors
made with a pipette tip. Cell migration was quantiÀed of the Sulfs are potential therapeutic agents for the
by measuring the width of the wounds at 0, 24, 48 treatment of NSCLC and other cancers in which the
and 72 hours. Colony formation in soft agar: One Sulfs are overexpressed
thousand cells were seeded into 60-mm dishes in a Keywords: Lung cancer, Sulf-2, Extracellular
suspension of 0.5% bacto-agar (Difco) in medium Sulfatase, Pharmacologic Inhibitor
supplemented with 10% fetal calf serum on top of a
bed of 0.5% bacto-agar (Difco) in the same medium.
Cells were plated on top of 1 ml of 0.5% agarose. Poster Session 1 – Novel Cancer Monday, 4 July 2011 12:15-14:15
Plates were incubated at 37ºC in 5% CO2. Medium
was removed and replaced with fresh medium every P1.104 THE MACROPHAGE
2 days. PI-88 was added on day 0 and replenished at STIMULATING PROTEIN (MSP)-RON/
the time of medium change every 2 days. Colonies MST1R AXIS IN MALIGNANT PLEURAL
that had formed after 15 to 30 days incubation were MESOTHELIOMA.
counted. All cell lines were seeded in triplicate and all Steven G. Gray1, David Easty1, Anne-Marie Baird1,
experiments were repeated a minimum of three times. Alex Soltermann2, Daisuke Nonaka3, Dean A.
Results: In previous work (Lemjabbar-Alaoui et Fennell4, Luciano Mutti5, Harvey I. Pass3, Isabelle
al. Oncogene, 2010), we have shown that Sulf-2 is Opitz2, Dearbhaile O’donnell6, Kenneth J. O’Byrne6
1
overexpressed in a set of non-small cell lung cancer Clinical Medicine, Trinity College Dublin/st James’
Hospital/Ireland, 2Zurich University/Switzerland, pathway and paracrine activation of macrophages.

3
Cardiothoracic Surgery, Nyu School Of Medicine/ The MSP-RON axis may be a novel therapeutic
United States Of America, 4Centre For Cancer target in mesothelioma.
Research And Cell Biology, Queen’s University Keywords: mesothelioma, receptor, Prognosis,
Belfast/United Kingdom, 5Dept Of Medicine, target
Laboratory Of Clinical Oncology, Hospital Of
Vercelli/Italy, 6St James’s Hospital And Trinity
College Dublin, Ireland/Ireland Poster Session 1 – Novel Cancer Monday, 4 July 2011 12:15-14:15
Background: Evidence supports a role for P1.105 IL-20 IS EPIGENETICALLY

macrophage activity in mesothelioma genesis. REGULATED IN NSCLC AND DOWN
Malignant pleural mesothelioma (MPM) is resistant REGULATES THE EXPRESSION OF
to chemotherapy, and receptor tyrosine kinases VEGF
(RTK) represent novel therapeutic targets. We Anne-Marie Baird1, Steven G. Gray2, Kenneth J.
previously identiÀed macrophage stimulating 1 O’Byrne3
1
receptor (MST1R/RON) as frequently activated Clinical Medicine, Trinity College Dublin/Ireland,
2
in MPM. Immunohistochemistry (IHC) studies Clinical Medicine, Trinity College Dublin/st James’
found high positivity for RON staining was an Hospital/Ireland, 3Oncology (hope), St James’s
independent predictor of favourable prognosis (J Hospital/Ireland
Clin Oncol 28:15s, 2010 (suppl; abstr 10583). We
therefore hypothesized that the MST1R/RON ligand, Background: IL-20 is a pleiotrophic member of the
Macrophage stimulating protein (MSP), may also IL-10 family and plays a role in skin biology and the
play a role in MPM. development of haematopoietic cells. It has potent
Methods: Expression and function of MSP was angiogenic, inÁammatory and chemo-attractive
examined in MPM. IHC was performed for MSP on characteristics with an involvement in rheumatoid
a TMA array of FFPE samples resected from 352 arthritis and atherosclerosis. It activates STAT3
patients. MSP was also immunoprecipated from through two receptor complexes, IL-20RA/IL-20RB
MPM cell culture medium and detected by Western and IL-22R1/IL-20RB, which in turn promotes
Blot analysis. ELISA was used to study MSP in proliferation, apoptosis resistance and immune
serum derived from n=20 patients with MPM vs tolerance. Recently, IL-20 has been demonstrated to
n=20 normal. Expression of RON was analysed on a have potential anti-angiogenic effects in non-small
second set of FFPE samples of MPM. cell lung cancer (NSCLC) by down regulating COX-
Results: Immunoprecipitation and western blot 2.
analysis detected MSP in culture medium from Methods: The expression of IL-20 and its cognate
MPM cell lines. The presence of MSP message was receptors (IL-20RA/B and IL-22R1) was examined,
conÀrmed by RT-PCR in MPM cells. Recombinant at both the protein and mRNA level, in a series of
MSP did not promote proliferation but was found resected fresh frozen tumour normal matched tissue
to reduce migration of MPM cells. By ELISA, sera samples from NSCLC patients. In addition, the
from patients with MPM contained immunoreactive expression of IL-20 family members was examined
MSP, but levels were not signiÀcantly different from at the mRNA level in a panel of NSCLC and normal
control patients. IHC was performed on a TMA array bronchial epithelial cell lines. To determine if this
of FFPE samples. 71% showed MSP expression family was epigenetically regulated in our cell
as follows: weak (32%), moderate (38%), intense lines, the effect of a histone deacetylase inhibitor,
(21%). Most mesotheliomas were double positives Trichostatin A (TSA-250 ng/mL) and a DNA
(RON/MSP), small subpopulations expressed MSP methyltransferase inhibitor, 5-aza-2-deoxycytidine
or RON alone, and a fraction were double negatives. (DAC-1 ƫM), was also studied. A ChIP assay was
Correlation of the IHC scores with clinico- performed to investigate the direct effect of TSA on
pathological and outcomes variables is ongoing. the IL-20 promoter region. The effect of recombinant
Conclusion: RON staining is an independent IL-20 on cellular proliferation and VEGF expression
predictor of favourable prognosis. MSP is frequently was also determined.
expressed in MPM. Co-expression of MSP and RON Results: The expression of IL-20 and its receptors
in MPM cells may indicate an autocrine signalling were frequently deregulated in NSCLC. The mRNA
level of IL-20RB was signiÀcantly elevated in AfÀliated Hospital Of Soochow University/China,

2
NSCLC tumours compared with normal tissue Department Of Geriatrics, The First AfÀliated
(p<0.01). At the protein level, two receptors, IL- Hospital Of Soochow University/China
20RB and IL-22R1, were signiÀcantly increased
(p<0.01) in the patient tumour samples. IL-20 and its Background: The expression of the co-stimulatory
receptors were found to be epigenetically regulated molecule CD28 and death receptor CD95 on T cells,
through histone post-translational modiÀcations which change with age, are considered as important
and DNA CpG residue methylation in NSCLC and immunological parameters of immunosenescence.
normal bronchial epithelial cell lines. Treatment It is well established that CD28 and CD95 are
with DAC reactivated the expression of IL-20RA in associated with tumorgenesis and tumor progression,
an adenocarcinoma (A549) cell line (p<0.01). IL- but the relationship between the age-related changes
20 treatment increased the cellular proliferation of of these two immunological markers and cancer in
a squamous cell line (SK-MES-1), however there the elderly is largely unknown.
was no effect observed in either A549 or a normal Methods: The levels of CD28 and CD95 mRNA
cell line (HBEC4). In addition, treatment with in peripheral blood mononuclear cells (PBMCs)
recombinant IL-20 resulted in decreased expression from sixty-three elderly patients (aged 60 years)
of VEGF (HBEC4, A549 – p<0.05) and its receptors with primary non-small cell lung cancer (NSCLC)
(VEGFR1, VEGFR2 and Nrp-1) at the mRNA level. were analyzed by real-time Áuorescence-based
Conclusion: While the anti-angiogenic properties quantitative polymerase chain reaction (FQ-PCR).
of IL-20 require further clariÀcation, this study In addition, twenty young patients (aged <60 years)
demonstrates that the IL-20 family are epigenetically with NSCLC, thirty elderly healthy donors and thirty
regulated by histone post-translational modiÀcations young healthy donors were enrolled as controls.
and DNA CpG methylation in NSCLC and normal Results: CD28 mRNA levels were signiÀcantly
cell lines. Our results for IL-20RA at the protein lower and CD95 mRNA levels were signiÀcantly
and mRNA level in the A549 cell line, conÀrm higher in elderly patients with NSCLC than in the
those of a methylation study, which observed a lost other groups. Similar results were found in elderly
of IL-20RA expression in approximately 26% of healthy donors comparing with young healthy
samples studied. Although this had no association donors. By Logistic regression analysis an increased
with survival, IL-20RA is found on the lung cancer risk of NSCLC was markedly associated with aging,
susceptibility locus 6q23-25 and may be associated down-regulation of CD28 mRNA and up-regulation
with sporadic lung cancer cases. We have also shown of CD95 mRNA, and CD28 mRNA had an obvious
that IL-20 possesses anti-angiogenic properties negative correlation with the CD95 mRNA. In
within the setting of NSCLC by down regulating addition, the mRNA levels of CD28 and CD95 in the
VEGF expression. IL-20 is signiÀcantly up regulated peripheral blood of the elderly patients was closely
by treatment with TSA and IL-20RA is reactivated associated with the tumor node metastasis (TNM)
by DAC. Therefore, our results would suggest that stages, grade of cell differentiation and lymph node
targeting this family via epigenetic means may be metastasis status, but not related to pathological
a viable therapeutic option in the treatment of lung types.
cancer. Conclusion: The results suggest a close relationship
Keywords: Non-small cell lung cancer, IL-20, between T cell senescence and NSCLC tumour
VEGF, epigenetics progress in the elderly, and that up-regulation of
CD28 mRNA or down-regulation of CD95 mRNA
in peripheral blood T cells may play an important
Poster Session 1 – Novel Cancer Monday, 4 July 2011 12:15-14:15 role in inhibiting oncogenesis and development of
primary NSCLC in the elderly.
P1.106 B7 AND FAS MRNA Keywords: Non-small Cell Lung Carcinoma,
EXPRESSION IN PERIPHERAL BLOOD immunosenescence, B7, Fas
MONONUCLEAR CELLS FROM
ELDERLY PATIENTS WITH PRIMARY A revised/updated abstract may be included in
NON-SMALL CELL LUNG CANCER the Late Breaking Abstract Supplement, available
Dong Jiang1, Shiying Zheng1, Hong Li2 at the 14th World Conference on Lung Cancer.
1
Department Of Cardio-thoracic Surgery, The First
Poster Session 1 – Novel Cancer Monday, 4 July 2011 12:15-14:15 with some clinicopathologic features of patients.
Therefore, methylation assays offer the promise of
P1.107 QUANTITATIVE METHYLATION a noninvasive test for detecting cancer. In addition,
OF MULTIPLE GENES IN NSCLC – IS IT the identiÀcation of cancer-speciÀc epigenetic
CANCER SPECIFIC? changes may be useful for molecular classiÀcation
Jelena Stojsic1, Milica Kontic2, Dragana Jovanovic1, and disease stratiÀcation. Genomic approaches
Susan Puumala3, Heather Nelson4 in NSCLC have the potential to advance our
1
Clinic For Pulmonology, Belgrade/Serbia, 2Lung understanding of underlying disease biology, to
Cancer, Clinic For Pulmonology/Serbia, 3Sanford improve current prognostic and treatment paradigms,
School Of Medicine/United States Of America, to identify new targets for treatment, ultimately
4
Univeristy Of Minnesota/United States Of America improving survival in patients with NSCLC and
providing an opportunity for personalized medicine.
Background: Detection of cancer-speciÀc Keywords: Quantitative Methylation, NSCLC,
methylation changes heralds an exciting new pyrosequencing
era in the diagnosis of cancer, its prognosis, and
therapeutic responsiveness, and warrants further
investigation in NSCLC. Aim of our study was to Poster Session 1 – Novel Cancer Monday, 4 July 2011 12:15-14:15
examine quantitative methylation patterns using
pyrosequencing in multiple genes in tumor, matching P1.108 ARSENIC TRIOXIDE INDUCES
normal lung tissue and blood of patients with non- APOPTOSIS IN HUMAN LUNG CANCER
small cell lung cancer. We also tracked possible CELLS THROUGH UPREGULATION OF
relationships between clinicopathologic features of P53 AND ACTIVATION OF CASPASE 3
patients and DNA methylation. Shiying Zheng1, Hong Li2, Dong Jiang1
1
Methods: Primary tumor samples (n=65), Department Of Cardio-thoracic Surgery, The First
corresponding nonmalignant lung tissues (n=65) and AfÀliated Hospital Of Soochow University/China,
2
blood samples (n=51) were obtained from NSCLC Department Of Geriatrics, The First AfÀliated
patients, treated with curative resectional surgery. Hospital Of Soochow University/China
Hypermethylation status was quantiÀed at multiple
CpG sites within each promoter in multiple genes- Background: Arsenic trioxide (As2O3) can induce
SOX1, RASSF1A, HOXA9, CDH13, MGMT, ESR1 clinical remission in patients suffering from acute
and DAPK by pyrosequencing. promyelocytic leukemia, through induction of
Results: Our results showed signiÀcant difference apoptosis and activation of caspases.Apoptosis is
between tumor methylation, normal tissue and blood regulated by gene products, which are conserved
samples for the most of the genes. Methylation in from nematodes to mammals. We investigated the
tumors was signiÀcantly higher then in normal lung potential use of As2O3 in human lung cancer and its
for SOX1, DAPK, RASSF1A, HOXA9 and CDH13. possible mechanisms.
Tumor samples had signiÀcantly higher methylation Methods: Human lung cancer cell lines A549 were
than blood samples for all genes except DAPK. treated with various concentrations (0.1 to 100 ƫM)
Tumor hypermethylation was more frequently for of As2O3 for 24-72 hours. Apoptosis was determined
adenocarcinoma at CDH13 and ESR1. A higher by acridine orange staining, Áow cytometry and
proportion of SSC tumors were hypermethylated DNA fragmentation. The protein levels of p53,
at HOXA9 and SOX1 compared to other types of p21waf1/cip1, c-myc, bcl-2 and bax were detected
NSCLC. Patients with stage four more likely had by Western blotting. Effects of As2O3 on caspase
hypermethylation at MGMT and patients with 3 protease activity, its protein concentration and
hypermethylation at HOX9 more likely had stage cleavage of poly-ADP ribose polymerase (PARP)
two and three tumors. Gender was associated with were also studied.
hypermethylation at CDH13 with females being Results: Triptolide inhibited cell growth in A549
more likely to have hypermethylated tumors. cells. We examined the antiproliferative effect of
Conclusion: Our results show that elevated As2O3 on human gastric cancer cell lines A549 by
methylation levels observed in genes SOX1, exposing them to different concentrations of As2O3
RASSF1A, HOXA9, CDH13, MGMT, ESR1 for 24 to 72hrs. Cell viability was determined by
and DAPK were cancer-speciÀc and associated MTT assay. When A549 cells were exposed to
As2O3 ranging from 0.1ƫM to 100ƫM, the growth Poster Session 1 – Novel Cancer Monday, 4 July 2011 12:15-14:15
of both cell lines was inhibited in a dose dependent
manner. P1.109 REPLICATION-DEFICIENT
As2O3 induced apoptosis in A549 cells following ADENOVIRUS-MEDIATED TRANSFER
a concentration- and time-dependent manner. OF B7-1 (CD80) CDNA INDUCES ANTI-
Morphological changes typical of apoptosis, TUMOUR IMMUNITY IN ISOLATED
including chromatin condensation, fragmentation HUMAN LUNG CANCER
of the nuclei, and formation of apoptotic bodies Shiying Zheng1, Dong Jiang1, Hong Li2
1
were observed in A549 cells after 12 hours with the Department Of Cardio-thoracic Surgery, The First
concentration of more than 1 ƫM. The percentage AfÀliated Hospital Of Soochow University/China,
2
of apoptotic cells increased in a time- and dose- Department Of Geriatrics, The First AfÀliated
dependent manner. Approximately 25% of the Hospital Of Soochow University/China
A549 cells underwent apoptosis with treatment
of 10 ƫM As2O3 for 24 hours. Apoptosis was Background: Lung cancer is one of the most
further conÀrmed by agarose gel electrophoresis common malignancies, and its overall incidence
of the genomic DNA. A characteristic pattern of is increasing. Although conventional therapy uses
nucleosomal-sized ladders of DNA fragments, which modalities such as surgery or chemotherapy, the
characterized programmed cell death, was detected therapeutic effects are poor, with a 5-year survival
after 24 hours exposure to As2O3 (1ƫM, 10ƫM) in rate of around 14%, due to widespread metastasis to
A549 cells. FACS analysis showed that As2O3 could various organs. In the murine system, introduction
induce apoptosis in A549 cells, with a typical sub- of the co-stimulatory molecule B7-1 into a tumour
diploid peak on the DNA histogram. can increase anti- tumour immunity and eradicate
Treatment resulted in a marked increase in p53 tumour growth.8–10 Few investigations have
protein level as early as 4 hours. Co-incubation with been conducted with human tumours to examine
p53 antisense oligo-nucleotide suppressed As2O3- the effect of B7-1 transduction on the generation
induced intracellular p53 over-expression and of CTL. It has been shown, however, that the
apoptosis. As2O3 increased the activity of caspase stimulation of autologous or allogenic lymphocytes
3, with appearance of its p17-kD peptide fragment, by B7- transduced melanoma cell lines and cervical
and cleavage of PARP with appearance of the 85-kD carcinoma cell lines expressing viral antigens
cleavage product, both in parallel with the induction induces a proliferative response and cytotoxicity
of apoptosis. The tripeptide caspase inhibitor zVAD- against tumours. To evaluate autologous lymphocyte
fmk or the speciÀc caspase 3 inhibitor DEVD-fmk responses to B7-1-transduced human lung cancer
both partially suppressed As2O3-induced caspase 3 cells, Interaction between the co-stimulatory
activation and apoptosis. molecule B7-1 (CD80) on antigen-presenting cells
Conclusion: Our study and others have shown that and its counter-receptor CD28 on T lymphocytes
lung cancer cells were more sensitive to As2O3 plays a key role in the induction of cellmediated
than other tumors. As2O3 inhibits cell growth and immune responses. Many tumours, including lung
induces apoptosis in lung cancer cells, involving cancer, lack expression of B7-1 and this has been
p53 overexpression and activation of caspase 3. The suggested to contribute to the failure of immune
potential use of As2O3 in treatment of lung cancer is recognition of these diseases. Based on this
worth further exploration. knowledge, we hypothesized that the co-stimulatory
Keywords: Arsenic trioxide (As2O3), Human lung signal delivered through the B7-1 molecule
cancer cell lines A549, cell growth, apoptosis expressed on lung cancer cells using replication
deÀcient adenovirus vector would induce efÀcient
A revised/updated abstract may be included in tumour immunity in T lymphocytes.
the Late Breaking Abstract Supplement, available Methods: To evaluate this hypothesis, we
at the 14th World Conference on Lung Cancer. constructed two adenovirus vectors: AdCMVhB7
(an E1- deleted-Ad5-based vector containing human
B7-1 cDNA driven by cytomegalovirus immediate
early promoter and enhancer) and AdNull (same
vector as above without expression of exogenous
gene) as control. Using these adenovirus vectors,
efÀcient generation of tumour immunity in T Background: Protein phosphatase 2A (PP2A) is a

lymphocytes was studied using primary cultured tumor suppressor enzyme, whose activity is inhibited
lung cancer cells and peripheral blood lymphocytes by the oncoprotein I2PP2A (inhibitor 2 PP2A) in
(PBL) obtained from patients with lung cancer. NSCLC cell lines. Our structural, molecular, genetic,
Results: Inoculation of lung cancer cells with 10 and pharmacologic studies reveal that PP2A activity
multiplicity of infection of AdCMVhB7 resulted is regulated by direct and selective binding of C18-
in rapid and efÀcient cell surface expression of ceramide to I2PP2A, which then relieves PP2A,
B7-1 molecule (> 90% of cells at 24 h). Cytolytic allowing it to exert its tumor suppressor function.
activity of PBL in 51Cr-release assay (E/T = 40) The freed C18-ceramide is then released in the serum.
demonstrated that effector lymphocytes induced Methods: NSCLC cell line and xenograft studies
by hB7-1 (+) lung cancer cells treated with were done by standard procedures. Cell lines and
AdCMVhB7could lyse parental lung cancer cells A549 xenografts were treated with FTY720, a
hB7-1 (–). In contrast, effector lymphocytes induced sphingosine derivative that targets I2PP2A, to
by lung cancer cells treated with AdNull as control demonstrated reduction in tumor proliferation and
virus or PBS as control could not lyse parental induction of apoptosis. We also measured C18-
lung cancer cells at all. Furthermore, cytolytic ceramide in the serum of the treated mice by liquid
activity of the effector lymphocytes induced by B7- chromatography/mass spectrometry (LC/MS).
1- transduced lung cancer cells was inhibited by Additionally, primary human NSCLC and adjacent
addition of anti-CD3 antibody. normal lung were examined for I2PP2A expression
Conclusion: These data demonstrate that primary- by immunohistochemistry (IHC).
cultured lung cancer cells treated with AdCMVhB7 Results: We found that I2PP2A is highly expressed,
would efÀciently generate tumour immunity in T while C18-ceramide levels are down-regulated in
lymphocytes. Adenovirus- mediatedhB7-1 gene the majority of primary human NSCLC specimens
transfer may be a useful means for gene therapy of compared to their adjacent normal lung tiussues.
lung cancer using adoptive immunotherapy. FTY720 was found to directly bind to I2PP2A through
Keywords: CTL, gene therapy, B7-1 (CD80), Lung a ceramide-binding domain resulting in inhibition of
cancer growth in the tested human lung cancer cell lines and
A549-Xenograft-derived tumors. The reduction in
A revised/updated abstract may be included in tumor size in senograft studies were accompanied by
the Late Breaking Abstract Supplement, available an increase in serum C18-ceramide levels.
at the 14th World Conference on Lung Cancer. Conclusion: Our studies suggest I2PP2A is a key
intracellular therapeutic target for NSCLC. I2PP2A
levels can be routinely estimated by IHC and therefore
Poster Session 1 – Novel Cancer Monday, 4 July 2011 12:15-14:15 the presence or absence of this target can be estimated
in diagnostic biopsy specimens. FTY720 targets
P1.110 TARGETING I2PP2A BY FTY720: I2PP2A and has been shown to decrease proliferation
A NOVEL, MECHANISM-BASED and enhance apoptosis in NSCLC cell lines and
TREATMENT STRATEGY FOR PATIENTS xenograft studies. Tumor response to FTY720 can be
WITH ADVANCED AND PREVIOUSLY measured by LC/MS in serum. Based on these novel
TREATED NON-SMALL CELL LUNG data a phase II clinical trial with FTY720 for the
CANCER (NSCLC). treatment of patients with previously treated advanced
Sahar Saddoughi1, George Simon2, Archana NSCLC that overexpress the I2PP2A oncoprotein is
Mukhopadhyay1, Yuri Peterson3, Angen Liu3, Can to be initiated soon. Detailed preclinical, xenograft
E. Senkal1, Joshua Oaks4, Danilo Perrotti4, Yusuf studies, and the design of the clinical trial will be
Hannun1, Besim Ogretmen1 presented at the meeting.
1
Biochemistry & Molecular Biology, Medical Keywords: oncoprotein, Non small cell lung cancer,
University Of South Carolina/United States Of I2PP2A
America, 2Hematology/oncology, Medical University
Of South Carolina/United States Of America, A revised/updated abstract may be included in
3
Hollings Cancer Center, Medical University Of the Late Breaking Abstract Supplement, available
South Carolina/United States Of America, 4Ohio at the 14th World Conference on Lung Cancer.
State University/United States Of America
Poster Session 1 – Novel Cancer Monday, 4 July 2011 12:15-14:15 Poster Session 1 – Novel Cancer Monday, 4 July 2011 12:15-14:15
P1.111 MALAT-1 NCRNA INFLUENCES P1.112 MICRORNA-218, A POTENTIAL

CELL MIGRATION, TUMOR GROWTH LUNG TUMOUR SUPPRESSOR GENE
AND PROGNOSIS IN NSCLC PATIENTS Morgan R. Davidson1, Santiyagu M.F. Savarimuthu1,
Lars H. Schmidt1, Tilmann Spieker2, Steffen Kylie R. Parsonson2, Maxine Tan2, Felicia Goh2,
Koschmieder1, Julia Humberg1, Antje Hascher1, Vandana Relan2, Ian A. Yang2, Nick K. Hayward3,
Alessandro Marra3, Ludger Hillejan3, Wolgang E. Rayleen Bowman2, Kwun M. Fong2
Berdel1, Carsten Müller-tidow1, Rainer Wiewrodt1 1
School Of Medicine, University Of Queensland/
1
Department Of Medicine A, Hematology, Australia, 2Department Of Thoracic Medicine, The
Oncology And Pulmonary Medicine, Westfälische Prince Charles Hospital/Australia, 3Oncogenomics
Wilhelms University, Münster/Germany, 2Institute Laboratory, Queensland Institute Of Medical
Of Pathology, Westfälische Wilhelms University, Research/Australia
Münster/Germany, 3Department Of Thoracic
Surgery, Niels-stensen-kliniken Ostercappeln/ Background: MicroRNAs (miRNAs) are a family
Germany of small, non-coding RNAs, regulating the activity
of ~20-30% of human genes, including numerous
Background: The functions of large non-coding cancer genes. We have recently identiÀed hsa-
RNAs (ncRNA) have remained elusive in many miR-218 as a potential tumour suppressor miRNA in
cases. MALAT-1 (Metastasis-Associated-in-Lung- lung cancer, located within a region of genomic loss
Adenocarcinoma-Transcript-1) is a ncRNA, that is in lung cancer with concordant reduction in miR-
highly expressed in several tumor types. 218 expression (Davidson et al, PLOS One, 2010).
Methods: Overexpression and RNA interference Therefore the aims of this study were to ascertain the
(RNAi) approaches were used for the analysis of functional effect of miR-218 on cancer phenotypes
the biological functions of MALAT-1 RNA. Tumor in cell lines and identify the genes and pathways
growth was studied in nude mice. For prognostic regulated by miR-218.
analysis MALAT-1 RNA was detected on parafÀn Methods: A549 lung cancer cells were transiently
embedded lung cancer tissue probes (n=352) using transfected with pre-mir-218 (over-express miR-218)
in-situ hybridization. or a scrambled pre-mir (negative control) for 24hrs-
Results: MALAT-1 was highly expressed in 48hrs. Phenotype assays (proliferation, matrigel
several human non-small cell lung cancer cell invasion and anchorage independent growth using
lines. MALAT-1 expression was regulated by soft agar) were performed. Post-transfection global
an endogenous negative feedback loop. In A549 mRNA expression was measured using Illumina’s
NSCLC cells, RNAi mediated suppression HumanHT-12 v3 arrays (as per manufacturers
of MALAT-1 RNA suppressed migration and protocol), analysed using BRB-ArrayTools (Version
clonogenic growth. Forced expression of MALAT-1 6.3.0-Beta_3; ) and overlayed with predicted miR-
in NIH 3T3 cells signiÀcantly increased migration. 218 targets identiÀed from at least two prediction
Upon injection into nude mice, NSCLC xenografts algorithms.
with decreased MALAT-1 expression were impaired Results: Our preliminary data has demonstrated
in tumor formation and growth. In-situ hybridization that over-expression of miR-218 in A549s
on parafÀn embedded lung cancer tissue probes was associated with a reduction in cancer cell
revealed that high MALAT-1 RNA expression in proliferation (28% reduction at Day 3; p<0.05) and
squamous cell carcinoma of the lung was associated invasion (51% reduction). However, no effect was
with a poor prognosis. observed in anchorage independent cell growth.
Conclusion: These data indicate that MALAT-1 A total, of 578 target genes were identiÀed by
expression levels are associated with patient two or more prediction algorithms, including
survival and identify tumor promoting functions of numerous oncogenes, such as KIT, RET, BCL9,
MALAT-1. DCUN1D1 and PDGFRA. Data from miR-218 target
Keywords: Non-small cell lung cancer, tumor identiÀcation will be presented at the meeting.
formation and growth, MALAT-1, RNA interference Conclusion: The preliminary data from this
study supports a role for miR-218 in tumour cell
proliferation and invasion, and suggests miR-218
may regulate cancer-related target genes. Combined reaching conÁuence. Hereafter, they were splitted
with our recent report, this study provides further and transfection of siRNA was performed in a non-
support for miR-218 as a strong candidate tumour viral manner with speciÀc siRNA targeting SRF in
suppressing miRNA in NSCLC.Supported by: National both cell lines .Cells treated with unspeciÀc siRNA
Health and Medical Research Council, Cancer Council (SCR siRNA) served as controls. qRT-PCR was
Queensland, Australian Lung Foundation, The Prince performed for mRNA expression levels. RNA from
Charles Hospital Research Foundation transfected cells was isolated, reverse transcribed
Keywords: microRNA, NSCLC, miR-218 and used for qRT-PCR. Normalized gene expression
was calculated by the _DCt method using GAPDH
as a reference, furthermore transfection efÀciency
Poster Session 1 – Novel Cancer Monday, 4 July 2011 12:15-14:15 was evaluated by Áow cytometry with FITC labeled
SCR siRNA. The analysis of cell proliferation was
P1.113 SIRNA MEDIATED SUPPRESSION determined with a CASY cell counter 3 days after
OF SERUM RESPONSE FACTOR IN transfection with SRF or SCR siRNA
NSCLC CELL LINES BY NONVIRAL Results: Transfection of the NSCLC cell lines
TRANSFECTION with increasing concentrations of FITC labelled
Tobias Walker1, Andrea Nolte2, Christina Makowiecki3, SCRsiRNA resulted in an increasing cell
Migdat MustaÀ3, Ulrich Stock3, Godehard Friedel4, Áuorescence, determined by Áow cytometry.
Hans-Peter Wendel2, Volker Steger3 Furthermore, transfection of the NSCLC cell lines
1
Department Of Thoracic, Cardiac And Vascular A549 and NCI-H460 with speciÀc siRNA against
Surgery, University Hospital Tuebingen/Germany, SRF resulted in a highly signiÀcant reduction of the
2
Div. Of Congenital & Paediatric Cardiac Surgery, intracellular SRF-mRNA concentration, respectively.
Clinical Research Laboratory, Children’s Hospital, CASY conÀrmation of cell viability demonstrated
Tübingen University Hospital/Germany, 3Department a highly signiÀcant survival of the cell lines treated
Of Thoracic, Cardiac And Vascular Surgery, with unspeciÀc siRNA similareley in contrast to
Tübingen University Hospital/Germany, 4Department application of speciÀc siRNA.
Of Thoracic Surgery, Schillerhoehe Hospital, Conclusion: These results demonstrate a reliable
Stuttgart/Germany transfectability of two different NSCLC subtypes by
siRNA in a non viral manner offering a multitude of
Background: Serum response factor (SRF) is a therapeutic targets by different siRNA. This might
well known transcription factor thereby involved be a valuable capacity of NSCLC- cells offering
in a multitude of gene regulation processes. In the different and valuable therapeutic capacities.
scope of cancer therapy it might be of particular Furthermore the highly signiÀcant knock-down of
interest because it is hardly involved in replicative intracellular SRF and the subsequently following
transactions with a known relation of reduced senescence conÀrmed by qRT-PCR and CASY
cell division connected with a diminished cellular respectively by speciÀc siRNA might offer some new
SRF activity. Although its prospective character therapeutic targets in the therapy of NSCLC.
has been known for a long time, no sufÀcient way Keywords: siRNA, Serum Response Factor,
could be found for its potential use in the therapy of NSCLC, liposomal transfection
NSCLC. Short interfering RNA (siRNA) could Àll
this deÀciency. Determined by its highly speciÀc
character, it might be of an outstanding interest in Poster Session 1 – Novel Cancer Monday, 4 July 2011 12:15-14:15
the Àeld of new concepts in the therapy of unsolved
therapeutic problems of NSCLC so far. This study P1.114 ALPHA-CATULIN
deals with questions of siRNA transfection efÀciency OVEREXPRESSION INCREASES
by liposomal and therefore non-viral transfection ALPHAVBETA3-INTEGRIN EXPRESSION
of NSCLC cell lines and the power of siRNA to AND PROMOTES LUNG CANCER CELL
transiently block cell division in NSCLC cell lines MIGRATION
by SRF-inhibition. Yuh-Ling Chen1, Szu-Ying Chiu1, Tse-Ming Hong2
1
Methods: NSCLC cell lines A549 (squamous Institute Of Oral Medicine, National Cheng Kung
epithelial tumour) and NCI-H460 (adeno carcinoma) University/Taiwan, 2Institute Of Clinical Medicine,
were cultured under standard conditions for National Cheng Kung University/Taiwan
1
Background: Ơ-Catulin is an 82-kDa Ơ-catenin-related CCRCB, Queen’s University Belfast/United
protein containing regions of strongly homology with Kingdom, 2University Of Liverpool/United Kingdom,
3
Ơ-catenin and vinculin. It has been known to regulate Centre For Cancer Bioinformatics, Queen’s
NF-ƩB through directly binding IKK-ơ and confer University Belfast/United Kingdom, 4St James’s
resistance to apoptosis, but little is known about the Hospital And Trinity College Dublin, Ireland/Ireland
functional role of Ơ-catulin in cancer progression.
Methods: Knockdown and overexpression of Ơ-catulin Background: Personalising therapy for non-small
gene were performed in lung cancer cells A549. The cell lung cancer has been validated as an effective
cell proliferation was determined by MTS assays. treatment paradigm. Somatic gene alterations
Cellular senescence was analyzed by a senescence- confer sensitivity to inhibition of growth survival
associated ơ-galactosidase activity staining. Cell pathways irrespective of underlying resistance to
invasion and migration assays were done in 24- chemotherapeutic agents, and enables efÀcient
well Transwell polycarbonate Àlters coated with or activation of BCL-2 family-dependent pro-apoptotic
without Matrigel. To determine the actin cytoskeleton signalling. In platinum resistant cancers this
reorganization, cells were stained with rhodamine- signalling is blocked, however the intrinsic pathway
conjugated phalloidin to visualize F-actin distributions. remains sensitive to exogenous BH3 death signals.
Density and length of Àlopodia were analyzed by Methods: Microarray proÀling coupled to focused RNAi
MetaMorgh imaging software. screening was used to reveal those resistance genes
Results: In the present study, we found that involved in derepression of proapoptotic BCL-2 family
knockdown of Ơ-catulin gene in lung cancer cells A549 proteins. Analysis of the effect of MYRIP expression on
dramatically decreases cell proliferation and contributes survival was generated from studying 6 NSCLC datasets
to cellular senescence. Ơ-Catulin overexpression from Gene Expression Omnibus which were paired with
doesn’t inÁuence cell proliferation but signiÀcantly survival time and status information. The toxic effect of
enhance cancer cell migration and invasion by MYRIP depletion on NSCLC and non-cancerous lung
increasing the Àlopodia density and length in A549 cells was determined by cell viability and clonogenic
cells. To dissect the underlying mechanism of Ơ-catulin- assays. Apoptotic induction was examined by caspase
promoted cancer cell migration and invasion, we found and PARP cleavage experiments, and fractionation of
that Ơ-catulin increases the expression of Àbronectin mitochondrial proteins. FACS analysis was used to
and Àbronectin-associated integrin Ơ5ơ1 and Ơvơ3. examine effects on cell cycle.
Contrarily, Ơ-catulin knockdown only decreases the Results: MYRIP/Slac2c, a gene hitherto associated
expression of Àbronectin and Ơvơ3. We also found that with vesicle trafÀcking but not apoptosis, was
NF-ƩB inhibitor, Bay117082, decreases the expression overexpressed in platinum resistant NSCLC cells.
of integrin ơ3 and suppresses Ơ-catulin-promoted cell In particular, cisplatin resistant cells expressed a
migration. Blocking Ơvơ3 signaling pathway by using heavier protein isoform of MYRIP which appeared
neutralizing antibody effectively inhibits Ơ-catulin- to be associated with the mitochondria. Silencing
promoted cell migration. of MYRIP induced BIM and BAX/BAK-dependent
Conclusion: Taken together, our present study mitochondrial apoptosis which was selective for
revealed that Ơ-catulin might through regulating NF- NSCLC, but not non-cancerous lung cells. In
ƩB activity to increase the expression of Àbronectin addition, loss of MYRIP induced S-phase arrest.
and Ơvơ3, and then promote cell migration. Conclusion: Overexpression of MYRIP is an
Keywords: migration, integrin, Àlopodia independent, poor prognostic factor suggesting that
targeting these genes may be therapeutically relevant.
In summary, MYRIP exhibits a previously unknown
Poster Session 1 – Novel Cancer Monday, 4 July 2011 12:15-14:15 survival function associated with suppression of pro-
apoptotic BCL-2 family proteins and maintenance of
P1.115 THE RAB27A EFFECTOR MYRIP cancer cell proliferation and survival.
IS AN ESSENTIAL REGULATOR OF Keywords: Novel Target Discovery, drug resistance,
SURVIVAL IN NON-SMALL CELL LUNG apoptosis
CANCER CELLS
Alex Chacko1, Puthen Jithesh2, Claire Grills3, Nyree A revised/updated abstract may be included in
Crawford1, Ian Paul1, Martin Barr4, Kenneth J. the Late Breaking Abstract Supplement, available
O’Byrne4, Dean A. Fennell1 at the 14th World Conference on Lung Cancer.
Poster Session 1 – Novel Cancer Monday, 4 July 2011 12:15-14:15 kinases with SP600125, PD098059, and LY294002,
respectively, showed a 2-fold increase in apoptosis
P1.116 TRAIL-INDUCED KINASE when combined with TRAIL. The activation of
ACTIVATION IN NON SMALL CELL MAPK p38 on the other hand was pro-apoptotic,
LUNG CANCER CELLS since its inhibition with SB203580 resulted in a
Kaamar Azijli1, Saravanan Yuvaraaj2, Maikel reduction of TRAIL-induced apoptosis in H460
P. Peppelenbosch3, Henk Dekker4, Jos Joore5, cells. In resistant A549 cells, however, Akt, ERK,
Godefridus J. Peters4, Steven De Jong2, Frank A. p38 MAPK, and JNK1/2 activation appeared to have
Kruyt2 anti-apoptotic activity. Furthermore, in these cells
1
Medical Oncology, Vu University Medical Center/ an increase in IƩBƠ phosphorylation was observed
Netherlands, 2Umcg/Netherlands, 3Erasmus MC/ that was not seen in H460 cells, where levels of
Netherlands, 4Vu University Medical Center/ phosphorylated IƩBƠ decreased after 1 hour that
Netherlands, 5Pepscan/Netherlands correlated with cleavage of RIP.
Conclusion: Thus suppression of NFƩB activation
Background: Non-small cell lung cancer (NSCLC) could be associated with TRAIL sensitivity. PepChip
is a disease with poor prognosis and novel kinase arrays, revealed the activation of kinases that
therapeutic approaches are greatly needed. Tumor are involved in cell migration, such as Rho/Rock in
necrosis factor (TNF)-related apoptosis-inducing A549 cells, and further investigations are ongoing.
ligand (TRAIL) is an interesting agent that is able In conclusion, we observed differential TRAIL-
to trigger apoptosis through interactions with dependent activation of p38 MAPK, JNK1/2, ERK,
TRAIL receptors. An important feature of TRAIL Akt and IƩBƠ in sensitive and resistant NSCLC
is its ability to induce apoptosis in a wide variety cells as well as in pathways that regulate migration.
of tumors without harming normal cells, making it The relationship with TRAIL antitumor activity is
an attractive anti-cancer therapeutic compared to currently further explored.
conventional anti-cancer agents. However, TRAIL Keyword: TRAIL NSCLC kinases
is also able to activate signaling pathways that are
involved in survival, proliferation and migration of
tumor cells. Thus, TRAIL-based therapies combined Poster Session 1 – Novel Cancer Monday, 4 July 2011 12:15-14:15
with inhibitors of such pathways are expected to
enhance therapeutic beneÀt. P1.117 TARGETING THE IGF-1R
Methods: In this study, we aimed to identify SIGNALLING PATHWAY IN NON-SMALL
and characterize kinases that are activated by CELL LUNG CANCER (NSCLC)
recombinant TRAIL in NSCLC cells. We monitored Lydia Forde1, Steven G. Gray1, Kathy Gately1,
the activation of a number of kinases known to be Kenneth J. O’Byrne2
1
involved in TRAIL signaling by Western blotting, Department Of Clinical Medicine, Trinity College
including p38 MAPK, JNK, ERK and Akt. In Dublin/Ireland, 2Oncology, St James’s Hospital/
addition we employed PepChip kinase arrays. With Ireland
these arrays 1024 peptide kinase substrate can be
screened in one experiment, whereby a comparison Background: Non-small cell lung cancer (NSCLC)
of kinase patterns between untreated and treated cells is the commonest cause of cancer related deaths
can be obtained. worldwide and has a very poor prognosis. Research
Results: NSCLC, H460 and A549 cell lines, which into cell signalling pathways has paved the way
are sensitive and resistant for TRAIL, respectively, for the creation of targeted therapies for patients.
were exposed to 50 ng/ml TRAIL for different Insulin-like growth factor receptor (IGF-1R)
periods of time (5 to 240 minutes) to evaluate the overexpression has been identiÀed in several tumour
kinetics of kinase activation. In H460 cells, TRAIL types and protects cells from apoptosis-inducing
induced the phosphorylation of p38 MAPK after 2 agents, including hypoxia and anti-cancer drugs.
hours and JNK1/2 after 3 hours. As the activation The IGF-1R pathway has emerged as an attractive
of these kinases can be both anti- and pro-apoptotic, target for anti-cancer drug development. This study
kinase inhibitors were used to explore this further. investigates whether the IGF-1R tyrosine kinase
In H460 cells the activation of JNK, ERK and domain may contain mutations/deletions that may
Akt had anti-apoptotic activity. Inhibition of these inhibit the effectiveness of targeted therapy. This
study also examines the regulation of the IGF Poster Session 1 – Novel Cancer Monday, 4 July 2011 12:15-14:15
binding proteins (IGFBP 1–6) by hypoxia and may
help in the design of new therapeutic uses for IGF-I/ P1.118 CHEMOTHERAPY INDUCED
IGF-IR inhibitors. INFLAMMATORY MARKERS AND
Methods: A cohort of 100 NSCLC patients who RELEVANCE FOR PROGNOSIS AND
had undergone lung tumour resection surgery RESPONSE IN RESECTED STAGE IIIA
were screened for mutations in the 6 exons of the NSCLC
tyrosine kinase (TK) domain of the IGF-1R. Each Philipp Huesecken1, Tobias Schulte1, Jan-Hendrik
exon was sequenced in both directions using a Egberts1, Roland Kurdow1, Thomas Becker1, Peter
direct sequencing method (AB3130). A SNP at Dohrmann1, Holger Kalthoff2, Bodo Schniewind1
1
codon 3129A>G, in exon 1 of the tyrosine kinase General And Thoracic Surgery, University Hospital
domain, was examined using a genotyping SNP Of Schleswig-holstein Campus Kiel/Germany,
2
assay (Applied Biosystems) in 200 NSCLC patients Molecular Oncology, University Hospital Of
and 866 control individuals. IGFBP expression was Schleswig-holstein, Campus Kiel/Germany
examined in NSCLC cell lines and human bronchial
epithelial cell (HBEC) lines by RT-PCR and Western Background: In addition to cell death chemotherapy
blot analysis. can induce various other mechanisms that
Results: No mutations or deletions were detected in inÁuence biological behaviour of tumour cells.
exons 2-6 of the IGF-1R TK domain in 100 NSCLC In the following analysis, the pro-inÁammatory
patients. A heterozygous SNP at codon 3129A>G and pro-invasive chemotherapy induced effects
was identiÀed in exon 1 of the TK domain. A were analysed for the non-small cell lung cancer
further 100 NSCLC patients and 866 control (NSCLC).
individuals were examined for both genotype and Methods: Cytotoxicity of 5 different cytotoxic drugs
allelic frequency of this SNP however there was was measured (cisplatin, etoposide, gemcitabine,
no signiÀcant difference between NSCLC patients paclitaxel, 5-FU) in 4 NSCLC cell lines. With
compared to control individuals. The presence of this ED20/50 PI-FACS cell cycle analysis and Àbroblast
SNP had no inÁuence on either IGF-1R expression layer invasion analyses were done. In ELISA/
or patient survival. IGFBP mRNA expression was Multiplex-FACS analyses induction of expression
examined in a panel of NSCLC and HBEC cell of 16 proteins (IL1ß, 4,6,8,10,12, TNF, VEGF,
lines. RT-PCR results showed that BP2 and BP3 MIP1a, 1b, angiogenin, bFGF, FAS-L, uPA, MMP2,
were expressed in all NSCLC cell lines and 3 out of 7, 9) were measured. In an orthotopic SCID mouse
5 NSCLC cell lines expressed BP1 and BP4. A549 model tumour growth, RNA and protein expression
had the highest expression of BP1-4 compared to of orthotopic growing tumors were analysed by
the other cells lines. No differences in BP2 and BP3 RT-PCR and Western Blot in a selection of the
expression were observed in A549 and H1299 cells aforementioned genes. Next to histologic regression
grown under hypoxia compared to normoxia over analyses corresponding analyses were performed
24 hours. BP3 was over-expressed in all HBEC cell in 32 patients (23 with / 10 without neo-adjuvant
lines grown under hypoxia compared to normoxia chemotherapy) with NSCLC in stage IIIA in resected
at 24 hours. No difference in BP3 expression was tumour material.
observed at the protein level in HBEC cell lines Results: The cell lines showed a different sensitivity
under hypoxia compared to normoxia at 24 hours. to the various cytotoxic drugs in PI-FACS and
Conclusion: A heterozygous SNP at codon viability analyses. For individual cell lines and
3129A>G, identiÀed in exon 1of the tyrosine cytostatica combinations an increased invasiveness
kinase domain, had no inÁuence on either IGF1R could be shown. The ELISA / FACS analysis
expression or patient survival. Further investigation demonstrated a universal stimulation of IL-8.
into the interaction and regulation of the IGFBPs Increased induction IL-8 was associated with an
in the IGF-1R signaling pathway is warranted to increased sensitivity towards chemotherapy. For
elucidate their role in NSCLC. the other proteins a speciÀc expression proÀle was
shown related to the drug / cell line combination.
In the orthotopically growing tumours the results
of could be reproduced on the mRNA and protein
level. Although histologic regression indices did
not correlate with oncologic long term outcome, days after reperfusion with intact nuclear and increased
increased expression of VEGF and MMP2 in tumor lamellar bodies in SIM group.
samples with neoadjuvant chemotherapy correlated Conclusion: Simvastatin exerts therapeutic effects
with an improved outcome in survival analyses (log in a rodent model of LIRI, mainly by promoting the
rank p<0.05). proliferation of ATII cells.
Conclusion: Chemotherapy is able to stimulate in Keywords: Alveolar, Ischemia, Reperfusion injury
vitro and in vivo a subset inÁammation associated
genes. Increased induction of inÁammatory A revised/updated abstract may be included in
genes was associated with enhanced sensitivity the Late Breaking Abstract Supplement, available
towards chemotherapy in vitro and improved long at the 14th World Conference on Lung Cancer.
term prognosis in vivo. Enhanced inÁammatory
responsiveness in NSCLC seems to be associated
with an increased sensitivity towards chemotherapy. Poster Session 1 – Technology and Models Monday, 4 July 2011
Keywords: Chemotherapy, InÁammation, NSCLC 12:15-14:15
P1.120 IMPROVEMENT IN THE

Poster Session 1 – Technology and Models Monday, 4 July 2011 DETECTION OF GENOMIC
12:15-14:15 ABERRATIONS WITH SINGLE
NUCLEOTIDE POLYMORPHISM
P1.119 SIMVASTATIN ATTENUATES ARRAYS USING MICRODISSECTED
LUNG ISCHEMIA-REPERFUSION SAMPLES
INJURY VIA THE PROMOTION Isabel Zudaire1, Alberto Orta1, María J. Pajares1,
OF ALVEOLAR TYPE II CELLS Angel Rubio2, María Ortiz-Estevez2, José A.
PROLIFERATION Martínez-Climent1, Ruben Pio1, Luis M. Montuenga1
1
Feng Jiang, Dong-Jie Feng, Lin Xu Biomarkers Lab. Oncology Division., Center Of
Thoracic Surgery, Cancer Hospital Of Jiangsu Applied Medical Research. University Of Navarra./
Province/China Spain, 2Group Of Bioinformatics, Ceit And Tecnun.
University Of Navarra./Spain
Background: We sought to explore the mechanism
of simvastatin to ameliorate lung ischemia Background: Microarray technology is a powerful
reperfusion injury (LIRI). tool for cancer research because of its ability to
Methods: A long-term survival model of rat lung simultaneously measure expression, copy number
ischemia reperfusion injury was steady established. and genotype of thousands of genes. The high
We randomly divided 72 male Sprague-Dawley resolution of this technology is conditioned mainly
rats into 3 groups: sham group (n=24); ischemia by the quality of the sample. Fresh or frozen samples
reperfusion (IR) group (n=24); simvastatin (SIM) with 100% of tumor cells are preferable. However
group (n=24). Lung tissues were collected at tumor tissue represents a mixture of tumor and
baseline, 1 day, 3 days and 7 days after LIRI. non-tumor cells. An excess of DNA from normal
Measured variables included surfactant protein-C cells could signiÀcantly diminish the sensitivity
(SP-C) expression determined by reverse of the detection of genomic aberrations such as
transcription polymerase chain reaction (RT-PCR), copy number changes and loss of heterozigosity
the proliferation proÀle of ATII cells evaluated (LOH). In order to evaluate the effect of normal cell
by immunoÁuorescence double staining and the contamination in the analysis of single nucleotide
ultrastructure of ATII cells. polymorphism (SNP) arrays, we performed a study
Results: Compared with IR group, the SP-C mRNA comparing microdissected and non-microdissected
level were signiÀcantly lower in SIM group at 1 day non-small cell lung cancer (NSCLC) tissues.
and 3 days after reperfusion (P<0.01 respectively). Methods: Tumors from surgical NSCLC patients
The number of SP-C/PCNA double positive ATII cells were used. From each patient, we selected two
displayed that compared with IR group, the proliferation different frozen tissue blocks containing around 70%
of ATII cells in SIM group was signiÀcantly increased of tumor cells. Tumor cells were microdissected
at 3 days after reperfusion. Ultrastructural analysis also from one block and the other was processed without
showed that ATII cells almost returned to normal at 3 microdissection. In order to perform a paired analysis,
DNA from blood was extracted from each patient. devices which are included in smart phones, such
Affymetrix GeneChip® Human Mapping 250K Nsp as iPhone ®, and tablet PCs, touch panal controls
arrays were used. Pre-ampliÀcation was not required. on monitors become rapidly popular in the world.
Array results were analyzed under R using the aroma. In this study, we have developed multi-touch panel
affymetrix package. A copy number paired analysis robotic arm control system for thoracoscopic surgery.
was performed using ACNE algorithm. For each Methods: Our multi-touch panel navigation system
sample, we quantiÀed the number of chromosomal consists of green laser guide maker, robotic arms with
segments with genomic aberrations (ampliÀcation, four spindles, multi-touch panel monitor, and PCs for
deletion and LOH), and the copy number variation control regulation. The PCs has the motion control
(CNV) estimated in each segment. program for exclusive use. We can see a green laser spot
Results: We found signiÀcant differences between on the surface of organ and touch the spot with right
microdissected and paired non-microdissected foreÀnger. The multi-touch panel monitor recognized
samples. CNV analysis showed that microdissection the Ànger-touch; thereby the tip of the robot arm is
allows a better estimation of the real CNV present in controlled just on the green maker. When we move
the tumor tissue. Differences were also remarkable your Ànger-touched point on the panel, the tip of the
in LOH, where microdissection allowed us to detect arm will follow the trace of the movement of the Ànger.
abnormal regions overlooked in the analysis of non- To appraise the value of our touch panel navigation
microdissected samples. for VATS operation, we performed the operation using
Conclusion: Microdissection signiÀcantly improves an animal model in the canonical animal laboratory
the sensitivity of SNP arrays for the detection of copy in Kobe, Japan. In the right-sided VATS operation for
number aberrations and LOH in frozen NSCLC tissue. the swine, we made an arterial-bleeding model from
Keywords: Lung cancer, genomic aberrations, SNP intercostals’ artery. Then, we tried blood stanching with
arrays, microdissection Argon plasma coagulation (VIO300D) controlled with
our touch panel navigation system.
A revised/updated abstract may be included in Results: Touch panel navigation system followed up
the Late Breaking Abstract Supplement, available the foreÀnger movement on the monitor closely and
at the 14th World Conference on Lung Cancer. rapidly. In the right-sided VATS operation of swine,
we could immediately stop bleeding with Argon
plasma coagulation controlled with our touch panel
Poster Session 1 – Technology and Models Monday, 4 July 2011 navigation system.
12:15-14:15 Conclusion: We demonstrated the ability of this
touch panel navigation system with green laser guide
P1.121 INTUITIVE TOUCH PANEL in swine operation. We have developed multi-touch
NAVIGATION SYSTEM FOR VATS panel robotic arm control system for thoracoscopic
Junichi Shimada, Kunihiko Terauchi, Daishiro surgery and succeeded in using our intuitive touch
Kato, Kazuhiro Ito, Masanori Shimomura, Hiroaki panel robotic control system for VATS model surgery.
Tsuneduka, Kaori Ichise Keywords: lung surgery, touch panel navigation,
Department Of General Thoracic Surgery, Kyoto VATS, robotic system
Prefectural University Of Medicine/Japan
Background: Improvement of medical technology Poster Session 1 – Technology and Models Monday, 4 July 2011
has resulted in the rapid and widespread use 12:15-14:15
of endoscopic surgery over the last 2 decades.
Development of VATS allows minimally invasive P1.122 ESTABLISHMENT OF A NOVEL
surgery to be performed via small, non-rib-spreading ORTHOTOPIC PERIPHERAL LUNG
incisions, and let the patients enable early physical TUMOR ANIMAL MODEL SUITABLE
recovery and comeback to normal life. However, FOR IMAGING AND THORACIC
when the lung is severely adhered the chest wall INTERVENTIONAL STUDIES
during VATS, the thoracic surgeon must do an Takashi Anayama1, Takahiro Nakajima1, Nona
operation with the electrical scalpel, while watching Zeitlin1, Michael Dunne2, Catherine Coolens3,
the operating Àeld directly or thoracoscopically. Thomas Waddell1, Shaf Keshavjee1, David Jaffray3,
While a lot of people begin to use multi-touch panel Kazuhiro Yasufuku1
1
Department Of Thoracic Surgery, Latner Thoracic showed chest wall invasion on Day 16 (n=2/2).
Surgery Laboratory, Division Of Thoracic Surgery, Radial type EBUS visualized the tumor in each
Toronto General Hospital, University Health cases successfully (n=7/7). EBUS measurement was
Network/Canada, 2Sttarr Innovation Centre, signiÀcantly correlated with the CT measurement
Radiation Medicine Program, Princess Margaret (n=9, CT: 22.0±15.1 vs EBUS: 20.3±12.2 (mm),
Hospital, University Health Network/Canada, Spearman rank correlation coefÀcient, rs=0.98,
3
Department Of Radiation Oncology, University p<0.01).
Of Toronto, Department Of Radiation Physics, Conclusion: Minimally invasive inoculation of
Radiation Medicine Program, Princess Margaret tumor cells into lung parenchyma is a reproducible
Hospital, University Health Network/Canada technique to make orthotopic peripheral lung VX2
tumor in rabbits. EBUS is useful to assess the size
Background: There is a need to develop an of the lung tumor in this model. This model may
orthotopic peripheral lung tumor animal model provide the useful platform for imaging and thoracic
for the development of both new diagnostic and interventional studies. This study was supported by
therapeutic modalities for lung cancer. Previous The Ontario Institute for Cancer Research (OICR)
reported techniques for establishment of Rabbit Keywords: Rabbit VX2 tumor model, Orthotopic
VX2 orthotopic lung tumor model such as peripheral lung cancer animal model, Endobronchial
percutaneous inoculation and inoculation from a ultrasonography, Minimally invasive technique
tracheostomy is invasive and is associated with
risks of pneumothorax and pleural dissemination.
The purpose of this study is to establish a minimally Poster Session 1 – Technology and Models Monday, 4 July 2011
invasive technique to make an orthotopic peripheral 12:15-14:15
lung tumor model which is suitable for both imaging
and interventional studies. P1.123 CREATION OF PULMONARY
Methods: New Zealand rabbits were anesthetised CARCINOID TUMOR CELL LINES
and intubated with an endotracheal tube. The guide Charles F. Thomas1, Sandra C. Tomaszek2, Tobias
sheath was inserted into the bronchus through Peikert2, Bharati Sanyal2, Shari Sutor3, Marie
the endotracheal tube and guided to the point of Christine Aubry2, Dennis A. Wigle2
1
interest under Áuoroscopy. A transbronchial needle Pulmonary & Critical Care, General Thoraic
aspiration needle was passed through the sheath for Surgery, Anatomic Pathology, Mayo Clinic/United
tumor inoculation. The suspension of VX2 tumor States Of America, 2Pulmonary And Critical Care
and collagen gel matrix (Matrigel) was inoculated Medicine, Mayo Clinic/United States Of America,
3
through the needle into the lung parenchyma General Thoracic Surgery, Mayo Clinic/United
with varying numbers of tumor cell set (group I : States Of America
n=3; 6.0 x 107, Group II : n=4; 1.0 x 107, Group
III: n=4 ; 2.0 x106, Group IV : n=4; 8.0 x 106). Background: Pulmonary carcinoid tumors account
Subsequent tumor growth was evaluated with both for 5% of all lung malignancies in adults. They
computed tomography (CT) and endobronchial comprise 30% of all carcinoid tumors after those
ultrasonography (EBUS) following euthanasia and found in the GI tract. Histologically they are
necropsy. classiÀed as typical or atypical. There are limited
Results: Lung tumor developed in the lung reagents available to study the biology of these
parenchyma in 12 out of 15 cases (80.0%). In the 7 rare tumors, and consequently no major advances
cases in which the tumors were grown in right Lower have been made for patient treatment. Complete
lobe, CT study revealed that the tumor sizes were surgical excision remains the only curative treatment
signiÀcantly smaller in group III ( Group III(n=3): due to the relative ineffectiveness of chemo- and
8.2±4.6 vs Group I,II and IV(n=6) 18.7±3.5 (mm), radiotherapy.
p<0.001), in which the tumors had grown up to 15- Methods: We established human pulmonary
20 mm in size without any pulmonary metastasis carcinoid tumor cell lines from surgically resected
on day 16 (n=3/4). Only 1 case out of the 10 cases tumors to provide models for testing novel
of tumor that grew in the right lower lobe showed chemotherapeutic agents and studying the biology of
chest wall invasion (n=1/10), whereas both of the these rare tumors. Tissue was harvested from three
2 cases with tumor grown in the right middle lobe patients with primary pulmonary typical carcinoid
tumors undergoing surgical resection. The tumor sacriÀce and longitudinal subgroups. Mice from the
was dissociated and mechanically homogenized into sacriÀce subgroups were euthanized 8 weeks (CG
a cell suspension and plated onto dishes in culture n=6, EG n=6), 23 weeks (CG n=6, EG n=7), and 35
media. The established cell lines were characterized weeks (CG n=12, EG n=11) after urethane injection.
by immunohistochemistry, western blotting, and cell Lungs were Àxed with formalin at constant pressure,
proliferation assays. Tumorigenicity was conÀrmed and the number and size of lesions measured on
by soft agar growth and the ability to form tumors in H&E stained sections. Mice on the longitudinal
a mouse xenograft model. subgroup (control n=11, emphysema n=10)
Results: Three human typical pulmonary carcinoid underwent microCT scans with respiratory gating at
tumor cell lines were created. All grew as adherent all time points and were sacriÀced after the last scan
monolayers in vitro, expressed neuroendocrine for tissue collection.
markers consistent with the primary tumor, and Results: The histological analysis of the sacriÀce
formed colonies in agar. A single cell line produced subgroups revealed that at week 35 the mean area
lung tumors in nude mice after intravenous injection. (mm2) per lesion was signiÀcantly larger (p<0.01)
Conclusion: We have created three human in the EG (1.14±0.74) than in the CG (0.90±0.65).
pulmonary typical carcinoid tumor cell lines as a tool Indeed, there is a greater number of large (area >
for understanding the biology of these rare tumors 3mm2) lesions (CG 14, EG 35). Contrarily, at 23
and for testing of novel therapeutic agents. weeks, EG lesions (0.21±0.09) were signiÀcantly
Keywords: Lung cancer, Neuroendocrine, Xenograft smaller (p<0.01) than CG lesions ( 0.42±0.15).
No differences in size were found at 8 weeks (CG
0.06±0.02, EG 0.05±0.02). Large lesions in both
Poster Session 1 – Technology and Models Monday, 4 July 2011 groups displayed the classical adenocarcinoma
12:15-14:15 phenotype, as shown by presence of nuclear atypia,
papillary morphology and invasive margins. In
P1.124 EMPHYSEMA PROMOTES LUNG addition, preliminary Àne histological analysis
CANCER PROGRESSION IN THE A/J- suggests that the ratio adenoma/adenocarcinoma
URETHANE MOUSE MODEL may be altered between both groups. The average
Gabriel De Biurrun1, Arrate Muñoz-Barrutia1, number of lesions per animal was signiÀcantly lower
Gabriel Heras1, Albert Ferrando2, Monica Ferreira3, (p<0.01) in the EG at 23 weeks (CG 14.67±2.01,
Gorka Bastarrika3, David Blanco1, Carlos Ortiz-de- EG 7.43±0.69). No differences were found either
Solorzano1, Luis M. Montuenga1 at 35 (CG 20.33±1.59, EG 18.55±1.78) or 8 weeks
1
Oncology Division., Center Of Applied Medical (CG 4.17±0.70, EG 4.50±0.62). The results obtained
Research, University Of Navarra/Spain, 2School Of by microCT analysis of the longitudinal subgroups
Sciences, University Of Navarra/Spain, 3Radiology, follow the same trend as those obtained by
Clinica Universidad De Navarra/Spain histology conÀrming the feasibility of doing in vivo
longitudinal studies of these models.
Background: Recent clinical studies suggest that Conclusion: We show that the combined elastase/
Chronic Obstructive Pulmonary Disease (COPD) urethane treatment causes larger lesions at advanced
patients suffering emphysema have higher risk of stages, suggesting that tumors grow faster and more
developing lung cancer than the average population. aggressively in emphysematous environment, where
We have tested this hypothesis on a mouse model, by the need for tissue repair affects proliferation rates.
studying the effect of elastase-induced emphysema In conclusion, our data suggest that elastase induced
prior to urethane-mediated lung cancer. emphysema promotes lung cancer progression in
Methods: Male A/J mice were split into two groups: mice. Molecular studies currently being performed
the control group received a single intraperitoneal could possibly determine the potential mechanisms
injection of urethane (100mg/100g); the emphysema involved in this promotion.
group received an injection of urethane 9 days after Keywords: Mouse model, Emphsema, MicroCT,
one oropharyngeal aspiration of porcine pancreatic Lung cancer
elastase (20U/100g). The latter caused remarkably
emphysematous lungs, measured by respiratory
function, micro-Computed Tomography (microCT)
and histology. Each group was in turn split into
Poster Session 1 – Technology and Models Monday, 4 July 2011 mice were imaged by a small animal PET/CT as
12:15-14:15 pre-treatment before administration of cetuximab on
day 1 and secondly imaged with the same procedure
P1.125 18F-FLUOROTHYMIDINE as post-treatment on day 3. In the PET/CT imaging
(18F-FLT) AS EARLY PREDICTOR group, tumor cell proliferative activity (Ki-67) was
OF TUMOR RESPONSE FOR ANTI- also determined and was compared with the non-
EPIDERMAL GROWTH FACTOR treated control group as control value.
RECEPTOR ANTIBODY IN HUMAN Results: There was no difference in tumor volume
LUNG CANCER XENOGRAFT between the control or cetuximab treatment groups
Satoshi Takeuchi1, Songji Zhao2, Yuji Kuge3, Yan on day 3, although the difference became signiÀcant
Zhao4, Ken-Ichi Nishijima4, Yasushi Shimizu1, Ichiro after day 8. Considering this result, we performed
Kinoshita1, Nagara Tamaki2, Hirotoshi Dosaka- ex vivo study and 18F-FLT-PET/CT on day 3 as early
Akita1 therapeutic evaluation. In the ex vivo study, 18F-FLT
1
Department Of Medical Oncology, Hokkaido uptake was speciÀcally high in tumor comparing
University/Japan, 2Department Of Nuclear with normal tissues and was decreased by cetuximab
Medicine, Hokkaido University Graduate School treatment as early as day 3. Radioactivity of 18F-FLT
Of Medicine/Japan, 3Central Institute Of Isotope in tumor were 0.098 ± 0.005 (%ID/g/kg) in the
Science, Hokkaido University/Japan, 4Department Of control group and 0.029 ± 0.010 (%ID/g/kg) in the
Tracer Kinetics & Bioanalysis, Hokkaido University cetuximab-treated group, respectively (p < 0.001).
Graduate School Of Medicine/Japan In the PET/CT imaging group, the decrease of
tracer uptake in tumor was clearly visualized after
Background: SpeciÀc inhibition of epidermal the treatment with cetuximab on day 3 while the
growth factor receptor (EGFR) is one of the high uptake of 18F-FLT in tumor was seen before
most promising treatment in the clinical setting. treatment on day 1. Ki-67 positive cells were 12.8 ±
Cetuximab, a chimeric monoclonal antibody 4.0% in the non-treated control group on day1 and
that binds to the extracellular domain of EGFR, 5.0 ± 1.5% in the cetuximab treated group on day3 (
has activity in various types of cancer. Because p = 0.01), respectively.
cetuximab is very expensive and has unique side Conclusion: These results suggest 18F-FLT-PET/CT
effects, the development of appropriate evaluation can be a useful predictor to evaluate a response to
for the therapeutic effects is necessary to use this molecular targeted drug such as cetuximab at a very
drug effectively. Measurement of tumor proliferative early time-point before a signiÀcant change of tumor
activity by PET using 18F-Fluorothymidine (18F-FLT) size.
may serve to assess early therapeutic effect. The Keywords: response predictor,
purpose of this study is to determine whether 18F-Fluorothymidine, cetuximab
18
F-FLT positron emission tomography/computed
tomography (18F-FLT-PET/CT) is useful to evaluate
a response to EGFR antibody cetuximab therapy Poster Session 1 – Technology and Models Monday, 4 July 2011
at very early time-points in human lung cancer cell 12:15-14:15
xenografts.
Methods: Human tumor xenograft model was P1.126 IDENTIFICATION OF
established in male BALB/c athymic mice with NEW RELATIONSHIP BETWEEN
human lung cancer cell line NCI-H1975. These EGFR MUTATION AND
mice were randomly assigned to four groups; tumor CLINICOPATHOLOGICAL FACTORS TO
growth follow-up, ex vivo study, PET/CT imaging ESTABLISH A PREDICTION MODEL OF
and non-treated control. Mice were administered EGFR MUTATION IN NON-SMALL-CELL
saline as control or cetuximab 1.0 mg on day 1. LUNG CANCER.
In the tumor growth follow-up group, tumor sizes Tsuyoshi Ueno1, Shinichi Toyooka1, Kenichi Suda2,
were measured by caliper on day 3, 5, 8, and 10 Junichi Soh1, Keitaro Matsuo3, Yasushi Yatabe4,
after the treatment. In the ex vivo study group, Shinichiro Miyoshi1, Tetsuya Mitsudomi2
radioactivity of 18F-FLT in tumor and other tissue 1
Cancer And Thoracic Surgury, Okayama University/
samples (%Injected Dose/g/kg) was measured using Japan, 2Aichi Cancer Center Hospital/Japan,
3
liquid scintillation. In the PET/CT imaging group, Division Of Epidemiology And Prevention, Aichi
Cancer Center Research Institute/Japan, 4Pathology Poster Session 1 – Technology and Models Monday, 4 July 2011
And Molecular Diagnostics, Aichi Cancer Center 12:15-14:15
Hospital/Japan
P1.127 INTEGRATED CARE PATHWAYS
Background: The EGFR mutation is the key (ICPS) FOR NON-SMALL CELL LUNG
information of geÀtinib and erlotinib treatments CANCER (NSCLC) PATIENTS (PTS):
for non-small-cell lung cancer (NSCLC) patients. A MULTIDISCIPLINARY QUALITY
Previously, we or others reported the association IMPROVEMENT PROJECT
of EGFR mutations with adenocarcinoma, sex Valentina Merlo1, Simona Rizzato1, Alessandro
and smoking dose. Here we have Ànd the new Follador1, Ciro Rossetto1, Marianna Aita1, Marianna
information of interaction between sex and smoking Macerelli1, Angelo Morelli2, Stefano Meduri3,
dose, and age on EGFR mutation. Based on new Maurizio Rocco4, Valeria Tozzi5, Gianpiero Fasola1
1
Àndings, we have established the statistical model to Dipartimento Di Oncologia, Azienda Ospedaliero-
predict EGFR mutation probability. Universitaria/Italy, 2Dipartimento Cardiotoracico,
Methods: With IRB approval, we reviewed the Azienda Ospedaliero-Universitaria/Italy,
3
medical records and EGFR mutation status of all Dipartimento Di Diagnostica Per Immagini,
1262 patients from two institutes (737 patients of Azienda Ospedaliero-Universitaria/Italy,
4
Aichi Cancer Center and 525 patients of Okayama Dipartimento Di Medicina Di Laboratorio, Azienda
University). The associations of EGFR mutation with Ospedaliero-Universitaria/Italy, 5Center For
histological types, smoking dose, sex, age, stage and Research On Health And Social Care Management,
these combinations were evaluated. Then best model Bocconi University/Italy
for prediction of EGFR mutation probability using
logistic regression with these factors was evaluated. Background: ICPs are structured multidisciplinary
All results were cross-checked by comparison of care plans for a speciÀc clinical condition; they
each institution result. describe the tasks to be carried out along with their
Results: EGFR mutation was found in 33% timing and sequence and the department involved.
(417/1262), 42.1% (406/964) in adenocarcinoma, ICPs have been proposed as quality improvement
17.4% (4/23) in adeno-squamouscarcinoma strategies of both clinical and organizational aspects
and 2.5% (7/275) in other histological types. In of patient-oriented care. Nowadays few data remain
adenocarcinoma, EGFR mutation was associated available to detail existing ICPs for NSCLC pts and
with sex, smoking dose represented by pack- the methodology for design an optimum care plan.
year (PY), interaction of sex and smoking To reliably assess current practice, quality of care
dose and age. The best model for prediction of indicators are needed, that is measurable elements of
EGFR mutation was: logit(probability)= -0.1562 practice performance for which there is evidence or
-0.5523*(1=male/2=female) -0.0652*PY(male) consensus that they can assess the quality of the care
-0.0308*PY(female) +0.2460*age/10. The EGFR provided. Aim of this project was to review current
mutation rate of male and PY=0 was 75.4% (52/69), clinical pathways in the care of NSCLC pts who
female and PY=0 was 57.8% ( 234/405). The EGFR were referred to the University Hospital of Udine,
mutation of male was greater decreased as PY Italy.
increasing (odds ratio OR=0.937) than that of female Methods: A multidisciplinary focus group was set
(OR=0.970). Increasing 10 age showed increasing up to:
the OR=1.279. 1. map the existing local care process for NSCLC
Conclusion: EGFR mutations were associated with patients from the Àrst hospital visit to the follow-up
sex, smoking dose, interactions of sex and smoking phase;
dose, and age. Our model for predicting EGFR 2. review literature and evidence-based guidelines to
mutations in adenocarcinoma patients can be a useful identify quality of care indicators and corresponding
tool for patient selection for EGFR-TKI treatment benchmarks in this setting. Quality indicators consist
in patients whose EGFR mutation status is not in intermediate outputs of the care process and
available. are able to assess both clinical, organizational and
Keywords: NSCLC, EGFR, smoking, sex, age, economical points of view of the care provided.
model 3. compare the set of indicators selected with the
current process of care in order to monitor the
quality of care delivered and assess the effective Dei Servizi Ospedalieri, Azienda Ospedaliero-
implementation of the guidelines within the universitaria/Italy, 3Dipartimento Cardiotoracico,
framework; Azienda Ospedaliero-universitaria/Italy, 4Center For
4. recognize key areas with room for improvement Research On Health And Social Care Management,
and develop proposals for redesign of the ICPs. Bocconi University/Italy
Results: Eleven quality of care indicators were
identiÀed. Indicators were used to survey the ICPs of Background: ICPs have been proposed as quality
175 NSCLC pts referred to the oncology department improvement strategies and represent a mechanism
of the Udine University Hospital in 2008. Data for 8 to encourage the use of guidelines into clinical
representative indicators are shown below: practice. They provide a means to improve
multidisciplinary communication and care planning
INDICATOR MEDIAN BENCHMARK and allow systematic collection and abstraction
Days from ¿rst evaluation in a Lung Unit to histological for audits, promoting change in practice and the
15 15-20 (A)
diagnosis
Surgical pts undergoing a CT-PET followed by a identiÀcation of research and development questions.
2 80-100 (A)
mediastinoscopy (%) In this study, the quality of the existing care process
Days from ¿rst Lung Unit to ¿rst Oncology Unit
evaluation (Stage IA-IIIA)
106 56-84 (B) for patients with NSCLC referred to a university
Days from ¿rst Lung Unit to ¿rst Oncology Unit
31 28-42 (B)
hospital has been assessed, in order to estimate
evaluation (Stage IIIB-IV)
the potential room for improvement and guide the
Pts multidisciplinary evaluation (%) 50 55 (A)
Days from histological diagnosis to surgery 49 28-35 (B) redesign of the ICP. Special attention was given to
Poor (>1) ECOG PS pts receiving a two-drug regimen (%) 1 0 (A) making the existing care process more appropriate
>3 lines of cytotoxic treatment (%) 0 0 (A) and reducing the avoidable costs.
Methods: 175 NSCLC cases referred to the
According to: (A) evidence-based guidelines or (B) Oncology Department of the Udine University
expert consensus Hospital from 1/1/2008 to 31/12/2008 were
identiÀed. A multidisciplinary focus group composed
Conclusion: By means of a limited set of quality of all the professionals involved in the management
indicators, we were able to verify the adherence of the care pathways of NSCLC patients was set up.
of routine clinical practice to clinical guidelines The focus group identiÀed eleven quality of care
and to elicit some critical issues in the care of indicators and corresponding benchmarks. They
NSCLC pts. Results need to be shared and discussed were gained from previously published studies or
with Hospital Managers, with the aim of guiding from international professional guidelines. By means
the redesign of ICPs and improving the clinical, of the electronic information system of both the
organizational and economic efÀciency of the care Hospital and the Oncology Department the quality of
process. care indicators were tested on the study population.
Keywords: Quality of care indicators, Benchmark, In cooperation with researchers of the Cergas Center,
Integrated care pathways Bocconi University, Milan, Italy, the extra costs
for inappropriate procedures were estimated by
the charges through which the regional health care
Poster Session 1 – Technology and Models Monday, 4 July 2011 system funds the hospital.
12:15-14:15 Results: The gap between current practice and the
benchmark objectives has been identiÀed, allowing
P1.128 INTEGRATED CARE PATHWAYS the quantiÀcation of the distance of real pathways
(ICPS) FOR NON SMALL CELL from the benchmark standards also in terms of
LUNG CANCER (NSCLC) PATIENTS: avoidable costs. The most critical area was early
AVOIDABLE COSTS ANALYSIS IN A disease stage patient management, but even the
QUALITY IMPROVEMENT PROJECT. follow up phase seems to be more intensive in
Gianpiero Fasola1, Simona Rizzato1, Valentina terms of visits and procedures than that suggested
Merlo1, Giovanni Maria Guarrera2, Giulia Zumerle2, by the guidelines. There were 46 unexpected
Lorena Gurrieri1, Tino Ceschia1, Emilio Lugatti3, biopsies: 30 patients had more than one biopsy
Isabella Giusepi4, Guglielmo Pacileo4, Valeria Tozzi4 (2, 3, 4 or 5 biopsies), with a total avoidable cost
1
Dipartimento Di Oncologia, Azienda Ospedaliero- of 7585.40€. There were 31 bronchoscopies: 24
universitaria/Italy, 2Dipartimento Di Organizzazione patients have more than one bronchoscopy with a
total avoidable cost of 3270.50€. The repetition of phantom organs such as skin, fat, muscle, liver and
these examinations was mainly due to an insufÀcient bones. The experiment was repeated Àve times for
amount of biological sample. There were 53 each type of needle.
unexpected CTs: 36 patients have more than one Results: The forces varied according to the type
CT before the surgical procedure because the last of organ and the size of the needle. During needle
CT was dated more than thirty days in advance with insertion phase, the friction force linearly increased
a total avoidable cost of 6312.30€. In summary by the depth in skin and muscle, while liver didn’t
the total estimated avoidable cost was 17,168.20€ add up any consistent amount of the reaction force.
(about 100 € per patient). Rather the reaction forces inside liver appeared
Conclusion: The study shows that analysis of ICP highly sensitive to the type of needle. During the
in NSCLC is feasible and allows the monitoring of extraction phase, a substantial negative force holding
the actual application of international guidelines the needle was initially induced, but the pattern
in a public and university teaching hospital, both showed linear decrease throughout liver, muscle and
in terms of better appropriateness and reduced skin soon after omental bursa region.
avoidable costs. This is only a Àrst simulation; Conclusion: The force needed to insert or extract
however the extension of this methodology could a biopsy needle for each organ and for each needle
produce interesting results that should be shared and can be assessed and modeled with the aid of 3D
discussed with the Hospital Managers in order to CT images. 3D visualization simulator would be
guide the redesign of ICPs. a useful tool to Ànd the optimal route for 3D CT
Keywords: Integrated care pathways, Avoidable image-guided biopsy if the properly modeled organ
Costs Analysis, Quality Improvement Project property is included in the simulator. Future research
will include the design of master/slave system with
force feedback for the precise control of the CT
Poster Session 1 – Technology and Models Monday, 4 July 2011 image-guided biopsy robot based on the analysis of
12:15-14:15 measured forces from this study.
Keywords: biopsy, phantom, force measurement,
P1.129 QUANTIFICATION OF NEEDLE robot,
INSERTION FORCE IN THE PRECISE
CONTROL OF 3D CT IMAGE-GUIDED A revised/updated abstract may be included in
BIOPSY the Late Breaking Abstract Supplement, available
Kwang Gi Kim1, Chang Min Park2, Hun Soo Shin1, at the 14th World Conference on Lung Cancer.
Min Tae Kim1, Jaebum Son1, Yung Ho Jo1
1
Biomedical Engineering, National Cancer Center/
Korea, 2Department Of Radiology, Seoul National Poster Session 1 – Technology and Models Monday, 4 July 2011
University Hospital/Korea 12:15-14:15
Background: In computed tomography (CT) image- P1.130 BIOCONDUCTANCE SCANNING

guided biopsy, a lesion is observed and the target TECHNIQUE AND PATIENT SAFETY/
tissue of biopsy is identiÀed using CT images prior ACCEPTABILITY IN SUBJECTS WITH
to the insertion of a biopsy needle. However, major INDETERMINATE MASSES BY LUNG CT
nerves and organs along the path of the biopsy Rex C. Yung1, Mingying Zeng2, Michael Garff3,
needle also need to be identiÀed to ensure safe Karleen Callahan4
1
and accurate biopsy. In this study, we measured Medicine, Oncology, Pulmonary & Critical Care,
the reaction force pattern during insertion and Johns Hopkins University/United States Of America,
2
extraction of the needle in a general purpose multi- Pulmonary And Critical Care Medicine, Johns
tissue phantom , for using it in later biopsy route Hopkins University School Of Medicine/United
optimization using a 3D image based simulator States Of America, 3Freshmedx/United States Of
Methods: The needle reaction force was measured America, 4Clinical Affairs, Freshmedx/United States
using a biopsy robot built in this lab, equipped with Of America
a force sensor located at the base of biopsy needle.
The forces required to insert and extract the needle Background: The bioelectrical properties of
were measured along the route, which was set to pass cancerous tissue are well characterized and vary
signiÀcantly from normal and benign tissue. We technology requires no specimen handling, and
tested a non-invasive Bioconductance Scanning differs from developing “biomarkers” by focusing
Platform (BSP) developed for the rapid acquisition strictly upon the characterization of an indeterminate
of transthoracic bioconductance measurements, or mass. This objective is clinically relevant and
the Computerized Bioconductance Test (CB Test). distinct from blood and sputum-based biomarkers
The CB Test evaluates speciÀc bioconductance wherein a positive result may occur in the absence of
properties of indeterminate lung masses. an identiÀed mass so the appropriate clinical action
Methods: The BSP delivers a safe current of is often complicated.
<25micro amps to measure bioconductance between Keywords: CB Test - Computerized Bioconductance
reference electrodes placed on the patient’s back or Test, BSP - Bioconductance Scanning Platform,
hands and a computerized bioconductance Probe Indeterminate Masses
(Probe). The operator is prompted to place the
Probe at 62 anatomical locations. Measurements
are sampled 25 times per second and recorded and Poster Session 1 – Technology and Models Monday, 4 July 2011
evaluated. Each measurement contains 9 attributes 12:15-14:15
of bioconductivity behavior acquired in less than
12 seconds. Certain locations include diagnostic P1.131 DEVELOPMENT OF A HIGH
information while others are controls. Stored data SENSITIVITY COLD-PCR METHOD
is analyzed to train a predictive classiÀer algorithm FOR THE DETECTION OF THE EGFR
that discriminates between masses with either MUTATIONS IN PLASMA OR SERUM
benign or malignant characteristics. This situation Philip Eastlake, Grant Wu, Yanggu Shi, Karissa
is analogous to genome-wide association studies Echtenkamp, Reyes Candau, Benjamin Legendre Jr,
where each marker has its own signiÀcance test. Our Katherine Richardson
Probe removes variability associated with moisture, Research & Development, Transgenomic, Inc./
skin type, and operator error (Reliability Index 0.989 United States Of America
and Correlation between Device Replicates 0.980).
The operator receives 1.5 days training to ensure Background: High sensitivity methods for detecting
uniformity of measurement and protocol compliance. somatic mutations are required in the discipline
Following the Test, a questionnaire asked: (1) of cancer therapy where key genetic changes are
Did measurement cause discomfort? (2) Did Test associated with EGFR antagonists’ effectiveness, e.g.
duration seem reasonable? (3) Would you undergo in the genes EGFR, K-RAS, PIK3CA, BRAF, p53
measurement again? and NRAS. To enrich for all types of substitutions,
insertions and deletions in a single assay, we have
developed EGFR exon-speciÀc Ice COLD-PCR
assays which preferentially amplify low levels of
mutant DNA in samples containing a vast excess
of wild-type DNA. Use of reference sequence
oligonucleotides (RS-oligos) complementary to
wild-type strands results in linear ampliÀcation of
Results: The BSP algorithm discriminated between wild-type sequences but exponential ampliÀcation of
the subjects with benign and malignant outcomes any mutant sequences present. This is not an allele-
with an ROC of 91%. No reported Adverse Events, speciÀc technique; therefore all mutations, both
Serious Adverse Events or Unanticipated Adverse known and unknown, are enriched and identiÀed in a
Device Effects were reported. One patient noticed single reaction.
a “little pressure”, and all responded that the testing Methods: NSCLC tumors harboring the EGFR
time was acceptable. 1 subject responded “maybe” L858R mutation and exon 19 deletions respond to
to undergoing repeat measurement and 2 subjects anti-EGFR therapy while those containing the exon
responded “no”. Of the 2 “no” responses, one 20 T790M mutation do not. Ice COLD-PCR methods
provided no reason and another cited excessive have been developed using RS-oligos, containing
travel from home to clinic. locked nucleic acids (LNAs), complementary to the
Conclusion: The BSP is non-invasive, safe, easy- wild-type sequence corresponding to the relevant
to-use and has high patient acceptability. This EGFR regions of exons 18-21.
Results: Ice COLD-PCR ampliÀcation of control this study, we examined the anti-cancer and
and L858 mutation plasmids followed by Sanger radiosensitizing effect of CH-205-O on human
sequencing had a limit of detection (LOD) of 0.1–0.5%. esophageal cancer cells.
Ice COLD-PCR was also used for detecting exon 19 Methods: Human squamous cell carcinoma (CE81T/
deletions; after Sanger sequencing, an LOD of 0.5% VGH and TE-2) and adenocarcinoma (BE-3 and
mutant DNA was achieved. DNA samples extracted SKGT-4) cell lines were kept in exponential growth
from plasma from NSCLC patients were tested by Ice status. MTT assay was used for cell viability. Cell cycle
COLD-PCR for both the L858R mutation and exon 19 was analyzed by using propidium iodide staining and
deletions. All mutations previously identiÀed by Sanger Áow cytometry. Mitochondrial transmembrane potential
sequencing were conÀrmed along with additional, was measured by DiOC6 staining and Áow cytometry.
previously undetected mutations. These new mutations Colony formation assay was performed for estimation
were detected due to Ice COLD-PCR’s ability to enrich of radiation surviving fraction. Xenograft of human
mutations in a wild-type background making them CE81T/VGH cells was established for evaluation of
detectable by DNA sequencing. Preliminary results for therapeutic activity in vivo.
detection of T790M and the G719X mutations will also Results: CH-205-O inhibited the viability of
be presented. human esophageal cancer cell lines, including
Conclusion: The results demonstrate Ice COLD- squamous cell carcinoma (CE81T/VGH and TE-
PCR’s utility for highly sensitive detection of 2) and adenocarcinoma (BE-3 and SKGT-4). The
EGFR mutations in DNA derived from plasma. estimated IC50 for these four cell lines was 3.4
Following Ice COLD-PCR, DNA sequencing can – 6.9 ƫM. CH-205-O induced a hypoploid cell
be used to verify the somatic mutations in samples population and morphological alterations typical
such as low tumor-load biopsies, formalin-Àxed of apoptosis in CE81T/VGH and BE-3 cells. This
parafÀn-embedded slides, Àne-needle aspirates, apoptosis induction activity was accompanied by
circulating tumor cells and circulating free tumour reduction of mitochondrial transmembrane potential,
DNA in plasma and serum. This method can also indicating an intrinsic apoptotic pathway involved.
be used to conÀrm low signal Pyrosequencing and Furtherrmore, CH-205-O treatment accumulated
next-generation deep-sequencing results. Coupled cell cycle at G2/M phase and enhanced the
with mutation detection methods such as Sanger radiosenstivity with a sensitizer enahncement ratio
sequencing, Ice COLD-PCR provides a new model up to 1.6 in CE81T/VGH cells. In vivo, CH-205-O
for highly sensitive, economical testing of EGFR inhibited the growth of CE81T/VGH xenograft
mutations to aid patient treatment decisions. without signiÀcant impact on body weight and white
Keywords: Ice COLD-PCR, Somatic mutations, blood cell counts.
Non-small cell lung cancer, EGFR Conclusion: CH-205-O is capable of inhibiting
growth and enhancing radiosensitivity of huamn
A revised/updated abstract may be included in esophageal cancer cells. Further assessment of
the Late Breaking Abstract Supplement, available mechanism is undergoing.
at the 14th World Conference on Lung Cancer. Keywords: radiosensitization, CH-205-O,
Esophageal cancer, Anti-cancer
Poster Session 1 – Technology and Models Monday, 4 July 2011

12:15-14:15 Poster Session 1 – Technology and Models Monday, 4 July 2011
12:15-14:15
P1.132 EFFEC OF NATURAL COMPOUND
CH-205-O ON HUMAN ESOPHAGEAL P1.133 REFINEMENT OF LUNG
CANCER CELLS METASTASIS MODEL BY ORTHOTOPIC
Yu-Jen Chen1, Chih-Wen Chi2, C. C. Chen2 THORACIC IMPLANTATION OF NON-
1
Department Of Radiation Oncology, Mackay SMALL CELL LUNG CANCER CELLS IN
Memorial Hospital/Taiwan, 2College Of Medicine MICE
And Nursing, Hungkuang University/Taiwan Szu-Hua Pan1, Chien-Hsien Chen2, Pei-Fang Hung3,
Yu-Chih Chao1, Yih-Leong Chang4, Chen-Tu Wu5,
Background: CH-205-O is an aromatic ester Win-Ping Deng6, Jeremy J. W. Chen7, Tse-Ming
compound isolated from Armillaria mellea. In Hong8, Pan Chyr Yang9
1
Institute Of Biomedical Sciences, Academia Sinica/ LCRMP-1 cells formed larger orthotopic tumors
Taiwan, 211. Institute Of Biomedical Sciences (P=0.003) and more metastatic lung tumor nodules
And Molecular Biology, National Chung Hsing (P<0.001) than the vector control cells. Besides, we
University/Taiwan, 3Graduate Institute Of Life could also observe several tumor nodules formed
Sciences, National Defense Medical Center/ at the other organelles such liver, heart and chest
Taiwan, 44. Department Of Pathology And Graduate wall which could only saw a spread image by IVIS
Institute Of Pathology, College Of Medicine, observation.
National Taiwan University/Taiwan, 5Department Conclusion: We developed a reÀnement lung
Of Pathology And Graduate Institute Of Pathology, orthotopic tumor implantation model without
College Of Medicine, National Taiwan University/ surgery, which is suitable to detect the development
Taiwan, 6Institute Of Biomedical Materials And of cancer metastasis in vivo and it may decrease
Engineering, Taipei Medical University/Taiwan, the risk of infection caused by surgery. Using this
7
Institute Of Biomedical Sciences And Molecular animal model, we can evaluate the effects of study
Biology, National Chung Hsing University/Taiwan, genes or drugs on cancer metastasis. In the past,
8
Institute Of Clinical Medicine, National Cheng most scientists use several models involving the
Kung University/Taiwan, 9Department Of Internal implantation of tumor cells intravenously, from the
Medicine, National Taiwan University College Of portal vein, or from the left ventricle to evaluate
Medicine/Taiwan the development of cancer metastasis, but all
these models only show you the effects on distant
Background: Lung cancer is the leading cause of metastasis. Through lung orthotopic implantation, we
cancer-related mortality, especially non-small cell can detect not only the distant metastasis but also the
lung cancer (NSCLC). Paramount to this problem true effects on primary cancer metastasis.
is the fact that approximately 85% of diagnoses are Keywords: Metastasis, Orthotopic Thoracic mouse
made when the tumor can no longer be removed model, Lung cancer
surgically, and among patients with early-stage
NSCLC, the relapse rate approximates 40% within 5
years after potentially curative treatments. Metastasis Poster Session 1 – Technology and Models Monday, 4 July 2011
remains to be the major cause of treatment failure 12:15-14:15
in lung cancer patients. Although more and more
complex molecular mechanisms have been found to P1.134 THE PRELIMINARY STUDY ON
be involved in cancer metastasis, it is infrequently to THE RELATIONSHIP BETWEEN TREE
be evaluated in vivo. SHREW LUNG CANCER MODEL AND
Methods: Tumor cells with different invasive BIOMATERIALS CENTERED
abilities were orthotopically introduced into the lung Kaiyun Yang, Guangqiang Zhao
parenchyma of 6-week-old SCID mice (supplied Thoracic And Cardiovascular Surgery, Yunnan
by the animal center at the College of Medicine, Tumor Hospital/China
National Taiwan University, Taipei, Taiwan; n=10
per group), and luciferase image were used to make Background: To explore the inÁuence of biological
sure the successfully inoculated into the pleura material implantation into the lung cancer mode of
cavity. 28 days after implantation, mice will be tree shrew. Provide useful help for the prevention and
sacriÀced by anesthesia with carbon dioxide, and all treatment of Biomaterial Centered Infection (BCI).
organs will be removed and Àxed in 10% formalin. Methods: Use different methods of immune
The image of each tissue was taken and the lung suppression to establish the tumor models of tree shrew.
nodules were counted under gross and microscopic Collect 26Adult healthy tree shrews, male and female
examination. The number of mice used for the half and half. 20 tree shrews were selected randomly
experiments (n=10) was based on the goal of having into 2 groups the control group and the experimental
98% power to detect a two-fold between-group groups. The control group for the negative control
difference in nodule number at P < 0.05. group were given only saline. The experimental group
Results: Recently, we identiÀed that LCRMP-1 is was divided into two groups the irradiaton group
a novel invasion enhancer. When A549/LCRMP-1 and cyclophosphamide group. 3 subgroups (R1 R2
overexpressing cells were orthotopically inoculated R3) in the irradiation group, were given 6Gy, 8Gy,
into the pleural cavities of mice, we found that A549/ 10Gy irradiation by electron accelerator respectively.
Cyclophosphamide group were treated with like most cancers, it must gain access to the host
cyclophosphamide for immunosuppressive treatment. vasculature system in order to grow. The induction
Each group were implanted with tumor cell suspension. of angiogenesis is regulated through a balance
Observe the survival of tree shrew and tumor situation of stimuli from the tumor and the surrounding
to select the best experimental conditions for Tree microenvironment including inÀltrating cells of
shrew lung cancer model. hematopoietic origin. Targeting angiogenesis has
Results: 1. The immune suppressed tree shrews been an active area of research however, tumor
which treated by Electron accelerator radiation relapse is common as not all cells undergo apoptosis/
processing were activities reduced, slow, inactive, necrosis and some cells may even develop a selective
eating less, and even antifeedant. After tree shrews growth advantage under hypoxic conditions.
inoculated tumor cell suspension 2 days, the tumor Traditionally, imaging tumor vasculature relied
growth can be seeing. Tumor was growth rapidly on serial immunohistological sectioning or use of
and tumor nodules became maximum at the 3rd CT or MRI imaging with an appropriate contrast
week, after which tumor was growth slow and some agent, however, the architectural resolution of the
nodules were narrowing. Blood cell analysis and vasculature was not ideal. We have developed a
thrombocyte counting showed that signiÀcant bone novel method for 3-dimensional quantiÀcation of
marrow suppression appeared in tree shrews after architectural changes to the tumor vasculature in our
irradiation. It recovered after 1 week and white cell syngeneic mouse model system.
count near normal at the 3rd week. P value >0.05 Methods: Murine cell lines were developed from the
and indicted immune system had recovered. 2. The p53R172Hrg/+ K-rasLA1/+ mouse strain at varying stages
tree shrews which immunosuppressive treated by of malignancy. Cell lines were stably transfected
cyclophosphamide were like the tree shrews treated with EGFP-Luc and sorted for the highest expressing
by electron accelerator radiation. Those animals cells, and were proÀled for their expression level of
had high mortality and had no tumor nodule growth various angiogenic cytokines. Tumors were grown
during the experiment. 3. The best condition to subcutaneously in 129/Sv wild-type syngeneic hosts
establish adult tree shrews tumor model maybe by injecting 5x105 cells over both the right and
8Gy irradiation by electron accelerator. 5×106 left Áank of 6 week old mice. Tumor growth was
XWLC-05 was used to inoculate in tree shrews. The monitored with bioluminescent imaging and after 2
survival rate was 63.89%, and the formed tumor rate weeks mice were perfused with a radio-opaque dye.
was.61.11%. Experimental animals were administered a vascular
Conclusion: The tree shrew tumor model can disrupting agent, 24 hours prior to euthanization,
be established by implanting XWLC-05 into the while control animals received vehicle only. Tumors
tree shrews whose immunological function was were excised, and Àxed, followed by high-resolution
suppressed by irradiation with Electron accelerator Micro-CT scanning. Three-dimensional tumor
radiation. analysis was obtained for total vessel volume, vessel
Keywords: Tree shrew, Animal lung cancer models thickness, vessel separation and tumor/vessel ratio.
Results: Results in progress, will be available by May
13, 2011 for the late-breaking abstract submission
Poster Session 1 – Technology and Models Monday, 4 July 2011 Conclusion: Using our novel method of imaging
12:15-14:15 the microarchitecture of the tumor vasculature we
are able to evaluate changes to the vasculature of a
P1.135 IMAGING THE TUMOR tumor in reponse to different agents. In addition, we
VASCULATURE IN A SYNGENEIC can quantify the effectiveness of drugs speciÀcally
MOUSE MODEL OF NON-SMALL CELL aimed at targeting the tumor vasculature by
LUNG CANCER visualizing, at high resolution, the changes that
Charlene M. Downey, Michelle Villemaire, Frank R. happen throughout the entire tumor vascular bed.
Jirik Keywords: angiogenesis, syngeneic mouse model,
Biochemistry And Molecular Biology, University Of micro-CT
Calgary/Canada
Background: Lung cancer is one of the leading the Late Breaking Abstract Supplement, available
causes of cancer-related death in the world, and at the 14th World Conference on Lung Cancer.
Poster Session 1 – Technology and Models Monday, 4 July 2011 installed was the SQL Server 2008; Clear Canvas
12:15-14:15 Image Server and Workstation; DCMTK DICOM
toolkit; RSNA Clinical Trial Processor CTP and
P1.136 RESEARCH PLATFORM FOR Matlab Runtime Component. Clear Canvas Image
DATA SHARING IN EUROPEAN Server is a PACS and was installed with a temporary
RADIOTHERAPY COLLABORATION partition (TempPACS) holding identiÀable DICOM
Pierluigi M. Granone1, Elisa Meldolesi2, Maria headers and a research partition (ResearchPACS)
Letizia Vita1, Giulia Carnassale1, André L.A.J. holding only de-identiÀed DICOM objects. SQL
Dekker3, Vincenzo Valentini2, Lorenzo Bonomo4, Server 2008 was used to host the ResearchDB,
Philippe Lambin3 OntologyDB and KeyDB as well as the database of
1
Department Of Thoracic Surgery, Policlinico the Clear Canvas Image Server. A linked server to
Universitario Agostino Gemelli/Italy, 2Radiotherapy, the clinical database containing medical data was
Policlinico Universitario Agostino Gemelli/Italy, setup. A synchronization mechanism for DICOM
3
Radiation Oncology, MAASTRO Clinic/Netherlands, and clinical data was set up and was scheduled to
4
Department Of Bio-sciences And Radiological run nightly as to minimize interference with clinical
Imaging, Policlinico Universitario Agostino Gemelli, work. To retrieve data from the ResearchDB and
Rome/Italy ResearchPACS, a VPN connection was established.
Results: The data-sharing infrastructure was
Background: To understand how clinical aspects implemented in two months (July-August 2010) at
and treatment decisions can affect outcomes is crucial low cost. As of January 2011, the ResearchDB holds
for current and future research. A key element to about 2600 patients and the ResearchPACS holds
accelerate progress in radiation oncology is storing about 5.000 de-identiÀed DICOM objects using a
high-quality data (e.g. clinical, biological, dosimetric, total of 1 TB storage. All new patients are added
imaging) that can help to improve and validate automatically to the ResearchDB and PACS through
predictive models for personalize prognosis and the nightly synchronization.
treatments. This process is connected to the concept of Conclusion: After obtaining institutional approvals
rapid learning based research, in which the routinely for the protection and use of the data, a data sharing
collected real-time clinical data drives the process of infrastructure was built. This platform permits to pool
scientiÀc discovery as a natural outgrowth of patient data from institutional databases and combine them
care. Considering that sharing data from institutional enhancing the capability to construct predictive models
databases can increase the quantity of high-quality that are more widely applicable and better powered
data available, an infrastructure able to join the Sacro to accurately identify key predictive factors (whether
Cuore University located in Rome (Italy) and the dosimetric, image-based, clinical, or biological).
MAASTRO Clinic of Maastricht (the Netherlands) Keywords: Technology development, data-sharing,
was built, for speciÀc research projects. predictive models, de-identiÀcation
Methods: Once obtained institutional approvals,
a research database (ResearchDB) was created
combining clinical information with diagnostic Poster Session 1 – Technology and Models Monday, 4 July 2011
imaging and treatment information (RT and non RT 12:15-14:15
data). A patient-centric data model was designed that
would enable queries for both medical and imaging P1.137 FACILE AND SENSITIVE
data. A coding scheme was employed in which a MUTATION DETECTION IN LUNG
secure-key database (KeyDB) holds the link between CANCER FROM NEVER SMOKERS
the random patient identiÀcation code (ResearchID) Jin Jen1, Jin S. Jang1, Adam M. Lee2, Hema
and all identifying data. This KeyDB is maintained Liyanage3, Ping Yang4, Robert B. Diasio2
1
by local hospital personnel and only accessible from Pulmonary And Critical Care Medicine, Mayo
within the hospital. In the ResearchDB, the patient is Clinic/United States Of America, 2Molecular
only identiÀed by a ResearchID which is a random, Pharmacology And Experimental Therapeutics,
non-sequential 9-digit number. To convert Italian to Mayo Clinic Cancer Center/United States Of
English standard terms local terms were mapped, America, 3Sequenom/United States Of America,
4
in the OntologyDB, to the SNOMED Clinical Epidemiology, Mayo Clinic/United States Of
Terms that were used as dictionary. The software America
Background: Lung cancer is the leading cause of EGFR and MET genes; one tumor had an EGFR and
cancer death worldwide. A signiÀcant fraction of a PIK3CA gene mutation; and one tumor had triple
the female lung cancer patients have never smoked. mutations involving EGFR, JAK2, and AKT1 genes.
Genetic studies showed that lung cancer from Clinically, the status of EGFR gene mutation was
smoker and non-smokers have different mutation not signiÀcantly different among sex, age, and tumor
spectrum which can contribute to signiÀcantly stage.
different therapeutic responses in the clinic. For Conclusion: We developed a MassArray based
example, epidermal growth factor receptor (EGFR) mutation detection panel for lung cancers from
gene mutations are more likely found in female never smokers. This makes it feasible to better direct
never smokers and these patients often beneÀt from and augment the treatment of lung cancer as well
gene targeted therapy by tyrosine kinase inhibitors as allowing us to rapidly survey a large number of
(TKI) such as geÀnitib. In contrast, lung cancers tumor samples and to examine the interplay between
from smokers are more likely to carry k-RAS gene gene mutations and clinical characteristics of lung
mutations and these patients do poorly with TKI cancer in never smokers.
treatment. Therefore, the ability to rapidly assess the Keywords: gene mutation, MassArray, non-smoker,
genetic status of the primary lung tumors can offer a Lung cancer
signiÀcant advantage in the clinic to improve patient
prognosis and therapeutic management. MassArray A revised/updated abstract may be included in
technology is a single nucleotide extension and mass the Late Breaking Abstract Supplement, available
spectrometry-based detection method (Sequenom, at the 14th World Conference on Lung Cancer.
San Diego, California). It is capable of identifying
and quantiÀcation single base mutations based on
the molecular mass difference of the allele speciÀc Poster Session 1 – Radiotherapy Monday, 4 July 2011 12:15-14:15
extension primers. Using this method, MassArray
panels can simultaneously analyze hundreds of P1.138 A PHASE II TRIAL OF
oncogene mutations in a single run and offers a ACCELERATED HYPOFRACTIONATED
rapid and sensitive screening tool for mutation THREE-DIMENSIONAL CONFORMAL
identiÀcation in clinical samples. RADIATION THERAPY IN LOCALLY
Methods: We Àrst screened 99 non-smoker (NS) ADVANCED NON-SMALL CELL LUNG
lung cancers using the MassArray based technology CANCER
and the commercially available OncoCartaTM Zheng-Fei Zhu, Min Fan, Kai-Liang Wu, Kuai-Le
panel which examines gene mutation status in 19 Zhao, Huan-Jun Yang, Gui-Yuan Chen, Guo-Liang
oncogenes and 238 mutations. We then developed Jiang, Li-Juan Wang, Sen Zhao, Xiao-Long Fu
a customized non-smoker lung cancer panel that Department Of Radiation Oncology, Fudan
focused on nine oncogenes most frequently affected University Shanghai Cancer Center/China
in the tested tumor samples. We evaluated this NS
speciÀc assay panel for its sensitivity and speciÀcity Background: Accelerated hypofractionated
to detect mutations using a variety of clinical radiotherapy (HypoRT) is a potential way to improve
samples including DNA from lung cancer cell lines, local control for non-small cell lung cancer (NSCLC)
fresh frozen lung tumors and formalin-Àxed parafÀn owing to the higher biological effect of larger
embedded tissues. fraction and shorter overall treatment time. However,
Results: In a survey of 99 primary lung cancers of HypoRT has often been avoided in curative treatment
mostly adenocarcinoma from never smokers, EGFR for a long time during two-dimensional radiotherapy
gene mutation was identiÀed in 48 (48.5%) samples. era, because large dose per fraction was often
In contrast, the rate of k-RAS gene mutation was less expected to accompany more side effects. With
than 5% (4 of 99 cases) while mutations in MET1/ the development of radiation techniques, renewed
MET2 (5), PIK3CA (3), ERBB2 (2), BRAF (2), and enthusiasm was given to HypoRT. The aim of
JAK, KIT, and AKT gene (1 each) accounted for this study was to evaluate the safety and efÀcacy
15% of all the mutations observed. Consistent with of accelerated HypoRT using three-dimensional
previous studies, no tumor had concomitant EGFR conformal radiation therapy (3D-CRT) in locally
and k-RAS or EGFR and ERBB2 gene mutations. advanced NSCLC.
However, four tumors had mutations involving both Methods: A total of 34 patients with stage III
NSCLC were enrolled between April 2006 and A revised/updated abstract may be included in
April 2008 at our hospital. All patients received the Late Breaking Abstract Supplement, available
accelerated HypoRT using 3D-CRT, omitting at the 14th World Conference on Lung Cancer.
elective nodal irradiation (ENI), to a total dose of
65-68Gy. Radiotherapy was given by two phases.
In the Àrst phase, a total dose of 50Gy was given Poster Session 1 – Radiotherapy Monday, 4 July 2011 12:15-14:15
in 20 fractions at 2.5Gy per fraction, once per day.
In the second phase of irradiation, the dose per P1.139 COMPARISON OF PLANNING
fraction was changed from 2.5Gy to 3Gy without TARGET VOLUMES BASED ON
any amendment of target volumes. All patients THREE-DIMENSIONAL CT AND FOUR-
received 2 cycles of induction chemotherapy, and 1-2 DIMENSIONAL CT SIMULATION
cycles of consolidation chemotherapy were given IMAGES OF NON-SMALL-CELL LUNG
to 31 patients. The primary outcome measure was CANCER
the proÀle of radiation toxicity. Treatment-related Feng X. Li1, Jianbin Li2, Ying-Jie Zhang1
1
toxicity was scored according to the Common Department Of Radiation Oncology, Shandong
Terminology Criteria for Adverse Events (CTCAE) Cancer Hospital/China, 2Radiation Oncology
version 3.0. The secondary endpoints included Department, Shandong Cancer Hospital/China
overall survival (OS), progression-free survival
(PFS), locoregional PFS (LR-PFS) and the pattern of Background: To compare positional and volumetric
initial failure. differences of planning target volumes (PTV) based
Results: Radiation-associated toxicities are shown in on axial 3D-CT and 4D-CT for the primary tumor of
Table 1. No patient experienced grade 4-5 radiation- non-small cell lung cancer (NLCLC).
associated complications. Median follow-up among Methods: Twenty-eight patients with 16 lesions
all patients was 20 months (range: 4-51 months) located in the upper lobe and 12 lesions in middle
and median follow-up of survivors was 45 months and lower lobes initially underwent 3D-CT scans
(range: 35-51 months). The median survival was followed by 4D-CT scans of the thorax under normal
19.0 months (95% CI: 11.-27.), and 2- and 3-year free breathing. PTVvector was deÀned the GTV
OS was 38.2% and 32.1%, respectively. The median contuored on 3D-CT and its motion vector: CTVs
time to progression was 10.0 months (95% CI: 7.4- were created by adding 7 mm to GTVs, then, ITVs
12.6), with 2- and 3- year PFS of 29.8% and 29.8%, were produced by enlarging CTVs isotropically
respectively. The 1-, 2-, and 3-year LR-PFS were based on the individually measured amount of
69.6%, 60.9% and 60.9%, respectively. No patient motion in the 4D-CT, lastly, PTVs were created
experienced isolated elective nodal failure as the Àrst by adding 3 mm setup margin to ITVs; PTV4D was
site of failure. deÀned on the fusion of CTVs on all phases of the
4D data: the CTV was generated by adding 7mm to
Table 1. Rate of radiation-associated toxicities the GTV on each phase, then, PTVs were produced
Toxicity Grade by fusing CTVs on 10 phases and adding 3 mm setup
1 (%) 2 (%) 3 (%) 4(%) 5 (%)
Pneumonitis 9 (26.5) 9 (26.5) 1 (2.9) 0 0
margin. The position of the target center, the volume
Pulmonary ¿brosis 22 (64.7) 0 0 0 0 of target and the degree of inclusion (DI) were
Pleural effusion 13 (38.2) 2 (5.9) 0 0 0 compared reciprocally between PTVvector and PTV4D,
Bronchial stenosis 3 (8.8) 1 (2.9) 0 0 0 and the 3D motion vector on the relative parameters
Esophagitis 15 (44.1) 5 (14.7) 2 (5.9) 0 0
were compared on the grouping.
Esophageal stenosis 0 2 (5.9) 0 0 0
Pericardial effusion 4 (11.8) 0 0 0 0
Results: The median of the 3D motion vector for
Skin toxicity 9 (26.5) 2 (5.9) 0 0 0 lesions in the upper lobe and in the middle and
Source: National Cancer Institute Common Toxicity Criteria version 3.0 lower lobe were 0.28cm and 0.70cm respectively.
A comparison of the target center coordinates only
Conclusion: In summary, this study suggests demonstrated signiÀcant spatial difference in the
that accelerated HypoRT using 3D-CRT omitting x axe for lesions in the upper lobe (z = -2.010, p =
ENI can be used in locally advanced NSCLC and 0.044), while in the z axe for lesions in the middle
warrants further investigation. and lower lobe (z = -2.136, p = 0.033). The median
Keywords: Non-small cell lung cancer, Accelerated of ratio of PTV4D and PTVvector was 0.75 and 0.52
radiotherapy, Hypofractionation respectively. A signiÀcant correlation was found
for the motion vector and the ratio of PTVvector and phase of 4D-CT were delineated based on 50% phase
PTV4D in both groups (r = -0.638, -0.850, p < 0.05). image. The position of the target center, the volume
For all patients, fhe median of DI of PTV4D in of target, the matching index (MI) and the degree
PTVvector was 66.39%, showed a signiÀcant inverse of inclusion (DI) were compared between different
correlation with the motion vector (r = -0.814, p volumes.
< 0.001); while the median of DI of PTVvector in Results: The difference of the center of GTV
PTV4D was 99.55%, showed a positive signiÀcant from different phase of 4D-CT and GTV_3D on
correlation with the motion vector (r = 0.613, p = three dimensional direction induced by respiration
0.001). motion was not statistically signiÀcant (F = 0.037,
Conclusion: The amplitude of tumor motion in p = 0.990). The ratios of GTV_0, GTV_20%,
the middle and lower lobe is larger than that in the GTV_50%, GTV_70% to GTV_3D were 0.94±0.18,
upper lobe. The location of PTVvector and PTV4D 0.95±0.18, 0.98±0.15 and 1.00±0.18 respectively.
demonstrate a signiÀcant difference in some a While the ratio of IGTV_10 to GTV_3D was
direction. PTV4D is smaller than PTVvector, the ratio 1.60±0.55, which showed a statistically signiÀcant
of PTV4D and PTVvector is correlated to motion vector correlation to the motion vector (r = 0.667, p <
of the tumor. As the amplitude of tumor motion 0.001). ID of IGTV_10 to GTV_3D was 0.59±0.16,
increases, the DI of PTVvector in PTV4D increases, which also showed a statistically signiÀcant
while the DI of PTV4D in PTVvector decreases. correlation to the motion vector (r = -0.420, p =
0.026).
Conclusion: The beginning time of 3D-CT is
Poster Session 1 – Radiotherapy Monday, 4 July 2011 12:15-14:15 random, which dose not show an intrinsic correlation
to some a phase of 4D-CT. The volume of GTV_3D
P1.140 COMPARISON OF PRIMARY is larger than that of GTV from single a phase of 4D-
GROSS TUMOR VOLUMES BASED CT, but signiÀcantly less than that of IGTV_10. As
ON THREE-DIMENSIONAL CT AND the amplitude of tumor motion increases, the degree
FOUR-DIMENSIONAL CT SIMULATION of GTV_3D covering IGTV_10 becomes less,
IMAGES OF NON-SMALL-CELL LUNG while the motion information included by IGTV_10
CANCER increases.
Jianbin Li, Feng X. Li, Ying-Jie Zhang Keyword: Non-small-cell lung cancer; Four-
Radiation Oncology Department, Shandong Cancer dimensional CT simulation ; Gross tumor volume;
Hospital/China Respiratory phase
Background: To compare positional and volumetric

differences of the gross tumor volume (GTV) Poster Session 1 – Radiotherapy Monday, 4 July 2011 12:15-14:15
delineated based on 3D-CT, single a phase of 4D-CT
and fused phase of 4D-CT for the primary tumor of P1.141 IMAGE-GUIDED
non-small cell lung cancer (NLCLC). HYPOFRACTIONATED SMALL VOLUME
Methods: Twenty-eight patients with NLCLC RADIO-THERAPY OF NON-SMALL CELL
suitable for three-dimensional conformal LUNG CANCER –FEASIBILITY AND
radiotherapy (3D-CRT) sequentially underwent 3D- CLINICAL OUTCOME
CT and 4D-CT simulation scans of the thorax under Stefan Janssen1, Carolin Koenig1, Michael Bremer1,
normal free breathing. During 4D-CT scanning, Martin Werner1, Johann Karstens1, Nicolas
real-time position management (RPM) system Dickgreber2, Tobias Welte2, Andreas Meyer1
1
simultaneously recorded the respiratory signals. Radiooncology, Mh Hannover/Germany,
2
The CT images with respiratory signal data were Pulmology, Mh Hannover/Germany
reconstructed and sorted into 10 phase group in a
respiratory cycle. Data sets for the 3D-CT and 4D- Background: Local hypofractionated stereotactic
CT scans were then transferred to Eclipse treatment radiation treatment of early stage non-small lung
planning software. GTV_3D from 3D-CT, GTV_0, cancer (NSCLC) represents a highly effective
GTV_20%, GTV_50% and GTV_70% from end- treatment alternative in medically inoperable
inspiration, mid-expiration, end-expiration and patients.
mid-inspiration of 4D-CT, and IGTV_10 from fused Methods: Between 06/07 – 12/10 65 patients
with NSCLC were treated with image-guided Background: Despite advances in treatment, 5
hypofractionated radiotherapy. UICC stage year survival for NSCLC remains poor. Radical
distribution was as follows: IA 19 patients, IB 15 radiotherapy regimes for NSCLC vary between
patients, IIB 5, IIIA 10 patients, IIIB 6 patients, centres in the UK. CHART was demonstrated to
and IV 10 patients, respectively. Mean age was 69 have a superior survival to standard radiotherapy
years. Histology revealed squamous cell carcinoma (60 Gray in 30 fractions). More recently hypo-
in 30 patients, non-squamous cell carcinoma in 25 fractionated radiotherapy (55Gy in 20 fractions) has
patients. Fractionation schedule used was 3 x 12.5 been shown to have similar outcomes to CHART.
Gy (n=36) prescribed to the encompassing 67% Methods: Retrospective audit from single institution
isodose line for peripheral primary tumours and 8 (Velindre Cancer Centre), using CANISC database.
x 6 Gy (n=26) or 8 x 5 Gy (n=3) prescribed to the Demographic, diagnostic, staging, treatment and
encompassing 80% isodose line for centrally located survival data were collected on all NSCLC patients
tumours. treated with radical radiotherapy between 2004 and
Results: Mean follow-up was 13.8 months (range 2009. Survival was analysed using Kaplan-Meier
0.87 – 41.33 months). Until now six patients (9.2 methodology.
%) developed a local recurrence, two of them in Results: 252 patients were treated with radical
combination with mediastinal lymph node failure. radiotherapy. 5 patients did not complete planned
One year actuarial local control rate was 93 %, radiotherapy. Median follow-up was 23 months.
overall survival was 79 %, respectively. Pneumonitis Median age was 71 years (range 42-87). 52% were
(CTCAE grade I and II) was seen in 14 patients male. 23% were stage IA; 29% stage IB; 3% stage
(21.5 %) after a median time period of 9.5 months. IIA; 13% stage IIB; 17% stage IIIA; 13% stage IIIB
No patient developed a pneumonitis CTCAE grade II and 2% stage IV (AJCC TNM Version 6). Stage
or higher. distribution was similar between CHART and non-
Conclusion: Image-guided hfSRT is effective and CHART patients. Histology: 27% had no histological
feasible in patients with non-operable NSCLC even conÀrmation; 33% NSCLC NOS, 27% squamous
in higher stages whenever local control is crucial and cell; 12% adenocarcinoma. 44% were treated with
there are contraindications against systemic therapy. CHART; 53% had hypo-fractionated radiotherapy
With acceptable acute and subacute side effects it (20 fractions); 3% had standard fractionation. 24%
is a valuable therapeutic option in interdisciplinary were treated additionally with chemotherapy as part
treatment schedules. of their planned radical treatment (neo-adjuvant
Keywords: stereotactic extracranial radiotherapy, or adjuvant); 28% of those who had CHART, 19%
Lung cancer, outcome of those who had hypo-fractionated radiotherapy.
Survival was similar across all histological groups
(including those with no histological conÀrmation),
Poster Session 1 – Radiotherapy Monday, 4 July 2011 12:15-14:15 CHART conferred no signiÀcant beneÀt for any
histological subtype. There was no signiÀcant
P1.142 SINGLE INSTITUTION AUDIT survival beneÀt for those treated with CHART in any
OF SURVIVAL AFTER RADICAL stage group. The median overall survival time for
RADIOTHERAPY FOR NON-SMALL CHART was 30 months and hypo-fractionated 35
CELL LUNG CANCER (NSCLC) AND months.
COMPARISON OF OUTCOMES OF Conclusion: This data supports previously published
CONTINUOUS HYPER-FRACTIONATED data that hypo-fractionated radiotherapy may be
ACCELERATED RADIOTHERAPY equivalent to CHART in routine practice. More
(CHART) VERSUS ONCE-DAILY patients in the CHART cohort had chemotherapy
HYPOFRACTIONATED RADIOTHERAPY as part of their planned radical treatment, either
Mick Button1, Hazel Bailey1, Alison Brewster1, neo-adjuvant or adjuvant despite age, stage groups
Rebecca Cox2, Carol Davies3, Louise Hanna1, Jason and histology being similar between the two groups
Lester1, Rosie Stevens1, Jake Tanguay1 (those having CHART and those having non-
1
Clinical Oncology, Velindre Cancer Centre/United CHART). Despite this there was still no survival
Kingdom, 2Cardiff University/United Kingdom, advantage for the CHART group for the cohort
3
Nevill Hall Hospital/United Kingdom as a whole or for any stage group or histological
subtype. This information is clinically helpful when
planning and counselling patients regarding radical function of patients was relatively favorable.
radiotherapy treatment options in NSCLC. Radiation pneumonitis was diagnosed by serial chest
Keywords: NSCLC, CHART, survival X-ray or computed tomography after radiotherapy
and its severity was determined by CTCAE
(Common Toxicity Criteria of Adverse Events)
Poster Session 1 – Radiotherapy Monday, 4 July 2011 12:15-14:15 version 4.0. Cut-off points from ROC (Receiver
Operating Characteristic) curve of MLD (mean lung
P1.143 PREDICTION OF RADIATION dose) and Vn (volume percentage of lung receiving
PNEUMONITIS THROUGH PULMONARY more than n Gy; range V5~V50 with 5 Gy interval)
DOSIMETRIC PARAMETERS IN were investigated to determine the sensitivity and
SIMULTANEOUS MULTITARGET speciÀcity in prediction of radiation pneumonitis.
HYPOFRACTIONATED RADIOTHERAPY Results: Radiation pneumonitis occurred in 37
USING HELICAL TOMOTHERAPY FOR patients (82.2%) and the incidence of grade II
MULTIPLE PULMONARY METASTASES or more radiation pneumonitis II was 26.6% (12
Chul-Seung Kay1, Ji Yoon Kim2, Eun Jung Yoo2, Ki patients) including three radiation pneumonitis
Jun Kim2 of grade III (6.6%). In development of radiation
1
Radiation Oncology, Incheon St Mary Hospital pneumonitis regardless of its severity, V30, V35,
Catholic University Of Korea/Korea, 2Catholic V45 and V50 were signiÀcant predictable parameters
University Of Korea/Korea (p<0.05) and 5.8% cut-off value of V30 was thought
the most powerful predictor (sensitivity 83.8%,
Background: High precision radiotherapy using speciÀcity 75.0%). On the other side, in grade II or
hypofractionation has been commonly used for more radiation pneumonitis, MLD, V5, V10, V15,
pulmonary metastases because tumorcidal dose V25 and V30 were signiÀcant parameters (p<0.05).
can be accurately delivered to the target without Of these parameters, MLD and V5 were shown as
increasing dose to adjacent normal lung. However, the most powerful parameter. Cut-off value of MLD
radiation pneumonitis is still major problem and was 13.2 Gy (sensitivity 91.7%, speciÀcity 63.6%)
sometimes fatal complication after radiotherapy. To and cut-off value of V5 was 77.8% (sensitivity
determine cut-off points of pulmonary dosimetric 91.7%, speciÀcity 60.6%). Age, sex, ECOG (Eastern
parameters for safe radiotherapy in pulmonary Cooperative Organization Group) performance
metastases, we retrospectively investigated the data status, number of targets, summation of PTVs,
from patients treated with simultaneous multitarget previous thoracic radiotherapy, chemotherapy, total
hypofractionated radiotherapy using helical dose and daily dose have no statistically signiÀcant
tomotheapy for lung metastases. correlation with radiation pneumonitis.
Methods: Total 45 patients were included and Conclusion: We can conclude that cut-off value
median age was 53 years old (range, 33~81 of MLD (13.2 Gy), V5 (77.8%) and V30 (5.8%)
years old). Their original malignancies were showed the powerful sensitivity and speciÀcity on
hepatocellular carcinoma (28.9%), breast cancer prediction of radiation pneumonitis, so we should
(15.6%), colorectal cancer (15.6), thymoma (8.9%), carefully consider them for safe simultaneous
salivary cancer (6.7%), sarcoma (4.4%), lung cancer multitarget hypofractionated radiotherapy using
(2.2%), endometrial cancer (2.2%) and kidney helical tomotherapy in lung metastases. However,
cancer (2.2%). The patients treated with previous further clinical study should be required to
thoracic radiotherapy and with chemotherapy within supplement or corroborate this outcome.
six months before the start of radiotherapy were Keywords: radiation pneumonitis, pulmonary
Àve (11.1%) and twenty (44.4%), respectively. dosimetric parameter, hypofractionated radiotherapy,
Average number of pulmonary metastases was multiple lung metastases
4.7 (median, 4; range, 1~10) and median value of
PTVs’ summation from multiple targets was 198.2 A revised/updated abstract may be included in
ml (range 17.6~1142.9 ml). Median 50 Gy (range, the Late Breaking Abstract Supplement, available
30~60 Gy) was delivered to PTV in 10 fractions at the 14th World Conference on Lung Cancer.
during 2 weeks. Normal lung volume not involved
by PTV (planning target volume) was from 1380.3
ml to 4340.3 ml (median 2446.8 ml). The pulmonary
Poster Session 1 – Radiotherapy Monday, 4 July 2011 12:15-14:15 and full IMRT plans occasionally resulted in
unacceptable hot spots outside the PTV. Three of
P1.144 DOSIMETRIC BENEFITS OF the patients were Ànally treated to a dose of only
A NOVEL INTENSITY MODULATED 54-62Gy, due to their performance score or clinician
RADIOTHERAPY (IMRT) TECHNIQUE choice. Data on early clinical outcomes will be
FOR TREATING LARGE VOLUME presented. Table 1. Dosimetric comparison of four
STAGE III LUNG CANCER planning techniques.
Wilko F.A.R. Verbakel1, Ellen Van Reij1, Lonka
Ladenius-Lischer1, Ben Slotman2, Suresh Senan2 conventional Full IMRT RapidArc H-IMRT
1 PTV V95 (%) 97.2 ± 1.6 97.4 ± 1.1 97.5 ± 0.5 97.8 ± 0.8
PTV V107 (%) 2.6 ± 4.1 1.6 ± 2.8 0.5 ± 0.5 0.02 ± 0.04
Netherlands, 2VU University Medical Center/
Total lung V20 (%) 33.4 ± 6.6 33.4 ± 6.2 30.3 ± 5.7 30.3 ± 5.7
Netherlands Contralateral lung V5 (%) 54 ± 13 46 ± 12 45 ± 9 36 ± 12
Total body V107 (cc) 44 ± 97 31 ± 49 15 ± 15 1.4 ± 2.1
Background: Delivery of doses >60Gy to large- Planning time (h) 2-5 2-4 1.5-2.5 1-2
volume Stage III lung tumours is often difÀcult

due to the need to limit low dose regions to lung Conclusion: This novel H-IMRT approach, which
tissue. Non- intensity modulated radiotherapy uses an IMRT component of 12% on average,
(IMRT) planning is often time consuming, use of enabled routine treatment of large volume stage
IMRT often increases low dose irradiation to the III tumours to 66Gy. It enables faster planning and
lungs. We clinically implemented a novel hybrid is superior to other IMRT techniques in reducing
IMRT (h-IMRT) approach for large tumors. In the ipsilateral (V20) and contralateral (V5) lung doses
present study, dose distributions in patients treated and dose hot spots.
using h-IMRT were compared to plans using 3 other Keywords: imrt, Radiotherapy, stage III NSCLC,
planning approaches. RapidArc
Methods: H-IMRT was used to treat 14 patients who
had an average PTV of 825cc (range 591-1258cc),
and who underwent concurrent chemo-radiotherapy Poster Session 1 – Radiotherapy Monday, 4 July 2011 12:15-14:15
to 66Gy. H-IMRT plans comprised of AP-PA
open Àelds of 15 MV, with an additional oblique P1.145 OPTIMAL 4D-CT BASED IMAGE-
PA Àeld avoiding the spinal cord, and planned to GUIDED RADIOTHERAPY IN LUNG
an average PTV dose of 58Gy. Each plan had a CANCER APPLICATIONS
3-Àeld IMRT component which was optimized to Stewart Gaede1, Emily Peat2, Brian Yaremko3,
supplement the conventional plan in order achieve Rashid Dar3, Edward Yu3, David Palma3, George
a Ànal homogeneous dose of 66Gy. Planning was Rodrigues3
1
performed using the Eclipse TPS (Varian Medical Physics And Engineering, London Regional
Systems) with objectives being: PTV V95>97%, Cancer Program/Canada, 2Department Of Civil
hot spots of >107% limited to <5 cm3, spinal cord Engineering, University Of Waterloo/Canada,
3
Dmax<50Gy and total lung V20 and contralateral Radiation Oncology, London Regional Cancer
lung V5 as low as possible. Plans of all 14 patients Program/Canada
were retrospectively replanned using either a full 3D
conformal technique (3Dconf) applying 5-9 static Background: The pitfalls of using a single
Àelds, a 2-arc RapidArc respiratory phase of a four-dimensional computed
(v10.0.11) or an IMRT technique, applying 6 Àelds tomography (4D-CT) dataset in image-guided
of 6 MV, all of which were chosen such that lung V5 radiotherapy (IGRT) of lung cancer include noisy
and V20 was optimally spared. Dosimetric data for images, inaccurate simulation of a free-breathing
all plans were compared and early follow-up data patient, and mis-registration with in-room free-
was analyzed. breathing Cone-Beam CT (CBCT) imaging.
Results: Phantom studies have shown that a low-pitch helical
Both H-IMRT and RapdiArc plans were rapidly CT scan or untagged average intensity projection
generated. H-IMRT consistently achieved the (untagged-IP) dataset for un-gated radiotherapy
combination of lowest V5 and V20 in combination or a subset average intensity projection (subset-
with smallest hot spots (Table 1). Both conventional IP) dataset for respiratory-gated radiotherapy can
overcome these pitfalls. Therefore, the purpose of Keywords: 4D-CT, IGRT, Respiratory Gating,
this work is to report on the clinical implementation Untagged Average CT
of respiratory motion management in lung cancer
applications in the IGRT era highlighting the beneÀts A revised/updated abstract may be included in
of these CT datasets. the Late Breaking Abstract Supplement, available
Methods: All lung cancer patients who are at the 14th World Conference on Lung Cancer.
candidates for radical radiotherapy received a
low-pitch helical 4D-CT using a Philips Big Bore
multi-slice CT scanner (Philips Medical Systems, Poster Session 1 – Radiotherapy Monday, 4 July 2011 12:15-14:15
Cleveland, USA). For tumour motion <= 7mm,
the untagged-IP was generated retrospectively by P1.146 FEASABILITY ANALYSIS
reconstructing a 3D- helical CT scan by using all the AND PRELIMINARY FINDINGS
projection data acquired during the 4D-CT scan. The OF A PROSPECTIVE STUDY OF
extreme phases from 4D-CT were then registered VARIATION IN BREATH HOLDING
to the untagged-IP to delineate the internal gross TIMES AT VARIOUS PHASES OF
tumour volume (IGTV). For tumour motion > 7mm, RESPIRATION DURING THE COURSE
the subset-IP was calculated over the range of phases OF RADIOTHERAPY INCLUDING THE
representing the intended respiratory gating window. EFFECT OF RESPIRATORY TRAINING
The GTV delineated on this dataset automatically IN LUNG CANCER PATIENTS IN A
incorporates the intended residual motion during DEVELOPING COUNTRY
gated delivery. For setup veriÀcation of un-gated Anusheel Munshi1, Jai P. Agarwal1, Sarbani G.
radiotherapy, the CBCT was registered to the Lakar1, Anil Tibdewal1, Anuradha Daptardar2,
untagged IP. Matching was performed on the tumour. Vincent Singh2, C S. Pramesh3, G Karimundackal3,
For gated radiotherapy, the CBCT was registered Kumar Prabhash4, Vanita Narohna4, Sandeep Tandon5
1
to the subset-IP. Matching was performed by Radiation Oncology, Tata Memorial Hospital/India,
2
encompassing the tumour by the full 4D-CT deÀned Occupational Therapy, Tata Memorial Hospital/
IGTV. To verify the gating window, an additional India, 3Thoracic Surgery, Surgical Oncology, Tata
gated 2D-kV anterior-posterior (AP) planar image Memorial Hospital/India, 4Medical Oncology, Tata
was compared to the gated AP digitally reconstructed Memorial Hospital/India, 5Pulmonary Medicine,
radiograph (DRR). Tata Memorial Hospital/India
Results: The untagged-IP dataset and subset-IP have
been used for treatment planning for 150 non-gated Background: Radiotherapy in lung cancer has
lung cancer patients since May, 2009 and 11 gated evolved from conventional 2 dimensional approaches
lung cancer patients since March, 2010, respectively. to 3 dimensional conformal radiotherapy(3D CRT),
A decrease in image noise (see Figure) was observed Intensity modulated radiotherapy(IMRT) and more
in all patients, making tumour delineation easier, importantly Image guided radiotherapy (IGRT).
especially in low contrast areas. This change in The aim of the present study is to Ànd the breath
practice also initiated the use of CBCT and gated holding times in the Indian population and to see
kV planar imaging for improved setup and gating the factors (patient related, disease related, training
window veriÀcation. related) that have a correlation with breath holding
times at various phases of the respiratory cycle.
These Àndings have implications in IGRT for lung
cancer and for other thoraco abdominal sites as well.
This abstract reports the feasibility and preliminary
Àndings of our study
Methods: All the patients of lung cancer being taken
for radical RT or chemoradiation were eligible for
Conclusion: The implementation of IGRT of lung the study. All the patients had IIIA or III B disease.
cancer radiotherapy in our centre was facilitated by Out of the proposed 100 suitable patients of Non
the use of the untagged-IP and the subset-IP. The small cell and small cell lung cancer(for radical
use of such imaging overcame the pitfalls of using a treatment) over a period of 2 years, 25 patients
single respiratory phase as the planning CT. have been accrued so far over a period of 4 months.
All suitable patients undergo a routine Pulmonary Poster Session 1 – Radiotherapy Monday, 4 July 2011 12:15-14:15
function testing (PFT). Subsequently, recording of
the breath hold is done at a) radiotherapy simulation P1.147 SUBMILLIMETRE ACCURACY
b) Àrst fraction of radiotherapy c) mid radiotherapy IS ACHIEVED WHEN USING
d) radiotherapy conclusion. After the recording at STEREOTACTIC RADIOSURGERY
“ a) ” patients are asked to perform deep breathing WITH A DEDICATED IMMOBILIZATION
exercises/ spirometer ball exercise to see the effect SYSTEM FOR PATIENTS WITH LUNG
of training on the breath holding times. Assessment OLIGOMETASTASES
is made to see the breath holding times in deep Shankar Siva1, Brent Chesson1, Yolanda Aarons1,
inspiration (DIBH), deep expiration (DEBH) Natalie Clements1, Tomas Kron1, Michael P.
and mid ventilation (MVBH) to see the effect of Macmanus2, David Ball1
1
respiratory training on the breath holding times. This Radiation Oncology, Peter MacCallum Cancer
shall also enable us to Ànd the number of beam on/ Centre/Australia, 2Department Of Radiation
off times required for the particular patient based on Oncology, Peter MacCallum Cancer Centre/
the breath hold timings. Australia
Results
Results: 25 patients have been accrued in the trial so Background: Stereotactic ‘Radiosurgery’ to
far. There were 12(48%) upper lobe, 3(12%) middle the lung refers to the delivery of a single dose
lobe and 10(40%) lower lobe tumours. 11 patients of high-precision radiotherapy. Treatments are
had left sided and 14 had right sided tumours. highly conformal, typically with narrow margins
All patients had stage IIIA or III B disease. In all from the estimated tumour position to the planned
patients, the recording at the four speciÀed times target volume. We report a veriÀcation study of
could be easily taken by the speciÀed method. The immobilization using a linear accelerator based
mean (SD) values in seconds at RT simulation were stereotactic treatment system for metastatic cancer to
as follows. DIBH 27.9 (11.43), DEBH 19.9(7.78), the lung.
MVBH 21.8(9.68). The compliance rate of patients Methods: Stereotactic ‘Radiosurgery’ with a single
with the speciÀed respiratory training schedule has dose of 26Gy was performed for 9 patients with
been 100% so far. The values after 1-2 weeks of pulmonary oligometastases. Patients were planned
respiratory training were 31.65(16.14), 21.1(8.13), using 4-dimensional computed tomography (4DCT)
23.2(12.2). The mid radiotherapy recording for to account for tumour motion. All patients were
the same parameters was 29.7(20.8), 19.1(10.4), rigidly immobilized on a dedicated stereotactic
22.1(11.9) respectively. At radiotherapy conclusion Elekta BodyFix® system (Medical Intelligence,
the respective parameters were 29.9 (25.7), 19.7 Schwabmuenchen, Germany). Patients were allowed
(13.4) and 25.8 (17.9). A formal analysis of the shallow free-breathing. Linear accelerated mounted
factors inÁuencing the breath holding time shall be slow acquisition CT (cone-beam CT) was performed
done after 100 patients have been accrued into the over one minute immediately prior to treatment.
trial. Pre-treatment tumour images were matched to
Conclusion: As of now, for each of the time points the planning 4DCT reference image with a zero
of measurement, DIBH>MVBH>DEBH. In our millimetre tolerance for treatment couch shifts. The
preliminary experience, deep inspiratory breath hold cone-beam CT was then repeated immediately after
is the best phase for breath hold for image guidance the couch shifts and at the mid-point of treatment
techniques in developing countries. Also there is a delivery in order to verify tumour position.
suggestion of beneÀcial effect of respiratory training Results: Initial mean shifts for pre-treatment soft-
on breath holding time. These Àndings need to be tissue matching were 1.9mm in the longitudinal,
conÀrmed after the stipulated number of subjects has 1.7mm medio-lateral, and 2.9mm in the ventero-
been accrued. dorsal axis, correlating to a mean shift of 2.1mm
Keywords: lung cancer patients, Breath holding ± 1.5mm (mean ± standard deviation) in any plane
times (range 0mm - 4mm). After initial shifts, the residual
error was <1mm in all planes prior to treatment
(mean 0.03mm ± 0.2mm). A mid-treatment cone-
beam CT was performed at a median time of 21
minutes. At mid-treatment, the mean displacement
discrepancy was <2mm in all planes (mean 0.4mm during treatment planning and delivery. The standard
± 0.6mm). Of the 9 pulmonary metastases, 5 technique at our institution is to treat patients without
were located in the right lower lobes, 3 in the external immobilization. We report clinical data in
left lower lobes, and 1 in the left upper lobe. No support of this.
pattern emerged correlating tumour location with Methods: The target for rapid, image-guided SABR
displacement. treatment was identiÀed with a 4-dimensional (4D)
CT scan that incorporated tumor motion. Patients
were imaged and treated in free-breathing, with no
external body immobilization, while comfortably
lying supine on a thin mattress with arm and knee
support. Before treatment delivery, a cone-beam
CT (CBCT) was performed to correctly position
the tumor in 4 directions (3 translational and 1
rotational). After the necessary corrections had been
carried out, then provided that the spine could be
visualized, stereoscopic spine x-rays (ExacTrac)
were acquired for the purpose of intra-fraction
position monitoring. These were repeated at the end
of treatment delivery and the difference in the two
sets of readings represented spine, and therefore
Conclusion: Patients were accurately immobilized patient, stability in 6 directions (3 translational and
throughout the treatment with submillimetre 3 rotational). SABR was delivered with a minimum
variation of tumour position throughout treatment. of 2 volumetric intensity-modulated arcs (RapidArc)
Reproducibility and immobilization are robust using on a Novalis Tx machine at a dose rate of 1000
a dedicated linear accelerator based stereotactic monitor units/minute, and with continuous infra-red
immobilisation system. positional tracking using external body markers.
Keywords: stereotactic, Radiotherapy, Results: For 109 treatment sessions from 30 patients
Immobilization, metastases (23M and 7F, median age 72yrs, range 38-90)
receiving a range of dose-fractionation schedules
(3x18Gy n=6, 5x11Gy n=8, 8x7.5Gy n=11, 12x5Gy
Poster Session 1 – Radiotherapy Monday, 4 July 2011 12:15-14:15 n=5) the mean time from start of CBCT acquisition
to start of Àrst treatment arc was 6.2 minutes (SD
P1.148 FAST DELIVERY OF 2.7, range 3.97-27.6). The mean time to deliver the
STEREOTACTIC ABLATIVE prescribed fraction dose was 4.1 minutes (SD 1.3,
RADIOTHERAPY FOR LUNG TUMORS: range 2.95-10.05). Mean absolute intra-fraction spine
IS RIGID PATIENT IMMOBILIZATION movement during treatment delivery was 0.3mm
NECESSARY? (SD 0.3), 0.4mm (0.4) and 0.5mm (0.5) in vertical,
Max Dahele, Ben Slotman, Wilko F.A.R. Verbakel, longitudinal and lateral directions respectively.
Suresh Senan Maximum motion in any direction was 2.8mm and
Radiation Oncology, VU University Medical Center/ 2.3 degrees of roll.
Netherlands Conclusion: Rapid SABR delivery is now
routine using volumetric intensity-modulated arc
Background: To date, stereotactic ablative therapy and CBCT. A simpliÀed and comfortable
radiotherapy (SABR) for early-stage peripheral non- approach to patient set-up and positioning achieves
small cell lung cancer has been associated with local comparable stability to that reported with near-rigid
control rates exceeding 90% in some studies. SABR immobilization devices, without the associated cost
requires high quality treatment plans that concentrate and complexity. Positioning can be veriÀed with
the dose on the tumor whilst sparing normal x-rays or CBCT when the infra-red tracking signal
tissues, and accurate tumor targeting, an important detects excessive body motion, and between arcs for
component of which is patient stability. For this selected patients and longer treatment sessions.
reason, some guidelines support the use of near- Keywords: Stereotactic ablative radiotherapy,
rigid Àxation devices to reduce patient movement Immobilization
Poster Session 1 – Radiotherapy Monday, 4 July 2011 12:15-14:15 patients had acute side effects: 10 headache, 2
nausea, 2 erythema of the irradiated skin. After PCI
P1.149 TOXICITY AND RESULTS six (13%) patients complained for late persistence
OF PROPHYLACTIC CRANIAL side effects: 3 for vertigo, 1 for nausea, 2 excessive
IRRADIATION IN PATIENTS WITH excitements, one for deterioration of hearing and
NSCLC. olfactory hyperaesthesia, one for weakness of
Marzena T. Gawkowska-Suwiĸska1, Alicja Heyda2, lower extremities. All patients developed alopecia
Aleksander Zajusz2, Elŧbieta Nowicka2, Katarzyna after PCI, in all patients but one hair re-grow was
Behrendt2, Grzegorz Plewicki2, Beata Smolska- observed between 1,5 and 6 months after PCI.
Ciszewska2, Monika Giglok2, Rafaã Tarnawski2 There were no hematological toxicity. Not statically
1
Iii Department Of Radiotherapy/ Department Of signiÀcant increase in hemoglobin level and WBC
Brachyteraphy, Maria Skãadowska-curie Memorial count was noted at the end of PCI. A decline in
Cancer Center And Institute Of Oncology, Gliwice testosterone level was observed, the difference
Branch/Poland, 2Maria Skãadowska-curie Memorial between testosterone level before and after 1 months
Cancer Center And Institute Of Oncology, Gliwice post treatment in Wilcoxon test was close to be
Branch/Poland statistical signiÀcant (p=0,062). Visual memory
did not change during examination. Visual – motor
Background: Prophylactic cranial irradiation is a function deteriorated immediately after treatment
standard treatment for patients with small cell lung (p<0,053) and 6 months later returned to basic level.
cancer. In NSCLC there are increasing amount of Slight but signiÀcant decrease
data supporting PCI. The aim of the study is to deÀne of performance IQ (p<0,011, 6 points) and increased
the toxicity PCI in a group of patients with NSCLC. difference between performance IQ and verbal IQ
Methods: From 1999 to 2007 47 patients with (p<0,011) were observed.. In MRI a slight atrophy
NSCLC treated in MCS Memorial Institute of in white matter was observed, involution of pituitary
Oncology in Gliwice underwent PCI. The total dose gland, and slight increase in CSF.
was 30 Gy dose per fraction was 2 Gy given once Conclusion: Prophylactic cranial irradiation in this
daily. The treatment was based on 3D planning. group of patients had relatively low, acceptable
Inclusion criteria were: NSCLC treated with curative toxicity although in 13 % of patients a late side
intent. The age of patients ranged from 42 to 73 effects of treatment were reported. Neurological test
years, with median 53, mean follow-up was 2, 8 revealed slight decrease of cognitive functions in
years. Survival was estimated by means of Kaplan- WAIS examination 6 months after treatment.
Meyer plots. Distance recurrences were recorded. Keywords: prophylactic cranial irradiation, NSCLC
Any complains and side effects were recorded
during the treatment and follow-up. Full blood
count was performed before and immediately after Poster Session 1 – Radiotherapy Monday, 4 July 2011 12:15-14:15
PCI. Alopecia was recorded, time for hair re-grow
was recorded. Pituitary function was estimated P1.150 NON-RESECTED NSCLC IN
by measuring serum testosterone level before, STAGES I - III: ACCELERATED (TWICE
immediately after PCI and during follow-up in 10 DAILY), DOSE-DIFFERENTIATED HIGH-
patients. Benton Visual Retention Test - BVRT, DOSE RADIOTHERAPY - MATURE
Bender Visual Motor Gestalt Test in Pascal were RESULTS OF A PROSPECTIVE STUDY
performed before and immediately after PCI (32 Karl Wurstbauer1, Heinz Deutschmann1, Christoph
pts) and 6 months after PCI (10pts). Suttel version Gaisberger1, Peter Kopp1, Manfred Kranzinger1,
and Wechsler Adult Intelligence Scale - Revised Florian Merz1, Helmut Schöller1, Michael
(WAIS-R) WAIS examination was performed before Studnicka2, Felix Sedlmayer1
1
(32pts) and 6 month after the treatment (10 pts). MRI University Clinic Of Radiation Oncology,
was performed before, immediately after PCI and Paracelsus Medizinische Privatuniversität/Austria,
2
during follow-up in 10 patients. Friedman Anova and University Clinic Of Pneumology, Paracelsus
Wilcoxon test were applied for statistical analysis. Medizinische Privatuniversität/Austria
Results: Mean survival was 1,7 years. 18 patients
developed distant metastases, 2 of the them (4, Background: Can the results of the current ‘state of the
2%) had brain metastases. During PCI 14 (30%) art’ treatment for patients with non-resected NSCLC
(simultaneous chemo-radiotherapy) be improved? compare favorably in all parameters with the results
Methods: Radiation doses are correlated to primary of simultaneous chemo-radiotherapies, at present
tumor size (mean number of 3 perpendicular considered ‘state of the art’ for non-resected NSCLC.
diameters) within 4 groups: <2,5 cm/ 2,5-4,5 cm/ Keywords: sequential chemo-radiotherapy, high
4,5-6,0 cm/ >6,0 cm; ICRU-doses of 73,8 Gy/ 79,2 dose radiotherapy, conformal radiotherapy, Non-
Gy/ 84,6 Gy/ 90,0 Gy, respectively are applied. To small cell lung cancer
macroscopically involved nodes 59,4 Gy median are
given (range 54,0-75,6 Gy; adapted to size and grade
of invasion). Fractional doses 1,8 Gy bid, interval Poster Session 1 – Radiotherapy Monday, 4 July 2011 12:15-14:15
>10h. Image guidance, margins GTV to PTV of 7
mm only are used, mostly with the conformal target P1.151 A PROSPECTIVE PILOT STUDY
splitting technique. 2 cycles chemotherapy are given TO INVESTIGATE THE USE OF 4DPET/
before radiotherapy, with an interval preferentially CT FOR PATIENTS WITH NON-SMALL
<10 days. Primary end points of this prospective CELL LUNG CANCER (NSCLC)
study are local and regional tumor control, secondary UNDERGOING RADIOTHERAPY (RT).
endpoints are survival and tolerability. Patients were Danny Duplan1, Yolanda Aarons2, Steven David2,
rigorously followed especially regarding locoregional Jason Callahan2, Alan Herschtal2, David Binns2,
tumor control (by systematic periodic CT and/or PET Belinda Campbell2, Aldo Rolfo2, Tomas Kron2,
scanning) and toxicity. With a median follow-up time Michael P. Macmanus2, David Ball2
1
of 29,9 months for patients alive (range 13,6-81,1 Radiation Oncology, Peter MacCallum Cancer
months) mature results are presented. Center/Australia, 2Peter MacCallum Cancer Center/
Results: Between 2004 and 2009 160 patients with Australia
164 histologically/ cytologically proven NSCLC
were enrolled. Stage I: 39 patients; II: 6 pts.; IIIA: Background: The standard of care for planning high
68 pts.; IIIB: 47 pts. Weight loss >5%/ 3 months: 38 dose radiotherapy (RT) for patients with a diagnosis
patients (24%). In 82 patients, mainly in stages II and of NSCLC at our institution is volumetric FDG-PET/
III, 2 cycles of chemotherapy before radiotherapy CT scan (3DPET/CT) acquired in treatment position;
were given. We observed 31 local recurrences, if PET/CT is unavailable then it is a 4 dimensional
distributed within the above described tumor size CT-scan (4DCT). 3DPET/CT is more sensitive than
groups as follows: 2/27, 20/94, 6/30 and 3/13. CT for tumour localisation, and may incorporate
Eight patients failed regionally. 92% of all failures ventilatory tumour motion due to the long acquisition
occured within two years after starting therapy. The time. However, partly because of this motion, the
overall local tumor control rate at 2 years is 77%. tumour edge is more difÀcult to deÀne with 3DPET/
The median overall survival time and the 2-/ 3-year CT than with CT. This study was undertaken to
overall survival rate are 26,5 months and 55% / 38%, determine if 4 dimensional PET/CT scan (4DPET/CT)
respectively. Excluding stage I patients and patients results in superior tumour deÀnition than with 3DPET/
with weight loss >5% during the three months CT, and if there are differences in radiotherapy
before diagnosis (for comparison with the trials treatment volumes generated using 4D vs 3DPET/CT.
presently deÀning the ‘state of the art’ treatment), the Methods: Patients were eligible if they had
median overall survival time is 27,1 months. Two pathologically proven NSCLC, were planned for
treatment-related deaths occurred 5 and 6 months high dose palliative (>36Gy) or radical (>60Gy) RT,
after the end of radiotherapy: pulmonary Àbrosis (in and there was some degree of tumour motion over
the pretherapeutic CT scans both patients showed the ventilatory cycle. They underwent sequential
already radiologic signs of pulmonary Àbrosis). The 3DPET/CT and 4DPET/CT scans in treatment
further acute toxicity was mild: pneumonitis grade position using an integrated PET/CT scanner (GE
3 in 6 patients; esophagitis grade 1/ 2/ 3 in 51/ 16/ discovery STE8 or Siemens Biograph). Reference
8 patients, respectively. One patient showed late tattoos and landmark measurements were used to aid
esophageal toxicity grade 3. Furthermore no late reproducibility. 3DCT was acquired Àrst, followed
toxicity scored >grade 1 was observed. by 3DPET. 4DCT and 4DPET were then acquired
Conclusion: The Àgures for locoregional tumor using the Varian Real Time Position Management
TM
control and survival are encouraging high; and in (RPM) system. This allowed us to yield 10 scans
general treatments are well tolerated. The results of respiratory gated CT data as well as 10 scans of
respiratory gated PET data each corresponding to Background: Stereotactic radiotherapy (SRT) has
one of 10 pre-determined phases of each patient’s recently been used for the treatment of early stage
respiratory cycle. These images were co-registered or small lung malignant tumors while standard
to create the 10 individual phases of the 4DPET/CT. method has not been established.We retrospectively
For each of these phases, a Gross Tumour Volume evaluated the efÀcacy and safety of SRT for non-
(GTV) was contoured by a radiation oncologist using small cell lung cancer (NSCLC) treated in our
a blend of PET and CT data following a standard hospital which is popular local community core
protocol used in our institution. This amounted to hospital for cancer treatment.
a total of 10 GTVs which were summed to create Methods: Between October 2007 and December
a single aggregate volume (V4D). We proceeded to 2010, 39 tumors of 37 patients were treated by
compare this volume to the GTV contoured by the SRT(mean age, 74 years old: stage I,n=22; stage
same physician on the 3DPET/CT (V3D). To do so, III,n=3; recurrence,n=14)
we used the difference between V4D and V3D (V4D - Results: Two patients with stage III NSCLC
V3D) as well as a Conformity Index (CI=2(V3DƗV4D)/ underwent SRT for primary tumors followed
(V3D+V4D)). A clinically signiÀcant difference was concurrent chemoradiotherapy for mediastinal lymph
deemed to exist between the V3D and V4D if the node metastasis. Risk-adapted SRT schemes were
relative difference between these volumes was used with the two total dose of 48 grays in 26 site
more than 5%. The CI was considered to represent and 52 grays in 5 site by 4 fractions, depending
a clinically signiÀcant difference between these on the patient’s risk for toxicity. All of the patients
volumes when its value was less than 0.95. completed the treatment. In one patient who had
Results: Five patients were available for analysis. For radiation pneumonitis before SRT, progression of
all patients, the difference between the V4D and V3D pulmonary Àbrosis was observed, and treated with
was consistently over 5% (15% to 59%). The V4D was steroid therapy. In the patients who underwent SRT
larger than the V3D in all 5 cases. Conformity Index was followed concurrent chemoradiotherapy, severe
consistently less than 0.95 (0.40 to 0.82) suggesting a adverse effects caused by SRT was not observed.
clinically signiÀcant difference between the V3D and V4D. In evaluable 37 tumors, the recurrence rates are
Conclusion: Our preliminary results revealed 14/37(37.8%). Median progression free survival
that the use of 4DPET/CT for planning of RT time was 13 months. The recurrence rate and median
in patients with moving tumours may generate progression free survival time of stage I subgroups
treatment volumes which are very different to the was 5/22(22.7%) and 17 months respectively.
ones contoured on a planning 3DPET/CT. This Conclusion: SRT is thought to be safe and effective
suggests better deÀnition of the tumour volume treatment for stage I NSCLC.For patients stage I
(with incorporation of motion) using 4DPET/CT. NSCLC, SRT can be comprehensive therapy for
This difference could be clinically relevant. Further surgical resection even in local community hospital.
patient accrual is necessary to conÀrm these Àndings. And SRT followed concurrent chemoradiotherapy
Keywords: 4DPET/CT, volumetric PET/CT, for stage III NSCLC was feasible in terms of safety.
3DPET/CT, planning Keyword: Stereotactic radiotherapy
Poster Session 1 – Radiotherapy Monday, 4 July 2011 12:15-14:15 Poster Session 1 – Radiotherapy Monday, 4 July 2011 12:15-14:15
P1.152 STEREOTACTIC RADIOTHERAPY P1.153 CLINICAL AND DOSIMETRIC

(SRT) AS COMPREHENSIVE THERAPY RISK FACTORS FOR RADIOTHERAPY
FOR NON-SMALL CELL LUNG INDUCED BONE INJURY (RIBI)
CANCER INCLUDING STAGE III AND FOLLOWING STEREOTACTIC BODY
RECURRENCE CASES RADIOTHERAPY (SBRT)
Yohei Futamura1, Toshiyuki Sawa1, Akane Horiba1, Mojgan Taremi1, Andrew Hope2, Max Dahele3,
Takashi Ishiguro1, Tsutomu Yoshida1, Takayoshi Patricia E. Lindsay2, Sharon Fung4, Tom Purdie2,
Iida2, Takaaki Hasegawa1 David A. Jaffray2, Laura A. Dawson2, Andrea
1
Respiratory Medicine And Oncology, Gifu Bezjak5
Municipal Hospital/Japan, 2Radiology, Gifu 1
Radiation Oncology, Southlake Regional Health
Municipal Hospital/Japan Center/Canada, 2Radiation Oncology, Princess
Margaret Hospital/Canada, 3Radiation Oncology, Vu gender (HR 4.43, 95% CI: 1.68 - 11.68) remained
University Medical Center/Netherlands, 4Department statistically signiÀcant risk factors. Based on the
Of Biostatistics, Princess Margaret Hospital/ dose-event curve, a D0.5 of 50 Gy is associated with
Canada, 5Department Of Radiation Oncology, an estimated 30% risk of RIBI. A nomogram was
Princess Margaret Hospital/Canada generated based on the multivariate model including
age, female gender and D0.5.When analyzed via
Background: Limited data exist to estimate risk of receiver operating characteristic (ROC), the Ànal
RIBI following SBRT. The purpose of this study was RIBI nomogram had an area under the curve (AUC)
to identify clinical and dosimetric factors associated of 0.93.
with RIBI and to develop a nomogram model to Conclusion: Both dosimetric and clinical factors are
estimate risk of RIBI following SBRT. correlated with risk of RIBI and should be included
Methods: Inoperable patients with early stage when modeling risk of toxicity. A nomogram using
non-small cell lung cancer, treated with SBRT, D0.5, age, and female gender may be useful to
who received 54 or 60 Gy in 3 fractions, and had estimate risk of RIBI following SBRT and requires
a minimum of 6 months follow up were selected validation.
for this retrospective institutional study. Archived Keywords: stereotactic body radiotherapy,
treatment plans were retrieved, ribs were delineated radiotherapy toxicity, rib fracture, nomogram
individually and treatment plans were re-computed
using heterogeneity correction. RIBI was identiÀed
by reviewing the serial CT images. Clinical and Poster Session 1 – Radiotherapy Monday, 4 July 2011 12:15-14:15
dosimetric factors were evaluated for their association
with rib fracture using logistic regression analysis; a P1.154 IS SBRT ALONE APPROPRIATE
dose-event curve and nomogram were created. FOR EARLY-STAGE NON-SMALL-
Results: 46 patients with median follow-up 25 CELL LUNG CANCER WITH PRIMARY
months (range 6 – 51m) were included. 41 fractured TUMOURS LARGER THAN 4CM?
ribs were detected in 17 patients; median time to Zishan Allibhai1, John Cho1, Soha Atallah1, Andrew
fracture was 21m (range 7 – 40m). Of 41 identiÀed Hope1, Anthony M. Brade1, Alex Sun1, Mojgan
fractured ribs the original radiologic report did Taremi2, Andrea Bezjak1
1
not report fracture in 37% (n=15). Analyses were Radiation Medicine Program, Princess Margaret
performed per rib and per patient. The mean of Hospital/Canada, 2Radiation Oncology, Southlake
the maximum point dose to any rib in 46 patients Regional Health Center/Canada
was 55.2 Gy + 17.9 Gy (range: 21.6 to 88 Gy). A
signiÀcant difference was noted between patients Background: While stereotactic body radiation
with no rib fracture (n=29) vs. patients with rib therapy (SBRT) has proven to be safe and effective
fracture (n=17), 50.2 Gy + 17.7 Gy (range: 21.6- in the management of early-stage non-small-cell
73.2 Gy), vs. 63.7 Gy + 15.3 Gy (range: 26.6-88 lung cancer (NSCLC), there is concern that larger
Gy) p = 0.02. 1095 ribs were available for analysis; tumours have poorer outcomes with higher rates of
the mean of maximum point dose to all ribs (1095) failure as well as potentially greater toxicity.
was 12.7 Gy + 17.5 Gy (range: 0.2 to 88 Gy). In Methods: Between October 2004 and October
non-fractured ribs (n=1049), the mean of maximum 2010, we treated 208 medically inoperable patients
point dose was 10.5 Gy + 10.2 Gy (range: 0.2- with T1-T2N0M0 NSCLC on a prospective REB-
87 Gy), and in the fractured ribs (n=46) was approved single-institution protocol. Patients were
48.5 Gy + 24.3 Gy (range 0.6-88 Gy) which was planned conformally using 4D-CT with 8-10 non-
statistically signiÀcant (p < 0.0001). On univariate coplanar beams. Typical dose regimens used for
analysis, age, dose to 0.5 cc of the ribs (D0.5), and peripheral tumours were 54-60 Gy/3 fractions or
the volume of the rib receiving at least 25 Gy 48/4 for peripheral tumours (only if <3 cm) while
(V25) were signiÀcantly associated with RIBI. As a central tumours were treated with 50/8 or 60/10.
signiÀcant cross-correlation exists between D0.5 and Cone-beam CT (CBCT) was used for daily tumour
V25 (Spearman coefÀcient 0.57, P < 0.001); only localization. Follow-up included regular medical
D0.5 was used for further analysis. In multivariate visits and serial CT scans (q3-6months). Post-SBRT
analysis age (HR 1.121, 95% CI: 1.04 –1.21), D0.5 radiological changes were carefully reviewed to
(HR 1.0009, 95%CI: 1.0007 – 1.0011), and female distinguish RT Àbrosis from possible local failure.
Patterns of failure, toxicity proÀle and survival Poster Session 1 – Radiotherapy Monday, 4 July 2011 12:15-14:15
outcome (calculated from start of SBRT) for tumour
size 4 cm and the effect of gross-tumour-volume P1.155 THE EFFECT OF SET-UP ERROR
(GTV) and planning-target-volume (PTV) size on ON DELIVERED DOSE IN CURATIVE
outcomes was determined. RADIOTHERAPY FOR NON-SMALL
Results: There were 28 patients whose primary CELL LUNG CANCER
tumour had a maximum dimension 4cm (median Aitang Xing, Lois Holloway, Shivani Kumar, Cesar
4.5 cm, range 4.0 - 5.7 cm). Eighteen patients were Ochoa, Shalini K. Vinod
treated using 54-60 Gy in 3 fractions, four 60/8, and Liverpool Hospital, Radiation Oncology/Australia
six 50/10, respectively. The increased use of central
dose regimens reÁected the tendency for larger Background: Setup uncertainties in the treatment
tumours to approach central structures. Median of lung cancer can lead to differences between
follow-up was 14.1 months (range 2-53 months). the planned and delivered dose. At our centre, a
Of the 28 pts, 2 (treated with 50/10 and 60/8) had literature-derived margin of 10mm in the transverse
likely local failure (LF) based on imaging (not direction and 15mm in the cranio-caudal direction is
biopsy proven), 5 had regional failure (RF) and 7 had added to the clinical target volume (CTV) to account
distant failure (3 with lung metastases only). One for setup uncertainty in curative radiotherapy for
of the patients with LF also had distant metastasis lung cancer. The aim of this study was to model the
(DM) while 4 of 5 patients with RF also had DM. impact of daily set-up variation on the delivered dose
The rate of LF, RF and DF-free survival was 92.9%, for lung cancer patients based on measured treatment
82.1%, and 75.0% respectively, while overall failure- set-up.
free-survival was 64.3%. The rate of local control Methods: Daily set-up deviation was measured
is similar to that previously reported for the entire utilising perpendicular planar imaging for 25 patients
patient cohort (median tumour size 2.4 cm, Taremi over 20 fractions of radiotherapy treatment and the
IJROBP 2011). The most common acute toxicity random and systematic set-up deviation determined.
was fatigue (19/28 patients), and the most common To model the effect of geometrical uncertainties on
clinically signiÀcant toxicity was symptomatic rib delivered dose distributions to the CTV over the
fracture (8/28 patients). However, the rate of G2-3 course of treatment a Monte Carlo (MC) and a direct
pneumonitis was 17.6%, substantially higher than method were used to simulate the delivered dose.
previously reported (10.2%). The average V20 was The MC method uses random shifts to replicate
9.1%. Within this cohort of patients, there was no the clinically measured deviations. In the direct
signiÀcant difference in control, toxicity or survival method, a treatment plan was created for each patient
outcomes between tumours larger or smaller than the incorporating the measured daily shifts for the Àrst
median tumour size of 4.5 cm. Similarly, there was 20 fractions. To evaluate the clinical coverage the
no difference in outcomes between tumours larger or resulting CTV covered by 95% of prescribed dose
smaller than the median GTV (34.7 cm3). Tumours was determined. These results were compared to the
with PTV’s larger than the median size (100.6cm3) ICRU guidelines and used to assess the adequacy
had similar pneumonitis rates despite having a of the current PTV margins and protocols for set-up
signiÀcantly higher V20 (p=0.01). veriÀcation.
Conclusion: For patients with early-stage NSCLC Results: The average systematic error for the group
treated with SBRT, we did not observe an effect of of 25 patients was 0.3cm(x), 0.54cm(y) and 0.25cm
tumour size on local control. However large tumours (z) and this was used for MC simulation. The
may extend closer to central structures and may average random error was 0.24cm(x), 0.46cm(y),
be at risk of local failure if lower SBRT doses are 0.16cm (z) with the greatest set-up error in the Y
used. However, there may be more toxicity (such as direction. The MC and direct methods for simulating
radiation pneumonitis) associated with treating larger delivered dose showed a maximum difference of
tumours, and this should be monitored carefully. 1.1 % (Table 1). The average CTV covered by the
Keywords: large primary, NSCLC, prospective, prescribed dose in the simulations was above 95%
SBRT for all patients except Patient 1. The original plan for
this patient had suboptimal coverage of the CTV due
to proximity to spinal cord, which worsened when
the isocentre shifts were applied.
Random Std(cm) CTV coverage

Patient Direct method MC method
(Medical Intelligence®). We contoured the ITV
No X Y Z Original plan modelled shifts modelled shifts using the maximum intensity projection in lung
1 0.26 0.42 0.41 89.22% 83% 84.1%
window. An ITV-PTV margin of 3 mm was taken.
2 0.089 0.150 0.182 100% 99.99% 99.80%
3 0.09 0.15 0.182 99.99% 99.65% 99.62%
The planning was performed on the average
4 0.18 0.59 0.21 98.02% 96% 96% scan using the Tomotherapy Hi-Art convolution
5 0.37 0.52 0.24 99.91% 99.87% 98.60% superposition algoritm. 99% of the PTV received
6 0.31 0.69 0.17 99.61% 99.18% 96.18% 100% of the prescribed dose. In the central part of
7 0.28 0.56 0.17 99.95% 99.66% 99.22%
the tumor an overdose of 20-25% was given. Dose
8 0.23 0.43 0.18 96.78% 96.15% 95.80%
Table 1: Measured random set-up error and resulting modelled CTV coverage from the
prescription was T1 peripheral tumor: 3 x 18 Gy,
original plan, the direct method and the Monte Carlo method. T2 tumor or adjacent to ribs: 5 x 12 Gy and T1-2
tumors with central location: 8 x 7.5 Gy, all three
Conclusion: The current PTV margins and set-up times a week. Before treatment a control MV-CT
veriÀcation protocols have resulted in delivered scan was performed. Table and gantry position
dose meeting ICRU guidelines in all but one patient. were corrected based on an automated registration
The direct and Monte Carlo methods were similar on bony structures adapted manually on the visual
in terms of modelling, the latter will be used to tumor shadow in relation to projected PTV/isodoses.
analyse the remaining patients. In the absence The treatment time ranged from 6 to 12 minutes.
of daily imaging, measurement of set-up error Patients were followed at regular intervals of 3
and resultant isocentre deviations is important to months.
evaluate adequacy of PTV margins in the curative Results: The median follow up period was 14.5
radiotherapy treatment of lung cancer. months. In one patient a symptomatic rib fracture
Keywords: Lung cancer, Set-up deviation occurred that was treated conservatively and 3
patients (3.4%) had grade 2-3 radiation pneumonitis
requiring temporary treatment with corticosteroids.
Poster Session 1 – Radiotherapy Monday, 4 July 2011 12:15-14:15 The median age for lung carcinoma patients treated
group was 73 years. Tumor staging was 55 T1, 19
P1.156 IMAGE GUIDED SBRT USING T2 and 3 (limited)T3. Histologic conÀrmation of
TOMOTHERAPY FOR STAGE I NSCLC: malignancy was derived in 23 patients. In total 13
FIRST CLINICAL RESULTS patients were previously treated with radiotherapy
Ernest J.A. Vonk, Andre Minken, Marloes I. Ten (4 patients, 50-55 Gy) or surgery (wedgeresection
Brinke, Margo C. Noordhoek (1), lobectomy (5), bi-lobectomy (1), pneumectomy
Radiotherapy, Riso/Netherlands (2)) for a previous malignancy. In total 21 patients
deceased of which 7 due to lung cancer. Median 1-
Background: For patients with stage I non-small and 2-year survival are 86% and 58%, which agrees
cell lung cancer (NSCLC) the common treatment with other studies. We observed 2 local recurrences
is lobectomy or pneumonectomy. However, a large with an act. 2-year local progression free survival
group of patients is medically inoperable due to of 95%. Simultaneously these recurrent patients
cardiac or pulmonary co-morbidity. In recent years showed also a regional or distant metastasis. One
stereotactic body radiotherapy (SBRT) proves to be patient had a solitary regional recurrence, 7 patients
a good alternative to surgery for these patients with had distant metastases without local recurrence
a high local control rate and few side effects Conclusion: SBRT with the tomotherapy Hi-Art
Methods: In 2007 we started with SBRT of lung system is a good solution and leads to a high local
tumors using the Tomotherapy Hi-Art system. control and low toxicity
We report the results of 89 patients treated for Keywords: SBRT, Stage I NSCLC, Tomotherapy
lungcarcinoma (75), local recurrent lung carcinoma
(2) or metastases (12). We treated patients with
SBRT with tumors <5 cm, which on CT scan
examination were suspicious for malignancy
(new or growing lesion with spiculae). A positive
PET-CT without evidence of hilar or mediastinal
lymphadenopathy was mandatory. During treatment
patients were immobilised with a vacuum bag
Poster Session 1 – Radiotherapy Monday, 4 July 2011 12:15-14:15 highest for tumor and heart, with Dice similarity
coefÀcients ranging between 0.83-0.86 and 0.87-
P1.157 VARIATION IN CONTOURING 0.92, respectively. Lower levels of agreement were
NORMAL ORGANS FOR STEREOTACTIC observed for esophagus and proximal bronchial
ABLATIVE RADIOTHERAPY: TRAINING tree with similarity coefÀcients between 0.51–0.72
ANALYSIS WITH AN INTERACTIVE and 0.58-0.66, respectively. The differences in
SOFTWARE TOOL (TACTICS) Dice coefÀcients between the different sites were
Eva Marrit Bongers1, Max Dahele1, Jayashree statistically signiÀcantly different (P <0.05).
Kalpathy-Cramer2, Clifton D. Fuller3, Suresh Senan1 Conclusion: Despite the use of an atlas, large
1
Radiation Oncology, Vu University Medical Center/ contouring variations in some critical organs were
Netherlands, 2Oregon Health & Science University/ observed, even in an institution where SABR is
United States Of America, 3Department Of Radiation routinely used for treating large and central tumors.
Onoclogy, University Of Texas Health Science TaCTICS can complement contouring guidelines
Center/United States Of America by objectively evaluating clinician contours against
a reference. Further efforts to develop software-
Background: Stereotactic ablative radiotherapy assisted training tools that also include real-time
(SABR) has achieved high local control rates with capabilities are justiÀed. Such tools might have a
minimal toxicity in the treatment of peripheral lung role in risk-management, quality assurance, and
tumors. Larger and more central tumors are now transferring SABR knowledge and techniques to
being treated, but the use of high doses and steep other regions.
dose-gradients near adjacent critical structures can Keywords: Stereotactic ablative radiotherapy,
increase the risk of toxicity. Inter-observer variation contouring variation, interactive software tool,
in contouring tumors and critical organs is well delineation
recognized and may contribute to suboptimal SABR
plans. We evaluated a novel approach to contouring
training using an interactive tool that is currently Poster Session 1 – Radiotherapy Monday, 4 July 2011 12:15-14:15
being developed to provide individual clinicians
with quality metrics and visual feedback of the P1.158 DETECTION OF EGFR GENE
delineation process. MUTATIONS IN PATIENTS WITH
Methods: The TaCTICS (Target Contour Testing/ ADVANCED NSCLC IN SLOVAK
Instructional Computer Software) tool is an open- REPUBLIC.
access, web-based application (http://skynet. Katarina Hlinkova1, Barbora Piackova1, Ivan Majer2,
ohsu.edu/tactics_nl/) being designed to evaluate Pavel Babal3, Lucia Copakova1
1
the similarity between submitted and reference Department Of Cancer Genetics, National
contours using quantitative metrics and graphical Cancer Institute/Slovak Republic, 2Department Of
displays. The quantitative metrics are derived using Pneumology And Phtisiology, Faculty Of Medicine
algorithms from the Insight Toolkit (ITK, http:// Comenius University/Slovak Republic, 3Department
www.itk.org/). Three thoracic radiation oncologists Of Pathology, Faculty Of Medicine, Comenius
with expertise in lung SABR delineated a large, University/Slovak Republic
central lung tumor and critical organs in accordance
with published guidelines (Kong FM, 2010). The Background: Somatic mutations of the EGFR gene
STAPLE (Simultaneous Truth and Performance in exons 18 to 21, particularly an in-frame 15 bp
Level Estimation) algorithm, which computes a deletion (delE746_A750) in exon 19 and the L858R
probabilistic estimate of the true segmentation mutation in exon 21, are associated with enhanced
(WarÀeld SK, 2004) was used to derive a single clinical responsiveness to EGFR tyrosine kinase
reference contour for each structure from the 3 inhibitors. Recently, the epidermal growth factor
expert contours. Subsequently, 3 radiation oncology receptor (EGFR) tyrosine kinase inhibitor geÀtinib
residents independently contoured the same tumor was approved in Slovak republic for the treatment of
and critical organs. Similarity metrics and images advanced NSCLC.
were generated. Methods: We established and validated methods
Results: The level of agreement between each for mutation screening of the EGFR gene by a
resident’s contour and the reference contour was high resolution melting analysis. HRMA assay
demonstrated a sensitivity of 1% of mutanted pneumonitis (RP)(RTOG grade 2 or more) in non

DNA in a background of wildtype DNA. The small cell lung cancer patients treated with combined
positive results of HRMA were conÀrmed by direct modality therapy.
sequencing. In samples containing less than 25% Methods: Between January 2008 to December
tumor cells, we were able to conÀrm positive HRMA 2010, 41 patients of non-small cell lung cancer
results by direct sequencing after the enrichment of were treated with combined modality therapy. 31
tumor-associated DNA by mutant-enriched PCR. were treated with concurrent chemoradiotherapy
Results: We examined 321 patients with advanced and 10 with neoadjuvant chemotherapy followed
NSCLC (193 cases of squamous cell carcinomas, by radiotherapy alone. Cisplatinum 50mg/m2
120 adenocarcinomas and 8 large cell carcinomas). d1,8,29,36 and etoposide 50mg/m2 d1-5,d 29-33 was
We analyzed 234 cytological specimens, 72 parafÀn administered concurrent to radiotherapy. All patients
embedded (FFPE) blocks and 12 tumors. Mutations underwent three dimensional treatment planning
of EGFR gene were detected in 36 cases (11%). (including dose volume histograms) and were treated
The in-frame deletions in exon 19 and L858R with curative intent to a dose of 50-66Gy. Patients
mutation in exon 21 were detected in 15 (44%) were treated only if the percentage of whole lung
and 12 (35%) cases, respectively. Two patients volume receiving 20 Gy ( V20) was less than 37%
had double mutations and one patient had L861Q and mean lung dose (MLD) was less than 20Gy.
mutation in exon 21. We found 2 types of mutations Pulmonary function tests (PFT), site of tumour,
in exon 18 of EGFR gene not previously described planning target volume and the various dose volume
(K712T and K715E). These patients with a novel parameters like the total (V20, V5 and MLD) and
mutations received GeÀtinib. Two patients have ipsilateral (V20 ipsi, V5 ipsi amd MLD ipsi) lung
T790M mutations without prior exposure to EGFR- dose–volume histogram (DVH) parameters were
TKI. Mutations of EGFR gene were found in 27 correlated with incidence of signiÀcant pneumonitis.
adenocarcinomas, 8 squamous cell carcinomas and 1 Results: Out of 41 patients, 31 patients were treated
large cell carcinomas. with 21 (53.4%) developed grade 2 pneumonitis.
Conclusion: Our results indicated that HRMA in The factors signiÀcantly correlating with radiation
combination with mutant-enriched PCR with the pneumonitis were V5 (p=0.04), V5 ipsi (p=0.007) ,
possibility of direct sequencing provides an effective V20 ipsi (p=0.012), and MLD ipsi (p=0.03). V20,
method for mutation screening of EGFR gene in MLD, PTV, PFT, site of tumour were not statistically
routine oncologic practice from various clinical signiÀcant. When the analysis was limited to patients
samples. receiving concurrent chemoradiation (n=31) factors
Keywords: EGFR mutations, HRMA, Direct correlating with radiation pneumonitis were V20
sequencing, mutant-enriched PCR (p=0.02), MLD (p=0.02),V20 ipsi (p=0.03), and
V5ipsi (p=0.02).PFT (Fev1<2litres/min) correlated
with MLDipsi. On multivariate analysis V20 ipsi
Poster Session 1 – Radiotherapy Monday, 4 July 2011 12:15-14:15 was retained as the most signiÀcant factor.
P1.159 IPSILATERAL LUNG DOSE PTV V20 V5 MLD V20ipsi V5ipsi MLDipsi
No RP group 564 25.9 38.1 14.5 47.5 57.3 24.4
VOLUME PARAMETERS PREDICT RP group 552 32.4 49.1 18.6 61.17 71.2 32.5
RADIATION PNEUMONITIS IN P value 0.86 0.06 0.04 0.08 0.012 0.007 0.031
ADDITION TO CLASSICAL DOSE
VOLUME CONSTRAINTS IN STAGE Table 1: Dosimetric constraints in RP
IIIA-B NSCLC TREATED WITH Conclusion: The correlation between pneumonitis
COMBINED MODALITY THERAPY and dosimetric constraints has been validated. Adding
Sushma Agrawal1, Sunil Kumar2, Shaleen Kumar1 ipsilateral V20, V5 and MLD to the classical total
1
Department Of Radiotherapy, Sanjay Gandhi Pgi/ lung constraints could reduce pulmonary toxicity in
India, 2Department Of Radiotherapy, Snajay Gandhi concurrent chemoradiation. V20ipsi, V5ipsi and MLD
Pgi/India ipsi are important if the classical total lung constraints
ie V20, MLD have not exceeded the constraints of
Background: To determine the correlation 37% and 20Gy respectively.
of clinical and lung dose volume parameters Keywords: ipsilateral lung, dose volume parameters,
(ipsilateral and whole lung) with signiÀcant radiation radiation pneumonitis
Poster Session 1 – Radiotherapy Monday, 4 July 2011 12:15-14:15 Results: PSPT resulted in the lowest dose to the
OAR, while keeping the dose to the target at 70 Gy.
P1.160 COMPARING RADIOTHERAPY The mean lung dose (MLD) reduced from 18.9 Gy
WITH PHOTONS AND PROTONS FOR for 3DCRT and 16.4 Gy for IMRT to 13.5 Gy for
NON-SMALL CELL LUNG CANCER: PSPT. The average integral dose was signiÀcantly
RESULTS OF A MULTICENTRIC IN higher for 3DCRT (59%) and IMRT (43%) than for
SILICO CLINICAL TRIAL PSPT, while the maximum doses to the spinal cord
Erik Roelofs1, Martijn Engelsman2, Coen Rasch3, were 6% and 11% higher, respectively, although
Lucas Persoon1, Sima Qamhiyeh1, Dirk De this was not signiÀcant. The mean dose to the heart
Ruysscher1, Frank Verhaegen1, Madelon Pijls- was lowered by 50% and 47%, respectively, while
Johannesma1, Philippe Lambin1 the V40Gy was reduced by 53% and 37%. The
1
Department Of Radiation Oncology (MAASTRO), V55Gy for the oesophagus was signiÀcantly higher
Grow – School For Oncology And Developmental for 3DCRT but lower for IMRT compared to PSPT
Biology, Maastricht University Medical Centre/ (31.0%, 26.4% and 28.3%, respectively).
Netherlands, 2Massachusetts General Hospital For 10 patients, the plans could be escalated to an
And Harvard Medical School (MGH)/United States MTD of around 87 Gy for all three modalities .
Of America, 3Netherlands Cancer Institute (NKI)/ The average integral dose was about 65% higher
Netherlands for photons than for protons. The MLD was 42%
higher for 3DCRT than for PSPT, while it was 40%
Background: Lung cancer remains the number one higher for IMRT. For the spinal cord, the maximum
cause of death among cancer patients in Europe and dose was 90% higher for IMRT than for PSPT. For
North America, despite the advances in its treatment the oesophagus, the maximum dose was about 72
options. Different approaches in combining surgery, Gy for all modalities. The mean dose to the heart
chemotherapy and radiotherapy to increase tumour for photons was double the dose for protons, while
control and to lower complication rates are the the V40Gy was 117% higher for 3DCRT and 57%
subject of intense investigation. higher for IMRT than for PSPT.
Within the radiotherapy Àeld, proton and also Conclusion: These results show a reduction of
carbon ion (C-ion) radiotherapy is gaining interest integral dose and the dose to the OAR when treating
and popularity because its advantage in ballistic with protons instead of 3DCRT or IMRT photons.
properties over conventional photon radiotherapy. Even with dose-escalation, PSPT is able to use its
To investigate the possible treatment beneÀt we beneÀcial dose distribution to give a high tumour
compared photon and proton radiotherapy treatment dose, while keeping the OAR dose lower than with
planning results for non-small cell lung cancer the photon modalities.
(NSCLC) patients in an international multicentric Keywords: In silico planning study, Particle therapy,
in silico trial: the Radiation Oncology Collaborative NSCLC, Radiotherapy
Comparison (ROCOCO).
Methods: Twenty-Àve consecutive NSCLC patients,
stage IA-IIIB, were prospectively included. On 4D Poster Session 1 – Radiotherapy Monday, 4 July 2011 12:15-14:15
FDG-PET/CT scans, the gross tumour, clinical and
planning target volumes and organs at risk (OAR) P1.161 CHANGES IN TUMOUR VOLUME
were delineated and subsequently uploaded onto DURING RADIOTHERAPY FOR
the central MISTIR data repository (www.mistir. LOCALLY ADVANCED NON SMALL
info). Three-dimensional conformal (3DCRT) CELL LUNG CANCER.
and intensity-modulated (IMRT) photon as well Sushma Agrawal, Sunil Kumar, Anil K. Maurya,
as passive scattered conformal proton therapy Shaleen Kumar
(PSPT) plans were created according to a strict Department Of Radiotherapy, Sanjay Gandhi Pgi/
planning protocol, including pre-deÀned patient India
setup accuracy, breathing motion and fractionation
schedules. The prescribed dose to the tumour was 70 Background: Dose escalation for lung cancer is
Gy in 35 fractions. Subsequently, dose (de-)escalation limited by normal tissue toxicity. We evaluated a
was performed by rescaling to the maximum tolerable sequential computed tomography scan to assess the
dose (MTD) of one or more of the OAR. possibility of adaptively reducing treatment volumes
by quantifying the tumor volume reduction occurring possibility of using an adaptive approach toward RT
during a course of radiotherapy (RT). of non–small-cell lung cancer to minimize the dose
Methods: A total of 20 patients underwent RT to normal structures and more safely increase the
for Stage III non–small-cell lung cancer with dose directed at the target tissues.
conventional fractionation; 10 received concurrent Keywords: nonsmall cell lung cancer, tumour
chemotherapy and radiotherapy (CONC) and 10 regression, adaptive radiotherapy
received neoadjuvant chemotherapy (NACT)
followed by external radiotherapy alone. One repeat
CT scan was performed at a nominal dose of 40 Gy. Poster Session 1 – Radiotherapy Monday, 4 July 2011 12:15-14:15
Primary gross tumor volume (GTV_P), gross nodal
volume (GTV_N) and planning target volume (PTV) P1.162 IMPROVING INTENSITY
were evaluated for regression. Both the image sets MODULATED RADIOTHERAPY
were spatially co-registered by rigid registration PLANS USED FOR HIGH-DOSE
(planning CT data with the repeat scan) for evaluation. CHEMORADIOTHERAPY IN STAGE III
Coordinates of centre of mass (COM) of both the NSCLC
GTV’s (GTV_P and GTV_N at pretreatment and at 40 Ellen J.F. Van Reij, Wilko F.A.R. Verbakel, Ben
Gy) were recorded to measure the spatial shifts. Slotman, Suresh Senan
Results: The mean (±SD) volume of GTV_P , Radiation Oncology, VU University Medical Center/
GTV_N and PTV in CONC arm before start of Netherlands
radiotherapy were 112.63(± 64.3), 13.1 (±9.4),
and 567 (±219) cc and that of NACT arm were Background: Concurrent chemoradiotherapy
67.85 (±49.4), 43.2 (±31.2), and 446.2 (±293) cc (CT-RT) is current standard treatment in stage III
respectively. At 40Gy mean GTV_P, GTV_N, PTV NSCLC, but it is accompanied by an increase in
in CONC arm were 39.5(±18.7), 11.0(±9.3) and pulmonary toxicity. Since 2008, we routinely applied
319.66 (±166.4)and that of NACT arm were 39.5 intensity modulated radiotherapy (IMRT) to achieve
(±47.9), 15.3 (±7.9)and 320.4(±187.2)cc respectively. a dose of 66 Gy for CT-RT in large and/or complex
The mean GTV_P, GTV_N and PTV reduction in tumor volumes. Previous reports suggested that
CONC arm were 73.05 cc (64.8%), 2.07 cc (15.7%) the volume of lung treated to low doses (e.g. V5)
and 248 (43.7%) cc and that of NACT arm was 28.31 was related to higher risk of radiation pneumonitis.
cc (41.7%), 27.9 cc (64.58%), and 125.8cc (28.2%) EORTC-guidelines recommend that lung toxicity
respectively .The difference in GTV_P in concurrent should be limited by restricting planning parameters
arm as compared to NACT arm was signiÀcant such as the V20 and mean lung dose to below 35%-
(p=0.02) resulting in a signiÀcant PTV difference 37% and 20-23 Gy, respectively. Prior to 2008, the
between the 2 arms (p=0.04).There was no statistically mean tumor dose used for CT-RT at our center was
signiÀcant difference (p=0.28)in the regression of 59.5 Gy, with corresponding V20 values of 26.6%
GTV_N between the two arms. In the CONC arm, and V5 of 54.8%. We evaluated IMRT planning
the mean ±SD COM shifts of GTV_P were 2.9mm parameters in all patients undergoing high-dose
(±10.5), -4.6mm(±9.4) and 0.3 mm(±9.5) and in the platinum-based CT-RT in order to evaluate the
NACT arm it were 1.4mm (±2.8), 2.1mm(±3.3) and compliance of planning constraints.
2.1mm (±5.3)in the x , y and z direction respectively. Methods: We reviewed dosimetry records of all 43
In the CONC arm, the mean ±SD COM shifts of stage III patients treated between 2008 and 2010
GTV_N were -1.6 (±4.5)mm, -4.6mm(±4.0) and with CT-RT using 3-weekly concurrent cisplatinum-
-4.6mm( ±4.0) and in the NACT arm it were 5mm (± etoposide. All plans utilized a hybrid-IMRT
6.5 mm), 0.2(±4.8) and 0.2(±4.8) mm in the x , y and technique to deliver doses of 66 Gy. The hybrid-
z direction respectively. IMRT technique consists of a base dose plan with 3
Conclusion: The results of this study have conventional open Àelds of 15 MV, optimized using
demonstrated considerable reduction in the GTV_P IMRT-Àelds in order to achieve a homogeneous
in both arms though higher in CONC (64.8%) arm planning target volume (PTV) dose. Planning dose
as compared to NACT (41.7%) arm. Although constraints used were V20<35%, V5<60% and V5
reduction in GTV_N volume was remarkable in contralateral lung as low as possible. The PTV dose
a number of patients but statistically it was found criteria required that 95% of PTV should receive
to be non signiÀcant.These observations raise the 95% of prescribed dose. Toxicity was analyzed
with Common Toxicity Criteria and Adverse Events clinically suggestive of stage I lung cancer at
(CTC-AE v4.0). Hyogo Ion Beam Medical Center (HIBMC)
Results: The median PTV size was 664 cc (range: retrospectively
236-1425); 27.9% (n=12) of patients had a T4- Methods: Between June 2001 and June 2009,
tumor and 25.6% (n=11) had a N3-nodal status. The a total of 63 patients with HULN, all of that
mean dose to PTV was 66.7 Gy. Mean lung dose were diagnosed as lung cancer on radiologic
was 16.6 Gy; median V20 was 27.3% (7-35.8%); examination, received proton or carbon ion
median V5 for both lungs was 50.8% (23.7-82.6%) radiotherapy at HIBMC. Among these patients,
while the median V5 contralateral lung was 26.1% 15 patients were excluded from this study because
(4-72%). V20 planning constraints were exceeded in seven were staged as IIA or IIB (UICC TNM
2 patients with T2N3M0 tumors with PTV-sizes of 2009) and six had other active malignancies.
422 and 727cc. Both had besides a V20>35%, a V5 Also excluded were two patients who were lost to
that exceeded 60%. A V5 total lung exceeding 60% follow-up. The remaining 48 patients (50 lesions)
was observed in 7 patients (median PTV-size 657cc), with stage I (T1a, 29; T1b, 15; and T2a, 6) were
5 of whom had stage IIIB disease (one patient identiÀed and retrospectively analyzed. Tumor size
with T4 and 4 patients with N3-disease). The V5 ranged from 8 to 50 mm in maximum diameter,
contralateral lung was signiÀcantly higher in patients with a median of 19 mm. Twenty-nine lesions
with cN3- disease (p=.005), especially in patients (58%) were treated with proton therapy of 52.8-
with contralateral mediastinal nodes (52.3-66.9Gy). 80 GyE/4-20 fractions and 21 lesions with carbon
In contrast, PTV-size for the entire group showed no ion therapy of 52.8-68.4 GyE/4-10 fractions.
correlation with poorer lung dosimetry. At a median Survival and local control were evaluated using the
follow-up of 9.9 months, only 16.3% (n=7) and 4.7% Kaplan-Meier method. Acute and late morbidities
(n=2) of all patients developed respectively grade 2 were assessed based on the Common Terminology
and grade 3 radiation pneumonitis. Criteria for Adverse Events (CTCAE) v3.0. The
Conclusion: The use of hybrid-IMRT planning median follow-up time was 28 months (range, 8-69
enables improved planning parameters in patients months). For T1 patients, subgroup analyses were
treated with CT-RT to 66 Gy. However, further performed to compare the results of HULN with
improvements in planning techniques are required those of histologically proven lung cancer (HPLC),
for selected subgroups of stage III NSCLC which have been previously published from our
who present with N3 disease, especially in the institution.
contralateral mediastinum. Results: The actuarial 3-year rates of overall
Keywords: imrt, locally advanced survival (OS), progression-free survival and local
control were 83%, 80% and 90%, respectively.
Local (marginal) progression occurred in 3 patients
Poster Session 1 – Radiotherapy Monday, 4 July 2011 12:15-14:15 (6%). Lymphatic and distant metastases were
observed in 5 patients (10%) and 7 patients (15%),
P1.163 PARTICLE THERAPY FOR respectively. As for grade 3 or greater morbidities,
HISTOLOGICALLY UNPROVEN LUNG grade 3 dermatitis was observed in 1 patient.
NODULES HIGHLY SUGGESTIVE The tumor size of HULN was signiÀcantly small
OF STAGE I LUNG CANCER ON as compared to that of HPLC. Furthermore, T1
RADIOLOGIC EXAMINATION patients with HULN showed better OS rates than
Osamu Fujii those with HPLC.
Radiology, Hyogo Ion Beam Medical Center/Japan Conclusion: This study showed that particle
therapy provided favorable outcome with
Background: Although pathologic conÀrmation acceptable toxicity, therefore serving as an effective
is essential for the treatment of small pulmonary treatment option for patients with HULN highly
lesions, it is difÀcult in some cases due some suggestive of stage I lung cancer on radiologic
medical problems. Nevertheless, these lesions examination.
could be candidates for radical treatment including Keyword: hibmc
particle therapy. The purpose of this study was
to analyze the results of particle therapy for
histologically unproven lung nodules (HULN)
Poster Session 1 – Radiotherapy Monday, 4 July 2011 12:15-14:15 Methods: The masses were created as above and
constituted the CTV within the simulated plans on
P1.164 DOSIMETRIC IMPROVEMENTS 10 patients who had previously been scanned and
IN A COHORT OF PATIENTS WITH treated in the department for thoracic malignancies
SIMULATED TRACHEAL TUMORS (and were deceased); these patients previous scans
RECEIVING INTENSITY MODULATED served as the planning phantoms for this study.
RADIOTHERAPY (IMRT) ACCOUNTING A 5mm isotropic margin was added to the CTVs
FOR OPTIMIZATION CONVERGENCE to create PTVs within the plans. The median
ERRORS (OCES) CTV volume was 4.5 ccs; PTV volume, 17.8 ccs.
Todd J. Scarbrough1, Samuel R. Faught2, Charles R. A nine-Àeld equally spaced coplanar static Àeld
Thomas3 beam arrangement was employed using dMLCs,
1
Radiation Oncology, Owensboro Medical Health 600MU/min dose rate. The PTV was optimized to
System/United States Of America, 2Radiation receive 100% of the Rx dose (60 Gy/30 fx). The
Oncology, Omhs/United States Of America, 3Dept Of maximum plan inhomogeneity at optimization was
Radiation Medicine, Ohsu/United States Of America set to be 62 Gy. A smoothing factor of 20/20 X/Y
was used for optimization. No other optimization
Background: In many commercially available parameters were utilized. Eclipse DVO v8.9.08 was
treatment planning systems (TPSs), when planning used for optimization. After initial optimization,
IMRT, the Áuence optimization process uses a plans were calculated using Eclipse AAA v8.9.08
different algorithm than the actual dose calculation (Plan 1). All plans were normalized such that
workspace. In the Eclipse treatment planning 95% of the PTV received 100% of the Rx dose or
system (v8.9.09.18617, Varian Medical Systems, more. PTV minimum, median and maximum doses
Palo Alto, CA, USA), for static Àeld IMRT, the were recorded, and PTV conformity indices (CIs)
Áuence optimization algorithm used is dose volume calculated. Next, each Plan 1 was re-optimized and
optimizer(DVO) v8.9.08. Of the calculation re-calculated (again using AAA) to correct for OCEs
algorithms available in Eclipse, there is evidence that using the method and tools of Zacarias and Mills
the analytical anisotropic algorithm (AAA v8.9.08) (Plan 2). A smoothing factor of 0/0 X/Y was used for
is signiÀcantly more accurate in predicting delivered OCE-corrected optimization. PTV minimum, median
dose in most clinical situations, especially air/tissue and maximum doses, and PTV CIs, were recorded
interface scenarios as encountered in lung or tracheal for each Plan 2. Plan metrics were compared using
carcinoma cases. However, the discrepancy in the the Mann-Whitney test.
DVO and AAA calculation algorithms induces Results: Plan 1 non-OCE and Plan 2 OCE-corrected
optimization convergence errors (OCEs) which are plans differed signiÀcantly. PTV minimum dose
especially noticeable in the TPS in these particular differed for Plan 1 vs 2 (median 56.5 Gy vs 58.3
clinical situations: doses become signiÀcantly Gy, p=0.0004). PTV median dose differed for Plan
inhomogenous within targets such that plans must 1 vs 2 (median 62.6 Gy vs 60.7 Gy, p=0.0002). PTV
be normalized to very low isodose lines in turn maximum dose differed for Plan 1 vs 2 (67.4 Gy vs
inducing unwanted high target inhomogeneities 62.2 Gy, p=0.0002). The CI differed for Plan 1 vs 2
and/or hot spots in the plan. Zacarias and Mills (J (median 1.77 vs 1.67, p=0.0002). Plan 1 calculations
Appl Clin Med Phys, 10:3061, 2009) have devised revealed signiÀcantly more target inhomogeneity
a Áuence summing method to correct for OCEs (median 112%) than Plan 2 calculations (median
in the Eclipse TPS by forcing the DVO to look at 104%), normalizing 95% of the PTV volumes to
calculated AAA results. We selected a non-random receive 60 Gy Rx dose or more.
cohort of 10 patients from our institution for this Conclusion: Correcting for OCEs in this simulated
treatment planning study and created, within the group of patients with intraluminal tracheal tumors
TPS, simulated tissue masses (using the assign CT resulted in signiÀcantly more conformal and
number function to voxels in the Eclipse TPS) within homogenous plans.
the mid-trachea 3 cm in longitudinal dimension and Keywords: Trachea, imrt
having AP and lateral dimensions equal to half the
diameter of the trachea. We then performed IMRT
plans on these simulated masses with or without
OCE corrections, and recorded the results.
Poster Session 1 – Radiotherapy Monday, 4 July 2011 12:15-14:15 to the primary tumor in three fractions. A total plan
will be calculated in NTD using the LQ-model,
P1.165 DESIGN OF A HYBRID STUDY: consisting of the simultaneous delivery of 3 SBRT
COMBINED STEREOTACTIC BODY fractions to the primary tumor and 3 x 2.75 Gy to
RADIOTHERAPY AND CONVENTIONAL the lymph nodes, and the conventional plan of 21 x
FRACTIONATION IN STAGE II AND 2.75 Gy to the lymph nodes. Fraction size of SBRT
III NON SMALL CELL LUNG CANCER is calculated depending on the MLD risk group that
WITH PERIPHERAL TUMORS is open for accrual, starting at a fraction dose of 18
Heike Peulen1, Eugène Damen1, Alize Scheenstra1, Gy and de-escalated to a minimum of 14 Gy (which
Jan jakob Sonke1, Harm Van Tinteren2, Paul Baas3, is a conservative estimation of a similar biologically
José Belderbos1 equivalent dose to 24 x 2.75 Gy using the LQL-
1
Radiation Oncology, NKI-AVL/Netherlands, model Ơ/ơ=10 and dt = 4) until an MLD is reached
2
Netherlands Cancer Institute/Netherlands, that is predicted to be safe. A planning study in ten
3
Thoracic Oncology, NKI-AVL/Netherlands eligible patients was performed and feasible [1].
Conclusion: A phase I/II dose escalation trial was
Background: Stereotactic body radiotherapy initiated, to detect the maximal tolerable MLD using
(SBRT) results in excellent local control with a hybrid treatment plan of combined SBRT and
low toxicity in stage I non small cell lung cancer CRT for stage II and III NSCLC. [1] E. Damen et al,
(NSCLC). In stage II and III NSCLC the site Extending the beneÀt of hypofractionated SBRT to
of failure after concurrent chemoradiotherapy stage II/III NSCLC: A feasibility study. J. Thorac.
is predominantly at the primary tumor site. To Oncol. 2010 May;5(5 Suppl 1): S69.
expand SBRT to stage II and III NSCLC patients, Keywords: hybrid, SBRT, conventional
we designed a phase I/II mean-lung dose (MLD) radiotherapy, NSCLC
escalation trial of combined SBRT to the peripheral
tumor and conventional radiotherapy (CRT) to the
hilar and mediastinal lymph nodes. Poster Session 1 – Radiotherapy Monday, 4 July 2011 12:15-14:15
Methods: Eligibility criteria are stage III or
inoperable stage II NSCLC treated with or without P1.166 INTENSITY MODULATED
concurrent or sequential chemotherapy, WHO 0-2 RADIOTHERPAY (IMRT) ENABLES
and peripheral lung tumors 5 cm. The primary RADICAL TREATMENT IN LOCALLY
endpoint is the maximum tolerated MLD, secondary ADVANCED LUNG CANCER PATIENTS
endpoints are locoregional control, overall survival WHO WOULD HAVE BEEN TREATED
and quality of life. Dose limiting toxicity (DLT) will WITH PALLIATIVE INTENT WITH 3D
be monitored using the Time-to-Event Continuous CONFORMAL RADIOTHERAPY (3D
Reassessment Method (TITE-CRM), which allows CRT)
continuous accrual of patients and iteratively updates Raj K. Shrimali1, Gareth J. Webster2, Lip W. Lee1,
the probability of DLT. Dose limiting toxicity was Neil Bayman1, Hamid Sheikh1, Michelle Bewley3,
deÀned according to the CTCAE v4; radiation Paul A. Burt1, Laura Pemberton1, Maggie A. Harris1,
pneumonitis grade 3, esophagitis grade 3, Abbas Chittalia1, Helen Lander1, Joanne Coote1, Phil
pulmonary bleeding grade 4 and skin toxicity Whitehurst2, Carl Rowbottom2, Corinne Faivre-Finn1
1
grade 4. Six risk groups will be deÀned, increasing Clinical Oncology, The Christie NHS Foundation
the MLD with 2 Gy in each step, starting with Trust/United Kingdom, 2North West Medical
an MLD 16 Gy. If 60 days post treatment the Physics, The Christie NHS Foundation Trust/United
estimated risk on DLT is < 15%, the next risk group Kingdom, 3The Wade Centre For Radiotherapy
is open for accrual, while the other (lower) risk Research, The Christie NHS Foundation Trust/
groups will be continuously reassessed on DLT. United Kingdom
Results: The design of this phase I/II dose escalation
trial to detect the maximal tolerable MLD using Background: IMRT improves the therapeutic ratio
a hybrid treatment plan is as follows. Eligible in lung cancer by decreasing high dose delivery to
patients will be treated with an IMRT treatment the spinal cord and lung tissue. In locally advanced
plan delivering 24 x 2.75 Gy in 5 weeks to the disease, dose constraints to organs at risk can be
pathological lymph nodes with concurrent SBRT unattainable with 3D CRT planning and high dose
palliative treatments are delivered instead. Keywords: Intensity Modulated Radiotherapy, Lung
Methods: Patients who would not have been suitable cancer, imrt
for radical radiotherapy according to our local dose
constraints were planned with IMRT (V20£35% and
spinal cord dose 44 Gy, for hypofractionated RT Poster Session 1 – Radiotherapy Monday, 4 July 2011 12:15-14:15
regimen or 48 Gy, for conventional RT regimen).
In some patients a 3D CRT plan was attempted, P1.167 EXPERIENCES OF PRE-TRIAL
whereas in others IMRT was deemed to be the QUALITY ASSURANCE (QA) FOR THE
only way to deliver a radical dose from the outset. CONVERT TRIAL. A MULTICENTRE
Static IMRT (<30 control points in total) was used RANDOMISED PHASE III TRIAL
and 44.8-66 Gy was delivered in 20-33 fractions FOR GOOD PERFORMANCE STATUS
using 5-8 6MV beams. Thirty-four patients, treated PATIENTS WITH LIMITED STAGE
between January 2009 and January 2011, were SMALL CELL LUNG CANCER
included in this retrospective analysis. CTCAE v3.0 Nicki Groom1, Elena Wilson2, Ethan B. Lyn3,
was used to grade toxicity. Corinne Faivre-Finn4
1
Results: 4 patients had two synchronous primaries, Clinical Oncology, Mount Vernon Hospital/United
1 patient had stage IIB NSCLC, 18 patients stage Kingdom, 2Clinical Oncology, The Royal Free
IIIA/IIIB NSCLC and 11 patients had LS-SCLC. Hospital/United Kingdom, 3Radiation Oncology,
Reasons for treating with IMRT were as follows: Cancercare Manitoba/Canada, 4Clinical Oncology,
high V20 (21 patients), high cord dose (1 patient), The Christie NHS Foundation Trust/United Kingdom
both reasons (12 patients). 13 patients were treated
with concurrent chemo-radiotherapy (5 SCLC and 8 Background: Patients in CONVERT are randomised
NSCLC). to either 45Gy in 30 fractions twice-daily or 66Gy
in 33 fractions once-daily (given concurrently with
Parameters Mean Range
cisplatin/etoposide). A radiotherapy QA programme
Gross Tumour Volume 77 cc 6.4 to 164. cc
Planning Target Volume 481.8 cc 177 to 1113 cc
was set up to eliminate inconsistencies across the
Cranio-caudal extent of the PTV 12.2 cm 6.5 to 19.0 cm various participating centres.
Whole Lung Volume 3593 cc 1917 to 6562 cc Methods: Pre-trial QA involves completion of a
PTV/ Whole lung Volume (%) 14.9 % 3.24 to 48.33 %
site speciÀc questionnaire and a treatment planning
Mean lung dose 16.8 Gy 6.77 to 23.8 Gy
V-20 (Mean of 4 plans with 3D CRT) 43.4 % 33 to 60.4 %
exercise, which tests the complete radiotherapy
V-20 (Mean of all the IMRT plans) 27.6 % 11.6 to 35.3 % procedure. Each participating clinician was asked
Improvement in V-20 (For the 14 patients who 11.6 % 2.7 to 27.7 % to select a previously treated patient, who Àtted the
had both 3D CRT & IMRT plans)
entry criteria for the trial, and provide disease and
V- 10 54.9 % 17.7 to 76.67 %
V-5 68.7 % 22.34 to 92.62 %
critical structure outlines, and a treatment plan for
Max dose to Spinal cord (EQD2) (Į/ȕ=.87) 34.5 Gy 24.4 to 41.25 Gy both arms of the trial. Radiotherapy QA guidelines
were distributed to each participating centre. We
25 patients developed oesophagitis, 23 (68%) grade reviewed our observations of patient selection,
2, 1 grade 3 (3%) and 1 grade 4, a stricture (3%). tumour and organs at risk outlining and treatment
No grade 3 (or higher) pneumonitis was reported. planning. We describe common deviations from trial
Median follow-up is relatively short at 8 months protocol and some of the challenges of running such
for the 19 patients still alive. Fourteen patients have a QA programme.
died due to disease progression and 1 due to other Results: In January 2011, 59 cancer centres across
causes. Of the 19 surviving patients, 2 have had local 8 countries had entered patients into CONVERT.
progression and 17 are progression free. The median Site speciÀc questionnaires were received between
survival is projected at 13 months and the 1-year April 2008 and January 2011. From the returned
survival is projected to be 56%. questionnaires and planning data, it was possible
Conclusion: Although resource intensive, IMRT to deÀne the type of equipment, techniques, beam
enables radical radiotherapy, where previously only energies and conÀguration and planning algorithms
high dose palliative radiotherapy was possible, with used, and to ensure that centres were adhering to
manageable toxicity. The impact of this technique CONVERT trial protocol. 65% of centres were using
on late toxicity, local control and survival will be type a algorithms, and 35% of centres were using
evaluated in further studies. type b. The deviations from trial protocol included:
1) patient selection: the most common being the Kingdom, 2Dept Of Clinical Oncology, Weston Park
inclusion of patients with a history of cancer or with Hospital/United Kingdom
evidence of metastatic disease. 11.4% of clinicians
submitted ineligible patients for the QA exercise. 2) Background: 55 Gy in 20 fractions is a widely
Disease outlining and expansion: 4.3% of centres used UK regimen for NSCLC radical radiotherapy
used incorrect margins and 8.6% incorrectly included treatment1. There is little phase 3 evidence for this
areas as Gross Tumour Volume 3) Organs at risk regimen and this study reports the outcome for
outlining: this was generally done well according patients treated in routine practice though recent
to the trial protocol, with the exception of the heart phase II studies have explored the addition of
and oesophagus outlining. In 64% of cases the heart chemotherapy to this schedule2,3.
was not outlined superiorly enough. The oesophagus Methods: All case notes and RT records of patients
was not outlined superiorly to the level of the cricoid with NSCLC treated with radiotherapy to a dose
cartilage in 24.3% of cases and inferiorly to the of 55 Gy in 20 fractions over a period of 5 years
level of the gastro-oesophageal junction in 4.3% of between Jan 2005 and Dec 2009 were reviewed.
cases. The oesophageal contours did not extend out Basic patient demographics, tumour characteristics,
to the fatty adventitia in 2.9% of cases. 4) Treatment use of prior chemotherapy and survival data were
planning: conformity of isodoses to the Planning collected, anonymised and descriptive statistics
Target Volume (PTV) was suboptimal in 32.9% of applied. Kaplan Mier curves were used for survival
submitted cases; initial Àndings suggest that some analysis and log rank test for comparison.
centres moving from type a to type b planning Results: 135 patients were identiÀed the median
algorithms, were inclined to increase their Àeld size age was 71 (41-87). 56% were male and 84% had
to try to achieve the level of PTV coverage that was histological conÀrmation. Tumour stages 1, 2, 3
possible with their original planning system/software and 4 were 34%, 19%, 44%, 3% respectively. The
version. WHO performance status was 0/1 and 2/3 in 77%,
Conclusion: Such a pre-trial QA programme helps 23% respectively. 34% received prior chemotherapy.
to ensure that centres conform to trial protocol, 99% received the prescribed treatment and toxicity
and should therefore reduce inconsistencies in was recorded using the RTOG toxicity scales.
radiotherapy planning across the participating One grade 3-5 toxicity was identiÀed (broncho-
centres that may confound the results of the study, oesophageal Àstula). Grade 1-2 pneumonitis was
particularly with respect to tumour targeting identiÀed in 26% and 23% of patients reported
and normal tissue toxicity. The QA programme grade 1-2 oesophagitis. Median overall survival
also provides an advice forum for clinicians and (OS) from diagnosis was 32 months; 1, 2, 3 and 5
physicists involved in the trial in each centre. Issuing year overall survivals were 82%, 61%, 40% and
QA guidelines is helpful to centres that may have to 18% respectively. Variables governing survival were
change their routine procedures to adhere to the trial analyzed using Log rank test. Statistically signiÀcant
protocol. prognostic features were stage (p=0.019) and prior
Keywords: Quality Assurance, Radiotherapy, chemotherapy (p=0.02) but not age, performance
CONVERT, Small cell lung cancer status, histology or PET staging.
Conclusion: This 4 week fractionated schedule is a
widely used radical radiotherapy regime in the UK.
Poster Session 1 – Radiotherapy Monday, 4 July 2011 12:15-14:15 This retrospective analysis reinforces other series4
in showing the treatment to be well tolerated with a
P1.168 ACCELERATED low toxicity rates and a promising median survival
HYPOFRACTIONATED RADIOTHERAPY of 32 months. There is a need for phase 3 studies
(RT) FOR NON-SMALL CELL LUNG to compare chemo-radiotherapy schedules using
CANCER (NSCLC): A SINGLE CENTRE this schedule with those that are conventionally
AUDIT OF OUTCOME USING 55GY IN 20 fractionated. Ref. 1. Price A. Results of a survey of
DAILY FRACTIONS. UK clinical oncologists. Presented at the Medical
Satya Garikipati1, Dev Srinivasan1, Nathaniel L. Research Council; 2001 2. Price A. et.al J Thoracic
Hatton1, Caroline Lee1, Patricia M. Fisher1, Jayaram Oncol2009:4(9) S587 3. Maguire J et.al. J Thoracic
Mohanamurali1, Matthew Hatton2 Oncol 2010;5(12):S558 3. Din O et.al J Thoracic
1
Clinical Oncology, Weston Park Hospital/United Oncol2009:4(9) S960
Keywords: NSCLC, Acclerated Radiotherapy Glc/tCr, Glx/tCr, Lac/tCr, Lip/tCr. The absolute
metabolite concentrations and metabolite ratios were
paired according to the examinations schedule and
Poster Session 1 – Radiotherapy Monday, 4 July 2011 12:15-14:15 subjected to the Wilcoxon matched pair test: exam.1
vs. exam.2, exam.1 vs. exam.3 and exam.2 vs.
P1.169 COMPARISON OF THE 1H exam.3. The analyses were performed separately for
MAGNETIC RESONANCE IN VIVO frontal and occipital VOIs.
SPECTROSCOPY (MRS) BEFORE AND Results: The Wilcoxon test showed no statistically
AFTER PROPHYLACTIC CRANIAL signiÀcant differences in the occipital NAWM
IRRADIATION IN PATIENTS WITH while in the frontal NAWM statistically signiÀcant
NSCLC. differences are observed only between exam.1
âukasz Boguszewicz1, Marzena T. Gawkowska- vs. exam.2 for both the metabolite absolute
Suwiĸska2, Maria Sokóã1, Anna Cichoĸ1, Blamek concentrations and ratios. These differences concern
Sãawomir1, Aleksander Zajusz1 the tCr (p = 0.027709), Lac (p = 0.017961) and Glc
1
Maria Skãadowska-curie Memorial Cancer Center (p = 0.0464) as well as Lac/NAA (p = 0.027993),
And Institute Of Oncology, Gliwice Branch/Poland, Lac/tCr (p = 0.017961) and Lip/tCr (p = 0.042523).
2
Iii Department Of Radiotherapy/ Department Of The prominent increase of Lac concentration as
Brachyteraphy, Maria Skãadowska-curie Memorial well as Lac/NAA and Lac/tCr ratios observed up till
Cancer Center And Institute Of Oncology, Gliwice 30 days after PCI could be explained by radiation
Branch/Poland damage leading to impaired lactate washout due
to post-irradiation edema, increase of lactate
Background: The 1H magnetic resonance in vivo concentration caused by radiation-induced cell-kill or
spectroscopy (MRS) is a versatile and powerful tool by disturbed glucose metabolism. Similarly, increase
for noninvasive investigation of tissue metabolism. in Lip/tCr ratio could be explained by disintegration
The high usefulness of this technique has been of cell membranes by ionization. Both Lac/tCr and
proved in many types of central nervous system Lip/tCr ratios reach the highest level immediately
diseases as well as in monitoring treatment effects. after irradiation (less than 30 days) and vary in a
Methods: The studied group consisted of ten wide range among individual patients.
patients (aged 42 – 73, median 53) whose underwent Conclusion: PCI induces alterations in brain
prophylactic cranial irradiation (PCI) as part of tissue metabolism visible in period less than 30
radical treatment for non small cell lung (NSCLC) days after irradiation. Both the metabolite absolute
cancer (the subgroup of patients from clinical trial concentrations and the ratios tend to normalize after
evaluated toxicity of PCI). The examined patients 90 days post treatment.
were treated with radical radiotherapy or chemo- Keywords: spectroscopy, prophylactic cranial
radiotherapy for locally advanced NSCLC. The irradiation
patients received 30 Gy in 15 fractions to the
whole brain. The patients were scheduled to three
consecutive spectroscopic examinations: before Poster Session 1 – Radiotherapy Monday, 4 July 2011 12:15-14:15
the PCI (exam.1), up till one month after PCI
(exam.2) and three months after PCI (exam.3). The P1.170 18F-FDG PET/CT SIMULATION IN
44 1H in vivo NMR spectra were acquired with the AN ALREADY PET/CT STAGED NSCLC
whole-body MRI/MRS 2T system operating at the PATIENTS. THE IMPACT ON INTER-
proton resonance frequency of 81.3 MHz during OBSERVER VARIATION AND NORMAL
the routine NMR examinations. For each patient TISSUE DOSE ESTIMATES.
the VOIs of 1.5x1.5x1.5 cm3 were located in left Gerard G. Hanna1, Kathryn J. Carson2, Jonathan
frontal and occipital normal-appearing white matter Mcaleese1, Viv P. Cosgrove3, Ruth L. Eakin1, David
(NAWM). The absolute concentrations of the main P. Stewart1, Ashraf Zatari4, Joe M. O’sullivan5, Alan
brain metabolites (NAA, Cho, mI, tCr, Glc, Glx, R. Hounsell4
1
Lac and Lip) were calculated as described in (5). Clinical Oncology, Cancer Centre, Belfast City
The metabolite concentrations were additionally Hospital/United Kingdom, 2Nuclear Medicine, Royal
presented as the following ratios: NAA/tCr, Cho/ Victoria Hospital, Belfast Health And Social Care
tCr, Cho/NAA, mI/tCr, Lac/NAA, Lip/NAA, Trust/United Kingdom, 3Department Of Medical
Physics, St James Institute Of Oncology, St James subgroup of those with atelectasis the mean PTVCT
University Hosptial, Leeds./United Kingdom, was 0.68 and was signiÀcantly improved to 0.78
4
Medical Physics, Cancer Centre, Belfast City when comparing PTVPET/CT (WSRT p=0.005). In all
Hospital/United Kingdom, 5Clinical Oncology, patients there was a signiÀcant reduction from the
Centre For Cancer Research And Cell Biology, median V20 based on the PTVCT (V20=19.3) to the
Queen’s University Of Belfast/United Kingdom V20 using the PTVPET/CT plan (V20=16.2, p<0.001).
In those with atelectasis a similar improvement
Background: In the treatment of NSCLC with was seen (PTVCT based V20=22.1, PTVPET/CT based
radiotherapy (RT) 18F-FDG PET/CT has been shown V20=19.7, p=0.005).
to reduce target volumes and normal tissue dose Conclusion: TV delineation based on PET/CT
estimates when used in the radiotherapy treatment simulation reduces mean lung dose estimates and
planning (RTP) process. This is particularly evident reduces interobserver variation, particularly in those
in those patients with atelectasis. However, this may patients with atelectasis. The potential reduction in
be due to improved baseline tumor staging as distinct lung dose estimates may permit RT dose escalation
from the impact that PET/CT may have at RTP in future clinical investigations. In addition to PET/
simulation. The impact of PET/CT simulation on CT staging, PET/CT RTP simulation may be of most
PTV volumes and normal lung tissue dose estimates beneÀt in those patients with atelectasis.
in a cohort of patients already PET/CT staged is Keywords: NSCLC, PET/CT, Target Volume
reported. Delineation, Radiotherapy
Methods: RTP PET/CT scans were performed on
28 already PET/CT staged NSCLC patients (stage
IA to IIIB; 14 received induction chemotherapy). Poster Session 1 – Radiotherapy Monday, 4 July 2011 12:15-14:15
In place of a RTP CT scan, patients were scanned
on a PET/CT scanner. In a virtual planning study P1.171 CLINICAL SIGNIFICANCE OF
4 radiation oncologists independently delineated PROGNOSTIC SCORES LUNG CANCER
the GTV on the CT (GTVCT) alone, and then on PATIENTS WITH BRAIN METASTASIS
PET/CT (GTVPET/CT). PTV were obtained using WHO TREATED WITH GAMMA-KNIFE
standardized expansion margins with no respiratory RADIOSURGERY
compensation. Dosimetry plans were generated Min Ki Lee1, Young Dae Kim2, Hosuk Lee2, Mi
following standard department procedures. The Hyun Kim2
1
mean percentage volume change (MPVC) from Internal Medicine, Pusan National University
the CT PTV (PTVCT) to the PET/CT PTV (PTVPET/ Hospital/Korea, 2Pusan National University
CT
) for each case was calculated for all patients Hospital/Korea
and for those with atelectasis alone. Interobserver
variation was assessed using the concordance index Background: Patients with lung cancer have a
(CI) and normal lung tissue dose estimates were high risk for development of brain metastases. And
calculated using the percentage volume of normal optimal treatment is very important for improving
lung receiving 20 Gy (V20). The Wilcoxin signed survival rate with patients who have brain metastasis.
ranks test (WSRT) was used for paired samples The purpose of this study was to analyze prognostic
comparison and the Mann-Whitney U (WHU) in scores in a population of lung cancer patients who
independent samples comparison. undergone gamma-knife radiosurgery.
Results: For all patients the median of the MPVC Methods: We anayzed 147 patients with brain
from PTVCT to PTVPET/CT was -2.3%. The MPVC metastases from lung cancer who treated with
from PTVCT to PTVPET/CT was -5.0% in those gamma knife radiosurgery (GKRS) to compare
with atelectasis (n=10) and was 4.3% with no prognostic scores for overall survival. Four available
atelectasis (WHU p=0.084). Assessing the impact scores for brain metastases were evaluated in
on interobserver variation, for all patients the patient with lung cancer group after gamma knife
mean GTVCT CI was 0.55 signiÀcantly improved radiosurgery.
to 0.59 for the mean GTVPET/CT (p=0.001). The We carried out a retrospective study through review
PTVCT CI was 0.74 and this improved to 0.78 of medical record to determine prognostic factors
comparing PTVPET/CT but this difference failed to and prognostic scores. Reviewed prognostic factors
reach signiÀcance (WSRT p=0.08). However in the are age, Karnofsky performance status, extracranial
metastases status, systemic disease status, number synchronous metastases and 30 patients had
of brain metastases and largest brain lesion metachronous metastases. As primary, 27 patients
volume. Calculated prognostic scores are recursive had a colorectal tumor and 13 patients a lung
partitioning analysis classiÀcation (RPA), score cancer. The rest was scored as other. Depending
index for stereotatic radiosurgery in brain metastases on tumor size and location, different treatment
(SIR), basic score for brain metastases (BSBM) and schedules were used. Thirty eight tumors were
graded prognostic assessment (GPA) score. treated with a total dose of 60 Gy (20 Gy/fr), 22
Results: The median age is 64.5 years (28-85years) with a single dose of 30 Gy, 8 with a total dose of
and small cell lung cancer, non-small cell lung 60 Gy (12 Gy/fr), 6 with a total dose of 50 Gy (10
cancer and patients not performed biopsy are Gy/fr), 6 with a total dose of 45 Gy (15 Gy/fr), 6
respectively 22 patients, 117 patients, 8 patients. with a total dose of 48 Gy (8 Gy/fr), 4 with a total
Using the Cox model analysis of survival, clinical dose of 56 Gy (8 Gy/fr) and 3 with a total dose of
signiÀcance was observed for RPA, SIR, BSBM and 45 Gy (9 Gy/fr). PTV = GTV + 5 mm. The dose to
GPA (, p=0.047, p=0.001, p=0.015 and p=0.033, the PTV was prescribed to the 70-90% isodose line.
respectively). The median follow up was 18 months (range, 1-53).
Conclusion: All fourl scores are achieved statistical The median age was 67 years old (range: 34-86).
signiÀcance in prediction of overall survival in brain Results: The 3-years overall survival for the whole
metastases patients from lung cancer underwent group was 42%. A signiÀcant better survival was
gamma-knife radiosurgery.The SIR score revealed found for patients with a central tumor compared to
as most superior accuracy and applicability among patients with peripheral tumor(s) (p=0.04, 3-years
studied scores. overall survival of 64% vs. 24%). The 3 years
Keyword: lung cancer, brain metastasis, prognosis overall survival for patients with synchronous
metastases was 45% compared to 42% for patients
A revised/updated abstract may be included in with metachronous metastases. The 3-years overall
the Late Breaking Abstract Supplement, available survival for the lung cancer patients was 38%, for
at the 14th World Conference on Lung Cancer. a colorectal patients 42% and for the remaining
patients 54%. The 2-years local control for a total
dose of 50 Gy or more was 83% compared to
Poster Session 1 – Radiotherapy Monday, 4 July 2011 12:15-14:15 46% with doses lower than 50 Gy (p=0.0001).
Thirty eight peripheral tumors treated with a total
P1.172 CENTRAL AND PERIPHERAL dose of 60 Gy in 3 fractions had a actuarial local
LUNG METASTASES TREATED control at 2 years of 84% compared to 57% from
WITH REAL-TIME TUMOR 22 peripheral tumors treated with a single dose of
TRACKING DURING STEREOTACTIC 30 Gy (p=0.01). Central tumors had a 2-years local
RADIOTHERAPY: A 5 YEARS control of 63%. Side effects were low, also in the
EXPERIENCE group of patients with central tumors.
Joost J. Nuyttens, Noelle Van Der Voort Van Zijp, Conclusion: Patients with a central solitary or
Mischa Hoogeman oligometastases should be treated because a 3-years
Radiotherapy, Erasmus MC-Daniel Den Hoed overall survival of 64% was found. Patients with
Cancer Center/Netherlands synchronous or metachronous lung metastases
had an almost equal 3-years overall survival of
Background: To report local recurrence rate and 45%. Real-time tumor tracking for lung metastases
survival of 56 patients with 93 solitary metastases treated with a total dose of 50 Gy or more resulted
or oligometases treated with the CyberKnife. in a 2-years local control of 83%. Central tumors
Methods: Fifty six patients had 93 metastases: 69 had a 2-years local control of 69%.
peripheral tumors and 24 central tumors. Central
tumors were deÀned as tumors <2 cm from the
trachea, main stembronchus, or oesophagus or
as tumors <6 mm from the heart or if they were
located in the mediastinum. Of the 93 metastases,
76 tumors were smaller than 3 cm and 17 larger
(range 5-52 mm). Twenty four patients had
Direction Within Tolerance n (%) Out of Tolerance n (%)

Poster Session 1 – Radiotherapy Monday, 4 July 2011 12:15-14:15
Right-Left 4 (8.7%) 5 (45.5%)
Superior-Inferior 5 (15.2%) 14 (58.3%)
P1.173 PATIENT POSITIONING DURING Anterior-Posterior 7 (16.7%) 9 (64.3%)
AND AFTER STEREOTACTIC BODY
RADIOTHERAPY (SBRT) FOR NON- Conclusion: CBCT successfully improves tumour
SMALL CELL LUNG CANCER (NSCLC) positioning to within acceptable tolerance. It is noted
USING CONE-BEAM COMPUTED that the post-treatment localisation errors are higher.
TOMOGRAPHY (CBCT) This could be a reÁection of long-treatment duration,
Asad Qureshi, Simon Hughes, David Landau, Clare which could be reduced with arc therapy IMRT. In a
Hartill, Keely Barnett, Kate Wildermuth, Alison minority of patients the end of treatment CBCT was
Gammie, Shahreen Ahmad out of tolerance. Those out of tolerance at the end
Clinical Oncology, Guy’s And St Thomas’ NHS of treatment are more likely to be out of tolerance
Foundation Trust/United Kingdom mid-treatment. If localisation errors are observed
mid-treatment, it may be necessary to increase
Background: Many centres performing SBRT use the number of mid-treatment CBCTs to maintain
CBCT to determine localisation errors and to perform positioning accuracy.
on-line corrections. We evaluated our localisation Keywords: SBRT, CBCT, Non-small cell lung
errors to investigate emerging patterns relating to cancer, Radiotherapy
tumour position or other variables and therefore
predict the need for further CBCTs/patient. This may
enable customisation of radiotherapy planning and Poster Session 1 – Radiotherapy Monday, 4 July 2011 12:15-14:15
delivery to the individual patient.
Methods: 14 patients received SBRT (3-5 fractions) P1.174 IMAGE GUIDED RADIOTHERAPY
for NSCLC. Immobilisation and positioning was (IGRT): ADAPTATION OF INTRA-
achieved with a custom thoracic board. A vacuum bag THORACIC ANATOMICAL CHANGES
was used on the majority of patients. Our protocol is VISUALIZED ON CONE BEAM CT FOR
to perform CBCT scans at set-up and mid-treatment LUNG CANCER PATIENTS DURING THE
with matching performed against the tumour. In COURSE OF IRRADIATION
addition a post-treatment CBCT was performed Maddalena M.G. Rossi1, José Belderbos2, Sanne
on completion of each fraction to study tumour Conijn1, Eva Schaake1, Joost Knegjens1, Peter
localisation and intrafraction motion. The couch Remeijer1, Jan Jakob Sonke1
1
position was adjusted when positional discrepancies Radiation Oncology, The Netherlands Cancer
exceeded 2mm in any direction. Any adjustments to Institute - Antoni Van Leeuwenhoek Hospital/
couch position were veriÀed with a repeat CBCT. All Netherlands, 2Department Of Radiation Oncology,
localisation errors were collected prospectively. The Netherlands Cancer Institute - Antoni Van
Results: A total of 248 CBCT scans were performed Leeuwenhoek Hospital/Netherlands
for 64 fractions of treatment. CBCT data suggests
that the average magnitude of initial set-up errors Background: Image guided radiotherapy (IGRT)
were reduced from 2.6mm (Right-Left), 3.9mm using cone-beam CT (CBCT) images of the
(Superior-Inferior) and 2.3mm (Anterior-Posterior) patient is widely applied in setup correction
to 1.0mm (R-L), 1.6mm (S-I) and 1.1mm (A-P). At protocols for stage III lung cancer. However
the mid-treatment point errors were reduced from these protocols do not take into account more
1.3mm (R-L) and 1.6mm (A-P) to 1.1mm (R-L) complex geometrical uncertainties which may
and 1.3mm (A-P). The error in the S-I direction result from multidimensional intra-thoracic
remained 1.8mm. At the end of treatment the average anatomical changes. Inadequate response to these
positional discrepancy was 1.5mm (R-L), 2.2mm changes could result in geographical misses
(S-I) and 1.7mm (A-P). Table showing the number which ultimately inÁuence the efÀcacy of the
of scans (n) out of tolerance (>2mm) at the mid- radiotherapy treatment. For example, in large and
treatment point separated into those who were within centrally located tumors atelectasis (progression
tolerance and those out of tolerance on the post- or resolvement) may cause displacements of
treatment scan. mediastinal structures resulting in shifts in tumour
position. Repetitive imaging of the patient during
treatment provides volumetric information on

intra-thoracic anatomy in addition to measuring the
position of the tumor necessary for accurate dose
delivery. This minimizes discrepancies between
treatment planning and delivery and provides
unique anatomical information which may result
in adaptive re-planning to account for the changes
observed. The purpose of this study was to evaluate
these changes and the frequency of adaptive
replanning using IGRT.
Methods: In this study, 180 consecutive lung
cancer patients (T1-4N0-3), treated with curative
intent between January 2010 to November 2010 Keywords: NSCLC, Anatomical changes,
were retrospectively analyzed. These patients were Conebeam CT scan
treated with or without concurrent chemotherapy
and Intensity Modulated Radiotherapy (IMRT) to
a dose of 66Gy (24x2.75Gy), or 51Gy (17x3Gy). Poster Session 1 – Radiotherapy Monday, 4 July 2011 12:15-14:15
Patients received repetitive 3D/4DCBCT for
setup veriÀcation using our clinical off-line setup P1.175 FEASIBILITY AND EARLY
correction procedure. The occurrence or resolving OUTCOMES OF STEREOTACTIC
of atelectasis, pleural effusion and other anatomical BODY RADIOTHERAPY IN EARLY
changes within the thorax were scored qualitatively LUNG CANCER AT THREE CANCER
together with the frequency of adaptive re-planning. CENTRES; ST. JAMES’S INSTITUTE
Results: In 83 (45%) of the 180 patients evaluated, OF ONCOLOGY, CLATTERBRIDGE
intra-thoracic anatomical changes were visually CANCER CENTRE AND JAMES COOK
detected on these CBCTs. Changes affecting the UNIVERSITY HOSPITAL (PART OF THE
position of tumour and/or lymph nodes were UK SBRT CONSORTIUM)
observed in 12% with 6% requiring a re-scan and Vicky Sangha1, Robin Prestwich1, John Lilley1, Alan
re-plan as the tumour and/or lymph nodes were no Needham1, Michael J. Flatley1, Michael P. Snee2,
longer fully within the treatment beam. In 2% of Clive Peedell3, Neil Richmond3, James Green3,
patients adaptation of the registration method due Angela Baker4, Alison Scott4, Pooja Jain4, Matthew
to tumour shrinkage was necessary.Minor changes Hatton5, Kevin N. Franks1
1
such as slight increases/decreases of atectelasis or St James’s Institute Of Oncology/United Kingdom,
2
pleural effusion were observed in 27% of patients Department Of Clinical Oncology, St James’s
without considerable displacement of the centre of Institute Of Oncology/United Kingdom, 3James Cook
mass of the tumour. University Hospital/United Kingdom, 4Clatterbridge
Conclusion: Image guided radiotherapy increased Centre Of Oncology/United Kingdom, 5Dept Of
the precision of radiotherapy in lung cancer patients Clinical Oncology, Weston Park Hospital/United
because of frequently seen intra-thoracic changes Kingdom
requiring radiotherapy treatment adaptation or
even re-planning. Volumetric information is Background: There is now good non-randomised
provided using IGRT which not only increases the evidence suggesting that SBRT is superior to
geometrical accuracy in patient alignment but also conventional radiotherapy with local control rates of
facilitates easy monitoring of anatomical changes over 80-90% being achieved with minimal toxicity.
resulting in a reduction of geographical misses Therefore, the UK SBRT Consortium was created to
which ultimately affect treatment outcome. develop SBRT in the UK. The UK SBRT Consortium
includes > 30 UK centres and with its Àrst guidelines
issued in April 2009. These guidelines provide
standard dose/fractionation regimes, radiotherapy
Q/A requirements and recommendations for data
collection. The Consortium aims to develop SBRT
across the UK and promote novel research.
Methods: We analysed patients treated with SBRT Poster Session 1 – Radiotherapy Monday, 4 July 2011 12:15-14:15
for early stage NSCLC (May 2009 and December
2010). The eligibility criteria were; peripheral early P1.176 PRELIMINARY RESULTS OF A
stage NSCLC (<5cm) which were either histologically PET BOOST TRIAL : A RANDOMIZED
conÀrmed or evidence of PET positivity and serial PHASE II DOSE-ESCALATION TRIAL
growth, medically inoperable due to comorbidities IN ADVANCED NSCLC WITH AN
and no cut off for lung function. Radiotherapy INTEGRATED BOOST TO THE PRIMARY
was planned with 4DCT or multiple helical CTs TUMOR OR TO THE HIGH FDG-UPTAKE
and a typical plan was generated using a 7-9 Àeld REGION WITHIN THE TUMOR
class solution and then optimised. All patients had José Belderbos1, Wouter Van Elmpt2, Eugène
image-guided RT with cone beam CT. Standard Damen1, Wouter Vogel1, Michel Öllers2, Harm Van
dose prescriptions were 54Gy in 3 fractions(#) (for Tinteren3, Jan Jakob Sonke1, J A. Burgers4, Anne-
peripheral lesions not close to ribs), 55Gy in 5# (when Marie C. Dingemans5, Dirk De Ruysscher6
1
the PTV overlapped the chest wall) or 60y in 8# Department Of Radiation Oncology, The
(patients previously treated with radiotherapy/or too Netherlands Cancer Institute - Antoni Van
close to pericardium) on alternate days, prescribed to Leeuwenhoek Hospital/Netherlands, 2Radiation
the isodose covering the PTV (typically~80%). Oncology, MAASTRO Clinic, Grow - School For
Results: 102 patients, mean age 74±9.2 SD, were Oncology And Developmental Biology, Maastricht
treated. Median follow-up is 6 months (range 1-20). University Medical Centre/Netherlands, 3Department
From the available data the T stage was T1(65pts), Of Biostatistics, The Netherlands Cancer Institute
20 had T1 and T2(20pts), T3(3) and T4(3) of which - Antoni Van Leeuwenhoek Hospital, Amsterdam,/
68 were deemed medically inoperable and 6 patients Netherlands, 4Thoracic Oncology, The Netherlands
refused surgery. The mean tumour size was 2.3cm Cancer Institute/Netherlands, 5Department Of
(range 0.8-4.7cm). For those with available data Pulmonology, Grow - School For Oncology And
the patients’ WHO PS was 1(45pts), 2(39pts) and Developmental Biology, Maastricht University
3(10pts). Mean FEV1 was 54% and DLCO 44%. Medical Centre/Netherlands, 6Radiation Oncology,
20pts received 54Gy/3#, 2pts 55Gy/3#, 74 pts MAASTRO Clinic/Netherlands
55Gy/5#, 1pt 52Gy/8#, 1pt 2 treatments of 55Gy/5#
for bilateral tumours, 3pts 60Gy/8# and 1pt 31Gy/3# Background: Purpose/Objective: In NSCLC patients
prior to early treatment cessation due to anxiety. optimizing loco-regional control is a necessity to
Grade 3 breathlessness occurred in 2 patients during improve treatment outcome. We initiated a multicenter
treatment, 10 patients had Grade 2 pneumonitis at 3 randomized phase II PET Boost Trial (NCT01024829)
months and one patient had Grade 4 hypoxia which trial on dose-escalation for advanced NSCLC patients
probably contributed to their death (G5). 1 local using Intensity Modulated Radiotherapy (IMRT).
recurrence; 3 patients regional recurrences; 3 regional Patients receive accelerated radiotherapy (66 Gy in
and distant metastases and 5 distant metastases alone. 24 fractions of 2.75 Gy) to the primary tumor and
12 patients (11.8%) relapsed. 20 (19.6%) patients involved lymph nodes with an integrated boost to the
have died - 3 from unrelated causes, 1 from Grade whole primary tumour (arm A) or the region within
5 hypoxia, 2 from probable COPD exacerbations, 6 the primary tumour with an FDG-uptake >50% of
unknown and 9 patients from progression (9%). the maximum SUV (arm B). Both treatment arms
Conclusion: The formatiation of the UK SBRT A and B are normalized (forced isotoxic mean lung
Consortium and subsequent guidelines has allowed dose (MLD)) to each other by performing dual arm
SBRT to be introduced in a controlled and safe treatment planning for every patient.
manner into the UK. At present 5 UK centres now Methods: The primary objective of this study is to
offfer SBRT with 10 expected by the end of the select the treatment arm with the most favourable
year. Our results conÀrm that SBRT appears to be local progression-free survival (LPFS) at 1 year.
well tolerated with low rates of acute toxicity and Based on an expected increase of local progression-
high rates of local control. The UK SBRT also aims free survival at 1 year of 15% (from 70 to 85 %)
to promote reseach with the proposed Surgery or a total of 53 patients per treatment arm will be
SBRT (SOS) trial in patients considered high risk for randomized. Secondary objectives are toxicity as
surgery and expand into other cancer sites. a function of radiotherapy dose and volume of the
Keyword: SBRT, early lung cancer, outcomes tissues irradiated, overall survival and quality of life.
Eligibility criteria are stage III or inoperable stage II Methods: From January 2004 to June 2009 17
NSCLC patients treated with or without concurrent patients (15 males 2 female; mean age 73 years) with
or sequential chemotherapy, WHO 0-2. Patients early Stage lung cancer (13 IA and 4 IB according to
are randomized if an integrated boost of 3 Gy per TNM 7th edition) underwent SBRT at our Institution
fraction (72 Gy total dose) to the entire primary tumor at average of 10 years (range 2-28 years) after lung
fulÀls the criteria of the organs at risk. The biological surgery (4 pneumonectomy, 13 lobectomy). In 13
corrected dose-constraint to lung is: MLD20 Gy. patients a histological diagnosis was not available due
Other dose-constraints: esophagus (V35<80%), to the high risk of complications. In this subgroup the
spinal cord (max. 52 Gy), brachial plexus (max. 66 lung nodules were considered malignant if increased
Gy), heart (mean dose<46 Gy) and the mediastinal in diameter at two CT-scans and positive at PET-
structures (max. 94 Gy). All constraints are in scan (clinical proof of malignancy). All patients had
biologically equivalent dose (EQD2). peripheral tumors (located more than 2 cm away from
Results: On February 1, 2011, 15 eligible patients airways or more than 1 cm away from major blood
were registered. Twelve patients were randomized vessels) and median disease volume was 5 cc (GTV).
and completed the 24 fractions. Median prescribed All patients underwent 4-dimensional computed
fraction dose for arm A 3.14 Gy and arm B 3.49 tomography (4D-CT) scans for SBRT target volume
Gy. Mean PTV dose delivered in 24 fractions to the deÀnition. Three fractions of 15 Gy were delivered
entire primary tumor were comparable: a median of during 1 week. Dose-constraints to organs at risk
74.3 Gy and 75.0 Gy for arm-A and B, respectively. damage were as follows: mean lung dose ipsilateral
Nine patients received concurrent chemotherapy and lung (MLD) < 15 Gy, spinal cord < 18 Gy, chest
for six patients no chemotherapy was prescribed. wall < 30 Gy; radiation doses were prescribed to the
Treatment toxicity was according to expectations. 80%-isodose encompassing PTV (Internal Target
Dysphagia was the most common side effect; with Volume plus 5 millimeter), with normalization to
30% grade 3 according to CTCAE v 4.0 and 15% 100% at the isocenter. SBRT was delivered with an
dyspnoe grade 3. No unexpected toxicities were Elekta Precise® Linear Accelerator, using 6-8 static
observed. One patient died shortly after the end of non-opposing, non-coplanar shaped Àelds, with 6-10
treatment due to a gastrointestinal bleeding during MV photons. Follow-up CT scans were obtained at 3
hospitalization for a myocardial infarction. months after SBRT for the Àrst 2 years, 6 months for
Conclusion: The PET Boost Trial, a randomized phase II the other 3 years, and then annually .
trial on dose-escalation for advanced NSCLC patients with Results: Median follow-up was 29 months. The
a boost to the primary tumor or a boost to the high FDG- SBRT was well tolerated, without any acute clinical
uptake region within the tumor, is ongoing and accruing toxicities; Àve patients developed a RTOG grade 2
well. Esophageal toxicity is severe, but manageable. radiological pulmonary late toxicities (over 90 days
Keywords: NSCLC, Radiotherapy, FDG PET, imrt after SBRT), without impaired pulmonary function.
No local failures were observed. Overall survival rate
was at 1 years was 94% and at 3 years 65%. The 1 and
Poster Session 1 – Radiotherapy Monday, 4 July 2011 12:15-14:15 3-years disease-free survival rates were respectively
82% and 59% with majority of events represented
P1.177 STEREOTACTIC RADIOTHERAPY by systemic failure (3 patients), one patient died for
FOR STAGE I LUNG CANCER AFTER haematological disease and one for cardiovascular
PREVIOUS LUNG RESECTION complication not related to radiation therapy.
Niccolò Giaj Levra, Alessia Silvia Guarneri, Conclusion: SBRT was a safe and well tolerated
Andrea Riccardo Filippi, Riccardo Ragona, Cristina treatment for patients with secondary Stage I lung
Mantovani, Umberto Ricardi tumors after previous thoracic surgery for NSCLC.
Department Of Medical And Surgical Sciences, Survival rates in this subgroup were similar to SBRT
Radiation Oncology Unit/Italy outcomes in previously untreated patients.
Keywords: Surgery, Radiotherapy, Lung cancer,
Background: Lung resection of new primary lung Early Stage
cancer after previous thoracic surgery is associated
with a high risk of complications. We retrospectively A revised/updated abstract may be included in
analyzed efÀcacy and tolerance of stereotactic body the Late Breaking Abstract Supplement, available
radiation therapy (SBRT) in this subgroup of patients. at the 14th World Conference on Lung Cancer.
VOICT VOIPET
Poster Session 1 – Radiotherapy Monday, 4 July 2011 12:15-14:15
OBS1 0.82 0.87
OBS2 0.76 0.86
P1.178 PRECISION AND ACCURACY
OBS3 0.82 0.85
IN LUNG CANCER GROSS TUMOR OBS4 0.75 0.82
VOLUME DEFINITION ON CT OR CT- OBS5 0.83 0.87
PET: AN INTEROBSERVER STUDY OVERALL 0.79 0.86
Anna Delana1, Andrea Bolner2, Elena Magri2, Nicola
Nagliati2, Mariangela La Macchia3, Loris Menegotti1, Table1 Student t-test performed on VOICT and VOIPET
Luigi Tomio2, Valentina Vanoni2 estimate a p-value of 0.01, which is considered
1
Physics, S. Chiara/Italy, 2Radiotherapy, S. Chiara signiÀcant.
Hospital/Italy, 3Radiotherapy, Atrep/Italy Conclusion: Despite the uncertain due to the
qualitatively contours obtained on CT-PET, that we
Background: The use of CT-PET imaging in correct with a quite large CTV margin, the precision
deÀnition of target is nowadays routinely used. The in GTV lung contouring on PET is comparable
porpuose of this study is to determine the precision with the precision in CT lung cancer contouring.
and accuracy in lung cancer contouring on CT However, the analysis performed on the volume
(GTVCT) or on CT-PET (GTVPET). overlapping index, VOICT and VOIPET, demonstrate
Methods: Five trained physicians determined GTVCT that GTV localization is signiÀcantly different
and GTVPET of 10 patients (pts) with lung tumour. between the two imaging modalities. We conclude
Three pts were affected by small cell carcinoma that PET imaging improve the accuracy in lung
limited disease (without lymph nodes involved), cancer deÀnition.
5 pts by a non small cell carcinoma early stage Keywords: CT-PET, Target deÀnition, Interobserver
(without lymph nodes involved) and 2 pts by a single Variability
lung metastasis. Two patients had atelectasys due
to the tumor. CT-PET was acquired in treatment A revised/updated abstract may be included in
position and fused with CT on Pinnacle TPS; the Late Breaking Abstract Supplement, available
GTVPET was determined qualitatively without using at the 14th World Conference on Lung Cancer.
any Standard Upteke Value (SUV). To measure the
precision in GTV lung deÀnition on PET and CT,
the calculation of the coefÀcient of variation (COVCT Poster Session 1 – Radiotherapy Monday, 4 July 2011 12:15-14:15
and COVPET) was performed: COV=s/m where s
and m are the standard deviation and mean value P1.179 MEDIASTINAL RECURRENCE
of GTVCT and GTVPET contoured for each patient AS THE SITE OF FIRST FAILURE FOR
from the 5 observers. COV measure the dispersion STAGE I NON-SMALL CELL LUNG
of GTVCT and GTVPET, between observers. To CANCER PATIENTS TREATED WITH
evaluate the accuracy in GTV lung contouring, the RADIOTHERAPY
volume overlapping index (VOICT and VOIPET) was Ryan Hogg1, Tsz Kin Lee2, Robert Macrae2, Scott A.
calculated. VOI consider the positional variability Laurie3, Jason R. Pantarotto2
1
of GTVCT and GTVPET, between observers: Faculty Of Medicine, University Of Ottawa/Canada,
2
VOI=2*(V1ÇV2)/ (V1+V2) where V1 and V1 are Radiation Oncology, The Ottawa Hospital Cancer
deÀned by two different observers. All combination Centre, University Of Ottawa/Canada, 3Medical
between the observers where considered. To Oncology, The Ottawa Hospital Cancer Centre,
determine statistical signiÀcance of the difference University Of Ottawa/Canada
between VOICT and VOIPET, Student t-test was
performed, with a p-value of 0.05 considered to be Background: A signiÀcant proportion of stage I
signiÀcant. non-small cell lung cancer (NSCLC) patients are
Results: Mean coefÀcient of variation for GTVCT is deemed inoperable and offered radiotherapy (RT) as
0.15 (SD 0.11) and for GTVPET 0.16 (SD 0.10). Mean an alternative curative treatment. Mediastinal staging
VOICT and VOIPET for the two imaging modalities for these patients is often less robust compared to
contoured by all the observers are summarized in the their surgical counterparts, implying a higher risk
table1: of inadvertently treating Stage II or III disease
inappropriately. This study is a single-institution
retrospective analysis of the nodal failure rate in Poster Session 1 – Radiotherapy Monday, 4 July 2011 12:15-14:15
stage I patients and associated factors.
Methods: All stage I biopsy-proven NSCLC patients P1.180 PRECISE ACCOUNTING
treated with RT alone to a dose of >50 Gy from 2002 FOR UNCERTAINTIES OF TUMOR
to 2009 were identiÀed. Patients whose treatment LOCATION IN NSCLC ALLOWS
Àelds electively included the hilum or any part of the INCREASING TARGET RADIATION
mediastinum and those without at least one post-RT DOSE WITHOUT INCREASING DOSE TO
computed tomography (CT) scan for follow up were ORGANS AT RISK
excluded. With ethics approval, scans identifying Georgy Shakirin1, Marnix Witte2, Wouter Van
mediastinal failure were reviewed and when failure Elmpt3, Matthieu Bal4, Dirk De Ruysscher3, Marcel
was not conÀrmed histologically, the date of the Van Herk2, Philippe Lambin3
1
Àrst CT scan demonstrating growth of a mediastinal Bio-molecular Engineering, Philips Research/
or hilar lymph node post-RT was recorded as the Netherlands, 2Department Of Radiation Oncology,
date of nodal failure. Correlation with pre-RT The Netherlands Cancer Institute, Antoni Van
staging investigations such as mediastinoscopy, Leeuwenhoek Hospital (NKI-AVL)/Netherlands,
3
endobronchial biopsy (with or without ultrasound), Department Of Radiation Oncology (MAASTRO),
or positron emission tomography CT (PET-CT) was Grow-school For Oncology And Developmental
performed. Details regarding any salvage curative Biology, Maastricht University Medical Centre/
therapy were recorded. Netherlands, 4Philips Healthcare/Netherlands
Results: Of 744 identiÀed cases, data from the Àrst
149 eligible patients assessed thus far is presented. Background: There is a known dose response
In addition to diagnostic CT, pre-treatment staging curve in NSCLC treated by radiation. Target dose
investigations included mediastinoscopy (9%), escalation strategies based only on a maximum
endobronchial biopsy (2%) and PET-CT (42%). predeÀned “safe” dose to organs at risk (OAR) are
103 tumors were < 3cm in diameter and 59 were becoming standard in radiation therapy of NSCLC.
> 3cm. 35% of tumors were adenocarcinoma, The dose inside the target can be distributed
19% squamous cell and the remainder not uniformly (uniform escalation) or increased to
otherwise speciÀed. 112 patients were treated with preselected subvolume(s) of the target (dose
conventional RT (dose range 50-66Gy over 13-33 painting). For both strategies it is crucial to take
fractions) and 37 with stereotactic body RT (54-60 uncertainties of tumor location appearing during
Gy over 3-8 fractions). Nodal failure was observed planning and irradiation into account. A classical
in 12% of patients and as the Àrst site of failure in way to this is a margin approach, i.e., extending the
5% (7 of 149). Of these 7 patients: 5 failed within clinical tumor volume (CTV) to the planning tumor
6 months of treatment, 7 had tumors in peripheral volume (PTV). A probabilistic approach developed
location, 4 were T1a, 2 had pre-treatment PET-CT, and implemented at NKI-AVL tests a distribution
0 had invasive mediastinal staging. One patient was of possible CTV locations based on systematic and
treated with salvage chemoradiotherapy as the other random uncertainties in target location. The aim of
6 were deemed to have a poor performance status at this work is to compare margin and probabilistic
time of failure. approaches for the two dose escalation strategies
Conclusion: Despite a low rate of invasive mentioned above.
mediastinal staging, isolated nodal failure in stage Methods: Treatment plans were designed using a
I NSCLC patients treated with RT alone is rare. A research version of the Pinnacle treatment planning
negative PET-CT may be enough to proceed with system (Philips) extended with probabilistic tools
deÀnite treatment to the primary alone. Data from (NKI-AVL). Probabilistic plans accounting for
the entire cohort will be further analyzed to assess patient systematic (ƙ=0.29 cm) and random (Ʊ=0.3
any differences in the pre- versus post-PET-CT era. cm ) set-up errors were generated using constraints
Keywords: Non-small cell lung cancer, Mediastinal working for a conÀdence level of 90%. Systematic
recurrence, Radiotherapy, Stage I set-up errors were simulated by shifting target
volumes with respect to the dose. The random errors
A revised/updated abstract may be included in were simulated by dose blurring. Margin based
the Late Breaking Abstract Supplement, available treatment plans used a 8 mm CTV to PTV margin
at the 14th World Conference on Lung Cancer. that is adequate for the above mentioned errors.
Margin based and probabilistic plans were created Poster Session 1 – Radiotherapy Monday, 4 July 2011 12:15-14:15
for these two dose escalation strategies: a) non-
speciÀc uniform dose escalation to the target and P1.181 HIGH-DOSE-RATE
b) dose boosting to the area of 50 % and more of ENDOBRONCHIAL BRACHYTHERAPY
SUV maximum derived from an FDG PET scan. FOR NON SMALL CELL LUNG
All plans were normalized to the same mean lung CARCINOMA: LONG TERM RESULTS
dose to ensure an “isotoxic” approach. The Ànal OF A CURATIVE STRATEGY
dose distribution was tested using a standalone SoÀa Rivera, Laurent Quero, Pierre Maroun,
Monte Carlo evaluation tool (NKI-AVL) which Stéphanie Wong Hee Kam, Claude Maylin,
creates 10000 histories of possible target positions Christophe Hennequin
according to the given systematic and random Radiotherapy, Hôpital Saint Louis/France
errors. Endpoints were mean dose (Dmean), dose to
98% (D98%) and to 2% (D2%) of target volume. Background: High-dose-rate endobronchial
Results: 12 plans were evaluated (margin based brachytherapy (HDR-EBBT) is an effective palliative
and probabilistic plans for uniform and SUV based treatment for tumoral endobronchial obstruction with
dose escalation strategies for 3 patients). For two no risk of professional radiation exposure and very short
plans D98% was slightly less for probabilistic plans. treatment time. The purpose of this study is to evaluate
In all other cases probabilistic plans outperformed outcomes after HDR-EBBT for limited inoperable
corresponding margin based plans. For CTV, on endobronchial carcinoma treated with curative intent.
average, D98% was 0.81 Gy higher, D2% was 5.36 Gy Methods: we retrospectively reviewed 229 patients
higher, Dmean was 5.29 Gy higher for probabilistic with non small cell carcinoma treated with HDR-EBBT
plans. For volume of high SUV uptake, on average, between January 1990 and December 2009. Among
D98% was 3 Gy higer, D2% was 7.18 Gy higher, Dmean them 126 patients with no extrabronchial spread were
was 8.38 Gy higher for probabilistic plans. treated with curative intent. They presented local relapse
Conclusion: Dose escalation techniques beneÀt after surgery (40.6%) or external beam radiotherapy
from probabilistic planning. An increase in mean (25.5%), or early inoperable stage with respiratory
target dose is achieved both for uniform dose insufÀciency (33.9%). Treatment consisted of 6 fractions
escalation and dose painting techniques without of 5 or 7 Gy, prescribed at 1 cm from the source (192Ir).
increasing toxicity. Probabilistic planning is a Results: With a mean age of 62 years (range, 43-86) and
useful tool for designing treatment plans for dose- a majority of male (90.6%) and squamous cell carcinoma
escalation of lung tumors. This “software based” (95.3%) mean follow-up was 4 years. Complete
dose-escalation could lead to better outcome in endoscopic and histologic response rate, 3 months after
NSCLC. This research was supported by the Center HDR-EBBT was 81.2%. At 3 and 5 years, local control,
for Translational Molecular Medicine AIRFORCE overall survival and disease speciÀc survival rates were
project. M. van Herk and P. Lambin contributed 60.3% and 51.6%, 47.4% and 24%, 67.9% and 48.5%,
equally to this work. respectively. High tumor volume (length>2cm, bronchial
Keywords: probabilistic planning, Radiation obstruction>25%, tumor visibility on CT scan) and
Therapy, dose escalation, margin previous endoscopic treatment were associated with a
higher risk of local failure. Disease speciÀc survival, but
A revised/updated abstract may be included in not overall survival, was associated with local control.
the Late Breaking Abstract Supplement, available Toxicities included 1,6% grade 5 haemoptysis (within
at the 14th World Conference on Lung Cancer. less than 3 months after HDR-EBBT procedure), 2.4%
grade 5 bronchial necrosis, 3.8% grade 3 and 8.5% grade
2 radiation bronchitis.
Conclusion: This large retrospective study indicates
HDR-EBBT is an efÀcient potentially curative
therapeutic strategy with acceptable toxicity proÀle in
patients with inoperable endobronchial carcinoma.
Keywords: High-dose-rate endobronchial
brachytherapy, endobronchial carcinoma, Non small cell
lung carcinoma
Poster Session 1 – Radiotherapy Monday, 4 July 2011 12:15-14:15 Poster Session 1 – Radiotherapy Monday, 4 July 2011 12:15-14:15
P1.182 ASSESSMENT OF GTV MOTION P1.183 CLINICAL TOXICITY AND EARLY

AND THE INFLUENCE FACTORS OUTCOME DATA OF PATIENTS WITH
DURING RESPIRATION FOR LUNG EARLY STAGE NSCLC TREATED WITH
CANCER USING FOUR-DIMENSIONAL STEREOTACTIC BODY RADIOTHERAPY
COMPUTED TOMOGRAPHY(4DCT) (SBRT) AT GUY’S & ST THOMAS’
Zongmei Zhou, Xiao Ju, Minghui Li, Luhua Wang HOSPITAL NHS FOUNDATION TRUST,
Department Of Radiation Oncology, Cancer UK
Hospital, Chinese Academy Of Medical Science Asad Qureshi, Simon Hughes, David Landau, Bhakti
(cams) Beijing/China Gajjar, Shahreen Ahmad
Clinical Oncology, Guy’s And St Thomas’ NHS
Background: This study was to assess the three- Foundation Trust/United Kingdom
dimensional gross tumour volume(GTV) motion
of lung cancer caused by respiration using four- Background: Stereotactic Body Radiation Therapy
dimensional computed tomography(4DCT),and to (SBRT) is being increasingly used as an alternative
analyse the inÁuence factors. treatment to surgery in medically inoperable stage
Methods: The 4DCT scans of up to 22 lung focus I non-small-cell lung cancer (NSCLC). Several
in 21 patients with lung cancer were analysed. studies have reported excellent clinical outcomes,
The gross tumour volume was contoured in all 10 and the treatment has now been adopted in many
respiration phases of 4DCT scans. The changes countries worldwide. SBRT has only recently
in volume of GTV, the 3D motion of the centroid, been implemented in UK cancer centres and was
boundary of GTV and the 3D spatial motion vector introduced at Guy’s and St Thomas’ Hospitals NHS
were caculated and the inÁuence factors were Foundation Trust, London, UK in November 2009.
analysed. We report early toxicity data on 14 patients treated at
Results: The average change in volume of GTV this Institution from a UK perspective.
was +14.3% 0.2%- 42.5-8.4% (0.4%-38.6%), the Methods: 14 patients with Stage 1 NSCLC were
GTV centroid average movement was (0.18±0.12) treated with SBRT. 11 were medically inoperable
cm,(0.20±0.16)cm and (0.53±0.59)cm for the and 3 refused surgery. All patients had pathological
medio-lateral, vertro-dorsal and cranio-caudal(CC) conÀrmation of malignancy. Patients were planned
direction. The CC movement was larger than other using 4DCT scanning technique on a Siemens
directions(P<0.05),and there were no signiÀcant scanner and treated with on-line conebeam CT
differences observed in 3D motion of GTV correction using the Elekta Synergy system.
boundary. The CC motion of tumour in lower Fractionation regimes used were 18Gy x 3 and
lobe was large than in upper lobe(P<0.05),and no 11Gy x 5 with a type B algorithm for radiotherapy
signiÀcant differences were found in other directions. planning. Toxicity was assessed using CTCAE v4.0
There was no signiÀcant correlation of the 3D criteria at baseline, prior to each treatment and at
movement of GTV to the adjacency, volume of GTV. follow-up. We report our institution’s toxicity data
Conclusion: GTV motion of patients with lung at baseline and 6-8 weeks post treatment to assess
cancer is individual, the CC movement is the most treatment tolerability and early treatment-related
obvious, using 4DCT to assess is comparatively toxicity.
accurate. The motion of lower lobe focus is larger. Results: Median age was 77years. 4 patients had
No signiÀcant correlation of the GTV motion to the T1aN0M0 tumours and 10 had T1bN0M0. Table
volume was observed. The inÁuence of adjacency to 1 shows the commonest toxicities. Most patients
the GTV motion still needs large sample study. had Grade 0, 1 or 2 toxicity. Only 1 patient, who
had numerous co-morbidities, described Grade 3
A revised/updated abstract may be included in dyspnoea and pain following treatment. One patient
the Late Breaking Abstract Supplement, available had a rib fracture, but there were no reports of
at the 14th World Conference on Lung Cancer. skin toxicity. There are no reported local or distant
recurrences at a median follow-up of 4 months. One
patient died 9 months after treatment due to non-
cancer or treatment-related causes.
Table showing baseline and early toxicity Patients underwent 4D-CT simulation with image
acquisition from 8 phases of the respiratory cycle.
Baseline toxicity 6-8 weeks post treatment
A gross tumor volume (GTV) was contoured on
Grade 1 Grade 2 Grade 3 Grade 1 Grade 2 Grade 3
Bronchospasm 7 5 0 4 2 0
the free breathing CT, and an internal gross tumor
Cough 9 2 0 11 2 0 volume (IGTV) encompassing the motion envelope
Dyspnoea 8 5 0 6 4 1 of the GTV was created. Patients were initially
Fatigue 12 2 0 5 3 1 positioned with orthogonal KV-matching to bony
Pain 6 0 0 5 1 0
anatomy followed by conebeam CT (CBCT),
wherein the CBCT-visualized tumor was matched to
Conclusion: SBRT is well-tolerated in early stage the IGTV from the simulation dataset. Intrafraction
NSCLC patients not suitable for curative surgery. motion was assessed on an immediate post-treatment
These patients have multiple co-morbidities and it CBCT, which was matched to the IGTV. 807 total
is therefore important that the treatment does not shift events were analyzed.
involve excessive toxicity. The toxicity data from our Results: The average CBCT-based shifts after
UK experience is similar to those of other countries initial KV matching to bony anatomy in the vertical,
and the early outcome data is at least as good as longitudinal, and lateral axes were: 2.5 mm (n=145;
conventional radiotherapy. Other centres have also Ʊ=3.5), 2.0 mm (n=145; Ʊ=2.8), and 1.7 mm (n=145;
reported long-term results comparable to radical Ʊ=1.7), respectively. The mean total shift vector
surgery. For these reasons, this treatment should be was 4.4 mm (n=435; Ʊ=4.0). There were 88 CBCT-
considered in other UK centres as an alternative to based shifts greater than 3 mm (37 vertical, 31
conventional radiotherapy in medically inoperable longitudinal, and 20 lateral shifts). The population
patients. systematic error (ȸ) and random error (Ʊ) were 0.33
Keywords: Radiotherapy, SBRT, Non small cell and 0.28 vertically, 0.24 and 0.32 longitudinally,
lung cancer, early toxicity and 0.16 and 0.18 laterally. Applying the Van Herk
margin formula, the optimal PTV for KV positioning
was 10.2 mm vertically, 8.3 mm longitudinally,
Poster Session 1 – Radiotherapy Monday, 4 July 2011 12:15-14:15 and 5.3 mm laterally. The average post-treatment
CBCT-based shifts were: 1.4 mm (n=124; Ʊ=1.7)
P1.184 A MOVING TARGET: IMAGE vertically; 1.5 mm (n=124; Ʊ=2.0) longitudinally,
GUIDANCE FOR STEREOTACTIC BODY and 0.9 mm (n=124; Ʊ=1.1) laterally. The mean total
RADIATION THERAPY vector shift was 2.8 mm (n=372; Ʊ=2.3). 39 shifts
Michael Corradetti, Kevin Teo, Nathan Anderson, were greater than 3mm (17 vertical, 20 longitudinal,
Lara Bonnar Millar, Christian Barlow, Ramesh and 2 lateral shifts). There was no correlation
Rengan between intra-fraction motion and patient age, body
Department Of Radiation Oncology, Hospital Of mass index, pulmonary function, or tumor size.
The University Of Pennsylvania/United States Of Pearson’s correlation analysis demonstrated a weak
America relationship between shift magnitude and treatment
time (r=0.2).
Background: Stereotactic Body Radiation Therapy Conclusion: This study shows that KV matching of
(SBRT) is a promising treatment for patients with the tumor to the IGTV required CBCT-based shifts
early-stage non-small cell lung cancer (NSCLC). greater than 3 mm in approximately 20% of cases,
Due to the large fractional doses and small treatment and intrafraction motion was greater than 3mm
margins employed, precise patient positioning is in approximately 10% of cases. Since the typical
critical. The aims of this study were to determine: (1) IGTV-PTV expansion employed in RTOG protocols
the accuracy of kilovoltage (KV) X-ray matching to is 3-5 mm, these data suggest that (1) orthogonal
bony anatomy for tumor positioning; (2) the optimal KV matching to bony anatomy is inadequate for
planning target volume (PTV) margin; (3) the accurate tumor positioning; (2) intrafraction motion
magnitude of intrafraction motion; and (4) whether can result in tumor motion outside the PTV; and (3)
treatment time or patient characteristics correlate further work is required to Ànd determinants of inter-
with intrafraction motion. and intra-fraction motion that may help guide the
Methods: 43 patients with early-stage NSCLC were individualized application of PTV margins.
enrolled on an image-guided radiotherapy protocol. Keywords: stereotactic body radiation therapy
(SBRT), Image-guided radiation therapy (IGRT), Multivariable competing risk regression models was
conebeam CT (CBCT), kilovoltage (KV) imaging used to assess the association between failures and
radiation therapy groups, adjusted for confounding
variables.
Poster Session 1 – Radiotherapy Monday, 4 July 2011 12:15-14:15 Results: There were 154 (31.3%) patients in the
ACRT group, 99 (20.1%) in STRT1 and 239 (48.6%)
P1.185 TREATMENT AND TOXICITY in STRT2. More patients in the ACRT group had
OUTCOMES USING ACCELERATED KPS 60 (p<0.001), more commonly presented with
RADIATION THERAPY FOR weight loss 10% (p<0.001), and had larger tumors
INOPERABLE NON-SMALL CELL LUNG (p<0.001). After adjusting for clinical variables, there
CANCER were no differences in the radiation groups in terms
Steven H. Lin1, Arya Amini1, Caimiao Wei2, Daniel of the patterns of local failure, distant tumor control
Gomez1, Kayoko Ohnishi1, Pamela K. Allen1, James or overall survival. Toxicity proÀles in the ACRT
D. Cox1, Ritsuko Komaki1 were signiÀcantly lower for grade 2 pneumonitis
1
Radiation Oncology, The University Of Texas MD (p=0.009), radiation dermatitis (p=0.001), nausea/
Anderson Cancer Center/United States Of America, vomiting (p=0.005), constipation (p=0.023), and
2
Biostatistics, The University Of Texas MD Anderson weight loss during treatment (p=0.002).
Cancer Center/United States Of America Conclusion: Patients receiving accelerated
radiotherapy had comparable local and distant
Background: While conventionally fractionated recurrence rates with no difference in overall
radiation therapy alone is an acceptable option survival compared to conventionally fractionated
for patients presenting with unresectable NSCLC radiotherapy, even though these patients initially
due to major comorbid diseases, the optimal dose presented with worse prognostic factors. Side effects
and fractionation scheme has not been established. were signiÀcantly less in the accelerated treatment
We hypothesize that accelerated hypofractionated arm compared to conventional fractionation.
radiotherapy will have similar efÀcacy without Overall, accelerated radiation therapy with 45 Gy
increased toxicity when compared to conventionally in 15 fractions is an acceptable treatment option
fractionated radiation therapy. for patients with inoperable tumors with poor
Methods: This is a retrospective analysis of 492 performance status and other major comorbidities.
patients diagnosed with NSCLC treated with Keywords: Inoperable, Accelerated Radiation
radiation therapy at MD Anderson Cancer Center Therapy, Poor prognostic factors, Non-small cell
between 1993 and 2009. Patients included in the lung cancer
study were medically or surgically inoperable, were
free of metastatic disease at initial workup and did
not receive concurrent chemotherapy. Patients were Poster Session 1 – Radiotherapy Monday, 4 July 2011 12:15-14:15
categorized into three groups. Group 1 received
45 Gy in 15 fractions over 3 weeks (Accelerated P1.186 HIGH LINEAR ENERGY
Radiotherapy (ACRT)) while group 2 received 60-63 TRANSFER (LET) RADIOTHERAPY IN
Gy (Standard Radiation Therapy 1, STRT1) and group THE TREATMENT OF RECURRENT
3 received > 63 Gy (Standard Radiation Therapy PREVIOUSLY IRRADIATED NON-SMALL
(STRT2). Chi-squared and Fisher’s exact tests were CELL LUNG CANCER (NSCLC)
used to analyze the associations between categorical Andre Konski1, George Chen1, Mike Joiner1, Laura
variables and radiation therapy groups. Kruskal- Kollar1, Shirish Gadgeel2, Antoinette Wozniak2
1
Wallis tests were used to assess the association Radiation Oncology, Wayne State University/
between continuous variables and radiation therapy Barbara Ann Karmanos Cancer Center/United
groups. Overall survival was calculated using the States Of America, 2Oncology, Karmanos Cancer
Kaplan and Meier method and comparisons were Institute/wayne State University/United States Of
made using the log-rank test. Multivariable Cox America
proportional hazards model was used to account for
confounding variables. Cumulative incidence of local Background: Few options are available for
failure and distant failure was estimated using the treatment of patients with symptomatic previously
method of subdistribution analysis of competing risks. irradiated non-small cell lung cancer once they
failed systemic therapy. The objective of this study Background: Three-dimensional (3D) conformal
was to report on our experience in the use of high beams are conventionally used in lung cancer
LET radiotherapy in the treatment of patients with stereotactic body radiotherapy (SBRT). Volumetric
recurrent previously irradiated non-small cell lung modulated arc therapy (VMAT) has been introduced
cancer (NSCLC). recently as a new lung SBRT treatment modality.
Methods: Between April 1993 and February 2011 As it usually delivers treatment in a shorter time,
18 patients, (8 F, 10M) were treated with fast neutron this modality promises the possibility of target
therapy for recurrent NSCLC. Equivalent dose misalignment due to patient motion during each
in 2 Gy fractions (EQD2) of photon and neutron treatment. The dose distributions of VMAT plans
radiotherapy were calculated with a alpha/beta ratio differ from standard 3D therapy. This study
of 3 for normal lung and 10 for tumor for photon quantiÀes dosimetric differences between the VMAT
radiotherapy and for normal lung and tumor for plans and the 3D ones. Furthermore, because a
neutrons. The radiobiologically equivalent (RBE) Áattening-Àlter-free (FFF) linear accelerator is now
factor of 3 was used for neutrons for the EQD2 commercially available, we also analyzed VMAT
dose calculation for lung and 4 for tumor. A total plans generated using the FFF beams (FFF-VMAT).
EQD2was calculated for primary and recurrent Methods: Fifteen lung cancer patients previously
treatment. Survival was calculated from the end of treated with 3D or VMAT SBRT were randomly
neutron radiotherapy. selected. For each patient, 3D, and coplanar and
Results: Median age at recurrence was 60 (range: non-coplanar VMAT plans and FFF-VMAT plans
40-92). Median pre neutron photon radiotherapy dose were generated to meet the same objectives with
was 61.5 (30-90) Gy at a median of 11 months (range: 5000 cGy to cover 95% PTV. Two dynamic arcs
3-36) prior to receiving neutron therapy. The median were utilized in each VMAT plan. The couch was
EQD2 previous photon dose was 60.6 Gy (range: 36- set at ± 5 degrees to the straight position for the two
90). The median neutron retreatment dose was 8NGy non-coplanar arcs in normal VMAT and FFF-VMAT.
(range: 5-15). Total combined EQD2 of pre and post- Pinnacle version 9.0 (Philips, Fitchburg WI) was
recurrent radiotherapy was 86 Gy(range: 66-120). used to generate plans. SmartArc was used for the
8/12 patients presenting with symptomatic disease VMAT planning. The conformity index (CI), which
were successfully palliated. The treatment was fairly is the ratio of the total volume receiving at least the
well tolerated with 3 patients having acute grade 1 prescription dose to the target volume receiving at
dermatitis, 8/18 having acute grade 2 esophagitis and least the prescription dose the conformity number
no patients with radiation pneumonitis. Mean overall (CN) which is the ratio of the target coverage to CI
survival was 5 months (0-28). and the gradient index (GI) which is the ratio of the
Conclusion: Neutron therapy provided excellent volume of 50% of the prescription isodose to the
palliative beneÀt with little acute toxicity in this volume of the prescription isodose were compared.
patient population with few therapeutic options. Results: The CI for the 3D, coplanar, non-coplanar
Future studies incorporating molecular markers for VMAT and non-coplanar FFF-VMAT plans ranged
radioresistance are planned to understand the biology from 1.20 to 2.45, 1.07 to 1.89, 1.07 to 1.79 and 1.07
of these tumors and their response to high LET to 1.72 respectively, with an average and standard
radiotherapy. deviation of 1.52 ± 0.33, 1.29 ± 0.21, 1.28 ± 0.18
Keyword: High LET Radiotherapy lung cancer and 1.28 ± 0.19 respectively. The CN values were
0.65 ± 0.11, 0.75 ± 0.10, 0.76 ± 0.09 and 0.76 ± 0.10
respectively. The GI values were 8.41 ± 3.78, 7.42
Poster Session 1 – Radiotherapy Monday, 4 July 2011 12:15-14:15 ± 2.98, 7.33 ± 3.00 and 7.87 ± 2.79 respectively,
indicating sharper dose fall-off in normal tissues
P1.187 DOSIMETRIC STUDY IN LUNG in VMAT plans. The GI values for the FFF VMAT
STEREOTACTIC BODY RADIOTHERAPY plans were slightly higher than that of other VMAT
USING VMAT TECHNIQUES plans. The mean dose to the PTV was 5348 ±
Geoffrey Zhang1, Thomas Dilling1, Lichung Ku2, 118, 5294 ± 125, 5291 ± 117 and 5279 ± 97 cGy
Craig Stevens1, Weiqi Li1, Vladimir Feygelman1 respectively. The total monitor units (MU) used in
1
Radiation Oncology, MofÀtt Cancer Center/United the plans were 1521 ± 159, 1652 ± 205, 1583 ± 209
States Of America, 2Radiation Oncology, Salem and 1744 ± 214 respectively. More MUs were used
Hospital/United States Of America in the VMAT plans than 3D ones. The FFF-VMAT
plans tended to use the highest number of MU. Results: 260 analyzed patients comprise 184 from
Conclusion: Besides the advantage of faster delivery China and 76 from US. RILT occurred at a rate of
times, VMAT plans demonstrated better conformity to 25.5%, 14.5% and 22.3% for the Chinese center,
target and sharper dose fall-off in normal tissues than US center and combined setting, respectively. The
the 3D plans for lung SBRT while maintaining mean mean FEV1%pred, FVC%, DLCO% and MLD for
target dose, though at the expense of additional MUs. entire group are 71.7%, 71.9%, 65.0% and 14.5
Keywords: radiotherapy dosimetry, lung SBRT, Gy, respectively. There is no signiÀcant correlation
VMAT between FEV1%pred and MLD (R2 = 0.024, P =
0.051). Mean FEV1%pred for RILT and non-RILT
patients are 81.7% vs. 75.1% (P = 0.054) in Chinese
Poster Session 1 – Radiotherapy Monday, 4 July 2011 12:15-14:15 population and 64.5% vs. 58.3% for Americans (P
= 0.348). In the combined population, RILT patients
P1.188 POOR BASELINE PULMONARY have remarkably higher FEV1%pred than non-RILT
FUNCTION MAY BE ASSOCIATED WITH patients (78.4% vs. 69.7%, P = 0.012). Using the
LOWER RISK OF RADIATION INDUCED median of FEV1%pred as a cutoff point, the incidence
LUNG TOXICITY: A POOLED ANALYSIS of RILT was 16.0% and 28.7%, respectively (P =
FROM CHINA AND US 0.014). No difference is observed in either FVC% or
Jingbo Wang1, Luhua Wang2, Jianzhong Cao2, DLCO% between patients with and without RILT.
Shuanghu Yuan1, Wei Ji2, Douglas Arenberg3, Under univariate analysis, FEV1%pred, MLD,
Randall K. Ten Haken1, Jianrong Dai2, Feng-Ming COPD are signiÀcantly correlated with risk of RILT.
(Spring) Kong1 FEV1%pred and MLD remain signiÀcantly associated
1
Radiation Oncology, University Of Michigan/United with RILT in multivariate analysis, with odds ratios of
States Of America, 2Radiation Oncology, Cancer 1.016 and 1.114. A traditional model using predictors
Hospital, Chinese Academy Medical Sciences & of MLD and COPD, yields a receiver operating
Peking Union Medical College/China, 3Internal characteristic (ROC) curve with the area under the
Medicine, University Of Michigan/United States Of curve (AUC) of 0.638 (P = 0.002). The addition of
America FEV1%pred slightly improves the AUC to 0.658
(95% CI: 0.578, 0.738, P < 0.001), corresponding to a
Background: Despite limited evidence, poor pulmonary sensitivity, speciÀcity and accuracy of 67.9%, 60.7%
function (PF) often leads to a contraindication for and 62.3%, respectively.
deÀnitive radiation therapy for lung cancer. This study Conclusion: Pre-RT FEV1%pred and MLD were
investigates whether baseline pulmonary function predictive of RILT. Poor baseline pulmonary function
predicts radiation induced lung toxicity (RILT) in did not increase the risk of RILT and might even be
patients with non-small cell lung cancer (NSCLC) associated with lower RILT probability, which has yet
receiving conformal radiation therapy (CRT). to be independently validated in larger patient cohorts.
Methods: This pooled analysis included NSCLC Keywords: Non-small cell lung cancer, radiation
patients from two centers (one in China and the other induced lung toxicity, Pulmonary function
one in US) who were treated with CRT between 2001
and 2009 and had pre-RT pulmonary function test
(PFTs). Baseline PF parameters recruited percent Poster Session 1 – Radiotherapy Monday, 4 July 2011 12:15-14:15
predicted value of forced expiratory volume at 1st
second (FEV1%pred), forced volume capacity P1.189 CLINICAL AND TECHNICAL
(FVC%) and diffusion capacity of lung for carbon ASSESSMENT OF RESPIRATORY
monoxide (DLCO%). Additional factors evaluated for GATED INTENSITY MODULATED
the risk of RILT included age, gender, smoking status, RADIOTHERAPY FOR LOCALLY
KPS, coexisting COPD, concurrent chemotherapy and ADVANCED LUNG CANCER
mean lung dose (MLD). Grade 2 RILT according to Alexander V. Louie1, George Rodrigues1, Philip Lee1,
the modiÀed common terminology criteria for adverse Brian Yaremko1, Rashid Dar1, Edward Yu1, David
event version 3.0 served as the primary endpoint, Palma1, Inge Aivas1, Stewart Gaede2
1
subject to pulmonary symptoms worsened by at least Radiation Oncology, London Regional Cancer
one grade over pre-RT levels without evidence of Program/Canada, 2Physics And Engineering,
tumor progression or other speciÀc etiology. London Regional Cancer Program/Canada
Background: Intensity-modulated radiation Conclusion: The use of concurrent respiratory-

therapy (IMRT) is an advanced radiation treatment gated IMRT and chemotherapy is safe and shows
delivery technique that can improve the therapeutic promising clinical outcomes in locally advanced lung
ratio. Thoracic tumors, however, pose a treatment cancer with signiÀcant tumor motion. The toxicity
challenge in optimizing the therapeutic ratio in part proÀle associated with this treatment is within
due to respiratory motion. Treatment simulation with clinical expectation.
a four-dimensional computed tomography (4DCT) Keywords: pneumonitis, esophagitis, imrt, 4DCT
scanner allows for assessment of tumor motion.
In situations where tumor motion is excessive,
the radiation beam can be gated to synchronize Poster Session 1 – Radiotherapy Monday, 4 July 2011 12:15-14:15
delivery of radiotherapy during the optimal point
of the patient’s respiration cycle. As the clinical P1.190 STEREOTACTIC BODY
use of concurrent chemotherapy and respiratory- RADIOTHERAPY FOR LUNG CANCER
gated IMRT in locally advanced lung cancer has USING EXACTRAC X-RAY 6D AND
not been well studied, we report our institution’s FOUR-DIMENSIONAL CONE BEAM CT
clinical outcomes and complications with this new IMAGE GUIDANCE
technology. Fen Wang1, Rajeev Badkul2, John Park1
1
Methods: According to our institutional protocol, Radiation Oncology, University Of Kansas Medical
non-small cell lung cancer (NSCLC) patients are Center/United States Of America, 2University Of
treated concurrently with cisplatinum and vinblastine Kansas Medical Center/United States Of America
and 64 Gy in 32 fractions and small cell lung cancer
(SCLC) patients are treated with cisplatinum and Background: To quantify the localization accuracy
etoposide and 60 Gy in 30 fractions. Beginning of lung cancer patients treated with ExacTrac x-ray
in early 2006, all thoracic cancer patients treated 6D and four-dimensional (4D) cone beam computed
radically were planned on a 4D-CT scanner. For tomography (CBCT)-guided Stereotactic Body
tumors with motion 7 mm, treatment is performed Radiotherapy (SBRT) and to calculate and validate
with respiratory-gated IMRT. We identiÀed thirty- planning target volume (PTV) margins to account for
four patients simulated for respiratory-gated IMRT the residual geometric uncertainties
between November 2006 and August 2010 from our Methods: 40 patients with small lung tumors
institutional database. From this group, we excluded were treated with SBRT using Brain Lab BodyÀx
four patients that were lost to follow-up (n = 3), immobilization to 50-60 Gy in three to Àve fractions.
or did not receive the prescribed treatment (n = 1). For each fraction, patient was aligned Àrst with
Toxicities were graded by the Common Terminology infrared-based optical positioning system using skin
Criteria for Adverse events version 3.0. Spearman’s markers. Patient position veriÀcation and adjustment
rank correlation was used to evaluate potential were made by fusing the stereoscopic radiographs
parameters predictive of symptomatic esophagitis or with simulation CT images using 6 degree of
pneumonitis. freedom (6D) fusion algorithms (bone registration).
Results: There were 24 NSCLC (10 = CBCT scans were then acquired for Ànal veriÀcation
adenocarcinoma, 11 = squamous cell, 3 = large cell) and adjustment of patient position by aligning tumor
and 6 SCLC patients. Median overall survival was position with simulation CT images (soft tissue
11.8 months (range 2.9 – 39.6 months), while 2-year registration). The couch shifts with image guidance
and 3-year overall survival were 45% and 30% were collected to determine set up margins
respectively. Local, regional, and distant recurrences Results: The alignment to skin markers with no
occurred in 2 (7%), 5 (17%), and 15 (50%) image guidance resulted in systemic (ƙ) errors of
patients respectively. Ten (33%) patients developed 3.95, 5.57, and 6.49 mm and random (ƣ) errors
symptomatic treatment-related pneumonitis ( grade of 4.22, 6.60, and 11.01 mm for the left-right,
2) while 6 (20%) developed symptomatic acute craniocaudal, and anteroposterior direction,
esophagitis ( grade 2). Using Spearman’s rank respectively. The margin required to account for this
correlation, V5, V10, V13, V20, and mean lung dose setup error was 12.83-23.93 mm. The difference
were not predictive of symptomatic pneumonitis. in the couch shifts obtained from ExacTrac x-ray
Similarly for esophagus, V50, V60, and Dmax were not 6D and CBCT resulted in systemic (ƙ) and random
predictive of symptomatic esophagitis. (ƣ) errors of 0.32-1.02mm and 0.48-0.83 mm,
respectively. The margin required to account for checked weekly with CBCT unless >0.7 cm
this setup error introduced using bony anatomy displacement persisted, for which continued CBCT-
(ExacTrac) as a surrogate for the target, instead of based correction was applied.
localizing the target itself, was 1.32-3.13mm. Results: 15 patients were enrolled and 11 completed
Conclusion: The CBCT soft tissue registration to the protocol. Across all CBCT, unidirectional shifts
localize the tumor in SBRT reduced the required ranged from 0.1 to 1.8 cm. The mean maximum
setup margin by up to approximately 3.13 mm displacement over the Àrst 5 CBCT was 1.05 cm
compared with ExacTrac bony registration as and over all subsequent CBCT acquisitions, it was
a surrogate for the target. This setup margin 0.93 cm. This relative lack of improvement was
reduction by using CBCT may not be necessary primarily due to 3 patients who had displacements
in conventional fractionated radiotherapy using >1.2 cm after the initial assessment period. One
ExacTrac image guidance was obese, one had orthotopic heart transplant with
Keywords: SBRT, IGRT physical difÀculties, and one had small cell lung
cancer showing continuous anatomic change in
response to treatment. Excluding these 3 patients,
Poster Session 1 – Radiotherapy Monday, 4 July 2011 12:15-14:15 the mean maximum displacement after the Àrst 5
CBCT was 0.67 cm. Figure 1 shows 3-D shifts as a
P1.191 INITIAL DETERMINATION OF function of day of treatment. Data for the 3 patients
SETUP ERRORS USING DAILY CONE- with persistent displacement are displayed as large
BEAM CT REDUCES SUBSEQUENT squares.
VARIATION OVER A LUNG CANCER
RADIOTHERAPY TREATMENT COURSE
Sue S. Yom1, Josephine Chen1, Michele Aubin1,
Olivier Morin1, Pierre Graff2, Martina Descovich1,
Jean Pouliot1
1
Radiation Oncology, University Of California San
Francisco/United States Of America, 2Service De
Radiothérapie, Centre Alexis Vautrin/France
Background: Variations of daily radiotherapy

setup necessitate larger planning margins around
clinical target volumes, increasing the toxicity of
lung radiotherapy. However, daily image guidance Conclusion: Conclusion: Propensity to systematic
can be onerous and delivers additional dose to the error can be identiÀed during the initial phase of
lung and other non-target organs. We implemented a radiation therapy. In most patients, eliminating
procedure to identify initial systematic errors using systematic error reduces the amplitude of
megavoltage Cone-Beam CT (CBCT), to determine displacements over the remaining treatment course
the feasibility of reducing subsequent variation over and conÀrms the validity of planning margins.
the course of treatment. One third of the patients had excessive persistent
Methods: Lung cancer patients scheduled to displacement requiring continued correction.
receive at least 3 weeks of radiotherapy were Additional research is needed to determine if setup
enrolled in a prospective imaging protocol. For 5 error reduction can be used to trim planning margins
consecutive sessions, a 5MU CBCT was acquired on an individualized basis, if the degree of variation
after conventional patient setup. CBCT-CT image can be predicted in advance from patient or tumor
registration was performed based on the position characteristics, and to what degree error reduction
of the carina and if speciÀed as clinically relevant, affects intrafractional motion.
target volumes or the spine. Planning margins were Keywords: image-guided radiotherapy, cone-beam
>=0.7 cm after accounting for motion. Therefore, CT
shifts were enacted for any unidirectional error >0.4
cm. After 5 CBCT were obtained, a permanent shift
was enacted to minimize the mean 3-dimensional
vector displacement from ideal. Patients were
Poster Session 1 – Radiotherapy Monday, 4 July 2011 12:15-14:15 A revised/updated abstract may be included in
P1.192 CONFIRMATION OF INTERNAL at the 14th World Conference on Lung Cancer.
TARGET VOLUME AND DOSIOLOGY
STUDY FOR LUNG CANCER USING 4D-
CT TECHNOLOGY Poster Session 1 – Radiotherapy Monday, 4 July 2011 12:15-14:15
Bai Tong1, Li Jianbin2, Yin Yong1, Lu Jie1, Zhu Jian1,
Liu Tonghai1 P1.193 PRELIMINARY RESULTS OF THE
1
Department Of Radiation Physics, Shandong FIRST 26 PATIENTS TREATED WITH
Cancer Hospital And Institute/China, 2Department STEREOTACTIC BODY RADIOTHERAPY
Of Radiation Oncology, Shandong Cancer Hospital (SBRT) FOR STAGE I-II LUNG CANCER
And Institute/China Edith Dieleman, Lon Uitterhoeve, Martijn
Kamphuis, Pieter Gangel, Rob Van Os, C.
Background: For the effect of breathing motion, it Koedooder, Niek Van Wieringen, Caro Koning,
is difÀcult to conÀrm the tumor accurately in lung Markus Wendling
cancer in the intensity-modulated radiotherapy Radiation Oncology, Academic Medical Center
(IMRT). This study is to conÀrm the internal target Amsterdam/Netherlands
volume (ITV) and compare the volumetric and
dosiology differences between 3D-CT and 4D-CT, Background: To evaluate toxicity, survival, local
using 4D-CT technology. recurrence (LR), regional recurrence (RR), and
Methods: Eight patients with primarily lung cancer distant metastases (DM) in 26 patients treated with
were enrolled and both 3D and 4D-CT were taken. SBRT for stage I-II lung cancer.
For each patient, 3D-CT was taken as reference Methods: Between 2009 and 2010, 28 tumours in 26
image and clinical target volume (CTV) was deÀned patients were treated with SBRT at our department.
on it. Extended CTV with setup margin was deÀned Median age of the patients is 75 years (range 51-
as PTV-3D; for each respiratory phase, CTV were 87). Fifty percent of the patients are female. In
drawn separately and mixed together as ITV, which two patients two lesions were treated. Pathologic
was extended as PTV-4D. Design different IMRT diagnosis was conÀrmed in 13 cases (46%). If no
plans on PTV-3D and 4D separately for each patient pathologic diagnosis was conÀrmed, the lesion
with same prescription doses, Àeld degrees and should be FDG positive and progressive in time.
optimization target functions. The differences of FDG-positivity of the tumours was found in 25
target volumes, dose distributions on targets and cases. Treatment plans were mainly based on PET-
organs as risk (OAR) were compared. CT in radiation position and Slow CT scans. The
Results: The volume is 150.67±86.67 cm3 for prescribed dose was 3 x 20 Gy for T1 tumours (n=
PTV-3D and 130.17±79.89 cm3 for PTV-4D, which 8), 5 x 12 Gy for T1 tumours with broad contact to
is 13.61% 8.51%~23.53% smaller. There is no the chest wall (n=11) and T2 tumours (n=5) and 8 x
signiÀcant difference of target conformal index (CI) 7,5 Gy (n=4) for large tumours and tumours nearby
and homogeneity index (HI). About the dose on OARs organs at risk.
(including lung, heart and spinal-cord), 4D plans have Results: Median follow-up was 6 months (range
lower dose to the 3D plans: V5, V10, V20 and V30 0 -15 months). Local recurrence free survival was
for total-lung is cut separately from 41.25%, 29.75%, 100% at 6 and 12 months. Regional recurrence free
21.25%, 13.00% to 38.13%, 27.00%, 17.25%, 9.13%; survival (see Àgure) was 81% at 6 and 12 months.
mean lung dose (MLD) is cut from 1103.63cGy to Metastases free survival at 6 and 12 months was
911.21cGy; mean heart dose is cut from 450.43cGy to 67% and 50% respectively. Overall survival was
372.20cGy; maximum dose for spinal-cord is cut from 87% and 65% at 6 and 12 months. Neither severe
3162.83cGy to 2967.63cGy. toxicity (grade 3) nor late toxicity was observed in
Conclusion: 4D-CT technology can be used to this patient group.
bridge the gap of missing or extending the target
volume on 3D radiotherapy. It will bring better
accuracy an lower dose on OARs as well.
Keywords: Lung cancer, Internal-target volume,
4D-CT
Conclusion: With limited follow-up, SBRT for lung cGy, respectively, compared with those in the
cancer showed a good control of LR and RR and was anatomic plans. The median reductions in the
well tolerated in the Àrst group of patients treated percentage of volume irradiated with >5 Gy, >10
with SBRT in the AMC, University of Amsterdam. Gy, >20Gy , >30Gy and >40Gy for functional
Keywords: SBRT, lungcancer, local control, lung in the functional plans were 6.50%, 10.21%,
regional recurrence 14.02%, 22.30% and 23.46% in 3DCRT planning,
respectively, and 3.05%, 15.52%, 14.16%, 4.87%,
A revised/updated abstract may be included in and 3.33% in IMRT planning, respectively. No
the Late Breaking Abstract Supplement, available greater degree of sparing of the functional lung was
at the 14th World Conference on Lung Cancer. achieved in functional IMRT than in 3DCRT.
Conclusion: Function-guided 3DCRT and IMRT
plannings both appear to be effective in preserving
Poster Session 1 – Radiotherapy Monday, 4 July 2011 12:15-14:15 functional lung in NSCLC patients.
Keywords: lung function, Lung cancer,
P1.194 THE APPLICATION OF Radiotherapy, lung perfusion
SPECT LUNG PERFUSION SCANS IN
PROTECTION OF LUNG FUNCTION
OF PATIENTS WITH LUNG CANCER IN Poster Session 1 – Radiotherapy Monday, 4 July 2011 12:15-14:15
RADIOTHERAPY
Jinhu Chen P1.195 COMPARATIVE STUDY
Radiation Physics, Shandong Cancer OF CONVENTIONAL AND 3D-
Hospital&institute/China CONFORMAL RADIOTHERAPY
IN LOCALLY ADVANCED LUNG
Background: The lung functional status could CANCER IN CONCOMITANT CHEMO-
be displayed on lung perfusion images. With the RADIOTHERAPY PROTOCOLS.
images, the radiotherapy plans of lung cancer could Aloke Ghosh Dastidar
be guided to more optimized. This study aimed to Radiotherapy, Amri Hospital/India
assess quantitatively the impact of incorporating
functional lung imaging into 3-dimensional Background: Treatment outcome of locally
conformal radiotherapy (3DCRT) and intensity- advanced lung cancer is not much encouraging
modulated radiation therapy (IMRT) planning for even after development of newer molecules of
non–small cell lung cancer (NSCLC). chemotherapeutic agents. Advancement in radiation
Methods: Ten patients with NSCLC who had techniques claims to improve treatment related
undergone radiotherapy were included in this study. toxicities and better tolerance to patients. The present
Before radiotherapy, each patients underwent CT study was to compare the conventional radiation
simulation and lung perfusion imaging with single technique (CRT) with the 3-Dimentional Conformal
photon emission computed tomography (SPECT). Radiotherapy (3D-CRT) in relation to tolerance,
The SPECT images were registered with simulation cardiac exposure, treatment outcome and quality of
planning CT and used to contour functional lung life in stage matched lung cancer patients. An open
(lung-F) and non-functional lung (lung-NF). Two randomized controlled trial.
3DCRT plans and two IMRT plans were designed Methods: Forty biopsy proved stage 3b squamous
and compared in each patient: two anatomic plans cell lung cancer (NSCLC) patients who were
using simulation CT alone and two functional plans inoperable at presentation were selected for
using SPECT-CT in addition to the simulation CT. concomitant chemo-radiation schedule. Twenty
Dosimetric parameters of the four types of plans patients (Group A) were treated by weekly
were compared in terms of tumor coverage and concomitant chemotherapy with inj. Paclitaxol
avoidance of normal tissues. Total radiation dose was 30mg/m2and external beam Radiotherapy with AP
set at 66 Gy (2Gy×33 fractions). portals in conventional fraction schedule of total
Results: In incorporating perfusion information dose of 54 Gy (40Gy in phase I and 14 Gy in phase
in 3DCRT and IMRT planning, the reductions II). Twenty patients (Group B) were treated by same
on average in the mean doses to the functional weekly regimen for chemotherapy and external beam
lung in the functional plan were 168 cGy and 89 Radiotherapy was given by 3D-CRT schedule to
deliver more precise and multiple portals of radiation Radiation Oncology (MAASTRO), Grow, Maastricht
Àelds to deliver total dose of 54 Gy (range 50.4Gy University Medical Centre/Netherlands, 3Department
– 54 Gy) with off-cord cardiac sparing planning. Of Radiation Oncology, The Netherlands Cancer
Patients of both groups were studied for acute and Institute, Antoni Van Leeuwenhoek Hospital (NKI-
late toxicity, tolerance, post treatment Quality of Life AVL), Amsterdam/Netherlands
and recurrence free survival on clinical, radiological,
DVH -dosimertic analysis and Lung function test Background: The brain is one of the major sites
report. of failure for stage III non-small cell lung cancer
Results: All twenty patients of both the groups (NSCLC), with approximately 22% of the patients
could complete successfully the chemo-radiotherapy developing brain metastases. The recent RTOG-0214
in deÀned time schedule. Tolerance to treatment trial showed a highly signiÀcant decrease in the
for radiation by conventional arm was poorer than incidence of brain metastases, assessed with brain
the 3D-CRT arm. Cough, weight loss, chest pain, MRI scans, from 18 % in the control group to 7.7
anorexia, dizziness, haemoptesis, nausea, vomiting, % in the Prophylactic Cranial Irradiation (PCI ) arm
muscle cramp were the criteria for comparison at 1 year. PCI in itself, however, induces adverse
between the two groups. Mean integral dose in group effects like neurocognitive deÀcits. These cognitive
A patients were higher than Group B patients. After side effects may be reduced by the application of
individual CT-scan based planning on Organ At Risk hippocampus avoiding PCI (HA-PCI). Within the
analysis - healthy lung tissue received more radiation Netherlands the NVALT-11 trial (a randomized
due 5-6cm margin for CTV in groupA compared phase III trial with or without PCI in stage III
to 1cm margin in Group B; Cardiac exposure – in NSCLC patients number NCT01282437) is currently
group A 40% of healthy heart compared to 15% of in performed. The patients with and without (HA)-PCI
group B received radiation. 60 % of group A patients have repeated tests for neurocognitive functioning
had progressive disease at 3month check-up CT-scan in a side study. We developed a simple technique
report and 40% in group B. Recurrence free survival using two lateral beams with a PTV coverage of
at 18 months were 30% and 40% respectively. 85% to deliver PCI while keeping the dose in the
Details of reports will be discussed. hippocampus as low as possible. This technique
Conclusion: Concomitant chemoradiation is the was compared with a complex technique using
standard care of therapy in stage 3b lung cancer. Volumetric Modulated Arc Therapy (VMAT).
Radiation and weekly Paclitaxel injection gives Methods: For 10 patients, the brain and
adequate tumor control. CT scan based treatment hippocampus were delineated on a CT scan matched
planning with judicious use of multi leaf collimators with a 3D T1 weighted MRI-scan. For the PTV,
save normal tissue, prevents OAR, alleviates classically deÀned as the whole brain volume minus
toxicities and improves tolerance. 3D-CRT thus the hippocampus volume with a 5 mm margin, 30 Gy
helps recurrence free survival and better quality of (12 fractions of 2.5 Gy) dose was prescribed. Two
life in locally advanced lung cancer. techniques were compared: a simple technique (A)
Keyword: Lung Cancer, Concomitant CT-RT using two opposing Àelds and a complex technique
(B) using Volumetric Modulated Arc Therapy
(VMAT). For technique A the collimator angle was
Poster Session 1 – Radiotherapy Monday, 4 July 2011 12:15-14:15 chosen such that two 1 cm leafs optimally block
the hippocampi. For technique B beam modulator
P1.196 HIPPOCAMPUS AVOIDING plans with 2 dual arcs with the couch @ 0° and 90°
PROPHYLACTIC CRANIAL (beam-on time: 4x180 sec = 12 min) were generated.
IRRADIATION FOR NSCLC PATIENTS: The maximum and mean dose to the hippocampus
USING A SIMPLE TECHNIQUE was calculated, as well as the volume of the PTV
Zdenko Van Kesteren1, José Belderbos1, Dirk De receiving 95% of the prescribed dose (V95%).
Ruysscher2, Agnieszka Olszewska1, Emmy Lamers1, Results: On average, the V95% of the PTV was
Eugène Damen1, Marcel Van Herk3, Corine Van 85.7 ± 0.6 % for the simple technique and 96.4 ±
Vliet-Vroegindeweij1 0.24 % for technique B. For the simple technique,
1
Department Of Radiation Oncology, The the average mean dose delivered in the hippocampus
Netherlands Cancer Institute - Antoni Van was 6.2 ± 0.3 Gy, the maximum dose was 11.9 ± 1.6
Leeuwenhoek Hospital/Netherlands, 2Department Of Gy. The mean biological dose (with Ơ/ơ = 2 Gy) to
the hippocampus for technique A was 3.9 ± 0.2 Gy centres have treated over 100 patients. SBRT for
versus 7.4 ± 0.55 Gy for the VMAT technique. lung lesions is only provided in 4 provinces and 6
Conclusion: Opposing Àeld HA-PCI is a of the 13 centres are located in Ontario. No centre
simple technique with a maximal sparing of the in the Maritimes is currently providing SBRT. 48Gy
hippocampus. By accepting the V95% of the PTV to in 4 fractions is the most common regimen (64%)
drop to 85%, an excellent sparing the hippocampus followed by 54Gy in 3 fractions (28%). Four centres
was achieved. This strategy is currently being tested are treating lesions within 2 cm of the proximal
in a randomized phase III trial (with or without PCI airways (‘central’), although only 1 centre is enrolled
in stage III NSCLC patients) with an additional in a clinical trial for central lesions. Seven centres
analysis of the neurocognitive sequels and the impact are treating pulmonary metastases. Most centres are
of PCI on neurological symptoms and health-related using a combination of coplanar and non-coplanar
quality of life. static beams. One centre is using respiratory gating.
Keywords: Hippocampus avoidance, profylactic Treatment times average 50 minutes per fraction
cranial irradiation, NSCLC, brain metastases (range 30 – 90). Peer review of the target volumes
occurs in only 6 centres and peer review of dose
distributions in 5. Five centres have no systematic
Poster Session 1 – Radiotherapy Monday, 4 July 2011 12:15-14:15 tracking of patient outcomes.
Conclusion: The use of SBRT for lung lesions has
P1.197 THE CURRENT USE OF increased dramatically within the previous 3 years,
STEREOTACTIC BODY RADIOTHERAPY however access continues to vary considerably
FOR LUNG TUMOURS ACROSS CANADA by geography. Techniques and doses vary across
Chad R. Lund, Mitchell Liu, Jonn Wu, Hannah institutions. Quality assurance and systematic
Carolan, Rob Olson, Devin Schellenberg tracking of outcomes remains sporadic.
Radiation Oncology, British Columbia Cancer Keywords: stereotactic body radiotherapy, Non
Agency/Canada small cell lung cancer, Oligometastases
Background: Stereotactic body radiotherapy

(SBRT) is a novel technique that can be used to Poster Session 1 – Radiotherapy Monday, 4 July 2011 12:15-14:15
deliver ablative doses of radiation to T1-T2N0
primary lung cancers or small lung metastases. P1.198 USING DURING-RT PET TO
Though clinical data demonstrates excellent INDIVIDUALIZE ADAPTIVE RT FOR
local control for lung lesions, the availability and PATIENTS WITH STAGE III NSCLC: A
utilization of SBRT for lung cancer across Canada is MULTICENTER PLANNING STUDY
unknown. Feng-Ming (Spring) Kong1, Ying Xiao2, Mitchell
Methods: In order to assess the use of SBRT Machtay3, Maria Werner-Wasik4, Gregory M.
for the treatment of primary lung malignancies Videtic5, Billy W. Loo6, Henry Wagner7, Elizabeth
and oligometastases to the lung, all Canadian M. Gore8, John Varlotto9, Sergio Faria10, Thomas
radiotherapy (RT) centres were identiÀed from a list J. Dilling11, Alex Sun12, Todd Swanson13, Luhua
provided by the Canadian Association of Radiation Wang14, James Galvin2, Randall K. Ten Haken1,
Oncology (CARO). English surveys were emailed Jeffrey Bradley15
1
to all centres and reminder emails were sent to those Radiation Oncology, University Of Michigan/
that did not respond. The survey was comprised United States Of America, 2Rtqa, Radiation
of 1 section each for lung, liver, spine, other (e.g. Therapy Oncology Group/United States Of
prostate) and for centres not currently using SBRT. America, 3Radiation Oncology, Case Western
Each section was to be representative of the practice Reserve University/hospitals/United States Of
at that centre at the time of survey completion. Lung America, 4Radiation Oncology, Thomas Jefferson
SBRT results are presented here. University/United States Of America, 5Radiation
Results: Thirty-two of the 41 RT centres (78%) Oncology, Cleveland Clinic/United States Of
in Canada responded. Currently, 45% (14/32) are America, 6Radiation Oncology, Stanford University
treating patients with SBRT, of which 13 (93%) & Cancer Center/United States Of America, 7M.s.
are treating lung tumours. Nine centres began Hershey Medical Center/United States Of America,
8
lung SBRT within the previous 3 years and only 3 Radiation Oncology, Medical College Of Wisconsin/
United States Of America, 9Penn State Hershey and 69/35, 55-82/30-41 and 13-132/14-49 cc during-
Cancer Institute/United States Of America, 10Mcgill RT, respectively. The mean sensitivity/speciÀcity
University Health Center - Montreal General for GTV and MTV from STAPLE analysis were
Hospital/United States Of America, 11H. Lee 86%/99% and 86%/98% pre-RT, 66%/98% and
MofÀtt Cancer Center/United States Of America, 51%/99% during-RT, respectively. MTV volumetric
12
Radiation Medicine Program, Princess Margaret variations between physicians were not signiÀcant
Hospital/Canada, 13University Of Texas Medical compared to GTVs in either pre- or during-RT
Branch/United States Of America, 14Radiation scans (P>0.05). OAR volumes showed the greatest
Oncology, AfÀliate Of University Of Michigan/ variations, with maximum upto 4 fold greater than
United States Of America, 15Department Of minimum for one structure. For adaptive plans, 11/14
Radiation Oncology, Washington University/United centers escalated PTV doses >74 Gy, the remaining
States Of America 3 decreased OAR doses. Overall, plan A generated a
mean PTV dose of 73 Gy (95% CI 73-75) with MLD
Background: This RTOG developing concept is of 21 (95% CI 19-21) Gy. Plan Bs PTV dose was
to individualize adaptive radiotherapy (RT) based escalated to a mean of 82 Gy (95% CI 79-84), with a
on PET response during concurrent chemoRT for MLD of 18 Gy (95% CI 18-19). Plan B reduced the
stage III lung cancer. This study aimed to examine means of mean esophageal, heart V40, esophageal
the consistency across institutions of: 1) PET-based V60, and maximum cord doses, with a small increase
metabolic tumor volume (MTV) contouring versus (1.1 Gy) increase in maximum esophageal doses. All
CT-based gross tumor volume (GTV); and 2) the plan Bs had MLD<20 Gy. Figure shows the detailed
dosimetry of dose-adapted plans they produced. dosimetric differences between plan Bs and As of all
Methods: Fourteen RTOG Centers/AfÀliates individual centers.
planned on pre-RT and “during-RT” PET-CT scans Conclusion: Although differences in tumor and
of one T4N2M0 NSCLC of the right lower lobe. The OAR delineations were seen, variations in CT-GTV
initial plan (A) based on pre-RT PET-CT was to 74 and PET-MTV either pre- or during-RT were not
Gy. An adaptive plan (B) used “during-RT PET-CT” signiÀcant. All centers generated “during-RT PET”-
to create an adapted boost, after 50 Gy to the initial based adaptive plans with either PTV dose escalation
planning target volume (PTV). The Ànal adaptive or OAR dose reduction.
plan limited total mean lung dose (MLD) to 20 Gy, Keywords: Adaptive radiation therapy, Non-small
and other organs at risk (OARs) to institutional cell lung cancer, PET-CT
or RTOG0617 criteria. Target/OAR volumes and
doses and doses to 95% of PTV were compared
between centers. Agreement between institutions was Poster Session 1 – Radiotherapy Monday, 4 July 2011 12:15-14:15
analyzed using simultaneous truth and performance
level (STAPLE), an expectation-maximization P1.199 ENDOBRONCHIAL
algorithm. BRACHYTHERAPY IN THE
Results: TREATMENT OF LUNG AND PRIMARY
TRACHEAL CANCER: ELEVEN YEARS’
EXPERIENCE WITH IRIDIUM-192 HIGH-
DOSE RADIATION
Rachele Z. Grazziotin1, Márcio L. Reisner2, Edson
Toscano3, Aureliano Sousa3, Célia M.P. Viégas1,
Carlos M.M. Araújo1, Mauro Zamboni3
1
Radiation Oncology, National Cancer Institute
Of Brazil/Brazil, 2Radiation Oncology, Clinicas
Oncológicas Integradas/Brazil, 3Thoracic Surgery,
National Cancer Institute Of Brazil/Brazil
Background: Lung cancer is the leading cause

The mean, 95% conÀdence interval (CI), and of cancer mortality in both men and women Most
minimum-maximum of GTVs/MTVs were 146/128, of the cases are diagnosed at stage III or with
134-158/117-140 and 111-203/69-165 cc pre-RT, metastatic disease. In stage III patients, 50 - 75%
have local recurrence and disease progression basis of the RTOG acute morbidity criteria, RTOG
within the irradiated Àeld occurs in 33 to 50% grade I toxicities occurred in 11 patients (25%).
within 15 months. The vast majority of patients with There were no cases of fatal hemoptysis, Àstulae or
obstructive lesions are not curable so it is desirable to abscesses.
palliate these patients as quickly as possible without Conclusion: This study showed a high objective
compromising their quality of life. This study’s aim palliative response of HDREB in most of patients
was to assess outcome and toxicity of iridium-192 with advanced endoluminal lung and tracheal cancer,
high-dose-rate endobronchial brachytherapy with minor non-fatal complications and a low
(HDREB) for palliation of endobronchial and morbidity rate.
tracheal carcinoma. Keywords: brachytherapy, tracheal cancer,
Methods: Forty two patients with endobronchial endobronchial lung cancer, Radiotherapy
lung and tracheal cancer underwent HDREB, in a
total of 110 insertions, between 1998 and 2009, at the A revised/updated abstract may be included in
National Cancer Institute, in Brazil. All patients had the Late Breaking Abstract Supplement, available
previously undergone external beam radiotherapy at the 14th World Conference on Lung Cancer.
with a median dose of 45Gy (ranging from 20
to 75Gy) and 5 (13%) were also submitted to
chemotherapy. Six patients presented relapse in the Poster Session 1 – Radiotherapy Monday, 4 July 2011 12:15-14:15
bronchial stump, six presented tracheal invasion and
11 presented bronchial relapse (six in the right and P1.200 A PILOT STUDY USING 4D
Àve in left bronchus). All patients were submitted PET/CT TO DEFINE THE ITV FOR
to a Áexible Àberoptic bronchoscopy, under local PATIENTS WITH NON-SMALL CELL
anesthesia, to visualize the tumor location. A hollow LUNG CANCER (NSCLC) UNDERGOING
closed ended catheter was advanced beyond the RADIOTHERAPY (RT)
site of the obstruction. The distal and proximal Yolanda K. Aarons1, Danny Duplan2, Steven David2,
tumor limits were measured and the catheter was Tomas Kron3, Jason Callahan4, Aldo Rolfo1, David
positioned 3- 6 centimeters distal to the tumor area. Binns4, Alan Herschtal5, Michael Macmanus2, David
The application was performed with a high dose rate Ball2
1
Ir-192 afterloading, and the dose was prescribed at Radiotherapy, Peter MacCallum Cancer Centre/
1 cm from the source. The response was assessed Australia, 2Radiation Oncology, Peter MacCallum
by bronchoscopy and chest computed tomography Cancer Centre/Australia, 3Physical Sciences, Peter
at the end of treatment and one month after the last MacCallum Cancer Centre/Australia, 4Medical
HDREB session. Survival time and symptom control Imaging, Peter MacCallum Cancer Centre/Australia,
5
were calculated from the date of initiation of the Centre For Biostatistics & Clinical Trials, Peter
endobronchial brachytherapy. Overall survival was MacCallum Cancer Centre/Australia
calculated using the Kaplan-Meier method.
Results: There were 34 (81%) men and 8 (19%) Background: This study builds upon earlier work
woman, (median age of 57,5 years, ranging from investigating 4-Dimensional CT (4DCT) compared
28 to 72 years old). Twenty-nine patients (69%) to volumetric Positron Emission Tomography/CT
had squamous cell carcinoma, 11 (25%) had (3DPET/CT), to delineate the Internal Target Volume
adenocarcinoma, and 2 had (4%) primary tracheal (ITV), since both scans account for tumour motion
cancer. Thirty-two patients (75%) were submitted in different ways. As compared with PET where a
to three sessions of HDREB 7,5 Gy and 8 (19%) halo of reduced SUV (Standardised Uptake Value)
received two sessions of HDREB 7,5 Gy each intensity surrounding the tumour is mostly attributed
with a 2-week interval. Two (6%) received only to the tumour moving over a long acquisition time,
one fraction of 7,5 Gy. Bronchoscopic complete 4DCT is thought to be the gold standard. Although
regression of tumor occurred in 32 patients (75%) acceptable agreement between 4DCT and volumetric
and partial response (more than 30%) was assessed PET/CT ITVs was established, an inherent co-
in 10 ( 25%) patients. Tumor regression was registration error existed between the scans since
correlated with symptomatic relief of dyspneia. The they were acquired on separate scanners at different
overall survival was 56% in 15 months of follow times. Furthermore, as 4DCT lacks biological
up. The treatment-related morbidity was low. On the information inherent to PET, not all the biologically
active components of tumours were contoured tumour were contoured on 4DCT, particularly in
accurately. With the introduction of 4DPET/CT at patients with nodal involvement. Further patient
our institution, we aimed to determine if 4DPET/ accrual is necessary to conÀrm these Àndings.
CT could provide biological information as well as Keywords: 4DCT, 4DPET/CT, ITV, Radiotherapy
accurately model the ITV. Another paper will discuss
comparisons between 3DPET/CT and 4DPET/CT
volumes, while this paper will examine the inÁuence Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15
of 4DPET to deÀne the ITV for patients with lung
cancer undergoing radiotherapy (RT). P1.201 THE SPECIFIC FEATURES OF
Methods: Patients with pathologically proven MANAGEMENT AT PATIENTS WITH
NSCLC, due to undergo high dose palliative COMPLICATED LUNG CANCER.
(>36Gy) or radical (>60Gy) RT, and had some Armen S. Benyan1, Sergey Y. Pushkin2, Nikolay V.
degree of tumor motion were enrolled. Sequential Lyas3
1
4DCT and 4DPET scans coupled with the Varian Thoracic Surgery, Samara Regional Clinical
RPMTM system were acquired on an integrated PET/ Hospital/Russian Federation, 2Samara Regional
CT scanner (GE discovery STE8) with patients in Clinical Hospital/Russian Federation, 3Samara
the RT treatment position. Ten scans of both gated Regional Oncologic Hospital/Russian Federation
CT and PET data corresponding to a phase of each
patient’s respiratory cycle were reconstructed and co- Background: The patients with complicated lung
registered in the RT treatment planning system. ITVs cancer by acute suppurative diseases need in phasic
were contoured individually by a single radiation application of different methods of treatment. At
oncologist using blended 4DPET and 4DCT data Àrst, sanation of suppurative focus in lung or pleura
using our institutions protocol. ITVs were then and diagnostics have to be done. And if inÁammation
summed to create an aggregate volume (V4DPET/ has regressed and malignant tumor is conÀrmed, it is
CT
) and compared an ITV based solely upon 4DCT necessary to continue speciÀc treatment of tumor.
(V4DCT). Methods: In the department of thoracic surgery from
Results: Data from Àve patients has been analysed, 2000 to 2009 years 129 patients with complicated
two of which had mediastinal disease. Volume lung cancer were treated. The onset of a disease
analysis showed ITVs generated using 4DPET/ has symptoms of acute inÁammation. Acute lung
CT were larger than 4DCT ITVs in all cases. The abscess was diagnosed at 42 patients, perifocal
% difference between V4DPET/CT and V4DCT as well cancer pneumonia – at 42, pleural empyema
as a Concordance (C=2(V4DPET/CTƗV4DCT)/(V4DPET/ – at 23, pleurisy – at 26 patients. At Àrst we
CT
+V4DCT)) was calculated. A clinically signiÀcant perform the management of purulent disease and
difference was deemed to exist between the V4DPET/ diagnostics of lung cancer. All patients received
CT
and V4DCT if the relative difference between these intensive antibacterial therapy. At 60 patients with
volumes was more than 5%. The concordance pulmonary destruction we performed draining and
was considered to represent a clinically signiÀcant biopsy by Àberoptic bronchoscopy. At 12 patients
difference between these volumes when its value with pulmonary hemorrhage X-ray endovascular
was less than 0.95. The difference between V4DPET/ occlusion of the bronchial arteries was done. At
CT
and V4DCT was consistently over 5% for both patients with pleural empyema we used draining (14
primary disease (12% to 28%) and nodal disease patients), surgical thoracoscopy with sanation and
(53%). Conformity Index for V4DPET/CT and V4DCT was biopsy (13 patients), and punctures (20 patients).
consistently inferior to 0.95 for both primary (0.59 Results: The results of Àrst treatment period can be
to 0.84) and nodal disease (0.13 to 0.45) suggesting evaluated by the possibilities of special treatment in the
a clinically signiÀcant difference between volumes second period. On that period, when diagnosis of lung
deÀned using 4DPET/CT compared to 4DCT alone. cancer was conÀrmed, we applied different methods
Conclusion: Preliminary results found ITVs of special treatment. Surgical treatment, including
generated using 4DPET/CT were larger and combined operations, was performed at 38 patients.
signiÀcantly different to those using 4DCT alone, There were: 14 pneumonectomies, 15 lobectomies, 4
demonstrating a clinical impact when using 4DPET bilobectomies, 3 atypical lung resections. 44 patients
to delineate the ITV. However, as 4DCT lacks were directed on a chemotherapy and radial therapy.
biological information inherent to PET, not all avid Mortality was 9 patients (7%).
Conclusion: At patients with complicated lung pediculated muscle Áap was successfully used.
cancer the phasic application of different methods Conclusion: Fistula between the respiratory
of treatment is necessary. Primary therapy of acute and gastrointestinal tracts is a potentially fatal
purulent disease helps to improving of results of complication requiring early intervention and
special treatment. recurrence or metastatic cancer must be ruled out.
Keywords: Tracheogastric Àstula,, Surgery,
Mediastinal infection,

Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15
P1.203 MIDDLE LOBE SYNDROME

CAUSED BY ENDOBRONCHIAL
MALIGNANT TUMOR
Krzysztof Kurowski1, Jolanta I. Matuszek2, Carlos
Francisco M. Nunez2
1
Thoracic Surgery, Hospital De Torrevieja/Spain,
2
Hospital De Torrevieja/Spain
Keyword: ararat
Background: Review of the major literature dealing
A revised/updated abstract may be included in with the right middle lobe syndrome (RMLS) shows
the Late Breaking Abstract Supplement, available that benign inÁammatory disease is the most common
at the 14th World Conference on Lung Cancer. etiological factor (62%). However, 22% of patients
reviewed had malignant tumors as a cause of the
syndrome. Bronchial occlusion is the pathophysiological
Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15 abnormality leading to the development of the RMLS
has been rejected by more recent authors.
P1.202 MANAGEMENT OF A DIFFICULT Methods: We described a case of a 26-year-old man
TRACHEOGASTRIC FISTULA who presented massive hemoptysis. He was found to be
Krzysztof Kurowski1, Jolanta Iwona Matuszek2, bleeding from a endobronchial tumor on the right middle
David Costa Navarro3 lobe oriÀce.
1
Thoracic Surgery, Hospital De Torrevieja/Spain, Results: The Surgical treatment was undertaken and
2
Division Of Anaesthesiology/Spain, 3Division Of superior bilobectomy was successfully performed.
General Surgery/Spain Postoperatively the patient was clinically and
radiologically disease-free.
Background: Granulomatous infection, foreign Conclusion: Diagnosis of right middle lobe syndrome
bodies, and trauma used to be the most common (RMLS) is mainly based on the presence of atelectasis
causes of benign acquired Tracheoesophageal of the right middle lobe of long duration. Rule out
Àstulas. acute right middle lobe pneumonia with repeat chest
Methods: Added to these were Àstulas from radiography within 3-4 weeks of initial onset. Surgical
complications of surgical procedures as treatment should be performed if malignancy is
Tracheogastric Àstula after Akiyama procede due suspected or if medical therapy fails.
to esofageal cancer appears as a rare complication. Keywords: Middle lobe syndrom, Endobronchial
Various treatment options have been described and tumor, Haemoptysis, Surgery
the general consensus is to use stents to cover them
and relieve patient symptoms, that in our case failed. A revised/updated abstract may be included in
Results: We describe a case in which a surgical the Late Breaking Abstract Supplement, available
treatment - closure of tracheogasrtric Àstula with at the 14th World Conference on Lung Cancer.
P1.204 THORACOSCOPIC TALC

PLEURODESIS WITH HYPERTHERMIC
INTRAPLEURAL CHEMOTHERAPY
TO TREAT NSCLC WITH PLEURAL
DISSEMINATION
Lei Yu, Jian-Ye Li, Fei Li, Yun-Feng Zhang
Department Of Thoracic Surgery, Beijing Tongren
Hospital, Capital Medical University/China Conclusion: Thoracoscopic talc pleurodesis with
hyperthermic intrapleural chemotherapy seems to
Background: The treatment of Non-Small-Cell be proÀtable to NSCLC with malignant pleural
Lung Cancer (NSCLC) with malignant pleural effusions and, along with chemoradiation, have an
effusions remains controversial. Its prognosis is encouraging impact on improving the survival time
poor. The purpose of our study is to discuss about of NSCLC with malignant pleural effusions.
thoracoscopic talc pleurodesis with hyperthermic Keywords: Non-Small-Cell Lung Cancer, malignant
intrapleural chemotherapy combined with pleural effusions, thoracoscopic talc pleurodesis,
chemoradiation to treat NSCLC with pleural hyperthermic intrapleural chemotherapy
dissemination.
Methods: From 2005 to 2008, there were 45 NSCLC
patients with malignant pleural effusions undergoing Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15
thoracoscopic talc pleurodesis with hyperthermic
intrapleural chemotherapy at our department. P1.205 SARCOMATOID CARCINOMA OF
With the help of video-assisted thoracoscopy, the THE LUNG; IS CURRENT SURGICAL
hyperthermic perfusion system was set up for INDICATION REALLY BENEFICIAL?
hyperthermic intrapleural chemotherapy. Before Joon Suk Park1, Yong Jik Lee2, Joung Ho Han3, Hong
the hyperthermic perfusion system worked, it was Kwan Kim1, Yong Soo Choi1, Jhingook Kim1, Young
necessary to heat Sodium Chloride 0.9% Normal Mog Shim1, Kwhanmien Kim1, Sumin Shin4
1
Saline 4500-5000ml up to 43°C and cisplatin Department Of Thoracic And Cardiovascular
(100 mg/m2) was added. The thoracic cavity was Surgery, Samsung Medical Center/Korea,
2
perfused at a speed of approximately 1.8-2.3 L/ Department Of Thoracic And Cardiovascular
min with 0.9% Normal Saline. The intrathoracic Surgery, Asan Medical Center/Korea, 3Deparment
temperature remained between 42°C to 43°C. The Of Pathology, Samsung Medical Center/Korea,
4
process of perfusion lasted for 2 hours. After that, Departement Of Thoracic And Cardiovascular
talc pleurodesis was made. 15 to 20 days after Surgery, Samsung Medical Center/Korea
thoracoscopy, chemotherapy and radiation therapy
were also involved one after another. Background: Sarcomatoid carcinoma of the lung
Results: There were no peri-operative deaths. is a rare and aggressive subtype of non-small cell
During the hyperthermic perfusion, patient’s core lung cancer (NSCLCa), with distinct differences
temperature varied from 36.2ºC and 39.3ºC and from other NSCLCa. Based on our experience, we
pulse from 58/m and 128/m. Intraoperative sinus explored the clinical characteristics, prognostic
tachycardia occurred in 4 old cases. No hematologic factors, and outcome of this tumor, seeking clues to
toxicity and nephrotoxicity was observed within diagnosis and treatment.
one week after surgery. Postoperative pneumonia Methods: Among 4212 patients who underwent
occurred in 3 old cases. 2 patients died within 3 curative resection for NSCLCa from September
months after the therapy. After this therapy, the 1994 to December 2009, the pathologic examination
metastasis in the pleural wall dwindled markedly in identiÀed 99 patients with sarcomatoid carcinoma.
11 patients (Figure 1). Median survival time for all Medical records of patients were reviewed
patients was 15.5 months (2 months to 51 moths). retrospectively.
No recurrence of pleural effusion was observed.
Results: Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15
P1.206 VIDEO-ASSISTED
THORACOSCOPIC SURGERY
LOBECTOMY FOR LUNG CANCER: THE
LEARNING CURVE
Hui Zhao1, Jun Wang2
1
Thoracic Surgery, People’s Hospital, Peking
University, Beijing/China, 2People’s Hospital, Peking
University, Beijing/China
Background: Video-assisted thoracoscopic surgery

(VATS) lobectomy is an acceptable alternative to
open lobectomy for treating early stage lung cancer.
As with any video-assisted surgical procedure, there
is a learning curve to overcome before becoming
The mean follow-up period was 16.07 months. proÀcient. In this study, the outcomes of 90
Thirty-six patients had pathologic stage I disease, consecutive VATS lobectomies for lung cancer were
31 stage II, 28 stage III, and 4 stage IV. Surgery evaluated to determine the learning curve for this
included 2 wedge resections, 67 lobectomies, 17 procedure.
bilobectomies, and 13 pneumonectomies. There Methods: A single group of surgeons performed
were 90 patients with pleomorphic carcinoma, 6 VATS lobectomy with systematic lymph node
spindle cell carcinoma, one giant cell carcinoma, dissection in 90 lung cancer patients between
one carcinosarcoma, and one pulmonary blastoma. September 2006 and January 2009. The patients
Overall 5-year survival was 54.3%. Forty-three were divided equally and chronologically into three
patients (43.4%) experienced recurrence and 42 groups (group A, B, and C), with group A being
of these died of the cancer. Pathologic T stage the earliest group of patients treated. Clinical data
as deÀned by the 7th IASLC staging system were collected. The operative time, blood loss,
was signiÀcantly associated with survival and number of dissected mediastinal lymph nodes and
recurrence (P = 0.004 and 0.002, respectively). Mean nodal stations, conversion rate to thoracotomy,
Positron Emission Tomography (PET) uptake was postoperative complications, duration of chest
signiÀcantly higher than other types of lung cancer drainage, and hospital stay duration were compared
(P < 0.0001). between the three groups.
Conclusion: The prognosis of sarcomatoid Results: There were no differences between the three
carcinoma was distinctly unfavorable than for other groups with respect to age, gender, size of tumor,
NSCLCa, especially in advanced disease. In the case pathological stage and operative procedure (table 1.).
of a large peripheral tumor with high PET uptake, The operative time and blood loss were signiÀcantly
intense effort should be made to obtain an accurate lower in groups B and C than in group A (P<0.01);
preoperative histological diagnosis. Indications however there were no differences between groups B
for surgery with sarcomatoid carcinoma should be and C. There were no differences among the groups
reconsidered. in the number lymph nodes harvested, conversion
Keywords: Positron Emission tomography, rate, postoperative complications, duration of chest
Sarcomatoid carcinoma of the lung, Non-small cell drainage, or hospital stay duration (table 2.).
lung cancer Conclusion: A learning curve for VATS lobectomy
existed in this series. The surgeon became more
proÀcient after 30 to 60 cases, and was able to
perform the procedure with decreased blood loss and
operative time.
Keywords: Lung cancer, Video-assisted
thoracoscopic surgery, lobectomy, Learning curve
Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15 of the affected chest wall) was performed and
followed by immediate intra-operative pathological
P1.207 LOBECTOMY FOR examination of the tumor. The deÀnitive diagnoses
INDETERMINATE LUNG TUMORS in Cases 1, 2, 3 and 4 were moderately differentiated
WITH A STRONG SUSPICION OF LUNG squamous cell carcinoma pT2aN2M1b (chest
CANCER wall), pleomorphic carcinoma pT4 (intrapulmonary
Noritoshi Nishiyama, Koshi Nagano, Nobuhiro metastasis in the right lower lobe) N1M1b (brain),
Izumi, Keiko Tei, Shoji Hanada, Hiroaki Komatsu bronchioloalveolar carcinoma pT3N0M0 (including
Thoracic Surgery, Osaka City University Hopspital/ the inÀltrative shadow around the tumor), and
Japan moderately differentiated papillary adenocarcinoma
pT1bN0M0, respectively.
Background: For tissue diagnosis of an Conclusion: In certain circumstances, lung tumors
indeterminate lung tumor with a strong suspicion of with a strong suspicion of lung cancer should
lung cancer, wedge resection is sometimes difÀcult be resected by lobectomy followed by thorough
because of tumor size or location. Intra-operative pathological examination, without pre-resectional
needle aspiration biopsy can be considered when diagnosis. One of these conditions is when
tumor biopsy via Áexible bronchoscopy (FB), or lobectomy is expected to result in a more favorable
using transthoracic needle aspiration biopsy (TTNA), patient status, regardless of deÀnitive diagnosis
fails to prove malignancy in tumors with a high where larger tumor volume is involved. A second
rate of false negatives. There are numerous lesions condition is when the lesion is deeply located near
where an easy wedge resection or TTNA cannot be the major pulmonary vessels, and is not a candidate
carried out, and lobectomy followed by thorough for wedge resection or segmental resection. The
pathological examination is required. following conditions are common to each case:
Methods: From April through September in 2010, curative resection should be performed, detailed
35 patients underwent lobectomy for primary lung informed consent is required including risks of
cancer. Of these, four patients with indeterminate lobectomy for deÀnitively benign disease, and the
lung tumors who underwent lobectomy followed by patient should have good tolerance to surgery.
thorough pathological examination were reviewed. Keywords: lobectomy, lung cancer surgery, lung
Results: The age and gender of case No.1 to 4 was cancer diagnosis
a 75-year-old man, a 70-year-old woman, a 46-year-
old man, and a 75-year-old woman, respectively.
The size and location of the lesion in each case Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15
was a 35 mm tumor in the left lower lobe, a 35 mm
tumor in the right lower lobe, a 7 cm mass in the P1.208 EXTENDING INDICATIONS OF
right upper lobe involving the chest wall, and a 20 ROBOTIC SURGERY FOR THORACIC
mm tumor in the left upper lobe near the pulmonary TUMORS
artery across the upper and lingular segments, Naohiro Kajiwara1, Masahiro Taira1, Koichi
respectively. Positive emission tomography showed Yoshida1, Masaru Hagiwara1, Masatoshi Kakihana1,
accumulation of SUVmax 2.9~3.5 in case No.1 and Hisashi Saji1, Jitsuo Usuda1, Tatsuo Ohira1, Norihiko
SUVmax 4.5 in case No.3 in the tumor and serum Kawate2, Norihiko Ikeda1
1
carcinoembryonic antigen (CEA) was elevated to Surgery, Tokyo Medical University/Japan, 2Health
13 ng/ml in case No.1 and 9 ng/ml in No.2 (normal Science And Social Welfare, Waseda University
range; < 5.0 ng/ml). In all four patients, although School Of Human Sciences/Japan
lung cancer was strongly suspected, transbronchial
biopsy through FB failed to prove malignancy. Background: Recently, we reported the utility of the
The patients were recommended surgery without da Vinci® Surgical System and its later version (the
TTNA. During surgery, intra-operative incisional da Vinci® S) for various types of anterior and middle
biopsy or needle biopsy were avoided because of the mediastinal tumors in clinical practice. We evaluated
possibility of a false negative result, or due to the the feasibility, safety and appropriate settings of this
tumor being in a difÀcult location to successfully system for the surgical treatment of these tumors.
achieve a deep puncture. In each case, lobectomy Methods: In this study, we evaluated extending the
(in Case 2 lobectomy was combined with resection indications for the surgical treatment of posterior
mediastinal tumors which including those located Methods: 10 patients aged 85 years or older who
beside upper vertebrae, beside the aorta and the chest underwent surgery for non-small cell lung cancer at
wall (including the pleura) using the da Vinci® S our hospital between 2000 and 2010 were studied.
Surgical System. The patients gave written informed The patients’ medical records were reviewed with
consent to undergo robotic surgery using the da type of operation, histological diagnosis, coexisting
Vinci® S Surgical System. disease, smoking history, postoperative morbidity,
Results: All resected tumors were benign tumors mortality and survival results.
histologically. Robotic surgery enables treatment Results: There were seven men and three women
for various types of tumors which are located in a with a mean age of 86.1 years (range,85-89). 7
variety of sites, such as the posterior mediastinum, patients were smoker. Coexisting disease was 5
and chest wall. In particular, to dissect tumors patients (one patient had FEV1% less70%, one
located beside the aorta, or beside upper thoracic patient had cardiovascular disease, one patient had
vertebrae are very difÀcult to reach, making resection FEV1 less1000ml, one patient had dementia and one
with the conventional video-assisted thoracoscopic patient had erythroderma). Adenocarcinoma was
surgery technique extremely difÀcult. However, identiÀed in 8 patients and squamous cell carcinoma
all such procedures by robotic surgery using the da was identiÀed in 2 patients. Lung resection was
Vinci® S were performed safely and more easily than performed 4 lobectomies, 3 segmentectomies
by conventional thoracoscopic surgery. and 3 wedge resections. All patients were clinical
Conclusion: Robotic surgery enables dissection stage1 and pathological stage1. The incidence
of thoracic tumors located in sites that are difÀcult of postoperative complications was 40%(atrial
to reach, more safely and easily than conventional Àbrillation 2 patients, heart failure 1 patient, delirium
video-assisted thoracoscopic surgery and less 1 patient). All patients are still alive(median follow-
invasively than by open thoracotomy. Care in up 29.5 months, range 2months-103months) and no
selecting the appropriate settings, which depend recurrence.
on tumor location, is the most important point Conclusion: Surgery in patients aged 85 years or
for robotic surgery for such lesions. Crucial to older affected by non-small cell lung cancer is safe
the success of these operations were selecting the and feasible when careful preoperative respiratory
appropriate placement and the angle of the da Vinci® and cardiac studies have been carried out. Long term
special surgical ports in relation to the target and survival for patients aged 85 years or older with early
patients’ position, which varied according to the stage lung cancer treated by pulmonary resection is
tumor location. expected.
Keyword: Robotic surgery Keyword: osamucha
Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15 Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15
P1.209 SURGERY OF NON-SMALL CELL P1.210 CHEST WALL AND STERNAL

LUNG CANCER IN THE ELDERLY RESECTION FOR PRIMARY OR
ESPECIALLY AGED 85 YEARS OR SECONDARY TUMORS, OUR
OLDER EXPERIENCE IN SINGLE UNIT IN
Osamu Kawamata ALBANIA.
Surgery, Onomichi Municipal Hospital/Japan Fadil Gradica1, Agron Menzelxhiu1, Alma Cami2,
Epaminonda Fype2, Fahri Kokiqi2, Ilir Skenduli1,
Background: Japan is becoming the aging Rezart Oketa1, Ilir Peposhi3, Zef Perduka3, Dhimitraq
society, and aging goes ahead through Onomichi Argjiri4, Fatmir Caushi1
1
in particular(75years and older 10.4% in Japan Thorax Surgery Service, University Hospital
comparison to 16.3% in Onomichi). Due to the aging Of Lung Disease/Albania, 2Anestesireanimation
of the general population, non-small cell lung cancer Department, University Hospital Of Lung Disease/
is a typical disease of the elderly, and is becoming Albania, 3Pneumologie, University Hospital Of
increasingly. This study investigated the criteria for Lung Disease/Albania, 4Pneumologye Department,
surgery in non-small cell lung cancer patients aged University Hospital Of Lung Disease/Albania
85 years or older.
Background: Chest wall resection involves Keyword: Sternectomy • Sternal tumor • Plastic
resection of the ribs, sternum, costal cartilages and repair • Long-term survival
the accompanying soft tissues and the reconstruction
strategy depends on the site and extent of the
resected chest wall defect . Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15
Methods: From December 2003, to December
2008, 18 patients underwent chest wall resection P1.211 ANATOMIC MISADVENTURES
and reconstruction with prosthetic material at the DURING ROBOTIC LOBECTOMY
University Hospital of Lung Disease ,thorax surgery Jane Upson1, Arthur T. Martella2
1
division . There were 18 patients (13 male and 5 Surgery, Phoenixville Hospital/United States Of
female ,rate M/F 13:5). The median age was 53 America, 2Surgery, University Of Pennsylvania/
years and ranged from 16 to 65 years. The indication United States Of America
for resection was primary chest wall and sternal
malignancy in 10 patients (55.5%) (5 patients Background: The robotic approach for lobectomy
osteosarcom 3 patients condrosarcom ,2 solitare offers certain advantages over the traditional VATS
plasmocitoma), recurrent chest wall malignancy in 3 approach. However, the high magniÀcation with the
patient(16.7%), contiguous lung cancer (NSCLC)in DaVinci Robot (10 – 15x), unfamiliar camera angles,
2 patient (11.1%), breast cancer recidive in 3 patient and the normal tendency for anatomic variations,
(16.7%).Often both ribs and sternum were included may lead to anatomic problems during robotic
in the chest wall resection. The median number lobectomy.
of ribs resected was 3 (range, 2-8 ribs). A partial Methods: We review 12 robotic lobectomy cases
sternectomy was performed in 12 patients (66.7%), that required conversion to a VATS procedure
and a subtotal sternectomy was performed in 6 or thoracotomy because of uncertainty about the
patient (33.3%). Two patients (11.1%) underwent anatomy. Three cases were at the home institution
pulmonary resection, which included upper and seven were at outside institutions.
lobectomy in 1 patient (5.5%), wedge excision in 1 Results: 12 patients (6 female, Mean age 68) had
patient (5.5%),two patients partial pericardectomi. attempted totally endoscopic robotic lobectomy
Results: Skeletal reconstruction was achieved with (RUL – 6, RLL - 3, LUL – 2, LLL – 1). There were
prosthetic material alone in 4 patients (22.2%) 3 identiÀable anatomic reasons for conversion.
and with Prosthetic materials covered by Áaps of Four patients were converted because of confusing
myocutaneous or muscle tissue were used (Prolen bronchial anatomy that upon direct inspection was
mesh and methylmethacrylat sandwich plastica)in due to a tendency for the dissection to drift up into
11 patients ( 61.1%), myocutaneous or muscle Áaps the lobe. This resulted in a need to divide more
alone in 2, and other techniques in the remaining 1. vessels and segmental bronchi beyond their branch
Soft tissue coverage was achieved with transposed points. Two additional RUL patients had uncertain
muscle in 14 patients, local tissue only in 1 patients. takeoff of the bronchus intermedius. Three patients
Muscles transposed included latissimus dorsi in 2 were converted during RLL due to confusion of a
patients, pectoralis major in 10 patients, serratus low take-off of the RML bronchus with the RLL
anterior in 2 patients. The resection was radical bronchus. 3 patients required conversion due to
in 15 cases and palliative in the other 3 cases . an incomplete minor and major Àssure making
No perioperative deaths occurred. After a median identiÀcation of normal structures difÀcult.
follow-up of 30 months, the overall 3-year survival Conclusion: Anatomic problems will occur during
was 48% and the 5-year survival 36%, with a median a totally endoscopic robotic lobectomy, particularly
survival of 40 months. In 10 patients with primary early in the learning of the procedure. Early division
tumor the 5-year survival after radical resection of all pleural attachments helps to isolate the target
was 53%, and in 8 patients with secondary invasion lobe from the rest of the lung. During RUL the minor
(direct extension or metastasis) the 5-year survival Àssure is frequently incomplete. Partially dividing
was 28% (median 25 months). the Àssure with an endoGIA stapler early on can help
Conclusion: Conclusions: Our experience maintain orientation. Use of the 4th arm improves
demonstrates that sternal resection is a safe and exposure and may facilitate moving from one area of
effective treatment, which may improve the patient’s dissection to another.
quality of life and achieve a long-term survival. Keywords: Davinci, Robotic, lobectomy
Results: For the 27 patients with distant metastasis

A revised/updated abstract may be included in alone, the 2-year progression-free survival rate
the Late Breaking Abstract Supplement, available after treatment was 17.7% with an 8 month of
at the 14th World Conference on Lung Cancer. median progression-free survival time. Of these
patients, 15 (56%) had oligometastatic disease.
The oligometastatic sites were the lung in 5
Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15 patients, brain in 3, bone in 3, lung and brain
in 2, adrenal gland in 1, and soft tissue in 1.
P1.212 POSTOPERATIVE Thirteen of the 15 patients Àrst received a local
OLIGOMETASTASES IN PATIENTS treatment, including radiotherapy or surgical
WITH NON-SMALL CELL LUNG resection. Three patients (lung, adrenal gland,
CANCER – CLINICAL MANIFESTATIONS soft tissue) received surgical resection, and 10
AND THE PROGNOSIS AFTER LOCAL other patients received radiotherapy. Two patients
TREATMENT with pulmonary oligometastases Àrst received a
Tokujiro Yano, Tsukihisa Yoshida, Yosuke systemic chemotherapy. On the other hand, of the 12
Morodomi, Kensaku Ito, Akira Haro, Yasunori patients with multiple metastases, 10 Àrst received
Shikada, Riichiroh Maruyama, Mitsuhiro systemic chemotherapy (3 platinum-doublets, 4
Takenoyama, Yoshihiko Maehara geÀtinib, 3 other agents). The remaining two patients
Surgery And Science, Kyushu University/Japan received best supportive care alone. The median
progression-free survival time was 15 months in the
Background: We previously reported a oligometastatic patients who received local treatment
retrospective study indicating the prognostic while it was 4 months in the multiply metastatic
impact of local treatment against postoperative patients who received systemic chemotherapy
oligometastases in patients with non-small cell (p<0.01).
lung cancer (NSCLC) (Yano et al. J Surg Oncol Conclusion: Local therapy, such as radiotherapy
2010; 102: 852-5). However, the previous study and surgery, is therefore suggested to be an effective
was not sufÀcient to determine the therapeutic Àrst-line treatment for patients with a postoperative
signiÀcance of local treatment against postoperative oligometastatic recurrence of NSCLC.
oligometastases since the conclusions were based Keywords: Non-small cell lung cancer,
on retrospectively collected data. In the present postoperative recurrence, Oligometastases, local
study, we observationally investigated postoperative therapy
oligometastatic cohorts and clariÀed the effect of
local treatment on the progression-free survival of
these patients. Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15
Methods: At Kyushu University Hospital from
October 2007 through December 2010, we P1.213 EVALUATION OF
experienced 44 consecutive postoperative recurrent RESECTABILITY OF LUNG CANCER
patients who had previously undergone complete INVADING LEFT MAIN PULMONARY
resections for NSCLC, which were performed ARTERY
from May 2004 through June 2010. The Àrst Mariko Fukui, Yoshikazu Miyasaka, Kazuya
recurrence site was loco-regional in 15 patients, Takamochi, Shiaki Oh, Kenji Suzuki
distant in 27 patients, and combined in 2 patients. Division Of Thoracic Surgery, Juntendo University
Of the 44 patients with recurrence, we reviewed School Of Medicine/Japan
27 patients with distant metastases alone for
their clinicopathological information, treatment Background: Left pnemonectomy is one of the
modality, and progression-free survival. The 27 most invasive procedures for lung cancer and
patients with distant metastases alone consisted of respectability frequently depends on the relationship
15 males and 12 females. The histologic types were between the left main pulmonary artery and lung
adenocarcinoma in 23, squamous cell carcinoma in cancer. The purpose of this retrospective study was
3 and other in 1. ‘Oligometastases’ was deÀned as to evaluate resectability of lung cancer invading left
limited recurrence with the potential to be controlled pulmonary artery and veins based on the Àndings on
with local treatment. thoracic computed tomography.
Methods: Retrospective study was performed Absence of pulmonary vein Áow indicated tumor
on consecutive 11 patients who underwent left embolus.
pneumonectomy for lung cancer at our institute Keywords: resectability, pneumonectomy, left, CT
between April 2008 and September 2010. The
radiological Àndings of thoracic computed
tomography were reviewed and investigated the Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15
relationship surgical outcome and these factors. The
distance between the left border of pulmonary artery P1.214 A RETROSPECTIVE STUDY:
and tumor is reviewed. PROGNOSTIC FACTORS OF STAGE IB
UPPER LOBE NON-SMALL CELL LUNG
Results: CANCER
Yang Shentu
Thoracic Surgery, Shanghai Chest Hospital/China
Background: Even after presumably curative

resection the 5-year survival rates are only 60–70%
in stage IB non-small cell lung cancer (NSCLC).
Existing studies viewed that compared to lower lobe
or middle lobe lung cancer, upper lobe lung cancer
was more prone to regional lymph node metastasis.
The purpose of this study is to explore the factors
related to the prognosis of stage IB upper lobe
NSCLC and the best way of lymph node dissection.
Methods: A retrospective study of 147 consecutive
subjects who had undergone curative resection for
stage IB upper lobe NSCLC was performed. Patients
who had received any adjuvant or neo-adjuvant
Left side pneumonectomy was performed on 11 chemotherapy were excluded. Survival time curves
patients. Ten were men. Five patients required were estimated using the Kaplan–Meier product
combined resection of other organs; left atrium in method and statistical differences were assessed
two, carina in one, eshophagus in one, esophagus using the log-rank test. The inÁuence of variables
and aorta in one. Among them, eight patients on the survival was analyzed by the Cox regression
underwent complete resection. Bronchial margin model.
was microscopically positive for tumor cells in Results: 3-year and 5-year overall survival rates
two patients, and one patient had residual cancer were 76.2% and 70.7% respectively; for patients
at esophagus. No surgical mortality was observed. with lesion in right upper lobe, they were 80.2%
Postoperative complications occurred in Àve and 73.5% respectively and for patients with lesion
patients (45%): atrial Àbrillation in two, leak of in the left upper lobe, they were 71.8% and 67.6%
esophagus in one, thrombocytopenia in one. As to respectively. There was no signiÀcant statistical
pulmonary artery, computed tomography revealed difference between the two groups in overall survival
tumor invading left main pulmonary artery in three (P=0.240). Both univariate and multivariate analysis
cases. The distance between the left border of showed that age, tumor size and number of removed
pulmonary artery and tumor (Figure1(d)) ranged 2.6 superior mediastinal lymph node stations were the
to 6.6mm. Among complete resection, 2.6cm is the important prognostic factors of stage IB upper lobe
shortest at our institution. As to pulmonary artery, NSCLC.
CT scan suggested pulmonary invasion. In patients Conclusion: In surgically treated stage IB upper
with absence of pulmonary vein Áow, 2 cases had lobe NSCLC patients, age, tumor size and number of
invasion and 3 cases had tumor embolus. Narrowed removed superior mediastinal lymph node stations
pulmonary vein was invaded. are the important prognostic factors of survival and
Conclusion: Invasion to pulmonary artery and vein lobe-speciÀc systematic lymph node dissection may
was predictable by CT Àndings. 2.6cm is limit for be a more efÀcient procedure.
pneumonectomy without extracorporeal perfusion.
A revised/updated abstract may be included in SCLC it was signiÀcantly worse – 0% and 18,6%
the Late Breaking Abstract Supplement, available respectively. Histological type of pulmonary
at the 14th World Conference on Lung Cancer. carcinoid was an important prognostic factor. The
5-year survival of patients with typical carcinoid
was signiÀcantly better: 100,0% versus 63,8% with
Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15 atypical carcinoid (p<0,05). The type of resection
did not inÁuence the survival. All patients after
P1.215 SURGERY OF NEUROENDOCRINE bronchoscopic resection of typical carcinoid are
LUNG TUMORS – A SINGLE alive without evidence of recurrence from 12 to
INSTITUTION EXPERIENCE IN 359 106 months. The prognosis in patients with positive
PATIENTS lymph nodes (N+) was worth then in patients
Oleg Pikin, Alexander Trachtenberg, Georgiy Frank, without lymph node metastases: 5-year survival rate
Konstantin Kolbanov, Victor Sokolov, Vladimir 43,6% and 86,2% respectively. The 5-year survival
Glushko, Ali Amiraliev in patients with stage I SCLC was 43,2%, stage II –
Thoracic Surgery, P.A.hertsen Moscow Research 22,0% and stage IIIA – 8,0%.
Institute Of Oncology/Russian Federation Conclusion: Neuroendocrine tumors of the lung
are heterogeneous group of pulmonary neoplasms.
Background: Neuroendocrine neoplasms of the Surgery with mediastinal lymphadenectomy is the
lung include pulmonary carcinoids (PC), large-cell treatment of choice for pulmonary carcinoid. The
neuroendocrine (LCNLC) and small-cell lung cancer most important prognostic factors are histological
(SCLC). The aim of this retrospecrive study is to type and lymph node status. LCNLC is a high-
evaluate how different prognostic factors (histology, grade neuroendocrine tumor with unfavourable
variant of surgical resection, lymph node status) outcome. Patients with stage I SCLC could be
impact on survival. treated in combination of surgery and chemotherapy,
Methods: 359 patients with pulmonary but its efÀcacy should be analyzed in prospective
neuroendocrine tumors were operated on in our randomized trials.
clinic from 1980 till 2009. According to WHO
criteria (1999), pulmonary carcinoid was diagnosed
in 235 (64,4%) (typical – in 138, atypical – in 97), Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15
LCNLC – in 12 (3,3%) and SCLC – in 112 (31,1%)
patients. Centrally located carcinoid was detected in P1.216 RESULTS OF VIDEO-ASSISTED
majority of patients – 192 (81,7%). Pneumonectomy THORACOSCOPIC PULMONARY
was performed in 36 (16,1%), lob/bilobectomy in 88 METASTASECTOMY
(37,4%), sleeve lobectomy – in 68 (28,9%), isolated Oleg Pikin, Konstantin Kolbanov, Vladimir Glushko,
sleeve bronchi resection – in 15 (6,4%) and sublobar Dmitriy Vursol, Ali Amiraliev, Dmitriy Astakhov
resection in 10 (4,2%) patients with pulmonary Thoracic Surgery, P.A.hertsen Moscow Research
carcinoid. Bronchoscopic removal of centrally Institute Of Oncology/Russian Federation
located carcinoid was performed in 18 (7,7%)
patients and was indicated in selective cases of Background: Video-assisted thoracic
typical carcinoid without evidence of peribronchial metastasectomy is not widely excepted and its
invasion. Mediastinal lymph node dissection was efÀcacy is controversial in patients with pulmonary
routinely performed in all cases. Metastases to the metastases of different origin. The study was aimed
regional lymph nodes were diagnosed in 3,0% of to evaluate short and long-term results of video-
patients with typical and in 32,9% of cases with assisted pulmonary metastasectomy in comparison
atypical carcinoid, while in patients with LCNLC with standard thoracotomy approach.
and SCLC metastases to the regional lymph nodes Methods: 94 consecutive patients with pulmonary
were detected in 66,7% and 61,6% respectively. All metastases operated on in the thoracic surgery
patients with SCLC received adjuvant chemotherapy. department of our clinic from 2004 till 2009
Results: Postoperative morbidity was 12,5% with were enrolled in the study. 80 patients undergone
mortality rate about 3,1%. The overall 5-year pulmonary metastasectomy for solitary lesion: video-
survival was 81,0% in patients with pulmonary assisted lung resection was performed in 42 patients
carcinoid, while in patients with LCNLC and (wedge resection – in 37, VATS lobectomy – in 5
patients), while standard postolateral thoracotomy Background: The azygos vein lobe is an anatomic
was used in 38 patients (control group). There were variant reported in 0.1 to 8% of the population and
no any differences in patients age, sex, histology results from an anomalous development of the right
of the primary tumor, disease-free interval, type lung upper lobe. Since the original description of a
of surgery (wedge resection/lobectomy) between tumor of the azygos vein lobe, in 1969, several cases
thoracoscopy and control group. Video-assisted have been reported in the literature. The presence of
pulmonary resections (11 – bilateral, 3 – unilateral) synchronous bilateral lung carcinoma is an other rare
using a hand-port for palpation were performed in 14 condition. Optimal treatment of synchronous lung
patients with multiple lesions. carcinomas remains controversial. The authors report
Results: Morbidity rate was 2,4% in thoracoscopy the Àrst clinical case of a 63 years old smoker man
group versus 5,3% in control group (not signiÀcant) after coronary artery bypass surgery, in which a chest
with no mortality. The mean hospital stay was 5,2 days x-ray revealed a large mass in the left upper lobe and
after video-assisted thoracoscopy resection versus 9,6 small lesion in the azygos vein lobe.
days after open procedure. Overall 1, 3 and 5-year Methods: The Computed Tomography and Positron
survival in thoracoscopy group was 87,8%, 54,3%, Emission Tomography of the chest revealed a 13mm
36,8% that was very similar to control group – 82,3%, positive speculated nodule in the azygos vein lobe
50,8% and 34,2% respectively. There were not any and a 60mm solid central mass of left upper lobe,
statistical differences in overall and disease-free without mediastinal lymphadenopathy or distant
survival between two groups (log-rank, 0.078). The metastasis. Needle Biopsy of the left lung mass
recurrence in the operated lung was diagnosed in 11,9% revealed a squamous cell primary lung carcinoma.
of patients (local – 4,7%) in the thoracoscopy group and The patient was planned for video-assisted surgery
in 10,5% of patients (local – 5,2%) in the control group of right lesion to exclude metastatic disease. At
(p>0.05). Among 14 patients with multiple metastases surgery the mediastinal pleura was open on the
operated on using a hand-port for palpation 7 additional azygos vein, the azygos lobe was removed beneath
lesions (metastases – 4, benign – 3) were found in 4 the vein and resected anatomically. Pathologic
patients. 5-year survival in patients after resection of examination revealed primary lung adenocarcinoma.
multiple metastases was 21,7%. The patient recovered from the Àrst operation and
Conclusion: Video-assisted thoracoscopy pulmonary left thoracotomy with left upper curative lobectomy
metastasectomy in patients with solitary subpleural was done two weeks later.
lesion is an effective and safe procedure with Results:
survival very close to the standard thoracotomy
approach. In patients with multiple metastases
video-assisted thoracic surgery using a hand-port
for palpation is minimally-invasive tool that helps to
Ànd small additional lesions.
P1.217 SYNCHRONOUS AZYGOS VEIN

LOBE ADENOCARCINOMA AND
LEFT UPPER LOBE SQUAMOUS CELL
CARCINOMA IN A MAN AFTER OPEN
HEART SURGERY.
Michael Papiashvilli1, Henri Hayat2, Letizia
Schreiber3, Lior Sasson1, Israel E. Priel4
1
Cardio-thoracic Surgery Department, Edith Wolfson
Medical Center/Israel, 2Department Of Oncology,
Edith Wolfson Medicalcenter/Israel, 3Department
Of Pathology, Edith Wolfson Medical Center/Israel,
4
Department Of Pulmonary Medicine, Edith Wolfson
Medical Center/Israel
200 mL/day and remained serous upon trying fatty

Our case showed the Àrst report of synchronous ice cream.
azygos vein lobe adenocarcinoma (Àg.1) and Results: Thirty-seven patients (2.3%) had
left upper lobe squamous cell carcinoma (Àg.2) postoperative chylothorax develop. There were 33
successfully treated surgically by combined men and 4 women with a median age of 69 years
thoracoscopic and open approaches. (range 44 to 84 years). The initial procedures were
Conclusion: The selected patients with synchronous pneumonectomy in 1 patient and lobectomy in
lung carcinoma may beneÀt from an aggressive 36 patients. Twenty-three (62%) patients had the
approach, Àrst distinguishing between contralateral condition cured with low fat diet only. Ten (27%)
metastasis and a second removing bilateral lung patients underwent OK-432 pleurodesis, and 8 of
cancer at early stages, that in our case obtained them were cured with continued low fat diet. These
optimal results also by preserving the postoperative 31 (84%) conservatively-cured patients resumed
lung function as much as possible. a normal diet at a median of 10 days after initial
Keyword: Synchronous lung carcinoma, Azygos surgery (range: 5 - 27 days). The remaining 6 (19%)
vein lobe carcinoma, Thoracoscopy, Lung Cancer patients underwent reoperation and were cured
and discharged at a median of 18 days after initial
surgery (range: 14 - 33 days).
P1.218 LOW FAT DIET FOR

CHYLOTHORAX AFTER PULMONARY
RESECTION AND LYMPH NODE
DISSECTION FOR PRIMARY LUNG
CANCER
Junji Yoshida, Teruhisa Takuwa, Keiju Aokage,
Tomoyuki Hishida, Mitsuyo Nishimura, Kanji Nagai
Department Of Thoracic Oncology, National Cancer
Center Hospital East/Japan
Background: We reviewed our experience with

iatrogenic chylothorax after pulmonary resection
for primary lung cancer to evaluate our low fat diet
management strategy.
Methods: From October 2003 through March Conclusion: Our management strategy of low fat
2010, a total of 1580 patients underwent lobectomy diet and OK-432 pleurodesis cured conservatively
or greater and systematic mediastinal lymph node more than 80% of chylothorax after pulmonary
dissection for primary lung cancer at our division. resection with systematic mediastinal lymph node
Chylothorax was diagnosed on the basis of chylous dissection within 4 weeks after initial surgery.
leakage from the chest tube and was conÀrmed Indicating surgical intervention based on chest tube
by an elevated triglyceride level (> 110 mg/dL) in drainage of more than 500 mL during the Àrst 24
the drainage Áuid. We initially treated chylothorax hours after low fat diet appeared valid.
patients conservatively with low fat diet (fat intake Keywords: chylothorax, primary lung cancer,
< 10 g/day), prohibiting any other fat-containing surgical resection, management
food or drink. If chest tube drainage was more than
500 mL during the Àrst 24 hours after low fat diet,
surgical intervention was indicated. If chest tube
drainage was more than 300 mL/day after 3 days of
low fat diet, we performed pleurodesis by injecting a
preparation of OK-432, penicillin-treated lyophilized
preparation of a Streptococcus strain, into the
thoracic cavity through a chest tube. A cure was
diagnosed when chest tube drainage was less than
Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15 pulmonary resection for lung cancer, are to make
operation time shorter and to reduce blood loss. Once
P1.219 IS HIGH-DOSE the ARDS has occurred for the lung cancer resection
GLUCOCORTICOID THERAPY patients, especially for the acute phase cases, the
EFFECTIVE FOR ACUTE RESPIRATORY immediate use of the high-dose glucocorticoid is
DISTRESS SYNDROME AFTER essential because the outcome of ARDS is very
PULMONARY RESECTION FOR LUNG lethal.
CANCER? Keywords: glucocorticoid therapy, acute respiratory
Ken Miwa, Yasuaki Kubouchi, Yohei Yurugi, Yuzo distress syndrome
Takagi, Tomohiro Haruki, Shinji Fujioka, Yuji
Taniguchi, Hiroshige Nakamura
General Thoracic Surgery, Tottori University Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15
Hospital/Japan
P1.220 SURGICAL TREATMENT FOR
Background: Acute respiratory distress syndrome OCTOGENARIANS WITH LUNG
(ARDS), a frequent lethal postoperative outcome, CANCER −RISK ASSESSMENT
follows after the pulmonary resection for a lung USING “LUNG AGE” AND CHARLSON
cancer. For patients in the acute phase stage, the CORMOBIDITY INDEX−
glucocorticoid infusion has been applied and has Hiroshige Nakamura, Yuji Taniguchi, Tomohiro
rescued some cases. The aim is to investigate the risk Haruki, Ken Miwa, Shinji Fujioka, Yuzo Takagi,
factors of ARDS and analyze the efÀcacy of a high- Yohei Yurugi, Yasuaki Kubouchi
dose glucocorticoid therapy in lung cancer patients General Thoracic Surgery, Tottori University
who have received the pulmonary resection. Hospital/Japan
Methods: Among 526 lung cancer with resection
cases from January 2005 to December 2010 in Background: With the increasing life span, elderly
our institution, 24 cases (4.6%) had preoperative patients with non-small cell lung cancer (NSCLC)
interstitial pneumonia, and 8 cases (1.5%) had are increasing. This retrospective study was designed
postoperative ARDS. to make a risk assessment of the surgical treatment
Results: We analyzed risk factors of ARDS for patients aged 80 years or older using “lung age”
(preoperative PaO2, %VC, FEV1.0%, CRP, LDH, and Charlson cormobidity index (CCI).
KL-6, area of interstitial pneumonia, degree of Methods: Patients aged 80 years or older with
emphysema, operative methods, operative time, NSCLC who received surgical treatment in the
perioperative blood loss, perioperative hypoxemia period of January 2000 to May 2010 were reviewed.
management, histology, histological grade, and Total number of patients was 68 (gender; 49 men
pathological stage). The operative time and the and 19 women, mean age; 82.5, range; 80 to 89).
blood loss during the operation were signiÀcant The surgical procedures comprised 37 lobectomy,
risk factors for ARDS. Among the 8 patients who 8 segmentectomy, and 23 wedge resection. “Lung
had developed ARDS after the cancer resection, 5 age” (the age of the average healthy individual
patients had preoperative IP, and 5 cases were in who would perform similar to them on spirometry)
acute phase and 3 in delayed phase. The patient was calculated using the methods advocated by the
with the ARDS received preoperative cralisromaisin Japanese Respiratory Society. Patients were classiÀed
and postoperative syverstat Na respectively for the in followed three groups by the difference between
prevention. For acute phase cases, they received “lung age” and “real age”. There were 14 patients in
syverstat Na and glucocorticoid for therapy. The low group A (”real age”-“lung age” > 5), 18 patients in
dose of glucocorticoid (the Àrst case 0.5g/day, the group B (5>=”real age”-“lung age” > -5), 36 patients
second case 1g/day for 3 days respectively) could in group C (”lung age”-“real age” > 5). Patients were
not rescue those patients from ARDS, so we applied also divided into two groups by CCI. There were
the higher dose of glucocorticoid, 3g/day for 3 days 52 patients with low CCI (CCI<3) and 16 patients
which resulted in 2 out of 3 rescued. Delayed phase with high CCI (CCI>=3). Operative complication
cases received 1g/day for 3 days of glucocorticoi and overall accumulative survival among groups
which rescued all. were analyzed and associated factors with operative
Conclusion: The keys to prevent ARDS after complication were investigated statistically.
Results: “Lung age” showed 69.5 years old in Group Hystological types were: squamous cell – 10, adeno
A, 82.3 in group B and 94.2 in group C. There were - 4, large cell - 2. At the time of diagnosis all patients
a lot of men and smokers in group C. The incidence were considered as unresectable or inoperable,
rate of respiratory complications and 5-year survival reasons were tracheal involvement (7), functional
rate were 7.1%, 85.1% in group A, 0%, 71.5% in intolerance to pneumonectomy (7) and N3 disease
group B, 19.4%, 56.5% in group C, respectively. On (2). Preoperative treatment included three cycles
the other hand, regarding CCI, patients with high of chemotherapy and two courses of endobronchial
CCI had signiÀcantly higher rate of men, smokers, PDT. During operation, after lung resection
sublobar resection of the surgical procedures. The (pneumonectomy – 8, carinal pneumonectomy
incidence rate of total complications and 5-year – 3, lobectomy - 5) intraoperative PDT of
survival rate were 17.3%, 71.4% in patients with resection margins (bronchial and vascular stumps,
low CCI, 50.0%, 53,3% in patients with high CCI. mediastinum) was done. Water-soluble chlorine e6
Logistic statistical analysis showed that ASA-PS, complex was used as a photo sensitizer in dose of
CCI, and “lung age” in respiratory complications 2 mg/kg. The interval between the injection and
and only CCI in all complications were signiÀcantly illumination was 2 hours. Red light at 662+1 nm
associated factors respectively . wavelength was used to achieve a total illumination
Conclusion: In the risk assessment of the surgical dose of 250 j/cm2.
treatment for octogenarian patients with lung Results: After preoperative treatment partial
cancer, “lung age” and CCI were very important response of tumor was achieved in all cases and
factors and also reÁect prognosis. Especially, for patients underwent surgery with radical intent.
patients with higher CCI, even if who underwent There was no any post PDT complication. 14
sublobar resection, having higher incidence rate of operations were R0, 2 – R1. No major postoperative
postoperative complications and poorer prognosis, complications noted except cardiac arrhythmia in
it will be very important to compare the outcome 3 patients (23%). Average period of follow-up was
with the less invasive treatments like stereotactic 16 months (4 to 30 months), all patients are alive
radiotherapy in the prospective study. without any signs of recurrence.
Keywords: NSCLC, Octogenarian, Surgical Conclusion: The Àrst experience of the combined
treatment, Lung age and CCI treatment including intraoperative PDT for
locally advanced NSCLC has shown safety and
effectiveness. Additional studies are needed to proof
Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15 the value of intraoperative PDT.
Keywords: Lung cancer, resection margins,
P1.221 INTRAOPERATIVE photodynamic therapy
PHOTODYNAMIC THERAPY - NEW
PROPOSED METHOD OF IMPROVING
SURGICAL RADICALISM IN STAGE III Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15
NSCLC
Andrey Akopov, Anatoly Rusanov, Garry Papayan, P1.222 OUTCOMES OF PATIENTS WITH
Valentina Molodtcova, Margarita Urtenova, Nikita LUNG ADENOCARCINOMA DIAGNOSED
Kazakov, Ivan Chistiakov TO HAVE PLEURAL DISSEMINATION
Research Institute Of Pulmonology, Pavlov State DURING SURGERY
Medical University/Russian Federation Madoka Kimura1, Haruyasu Murakami1, Hiroaki
Akamatsu1, Akira Ono1, Takehito Shukuya1,
Background: Incomplete resections for locally Hirotsugu Kenmotsu1, Yukiko Nakamura1, Asuka
advanced lung cancer remain an important Tsuya1, Tateaki Naito1, Toshiaki Takahashi1,
problem that needs to improve surgical techniques Masahiro Endo2, Takashi Nakajima3, Haruhiko
and options for combine treatment. To increase Kondo4, Nobuyuki Yamamoto1
1
the radicalism we proposed an intraoperative Division Of Thoracic Oncology, Shizuoka Cancer
photodynamic therapy (PDT) of resection margins. Center/Japan, 2Diagnostic Radiology, Shizuoka
Methods: 16 patients with central non small cell Cancer Center/Japan, 3Diagnostic Pathology,
lung cancer (12 men, 4 women) were prospectively Shizuoka Cancer Center/Japan, 4Division Of
included in the study (10 - IIIb, 6 – IIIa). Thoracic Surgery, Shizuoka Cancer Center/Japan
Background: Pleural dissemination detected Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15
by computed tomography is considered to be
unfavorable for patients with lung adenocarcinoma. P1.223 BLOOD COAGULATION FACTOR
However, the prognosis of patients with lung XIII IN PULMONARY RESECTION
adenocarcinoma diagnosed to have pleural Koshi Nagano, Notitoshi Nishiyama, Nobuhiro
dissemination at the time of surgery has not yet been Izumi, Takuma Tsukioka, Keiko Tei, Shoji Hanada,
fully assessed. Hiroaki Komatsu, Hidetoshi Inoue, Shigefumi
Methods: To describe the outcomes of platinum- Suehiro
based chemotherapy in patients with lung Thoracic Surgery, Osaka City University/Japan
adenocarcinoma in whom pleural dissemination
was found at exploratory thoracotomy with or Background: Alveolar Àstula is a common
without a videoscope, we reviewed the clinical complication after pulmonary resection and its
records of patients with lung adenocarcinoma who management is difÀcult in many cases. Blood
were admitted to Shizuoka Cancer Center between coagulation factor XIII is known to play a role
September 2002 and April 2009. in wound healing. We evaluated the possible
Results: A total of 19 patients were included in this association of peri-operative changes in blood
study. The median age was 65 years (range, 48-80 coagulation factor XIII with HbA1c that is a risk
years). Seven patients (37%) were females, and 8 factor for prolonged alveolar Àstula as well as with
patients (42%) were never-smokers. The EGFR total protein (TP) and albumin, and the possible
mutation data for 10 patients (53%) was available. Of association of post-operative factor XIII with
the 10 patients, 6 patients (60%) were positive for a duration of chest tube drainage.
mutation; 5 had exon 19 deletions and 1 had an exon Methods: In 27 patients who underwent pulmonary
21 point mutation (L858R). The PS, clinical TNM resection at our department and experienced
stage and platinum-based chemotherapy regimens air leakage for at least 2 days after-operation.
were as follows: 17 patients with PS 0, 2 patients with Preoperative factor XIII level was compared with
PS 1; 7 patients with stage IA, 8 patients with stage the value measured at 5 days postoperatively. Pre-
IB, 1 patient with stage IIA, 3 patients with stage operative HbA1c, TP, and albumin (measured within
IIB; 13 patients received carboplatin and paclitaxel, 7 days pre-operatively and at 5 days post-operatively)
2 patients received carboplatin and nab-paclitaxel, 1 were also measured as an indicator of nutritional
patient received carboplatin and gemcitabine, 1 patient status. We evaluated the relationship between factor
received carboplatin and paclitaxel plus bevacizumab, XIII and HbA1c, between factor XIII and TP, between
1 patient received cisplatin and pemetrexed plus factor XIII and albumin, and between post-operative
VEGFR-TKI, 1 patient received cisplatin and factor XIII and duration of chest tube drainage. For
gemcitabine. Of the 19 patients, 7 patients (37%) statistical analysis, t-test was used.
received additional EGFR-targeted therapy (geÀtinib Results: Six patients experienced a decrease in
or erlotinib). The median follow-up time was 30.7 factor XIII to 70% or under normal range that was
months (range 20.6-54.1 months). The median indication for administration of blood coagulation
number of treatment cycles of Àrst-line platinum- factor XIII. Patients were stratiÀed by pre-operative
based chemotherapy was 4 (range, 1 to 6 cycles), and HbA1c (within normal vs. higher than normal),
the overall response rate was 21.1% [95% conÀdence total protein and albumin measured 5 days post-
interval (95% CI), 8.5-43.3]. The median progression- operatively (within normal vs. lower than normal) to
free survival and overall survival were 10.4 months compare pre-operative and post-operative value of
(95% CI, 6.3-18.4) and 50.6 months (95% CI, 27.8- factor XIII. In this analysis, no signiÀcant difference.
not reached), respectively. Among the 17 patients who Conclusion: Factor XIII promotes crosslinks of
had reported sites of Àrst failure, 9 patients (53%) Àbrin in the early stages of wound healing. Thus,
developed locoregional tumor progression. factor XIII is considered to be consumed for lesion
Conclusion: Patients with lung adenocarcinoma in repair. Patients with diabetes mellitus, who show
whom pleural dissemination is found at surgery tend delayed wound healing, were expected to show
to have a favorable prognosis for survival. Additional a larger post-operative decrease in factor XIII
local treatment may therefore improve their clinical compared to non-diabetic patients. However, no
outcomes. signiÀcant difference.
Keywords: Pleural dissemination, Chemotherapy Keywords: Blood coagulation factor XIII, Alveolar Àstula
Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15 offer favorable postoperative outcomes as well as
saving pulmonary reserve and morbidities from
P1.224 LONG-TERM RESULT OF pneumonectomy. It must be considered preferentially
PARENCHYMA-SAVING CARINA over sleeve pneumonectomy for tumors invading
RECONSTRUCTION IN THORACIC carina.
MALIGNANCY Keywords: Carina reconstruction, Thoracic
Joon Suk Park1, Young Mog Shim1, Jhingook Kim1, malignancy
Hong Kwan Kim1, Sumin Shin2
1
Department Of Thoracic And Cardiovascular
Surgery, Samsung Medical Center/Korea, Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15
2
Department Of Thoracic And Cardiovascular
Surgery, Samsung Medical Center/Korea P1.225 PLACE OF COMBINED LUNG
RESECTION IN THE COMBINED
Background: In selected patients with TREATMENT OF RESECTABLE STAGE
tracheobronchial malignant tumors involving carina, II B AND III NON–SMALL-CELL LUNG
surgery can offer a chance of cure. However, due CANCER
to technical and oncological issues, most of carina Andrey V. Vazhenin, Marina N. Mironchenco,
reconstruction has been sleeve pneumonectomy, Andrey A. Lukin, Elena U. Lukina, Evgeniy O.
which is still associated with high early and late Manzhirev, Iakov A. Gnatuk
morbidity. Based on our experience, we explored Thorax Surgery, Chelabinsk Regional Oncology
the feasibility of parenchyma-saving carina Clinic/Russian Federation
reconstruction.
Methods: Between July 1996 and December 2010, Background: To evaluate whether combined lung
24 patients underwent surgery for malignant tumors resection and adjuvant radiotherapy could improve
involving carina, and their medical records and survival in respectable stage IIb, and III non–small-
follow-up data were retrospectively analyzed. cell lung cancer (NSCLC).
Results: Among the 24 patients, 18 had squamous Methods: Retrospective comparison of parallel
cell carcinoma, 5 had adenoid cystic carcinoma, groups is lead. It is included 135 pations with IIb,
and 1 had mucoepidermoid carcinoma. All patients III stage NSCLC. The combined lung resection or
had T3 or T4 tumors. Six parenchyma-saving pneumonectomy was executed to each patient. All
carina reconstructions with (n=5) or without (n=1) patients were divided into 4 groups. Group A consist
right upper lobectomy were performed via right of the patients with were made only pneumonectomy
thoracotomy. The other 18 patients received sleeve (n=60), group B consist of the patients, were undergo
right pneumonectomy via right thoracotomy (n=16) pneumonectomy and adjuvant radiotherapy (n=32).
or sleeve left pneumonectomies via sternotomy (n=1) The group C included the patients with were made
and bilateral thoracotomy (n=1). All the anastomoses only combined lobectomy or combined bilobectomy
were intact on follow-up bronchoscopic examination. (n=24), and group D included the patients with
No operative mortality occurred. Of patients with 18 were made combined lobectomy or combined
sleeve pneumonectomy, 2 experienced postoperative bilobectomy and adjuvant radiotherapy (n=19). It
acute respiratory failure, and another 2 had delayed has been executed 92 pneumonectomy (68,1 %),
postpneumonectomy empyema. One patient with 39 combined lobectomy (28,9 %) and 4 combined
carina reconstruction with RULobectomy underwent bilobectomy (3 %). Among them was 25,2 % of the
esophagocologastrostomy 8 years later due to expanded operations, 34,1% expanded and combined
delayed bronchoesophageal Àstula. During the operations, 28,1 % - combined resections and
median follow up of 30.0 months, 4 loco-regional 12,6 % - typical pneumonectomy. The most often
recurrence and 4 distant metastases were observed type of the combined operations was vasculoatrial
(7 after sleeve pneumonectomy and 1 after carina - 51 % (53 resections). The less often type was
reconstruction with RULobectomy). Ten late parietalodiaphragm resections - 13 % (13 resections).
deaths occurred and 5-year overall and disease-free There was executed 36 % of tracheobronhoplastycal
survivals were 54.3% and 59.9%, respectively. resections. In total 103 resections of thorax organ
Conclusion: Parenchyma-saving carina have been executed.
reconstruction for thoracic malignancy could Results: Postoperative Morbidity was 4,4 %
(p <0,05). It has met only in group A, surgical recurrent lung carcinoma involving the hilum and
treatment, included pneumonectomy. Postoperative mediastinum.
complications was 18,5 %. There was 14,8 %, after Methods: This study is a retrospective review
the pneumonectomy executing, and 3,7 % after the of 70 patients undergoing EBUS-TNBA for
combined lobectomy executing (p <0,05). Survival mediastinal lymphadenopathy from March 2009 -
rate in group A: at 1year: 57,2 %, at 3 years - 24 December 2010. A total of 30 lymph node stations
%, at 5 years - 21,2 %. In group B 1, 3 and 5-years were biopsied in 27 patients who were diagnosed
survival was 62,5 %, 34,4 % and 25 % accordingly. with lung carcinoma or suspected of having lung
In group C, at 1 year survival was 69,7 %, at 3 carcinoma. The EBUS bronchoscope contains a
years - 39,2 %, and at 5 years - 26,1 %. Results curvilinear ultrasound probe at the distal end of the
of treatment of patients of group D it is a little bit bronchoscope, which provides a linear continuous
better, than in the previous groups. At 1 year survival B-mode ultrasound image and color Doppler
was 76 %, at 3 year - 40 %, and at 5 years - 26,3 % capability to allow identiÀcation of vascular
(p> 0,05). structures. EBUS-TBNA was performed under
Conclusion: 1. There were not statistically general anesthesia. A 21-gauge biopsy needle was
signiÀcant of survival between Methods of the placed into the lymph node under direct ultrasound
local control of lung cancer, such as surgical guidance. Rapid onsite cytology was utilized in the
and radiotherapy. 2. The Àrst choice for surgical operating room to conÀrm adequacy of diagnostic
treatment of patients with Resectable Stage II b material and for preliminary diagnoses. The
and III Non-Small-Cell Lung Cancer is Combined observation of moderate to abundant numbers of
lobectomy. There is statistically signiÀcant the lymphocytes or pigmented histiocytes served as an
decrease Postoperative Morbidity and Postoperative indicator of adequate sampling of lymph nodes that
complications. are free of metastatic carcinoma. The prevalence,
Keywords: combined treatment, combined lung sensitivity, speciÀcity, positive predictive value, and
resection, resectable Non–Small-Cell lung cancer negative predictive value were calculated. Procedure
related complications were also recorded.
A revised/updated abstract may be included in Results: A total of 30 lymph node stations
the Late Breaking Abstract Supplement, available were sampled in 24 patients with a diagnosis of
at the 14th World Conference on Lung Cancer. lung carcinoma and 3 patients with suspicious
lymphadenopathy that was concerning for lung
carcinoma. Twelve of the lymph node biopsies
Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15 were to evaluate recurrent lung carcinoma. Seven
hilar lymph nodes [6 right and 1 left] were biopsied
P1.226 ENDOBRONCHIAL ULTRASOUND with EBUS-TBNA. Nine paratracheal lymph
IS HIGHLY EFFECTIVE FOR THE node stations [8 right and 1 left] were biopsied.
DIAGNOSIS OF LUNG CARCINOMA AND A total of 14 subcarinal lymph node stations were
ENABLES EGFR MUTATION ANALYSIS sampled. Nineteen of the biopsies demonstrated
Robert E. Merritt, Chuong D. Hoang, Richard I. Non-small cell lung carcinoma and two cases
Whyte, Joseph B. Shrager involved small cell carcinoma. There was one
Cardiothoracic Surgery, Stanford University/United case involving mesothelioma. Three of the cases
States Of America were non-diagnostic. Five of the biopsies yielded
moderate lymphocytes with no evidence of lung
Background: Mediastinoscopy has been the gold carcinoma. The prevalence, sensitivity, speciÀcity
standard for biopsying mediastinal lymph nodes were 76.6%, 87%, and 100 % respectively. There
for staging and diagnosis of lung carcinoma. were no complications or operative mortalities. The
Endobronchial ultrasound with transbronchial hemorrhage rate was 0%. All the patients underwent
needle aspiration (EBUS-TBNA) has become a less Positron Tomography scanning (PET). The mean and
invasive alternative to mediastinoscopy. The role median SUV max values of the lymph node stations
of EBUS-TBNA in lung cancer staging remains were 7.1 + 5.7 and 5.4 respectively. The mean and
unclear; however, this technique may provide a medium size of the lymph node stations was 15.4
safe and effective mechanism for the diagnosis mm + 8.6 mm and 12.5 mm respectively. A total of
of new cases of lung cancer as well as cases of eight of the lymph node station biopsies were tested
for EGFR mutations and all were successful. lung Àeld on CT and candidate for the intentional
Conclusion: EBUS-TNBA provides a safe and segmentectomy were enrolled in this study.
effective alternative to mediastinoscopy for the Preoperative tumor size and tumor disappearance
diagnosis of lung carcinoma in patients with PET rate (TDR) were measured by high-resolution CT
positive lymphadenopathy. Recurrent lung cancer (HRCT). We analyzed their lymph node metastatic
involving the mediastinum or hilum can be accessed patterns, and identiÀed clinical and radiological
with EBUS-TBNA for diagnosis. EGFR mutation factors to predict nodal metastases.
analysis can be successfully performed on the cell Results: Of all patients, 34 patients (11%) had
blocks prepared from the aspirates. lymph node metastases (pN1: 10, pN2: 24).
Keyword: lung cancer diagnosis Compared with the pN0 patients (n = 273), mean
tumor size and TDR on preoperative HRCT of node
positive patients were signiÀcantly larger and lower,
Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15 respectively. All 34 node positive patients revealed
TDR less than 0.25. Metastasis to lsNs (#11, 12, 13)
P1.227 REASONABLE EXTENT OF was observed in 22 patients (7% of all patients, 11%
LYMPH NODE DISSECTION AT of TDR<0.25 patients, pN1: 9, pN2: 13). Among
INTENTIONAL SEGMENTECTOMY them, 4 patients (18%) had metastases in the #13
FOR SMALL-SIZED PERIPHERAL station which belonged to the different segmental
NON-SMALL CELL LUNG CANCER - bronchus (ds13) from the primary tumor. Although
FROM THE CLINICOPATHOLOGICAL it is technically demanding to dissect ds13 during
RESULTS OF THE CASES WHO segmentectomy, all 4 patients had other metastases
UNDERTOOK LOBECTOMIES in #12 or mediastinal station. No patients had sole
WITH SYSTEMATIC LYMPH NODE metastasis in ds13 station.
DISSECTIONS - Conclusion: Advisable extent of dissection for
Yuki Matsumura1, Tomoyuki Hishida1, Junji an intentional segmentectomy for small (2cm)
Yoshida1, Mitsuyo Nishimura1, Genichiro Ishii2, peripheral NSCLC includes lobar-segmental nodes
Keiju Aokage1, Masayuki Nakao3, Akikazu Kawase1, belonging to tumor-located segment as well as hilar
Kanji Nagai1 and mediastinal nodes. Nodes along the adjacent
1
Department Of Thoracic Oncology, National segmental bronchi are not required to be inspected.
Cancer Center Hospital East/Japan, 2Pathology On the other hand, systematic lymph node dissection
Division, Research Center For Innovative Oncology, might not be necessary for tumors with TDR0.25
National Cancer Center Hospital East/Japan, on preoperative HRCT.
3
Division Of Thoracic Surgery, National Cancer Keywords: segmentectomy, lymph node dissection
Center Hospital East/Japan
Background: Currently randomized clinical trials the Late Breaking Abstract Supplement, available
are ongoing to evaluate segmentectomy compared at the 14th World Conference on Lung Cancer.
with lobectomy for peripheral cT1aN0M0 non-
small cell lung cancer (NSCLC). When the
surgeon encounters a positive lymph node during Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15
segmentectomy, the operation should be converted
to a lobectomy. However, the proper extent of P1.228 PROSPECTIVE STUDY OF RADIO-
dissection, in particular, extent of lobar-segmental FREQUENCY ABLATION THERAPY
node (lsN) dissection, is unclear. The purpose of this FOR THORACIC MALIGNANCIES
study is to clarify the reasonable extent of dissection EVALUATING BY FDG-PET
during an intentional segmentectomy for small Hiroyuki Suzuki1, Yuzuru Watanabe1, Takumi
peripheral NSCLC. Yamaura1, Satoshi Mutoh1, Naoyuki Okabe1, Hiroshi
Methods: We reviewed the records of the patients Yaginuma1, Takeo Hasegawa1, Yoko Odashima1,
who underwent lobectomies and systematic lymph Atsushi Yonechi1, Jun Ohsugi1, Mika Hoshino1,
node dissections for cT1aN0M0 NSCLC from 1992 Mitsunori Higuchi1, Yutaka Shio1, Akio Ohishi2,
to 2009. Among them, a total of 307 patients whose Hiroshi Honjo3, Mitsukazu Gotoh4
1
nodule was located in the outer third peripheral Thoracic Surgery, Fukushima Medical University/
Japan, 2Thoracic Surgery, Fukushima Red Cross Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15
Hospital/Japan, 3Radiology, Shirakawa Kosei
General Hospital/Japan, 4Regenerative Surgery, P1.229 SURGICAL RESECTION OF
Fukushima Medical University/Japan CLINICAL T4 NON-SMALL CELL LUNG
CANCER INVADING GREAT VESSELS
Background: Computed tomography (CT)- AND LEFT ATRIUM.
guided radio-frequency ablation therapy (RFA) Toru Bando1, Toshi Menjyu1, Toshihiko Sato1,
is minimally invasive treatment modality for Fengshi Chen1, Tsuyoshi Shoji1, Takuji Fujinaga1,
patients with several types of solid cancer. It has Makoto Sonobe1, Hiroaki Sakai1, Ryo Miyahara1,
also been applying for the treatment of thoracic Cheng-Long Huang1, Kenichi Okubo2, Hiroshi Date1
1
malignancies as a local treatment. RFA technique Thoracic Surgery, Kyoto University Hospital/Japan,
2
is thought to be safe and effective for patients Tokyo Medical And Dental University/Japan
with thoracic malignancy. However, assessment of
therapeutic efÀcacy following RFA procedure is not Background: We retrospectively analyzed the
well established. Lately, several studies showing results of surgical resection in patients with non-
the beneÀt of 18-Fluoro-deoxyglucose positron small cell lung cancer invading the great vessels
emission tomography (FDG-PET) in RFA for and left atrium in order to determine the appropriate
thoracic malignancies have been reported. However, treatment of the locally-advanced disease.
optimal follow-up schedule using FDG-PET are Methods: Between January 2001 and December
still controversial. In this report, we are showing the 2010, 1357 patients underwent surgical resections
long term results on patients treated with RFA and for primary lung cancer at our hospital. Among them,
efÀcacy of FDG-PET as an evaluation tool for early we reviewed the records of 27 patients (2.0%) with
detection of local recurrence. clinical T4 non-small cell lung cancer invading great
Methods: Twenty patients have enrolled in this vessels (aorta, superior vena cava, intrapericardial
study and 24 ablations have been performed. They pulmonary artery, and bracheocephalic and
were 15 males and 5 female with a mean age of 72 subclavian vessels) and left atrium. Of the 27
years (range of 34-85 years old). Seven lesions were patients, 22 were male and 5 were female. Their
primary lung cancer, 17 lesions were metastatic ages ranged from 44 to 76 years with the average
or recurrent tumor. Tumor size was 0.4-3.3cm in of 62.3 years. The histologic type was squamous
diameters (mean: 1.5cm). CT and FDG-PET analyses cell carcinoma in 17 patients, adenocarcinoma in 6,
were scheduled to perform pre and post (7-14days pleomorphic carcinoma in 2, adenosquamous cell
after RFA and 3-6 months after RFA) treatment. carcinoma in 1, and large cell carcinoma in 1.
Results: No mortality was noted. Seventeen adverse Results: The overall 5-year survival rate and
events out of 24 ablations (58.3%) including 13 disease-free 5-year survival rate for the 27 patients
pneumothorax, 2 pains and 2 fevers were observed. were 35.7%, and 27.8%, respectively. The operative
With a median follow-up of 40 months (range 1-62 mortality was 0%, and hospital mortality was
months), overall 5years-survival rate were 75.8%, 3.7% (n = 1). Mean follow up time of 37.1 months
local recurrences were observed in 4 lesions (2-years revealed 11 locoregional recurrences and 8 distant
local control rate were 86.1%) and distant metastases recurrences. Eleven patients died of lung cancer,
followed by RFA were observed in 9 patients. and 3 died of other diseases, the remaining 13 are
Positive FDG-PET results 7-14days after RFA was alive 10 to 118 months postoperatively. Twenty
not correlated with recurrence, whereas 3-6 months patients received preoperative treatments, chemo-
after RFA weakly correlated with local recurrence radiotherapy in 10 patients, and chemotherapy
(p=0.07) in 10. Out of the 20 patients after preoperative
Conclusion: RFA for thoracic malignancy has treatments, postoperative pathological examination
conÀrmed to be a safe and feasible technique. FDG- revealed no invasion of great vessels or left atrium
PET analysis 3-6 months after ablation could be a in 13 patients. Among the 13 patients, 3 survived
useful evaluation tool for local control. longer than 5 years, and the other 3 survived longer
Keywords: Thoracic malignancy, radiofrequency than 3 years. Pneumonectomy was performed in
ablation, FDG-PET 9 patients, bilobectomy in 2, and lobectomy in
12. The left atrium was resected in 6 patients, the
adventitia of the aorta in 4, the pulmonary artery in
4, bracheocephalic or subclavian vessels in 2, and (LWLS), and tumor diameter of 5 mm or less in

the superior vena cava in 1. A total of 20 patients the mediastinal window level setting (MWLS).
underwent complete resection. Postoperative After obtaining informed consent from patients, we
surgical site infection (empyema, mediastinitis, performed limited lung resection under these criteria
chest wall abscess, etc.) developed in 5 patients, and conÀrmed the absence of cancer cells on the
and reoperation for the infection was necessary in surgical margin in frozen sections.
3. Although the completeness of resection did not Results: Between November 2004 and December
signiÀcantly inÁuence survival, operative procedure 2010, we performed limited lung resection for 52
of pneumonectomy, and resection of the adventitia of lung cancer patients under the aforementioned
the aorta were signiÀcant risk factors for survival. criteria. In all, 8 segmentectomies and 44 wedge
Conclusion: Surgical resection of the locally- resections were performed. Tumor sizes ranged from
advanced disease can be an adequate therapeutic 5 mm to 26 mm (average, 13.2 mm) in the LWLS
option for selected patients. Induction chemo- and from 0 mm to 5 mm (average, 0.6 mm) in the
radiotherapy may improve the outcome of the MWLS. Histopathological type of all the patients
locally-advanced NSCLC. Minimally invasive was adenocarcinoma; 48 patients had AIS or MIA,
approaches, such as transmanubrial approach, and and another 4 patients invasive adenocarcinoma but
less invasive resection, would be preferable for these showed no vascular invasion and refused to undergo
patients. further treatment. Median follow-up period was
Keyword: cT4 NSCLC invading GV and LA 25 months. None of the cases showed recurrence;
however, 1 patient died.
Conclusion: It was difÀcult to make a deÀnite
Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15 diagnosis of AIS and MIA on the basis of
preoperative HRCT Àndings. Although the
P1.230 LIMITED RESECTION FOR observation period was short, there was no case of
LUNG CANCER THAT SHOWED recurrence. The indication for limited lung resection
GROUND-GLASS APPEARANCE ON based on HRCT Àndings might be a suitable option.
PREOPERATIVE HIGH-RESOLUTION Keywords: Limited Resection, Lung cancer,
COMPUTED TOMOGRAPHY Ground-glass Appearance
Yuji Asato1, Moriyuki Kiyoshima1, Motohiro Sato2,
Tatsuo Iijima3, Ryuta Amemiya1
1
Respiratory Surgery, Ibaraki Prefectural Central Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15
Hospital & Cancer Center/Japan, 2Radiology,
Ibaraki Prefectural Central Hospital & Cancer P1.231 BILATERAL SPONTANEOUS
Center/Japan, 3Pathology, Ibaraki Prefectural PNEUMOTHORAX AS A COMPLICATION
Central Hospital & Cancer Center/Japan OF METASTATIC THIN WALLED
CAVITARY PULMONARY
Background: Lung adenocarcinoma in situ (AIS) ANGIOSARCOMA
and minimally invasive adenocarcinoma (MIA) are Gustavo A. Lyons1, Silvia Quadrelli2, Lorena
not associated with vascular invasion or lymph node Maldonado2, Carlos Silva3, Domingo J.
metastasis. Hence, limited resection for these tumors Chimondeguy1, Cesar Delgado2, Felipe Chertcoff2,
would be a good therapeutic option. These tumors Juan C. Spina4
1
show ground-glass opacity (GGO) on high-resolution Thoracic Surgery, Buenos Aires British Hospital/
computed tomography (HRCT). Since November Argentina, 2Respiratory Medicine, Buenos Aires
2004, we have been deÀning AIS and MIA on the British Hospital/Argentina, 3Oncology, Buenos Aires
basis of the Àndings of preoperative HRCT and have British Hospital/Argentina, 4Radiology, Buenos Aires
been performing limited resection for these lesions. British Hospital/Argentina
We reviewed the appropriateness of our eligibility
criteria. Background: Angiosarcomas are rare malignant
Methods: The following were the indications for tumors of vascular origin, accounting for 2 to 3% of
limited resection based on HRCT Àndings: tumor all sarcoma, and regardless of their sites of origin,
diameter of 3 cm or less, appearance is pure or are particularly likely to metastasize to the lung.
mainly GGO in the lung window level setting Methods: We report an unusual case of simultaneous
bilateral spontaneous pneumothorax, secondary to metastatic squamous cell carcinoma. However, a

metastases from angiosarcoma of the scalp. thin-walled cavitary lesion is usually not considered
Results: In August 2008, a 65 year old man to be a malignancy. Although prognosis of
was detected a lesion on his scalp. Histologic angiosarcoma is poor, in the presence of persistent
examination disclosed it to be an angiosarcoma. The air leak, videothoracoscopy allows wedge resection
patient received chemotherapy and radiotherapy of the tumor and mechanical pleurodesis to be
with adequate local control. Two years later, he performed safely and it is an option that should be
was noted to have a right lower lobe and left lower considered.
lobe cystic lesions on a chest CT scan without any Keywords: Angiosarcoma, Pneumothorax, Cavitary
distinct pulmonary solid nodules or masses. A new pulmonary, Metastatic pulmonary
CT revealed signiÀcant bilateral pneumothoraces. A
closed thoracostomy was performed with complete
reexpansion. Fifteen-days later he was admitted Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15
to our hospital because of severe dyspnea. A CT
showed large bilateral pneumothoraces (Figure). P1.232 CLINICAL PREDICTORS
Bilateral closed-tube thoracostomies were put in OF MEDIASTINAL METASTASIS
place. Both lungs were only partially expanded. IN PATIENTS WITH SURGICALLY
As moderate air leak persisted bilaterally, video- RESECTABLE NON-SMALL CELL LUNG
assisted thoracoscopic evaluation of his right CANCER.
hemithorax was performed Àrst disclosing two Gustavo A. Lyons1, Silvia Quadrelli2, Carlos Silva3,
ruptured cystic lesions. A wedge resection of these Domingo J. Chimondeguy1, Matías Lescano1
1
lesions was performed followed by talc pleurodesis. Thoracic Surgery, Buenos Aires British Hospital/
His postoperative course was uneventful and seven Argentina, 2Respiratory Medicine, Buenos Aires
days later the procedure was performed on the left British Hospital/Argentina, 3Oncology, Buenos Aires
hemithorax with similar Àndings and results. The British Hospital/Argentina
biopsy specimen of the lung showed metastatic
angiosarcoma. Background: Accurate preoperative staging is
essential for patients with lung cancer in order to
identify mediastinal lymph node metastasis. In this
retrospective study we identiÀed potential clinical
predictors of N2 metastasis in order to deÀne
a subset of patients that should receive a more
extensive evaluation of the mediastinum before
deÀning surgical treatment.
Methods: Patients with NSCLC were included if
they underwent pulmonary resection with curative
Conclusion: Metastatic pulmonary angiosarcoma intent. Cases were excluded if they had small cell
exhibits in chest radiography bilateral peripheral lung cancer or if they had received neoadjuvant
solid nodules that are often accompanied by chemotherapy. Clinical and pathology records of
inÀltrates. CT Àndings of metastatic angiosarcoma each patient were analyzed in order to identify
have been described only in case reports or small potential predictive factors for N2 metastases. The
series. In a Japanese series of 24 patients (Tateishi, U analyzed variables were size of the tumor, age,
et al. AJR 2003), the commonest CT manifestations gender, symptoms, side, location, histology and chest
were multiple solid nodular lesions and multiple CT Àndings. During surgery, bronchopulmonary,
thin-walled cysts, often mixed with hemorrhagic hilar and mediastinal lymph nodes were
changes. The most common presenting symptom systematically sampled. Unpaired t tests were used
of pulmonary metastasis in angiosarcoma was to compare differences in continuous variables, and
haemoptysis, and only a few cases presented with chi-square test statistic or Fisher´s exact test for
spontaneous pneumothorax, pneumomediastinum categorical variables. Univariate and multivariate
or pulmonary haemorrhage. Cavitary pulmonary logistic regression models were used to ascertain
metastases are an infrequent but well-known the association between individual factors and the
phenomenon, most commonly associated with presence of mediastinal metastasis.
1
Results: Four hundred and fourteen patients were Department Of Surgery, Faculty Hospital
included (males, 74.3%, mean age 61.2 ±9.8 years). Masaryk University Brno/Czech Republic, 2Dept.
Patients with positive pathological N2 (n=89) nodes Of Comprehensive Oncological Care, Masaryk
were no different from node negative patients with Memorial Cancer Institute/Czech Republic, 3Dept.
regard to age and sex distribution. Patients with Of Radiology, Masaryk Memorial Cancer Institute/
positive N2 disease had statistically signiÀcant larger Czech Republic, 4Dept. Of Pathology Faculty
mean tumor size (5.1 ± 1.86 versus 3.9 ± 1.14 cm Hospital Bohunice, Faculty Of Medicine Masaryk
, p < 0.001) but were not different in histological University/Czech Republic
distribution. Preoperative CT scan was more likely
to demonstrate suspected N2 metastasis in the node- Background: Czech pioneering of pulmonary
positive patient group (38.2% vs 2.4%, p= <0.0001). segmentectomy for cancer.
Univariate analysis identiÀed two signiÀcant Methods: Pulmonary opacity suspect of lung
predictors of N2 disease: a tumor larger than 3 cm cancer without enlargement of lymphnodes on CT
on CT scan and a clinical suspicion of mediastinal imaging was detected in twenty persons from high
metastases (cN2). Using multivariate analyses, both risk group (n=305) by follow up through 5127
of these remained signiÀcant predictors of pN2 examinations during the period of 1999-2008 yrs.
disease. Comparation between patients with positive Proven non small cell lung cancer and tumours
and negative N2 nodes of uncertain histopathology with diameter up to
20mm were indicated to segmentectomy (Figure
Variable pN2 (N=89) Node negative (N=325) p
1) . Borderline diameter for segmentectomy of a
Age (mean ± SD) 59,5 ± 9,1 61,6 ± 8,7 0.065
Gender (Male %) 71,9 75,3 0.590
metastatis was 30 mm. They were implemented
Symptoms from primary tumor (%) 51.7 40.0 0.063 21 Overholts procedures. The histopathology was
Tumor > 3 m in CT (%) 79.8 60.9 0.000 stated under hematoxylin-and-eosin staining and
Solitary pulmonary nodule (%) 21.3 33.2 0.042
immunohistochemistry examination. Figure 1.
Right side (%) 59.5 58.4 0.949
Upper lobes (%) 34.8 38.4 0.615
Scheme of the Surgical Lung Segment
Central location (%) 32.6 25.2 0.210
Squamous (%) 20.2 25.2 0.668
Adenocarcinoma (%) 64.0 63.1 0.965
Mediastinal metastasis suspected on
38.2 2.4 0.000
CT (%)
Conclusion: Our Àndings suggest the predictive

value of tumor size, and CT-related suspicions for
N2 disease, especially for those patients with Stage
I disease. These results can help to determine which © Marek Malik Legend to Figure 1 1 –
patients should undergo invasive mediastinal staging. intersegmental pulmonary vein 2 – intrasegmental
The routine use of mediastinoscopy in cN0 patients pulmonary vein 3 – subpleural pulmonary vein 4
with tumors smaller than 3 cm (T1) does not appear – pulmonary artery segmental branch 5 – segmental
to be justiÀed in view of the low incidence of occult lymphnodes 6 – subsegmental lymphatics 7 –
N2 disease. segmental bronchus 8 – intersegmental space 9 –
Keywords: Mediastinal staging, Tumor size, Lung visceral pleura
cancer, Lymph nodes metastasis Results: Nine non - small cell lung cancers, six
metastases, and six benign lesions were found
histopathologically. No local recurrence and no
Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15 involvement of regional lymphnodes were recorded
postoperatively in both cancer series with median
P1.233 PULMONARY SEGMENTECTOMY age of 63 yrs (range 45-79) and median duration
FOR TUMOUR. A MIDDLE EUROPEAN of follow up 35 months. No perioperative 30-days
VIEW mortality was registered. Six distant recurrences
Horvath Teodor1, Stanislav Špelda2, Ilona appeared, 3 in NSCLC and 3 in extrapulmonary
Kocáková2, Helena Bartoļková3, Marta ÿíhalová4, cancer patients. Five cancer-patients died, three of
Mojmír Moulis4, Barbora Garajová1, Jindŉich them through the general progression of the disease,
Vomela1 two deaths were non-cancer related. Patients with
NSCLC represent 1‰ among all operated Czech metastases, including surgical procedures and
pacients with lung cancer of the period. pathologic results, were registered. Univariate and
Conclusion: Lung segmentectomy seems to multivariate analysis were carried out to identify
accomplish local control of early stage NSCLC and signiÀcant prognostic factors related to overall
pulmonary metastasis of extrapulmonary cancer. survival.
Broad multidisciplinary collaboration focused on Results: There were 398 cases included in Ànal
early stage disease is needed. analysis. Median follow up was 24.4 months.
Keyword: Early Lung Cancer; Segmentectomy; Median age was 35 years. Preferred surgical
Lymphadenectomy. approach was posterolateral thoracotomy in 309
cases (77.6%) Metastases were resected with a
A revised/updated abstract may be included in wedge resection in 297 cases (74.6%), with an
the Late Breaking Abstract Supplement, available anatomic segmentectomy in 63 patients (15.8%),
at the 14th World Conference on Lung Cancer. while lobectomy and pneumonectomy were
performed in 42 (10.6%) and 10 cases (2.5%)
respectively. Complete resection was achieved in
Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15 351 patients (88.2%). Median overall survival for
all patients was 81.9 months. The overall 10-year
P1.234 SURGICAL RESECTION OF survival was 64.3% for germ-cell tumors, 57.8%
LUNG METASTASES. RESULTS FROM for cervical cancer, 46% for osteosarcoma, 28.7%
398 PATIENTS TREATED AT A SINGLE for breast cancer, 24.3% for soft-tissue sarcoma and
INSTITUTION 21.4% for renal cancer. Factors related to overall
Jose F. Corona-Cruz1, Luis M. Dominguez-Parra1, survival in multivariable analysis were complete
Miguel Rios-Trejo2, David Saavedra-Perez2, Digna resection (0.7 HR [95% CI 0.48 - 1.0] p= 0.05) and
Pachuca2, Edgardo Jimenez-Fuentes1, Leon Green- the interval free of metastases > 6 months (1.4 [1.001
Schnneweiss1, Enrique Guzman-de Alba3, Alejandro - 2.06] p=0.049)
Eduardo Padilla-Rosciano1, Oscar Gerardo Arrieta- Conclusion: Our results are according with
Rodriguez4 previously reported series of lung metastasectomy,
1
Surgical Oncology, Instituto Nacional De and really encourage the surgical resection of lung
Cancerologia/Mexico, 2Laboratory Of Experimental metastases for prolonging overall survival in well
Oncology, Instituto Nacional De Cancerologia/ selected patients. This is especially true for those
Mexico, 3Thoracic Surgery, Instituto Nacional De patients with an interval free of metastases longer
Enfermedades Respiratorias/Mexico, 4Medical than 6 months and those that undergo a complete
Oncology, Instituto Nacional De Cancerologia resection.
Mexico/Mexico Keywords: metastases, lung metastasectomy,
thoracic neoplasms
Background: Pulmonary metastases are a common
problem in oncologic patients, and although most
of them are not curable, well selected cases may Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15
be amenable for surgical treatment. There are not
randomized trials that compare surgery to any other P1.235 PREOPERATIVE SERUM VALUE
form of treatment, however small series and an OF SIALYL LEWIS X IS ASSOCIATED
International Registry has conÀrmed an advantage WITH PATHOLOGICAL STAGE
in survival for those patients that undergo complete AND SURVIVAL IN PATIENTS WITH
resection. We present a single institution experience SURGICALLY TREATED SMALL CELL
with pulmonary metastasectomy from several LUNG CANCER
primary tumors. Takashi Iwata1, Noritoshi Nishiyama1, Koshi
Methods: We retrospectively reviewed all patients Nagano1, Nobuhiro Izumi1, Keiko Tei1, Shoji
treated with lung metastasectomy from January 1990 Hanada1, Hiroaki Komatsu1, Kiyotoshi Inoue2,
to December 2008. Preoperative assessment and Masahide Kaji2, Shinzoh Kudoh3, Shigefumi
surgical indication was according to international Suehiro1
1
recommendations. Clinical variables as well as Department Of Thoracic Surgery, Osaka City
those related to the primary and to the pulmonary University/Japan, 2Department Of Thoracic
Surgery, Osaka City University Graduate School Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15
Of Medicine/Japan, 3Department Of Respiratory
Medicine, Osaka City University Garaduate School P1.236 5-YEAR SURVIVAL OF NON-
Of Medcine/Japan SMALL CELL LUNG CANCER
PATIENTS AFTER RADICAL SURGERY
Background: We investigated various tumor SIGNIFICANTLY DEPENDED ON PHASE
markers in patients with surgically treated small cell TRANSITION “EARLY-INVASIVE
lung cancer (SCLC) to identify the markers closely CANCER”, LYMPH NODE METASTASES
correlated to pathological staging and to predict AND CELL RATIO FACTORS
survival by retrospective analyses. Oleg Kshivets
Methods: Thirty-six patients with SCLC were Surgery, Siauliai Public Hospital/Lithuania
revealed by reviewing our cancer registry database
between 1990 and 2007. The patients were grouped Background: We examined factors associated with
according to clinical and pathological stages. low/high-risk of generalization of lung cancer (LC)
Clinical features and survival curves were calculated (T1-4N0-2M0) after complete (R0) lobectomies/
and compared for each group. Receiver operating pneumonectomies.
characteristic (ROC) curves were calculated for Methods: We analyzed data of 602 consecutive
serum levels of various tumor makers to predict the LC patients (LCP) (age=57.5±8.1 years; tumor
pathological stage. The cut-off value was calculated size=4.4±2.3 cm) radically operated and monitored
from the ROC curve of the signiÀcant marker. in 1985-2010 (m=536, f=66; pneumonectomies=222,
Survival in patient groups divided by the new cut-off lobectomies=380, combined procedures with
value was calculated. resection of pericardium, atrium, aorta, VCS,
Results: Serum levels of various tumor makers were carina, diaphragm, esophagus, liver, chest wall,
not signiÀcantly different between the pathological ribs, etc.=155; squamous cell carcinoma=367,
stage groups, except for serum sialyl Lewis X (SLX). adenocarcinoma=192, large cell carcinoma=43;
Patients with pathological stage 1 disease had a T1=215, T2=232, T3=114, T4=41; N0=377,
signiÀcantly longer survival than those with stage 2A N1=118, N2=107; G1=150, G2=180, G3=272; early
or more (p = 0.0313), whereas differences in survival LC: LC till 2 cm in diameter with N0=110, invasive
among equivalent clinical stages were not signiÀcant LC=492) was reviewed. Variables selected for 5-year
(p = 0.6386). ROC curve of SLX was signiÀcantly survival (5YS) study were input levels of blood
correlated to pathological stages (p = 0.0136). The cell subpopulations, TNMG, tumor size. Survival
calculated SLX cut-off value was 25.1 U/ml, with curves were estimated by Kaplan-Meier method.
80% sensitivity and 70% speciÀcity. Five-year Differences in curves between groups were evaluated
survival of patients selected by this new cut-off was using a log-rank test. Neural networks computing,
82.5%, whereas that with the standard cut-off (38.0 multivariate Cox regression, clustering, discriminant
U/ml) was 55.9%. analysis, structural equation modeling, Monte Carlo
Conclusion: Serum SLX values were associated and bootstrap simulation were used to determine any
with pathological stage and survival after surgery signiÀcant regularity.
in SCLC patients and may be useful in determining Results:
the best candidate for surgical treatment even with a Overall life span (LS) was 1973.4±1466.8 days and
reduced cut-off value. cumulative 5YS reached 67.9%, 10 years - 59.2%,
Keyword: Lung cancer, Small cell carcinoma, 20 years - 29.9%. 371 LCP lived more than 5 years
Tumor maker, Surgery, Outcome without LC. 186 LCP died because of LC. Cox
modeling displayed (Chi2=171.3, df=6, P=0.000)
A revised/updated abstract may be included in that 5YS of LCP signiÀcantly depended on: phase
the Late Breaking Abstract Supplement, available transition (PT) early-invasive LC in terms of
at the 14th World Conference on Lung Cancer. synergetics, PT N0--N1-2, cell ratio factors (CRF)
(ratio between cancer cells:CC and blood cells
subpopulations) (P=0.000-0.011). Neural networks,
genetic algorithm selection and bootstrap simulation
revealed relationships between 5YS and PT early-
invasive LC (rank=1), PT N0--N1-2 (rank=2),
erythrocytes/CC, healthy cells/CC, thrombocytes/ little long instruments for usual thoracic surgery. The
CC, segmented neutrophils/CC, monocytes/CC, most characteristic point of our method is that the
leucocytes/CC, stab neutrophils/CC, lymphocytes/ operator mainly watched the operative Àeld directly
CC, eosinophils/CC. Correct prediction of 5YS through the small main wound, and assistants watch
was 100% by neural networks computing. Cox it by video monitor. So we do not enlarge wounds
Regression: Dependent Variable: 5YS (LCP=602); for lymphnode dissection or other complicated
Chi2=171.334; df=6; P=0.0000 manipulations.
Results: Operation time: from 76 to 407 (mean 204)
Beta t-value Wald P
PT early-invasive LC -1.26048 -3.1602 9.98697 0.001578
minutes. Bleeding: from 0 to 1010 (mean 136) ml.
Leucocytes/CC -0.98620 -4.1127 16.91422 0.000039 Seven cases with bronchoplasty (including 3 cases
Stab Neutrophils/CC 1.01536 2.51917 6.34619 0.011768 of sleeve lobectomy) and 5 cases with pulmonary
Segm.Neutrophils/CC 1.05533 4.22974 17.89070 0.000023
angioplasty were all performed through the same
Lymphocytes/CC 0.79332 2.98631 8.91802 0.002826
PT N0--N1-2 1.07588 7.32680 53.68200 0.000000
wounds. No case needed to enlarge the wound for
hemostasis or other reasons except for removal
Conclusion: 5YS of LCP after radical procedures of large tumors. Histology: adenocarcinoma 141,
signiÀcantly depended on: 1) PT early-invasive LC; squamous cell carcinoma 40, large cell carcinoma 7,
2) PT N0--N1-2; 3) CRF. small cell carcinoma 5, and others 19. Pathological
Keywords: Prognosis, Lung cancer, Surgery stage: IA 104, IB 52, IIA 12, IIB 18, IIIA 27, IIIB 3,
and IV 1. Duration of postoperative drainage: from
1 to 16 (mean 2.7) days. Post operative hospital
Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15 stay: from 2 to 22 (mean 4.9) days. One hundred
and thirty cases (60%) were discharged by 4th
P1.237 THE EASIEST AND THE SAFEST postoperative day. The main reason of delay of
WAY OF VIDEO ASSISTED THORACIC discharge was at a request of a patient, followed by
SURGERY FOR LUNG CANCER prolonged air leakage. There is no cases of hospital
Shogo Toda, Tsunehiro Ii death, and there was no major complication. Patients
General Thoracic Surgery, Otsu Municipal Hospital/ in pathological stage IA have no recurrence so far.
Japan Conclusion: Though the wound is small, we
operate mainly directly, and the thoracoscope
Background: Video assisted thoracic surgery is used additionally. As we can perform certain
(VATS) is now one of the most important methods manipulations, even bronchoplasty or angioplasty
for lung cancer operation. It seems to be less can be done by same methods. And the
invasive and more cosmetic than the operation under manipulations are almost the same as that of usual
standard thoracotomy. But it also seems to be more operation for lung cancer, for doctors who are not
difÀcult to operate because of inaccuracy of handling used to VATS, our method would be easy to learn
instruments under thoracoscopic vision. And it and would have good results.
sometimes seems to be questionable if sufÀcient Keywords: Lung cancer, operation, VATS
curability is obtained by VATS. The aim of this study
is to present the method and advantages of our video
assisted thoracic surgery. Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15
Methods: Two hundred and seventeen cases
(male 140, and female 77) of lung cancer were P1.238 ASSESSMENT FOR LUNG
operated by VATS from April 2004 to December RESECTION SURGERY IN LUNG
2010. Age: from 25 to 88 years old (mean 66). CANCER PATIENTS; ALL MAY NOT
Lobectomies (including bilobectomies) with NEED CARDIO PULMONARY EXERCISE
systematic lymphnode dissection were performed. TESTING(CPET).
The main wound was usually 3.5 to 4cm long on Samantha C. Herath, Fiona Horwood
the 4th intercostal space of mid-axillar line with 2 Respiratory Medicine, Middlemore Hospital/New
small wounds for insertion of a thoracoscope and Zealand
other instruments. Only a plastic wound retractor for
traction of soft tissues was attached. We do not use Background: Resectable lung cancer requires major
special instruments for endoscopic surgery, but use a surgery. Pre-operative evaluation is important to
ensure beneÀt. Current practice involves a battery of Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15
lung function testing (LFT) including CPET for all
patients considered for surgery. P1.239 SURGICALLY TREATED
Methods: This is a retrospective clinical audit. All EPITHELIAL NON SMALL CELL LUNG
pre-operatives LFT from 2009- 2010 were analysed. CANCER PATIENTS: PATTERNS OF
We compared the predicted risk for lobectomy and RELAPSE AND OUTCOME
pneumonectomy; calculated using combination Shoshana Keren-Rosenberg1, Olecia Goldman1,
FEV1/ DLCO testing alone (According to British Eduard Grikstas1, Michelle Leviov1, Anna Rabkin1,
Thoracic Society(BTS) Guidelines 2002-see below Larissa Leizin1, Natalia Sikorsky1, Israel Serapov2,
for calculation and risk), to that of measured Mariana Steiner1
1
Vo2 peak reached during CPET.Patient record Oncology, Lin Medical Center/Israel, 2Thoracic
were followed up and immediate postoperative Surgery, Carmel Medical Center/Israel
complications were recorded. BTS guidlines 2002-
on selection of patients with lung cancer for surgery Background: From 2001 to 2008, 146 operated
published in Thorax2001;56:89-108 Predicted NSCLC patients were treated at our oncology center.
FEV1 = (pre operative measured FEV1*(19 - no Methods: Their Àles were retrospectively reviewed
of segments removed)/19, Predicted DLCO=(pre in order to examine the patterns of relapse and the
operative measured DLCO*(19 -no of segments general outcome.
removed)/19, Risk Categorisation: High risk = Results: Their median age was 70.6 years (43-91).
(predicted FEV1 & DLCO < 40%), Indeterminant= 60% were male. 75% had stage I disease, 10% stage
(any other FEV1/DLCO combination),Low risk = II and 15% stage III. 88% of patients were referred
(predicted FEV1 & DLCO > 40%). after curative operation while 12% were operated
Results: 44 patients were considered for lung after neoadjuvant therapy. Lobectomy was performed
resection. Mean age; 64.9 +/- SD10.7. 66% were in 79% of patients, 12% underwent pneumonectomy
Male. The predicted high risk group for lobectomy and 9% wedge resection of lesion. 29% of patients
on combination FEV1/DLCO was identiÀed to be had squamous cell carcinoma, 40% adenocarcinoma,
having an oxygen uptake (Vo2 peak) of 14 or less 27% bronchoalveolar carcinoma and 4% other
consistently. Twenty patients proceeded to surgery histologies. 18% of patients had adjuvant therapy
.No one with predicted high risk had surgery. The (13% platinum based chemotherapy and 5%
post-operative complication rate was low. No deaths radiotherapy). During a median follow up of 46
occured.VO2peak for lobectomy patients was mean months (1.5- 118) 21% of patients relapsed. Median
21.1 +/- 6.7 SD with a minimum of 13.4ml/kg/min. time to relapse was 15 months (2.5-85). Relapse
occurred in 15% of stage I patients, in 29% of stage
II and in 56% of stage III patients. 27% of patients
who recurred had loco-regional recurrence, 66%
had distant metastases and 7% had both. In 43% of
patients relapse was detected by clinical symptoms
while 57% of relapses were detected by routine
Conclusion: There is good correlation between tests. Median survival from relapse was 10 months
calculated (using predicted FEV1/DLCO) and (1-60). At present, 58% of patients are alive with no
measured (using VO2 peak) surgical risk. The high evidence of disease, 4% are alive with disease, 22%
risk group may be deemed unÀt for surgery with died of lung cancer, 1.5% died in the preoperative
DLCO and FEV1 alone without the need for further period (after neoadjuvant chemotherapy) and 14.5%
testing. In our unit we found a cautious approach to died of unrelated causes. 5 year actuarial survival
surgery and low complication rates. rate was 74% for stage I disease, 67% for stage II
Keywords: NSCLC, Surgery, risk, exercise testing and 40% for stage III disease. Patient’s gender, age
and histological type did not inÁuence survival.
Conclusion: We conclude that our data is similar to
other presented results in operated lung carcinoma.
Relapse is usually incurable whether detected
clinically or by routine follow up testing.
Keywords: lung-cancer, relapse, survival, Surgery
P1.240 A PURELY RETICULAR P1.241 POSTOPERATIVE ACUTE

PULMONARY CT PICTURE CAN WELL EXACERBATION OF PULMONARY
REPRESENT A LUNG CANCER (REPORT FIBROSIS IN LUNG CANCER PATIENTS
OF THREE CASES) AND PREOPERATIVE CT FINDINGS
Hiroki Hayashi Motoki Yano1, Hidefumi Sasaki1, Satoru Moriyama1,
Surgery, Kanto Central Hospital/Japan Yu Hikosaka1, Katsuhiro Okuda1, Keisuke Yokota1,
Masaki Hara2, Yoshitaka Fujii1
1
Background: We have recently experienced that Oncology, Immunology And Surgery, Nagoya City
Reticular pattern on chest CT Ànding is not rarely University Graduate School Of Medical Sciences/
of a lung cancer. We report three cases to warrant Japan, 2Radiology, Nagoya City University/Japan
an early intervention to treat such a patient.
Methods: We analyzed three patients who resected Background: Acute exacerbation (AE) of pulmonary
lung cancer following thoracotomy in spite of a Àbrosis in lung cancer patients with idiopathic pulmonary
reticular pattern of the lesion on chest computed Àbrosis (IPF) often leads to postoperative mortality.
tomography, in Kanto Central Hospital during However, AE may occur in the patients who have not
2010. been diagnosed with IPF preoperatively, and it is difÀcult
Results: Case1. A 79-year-old man whose chest CT to predict which patient will develop AE postoperatively.
Àlm showed a purely reticular pattern shadow in Methods: We have conducted a retrospective study of
the left lower lobe. Adenocarcinoma was diagnosed 481 consecutive patients who underwent lung cancer
by transbronchial lung biopsy (TBLB). FDG-PET surgery since January 2004. Even if the patients had
conÀrmed abnormal accumulation in the same not been diagnosed with IPF, they were rerolled if they
legion. Left lower lobectomy was performed 21 had Àbrous changes in preoperative high resolution
days after TBLB. Case2. An 80-year-old man CT. Sixty-two patients with such Àndings have been
complained of bloody sputum, whose chest CT included. AE was analyzed un reference to radiological
showed a reticular pattern shadow in the right lower and laboratory Àndings.
lobe. FDG-PET showed an abnormal accumulation Results: AE was observed in 6 of 62 patients; 1/7 with
in the same legion. Right lower lobectomy was usual interstitial pneumonia (UIP) pattern, 1/16 with
performed 42 days after TBLB. Case3. A 75-year- cellular non-speciÀc interstitial pneumonia (cNSIP)
old man, whose chest CT Àlm showed a reticular pattern, 4/25 with Àbrotic non-speciÀc interstitial
pattern shadow in the segment 6 of the right lobe. pneumonia NSIP (fNSIP) pattern, and 0/14 with
FDG-PET showed a normal accumulation in unclassiÀed Àbrous changes (UFC) pattern. High KL-6
the region. Adenocarcinoma was diagnosed by appeared to be a prognostic factor of AE. In patients who
a wedge ressection. Right lower lobectomy was underwent limited surgery with partial resection, AE was
subsequently performed. not observed.
Conclusion: Three cases that we hereby reported Conclusion: AE may develop in the patients with not
warrant an exploratory thoracotomy for a possible only UIP but also with NSIP pattern. In patients with a
lung cancer in cases. Which present with a localized high risk of AE; high KL-6, limited surgery may be an
purely reticular shadow in the lung, even when option.
Interstitial pneumonitis may well be in the top of its Keywords: acute exacerbation, pulmonary Àbrosis,
differential diagnosis. Lung cancer
Keyword: Reticular pattern
A revised/updated abstract may be included in Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15
at the 14th World Conference on Lung Cancer. P1.242 PERCUTANEOUS CT-GUIDED
RADIOFREQUENCY ABLATION FOR
NSCLC:PRELIMINARY REPORT
Yi Zhang, Xiuyi Zhi, Liu Baodong, Mu Hu
Thoracic Surgery Dept., Beijing Lung Cancer
Center, CMU/China
Background: Although the most effective treatment Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15
for lung cancer is surgery at present, 70% of lung
tumors are not suitable for potentially curative P1.243 ROUTINE MEDIASTINOSCOPY
resection. There are two main reasons that account VERSUS ROUTINE POSITRON
for the unsuitability of surgery as the prime treatment EMISSION TOMOGRAPHY (PET) AND
modality: advanced stage due to lack of effective early SELECTIVE MEDIASTINOSCOPY.
diagnostic method and poor operation tolerance due MATURE RESULTS OF A CLINICAL
to advanced age or co-morbid medical conditions. PROTOCOL FOR STAGING NON-SMALL
In recent years, Radio Frequency Ablation (RFA), CELL LUNG CANCER
a newly-developed local physiotherapy, has been Sergi Call1, Ramon Rami-Porta1, Carme Obiols1,
applied as an alternative therapeutic strategy for lung Mireia Serra1, Sonia Gonzalez2, Roma Bastus-
cancer, receiving remarkable clinical effect. Piulats2, Montserrat Domenech3, Jose M. Gonzalez4,
Methods: From March 2007 to Dec 2010, two- Montserrat Ysamat4, Lidia Canales5, Jose A. De
hundred twenty-six patients with two-hundred Àfty Marcos5, Guadalupe Gonzalez-Pont6, Enric Barbeta7,
NSCLC or metastases lesions underwent percutaneous Josep M. Soler8, Josep Belda1
1
CT guidance RFA with RITA electrodes. Contrast– Thoracic Surgery Service, Mutua Terrassa
enhanced CT was performed immediately, 1 month, University Hospital/Spain, 2Oncology/hematology
and then every 3 months after RFA to evaluate the Service, Mutua Terrassa University Hospital/
response and result to therapy. Spain, 3Oncology Department, Althaia (Xarxa
Results: Ten (1.6%) lesions showed complete Assistencial De Manresa)/Spain, 4Centro Tecnologia
necrosis, 176 lesions (70.4%) showed partial response, Diagnostica (CTD), Mutua Terrassa University
contrast CT revealed cavity formation or scar Hospital/Spain, 5Diagnostic Imaging Service, Mutua
formation. 51 lesions (20.4%) with stable disease, Terrassa University Hospital/Spain, 6Department
19 lesions (7.6%) showed progressive disease and Of Pathology, Mutua Terrassa University Hospital/
received second session of RFA. The density of 242 Spain, 7Respiratory Unit, Hospital General De
lesions was lowered (96.8%). Post-procedure PET Granollers/Spain, 8Radiation Oncology Department,
or SPECT showed loss of virtually all FDG activity Institut Oncologic Del Valles/Spain
in the previously positive areas in 205 of 250 lesions
(82.4%). No procedural mortality occurred. Minor Background: In 2004, routine positron emission
complications included small pneumothorax in 26, 4 tomography (PET) was introduced in our staging
requiring drainage, intrapulmonary hemorrhage in 4, protocol to evaluate the metabolic activity in the
chest pain in 14, cough in 10.Side effects (moderate- mediastinum and to rule out extrathoracic disease.
grade fever <38.5 ƒ, and/or chest pain) were The objective of this study is to compare the accuracy
commonest complications, however, most of them of our current clinical staging protocol with selective
were cured within a couple of days. surgical mediastinal exploration (SME) based on PET
Conclusion: This pilot clinical study demonstrates and the previous protocol with routine SME.
that CT-guided RFA is a relatively safe, effective and Methods: From 1994 to 2003, routine SME
promising procedure for the treatment of inoperable (mediastinoscopy, parasternal mediastinotomy or
NSCLC. Follow-up CT scan is helpful in assessing the extended cervical mediastinoscopy) was performed
effect of RFA, accurate localization of the electrode to 655 patients with NSCLC as the last clinical
needle and searching possible complications. PET staging procedure prior to thoracotomy. Those with
or SPECT is also a good and sensitive procedure for no mediastinal involvement underwent thoracotomy
follow-up, providing good discrimination between for lung resection (T) and systematic nodal
residual granulation tissue and recurrent tumor. dissection (SND). From 2004 to 2010, PET was
Keyword: radiofrequency ablation；lung tumors； routinely done in 625 patients. SME was reserved
computed tomography for those with positive mediastinal or hiliar uptake
on PET, large lymph nodes on CT scan or central
A revised/updated abstract may be included in tumors. The remaining patients and those with
the Late Breaking Abstract Supplement, available negative SME underwent T and SND. SND was
at the 14th World Conference on Lung Cancer. considered the gold standard to compare the negative
results of PET and SME. Pathological Àndings were
reviewed and staging values were calculated using
the standard formulas. atelectasis requiring bronchoscopy and respiratory

Results: The staging values of each period are distress necessitating ICU admission. We endeavored
described in table 1. In the routine PET protocol, to develop a standardized post-operative respiratory
43 (6.8%) patients with pN2 disease were clinically therapy pathway to improve perioperative outcomes.
understaged and underwent T. This rate is not Methods: A multidisciplinary team composed of
statisticallly different from the 6.1% pN2 (40 thoracic surgeon faculty, physician assistants, nurses
patients) found in routine SME period. Table1. and respiratory therapists developed an evidence-
Staging values of each period. based pathway that would provide intensive RT for
thoracic surgery patients beginning in the recovery
Staging Protocol with Staging Protocol with Selective room and continuing for 72 hours in their stay on a
Routine SME SME based on PET
thoracic surgery progressive step-down unit (Figure
N 655 625
1). Once the pathway was approved by the faculty,
Sensitivity 0.85 0.81
Speci¿city 1 1
the entire RT and thoracic surgery care teams were
PPV 1 1 in-serviced to pathway content and implementation.
NPV 0.90 0.90 Instructional postings were placed throughout the
Accuracy 0.94 0.95 step-down unit. Key team members were chosen
as “pathway champions” to help coordinate and
Abbreviations: N: number of patients; PPV: Positive implement the changes. A Progress Scoring Tool was
Predictive Value; NPV: Negative Predictive Value. developed to determine achievement by the patient
Conclusion: The staging protocol with routine PET of recovery benchmarks.
and selective SME saves up to 25% of SME and
yields a similar rate of pN2 disease compared to
routine SME. Therefore, if availble, PET and SME
should be thoughtfully combined in the clinical
staging of NSCLC.
Keywords: Staging, PET, Mediastinoscopy
P1.244 ESTABLISHMENT OF A FIRST

72 HOUR CHEST PHYSIOTHERAPY
PATHWAY IN A THORACIC SURGERY
ONCOLOGY PROGRAM TO REDUCE Results: The pathway identiÀed 4 cohorts of
POSTOPERATIVE PULMONARY patients (Low Risk, Moderate Risk, High Risk
COMPLICATIONS and Acute Risk). Low risk patients received deep
Felicia Tanner-Corbett, David T. Cooke, Patrica breathing and incentive spirometry (IS) exercises
Brown, Royce F. Calhoun by the registered nurse (RN) four times /day (QID).
Division Of Cardiothoracic Surgery, University Of Moderate risk patients received positive pressure
California, Davis Medical Center/United States Of therapy twice/day in addition to IS QID. High risk
America patients received a percussion vest or intrapulmonary
percussive ventilation (IPV) three times /day in
Background: Thoracic surgery, especially pulmonary addition to IS QID. Acute risk patients received
resection for lung cancer, poses a unique set of percussion vest or IPV every 6 hours in addition to
challenges that require intensive respiratory therapy incentive spirometry QID. Bronchodilators were
(RT) in order ensure successful patient outcomes initiated in most patients. Moderate through acute
and expedited recovery. Patients require aggressive risk patients were re-evaluated every 24 hours using
pulmonary hygiene to achieve lung expansion a Progress Scoring Tool. Continuation, change or
after single lung ventilation in the operating room. discontinuation of therapy was determined by the
There is a limited window of time to optimize Progress Scoring Tool score. Implementation of this
patient postoperative pulmonary function and avoid intensive program resulted in marked decrease in the
complications such as hospital acquired pneumonia, number of thoracic surgery patients needing transfer
to the intensive care unit secondary to respiratory cardiac, hepatic and renal disease were excluded
complications. Hospital length of stay for patients from the study. All patients underwent arterial blood
undergoing video-assisted thoracic surgery (VATS) gases and lung spirometry prior to surgery, and
also decreased. they were intubated with a left-sided double-lumen
Conclusion: Multidisciplinary collaboration endobroncheal tube during general anesthesia. Our
between thoracic surgery faculty, nursing, physician indication for using NO (20 ppm) is severe hypoxia
assistants and other allied health clinicians can (SpO2<90%) occurred at one lung ventiration (OLV)
lead to successful implementation of a needed with 100% O2 during general anesthesia.
Àrst 72 hours thoracic surgery respiratory therapy Results: Patients were performed standard
postoperative pathway to the beneÀt of the patient. radical lobectomy with mediastinal lymph node
Further metrics determining effects on other dissection. Histological types of lung cancer were:
cardiopulmonary complications and a cost savings adenocarcinoma (n=7), squamous cell carcinoma
analysis is forthcoming. (n=3), large cell carcinoma (n=1), meta from thyroid
Keywords: Surgery, Respiratory Therapy, Clinical carcinoma (n=1). Pathological stages were: Stage I
Pathways, Lung cancer (n=6), Stage II (n=2), Stage III (n=3) and Stage IV or
metastasis (n=1). OLV was performed for 188±68.7
(min), and inhaled NO was used for 103.7±56.1
Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15 of the period. PaO2 improved from 62.4±6.1
(mmHg) to 96.5±41.2 (p=0.034) under identical
P1.245 CLINICAL MAINTENANCE OF ventilating conditions (FiO2 1.0) with inhaled NO,
NITRIC OXIDE INHALATION DURING and PaCO2 was not affected: (46.5±4.3 to 45.5±4.0).
GENERAL ANESTHESIA TO SURGICAL Furthermore systemic blood pressure, heart rate were
TREATMENT FOR LUNG CANCER WITH not affected after NO inhalation. Complications due
RESPIRATORY DISTRESS SYNDROME to the use of NO did not occur prior to and following
Fumiaki Watanabe1, Toshiya Tokui1, Shuhei Kogure1, the surgery. The surgery went well without speciÀc
Naoki Yamamoto1, Uhito Yuasa1, Sekira Shoumura1, problems.
Sigehito Kondou2, Motoaki Tanigawa2, Yuko Hara3 Conclusion: The maintenance of NO inhalation
1
Thoracic Surgery, Yamada Red Cross Hospital/ during general anesthesia with respiratory distress
Japan, 2Respiratory Medicine, Yamada Red Cross syndrome would be beneÀcial to surgical treatment
Hospital/Japan, 3Department Of Anesthesiology, for lung cancer. In addition, inhaled NO provide
Yamada Red Cross Hospital/Japan high-quality perioperative care at lower cost than
other treatment. This review also highlights the
Background: Inhaled nitric oxide (NO) is occasionally application of inhaled NO to surgical treatment for
used to treat hypoxemia for adult patients with acute lung cancer with respiratory distress syndrome,
respiratory distress syndrome in the intensive care strategies to augment the efÀcacy of inhaled NO, and
unit. Moreover, inhaled NO is currently indicated for potential applications of the systemic effects of the
the treatment of term and near-term neonates with gas.
hypoxemia and pulmonary artery hypertension. Since Keywords: Surgical treatment, perioperative care,
regulatory approval, several studies have suggested nitric oxide inhalation, Lung cancer
that NO inhalation can prevent chronic lung disease.
However, it is controversial whether or not to maintain
inhalation of NO during general anesthesia.We studied Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15
efÀcacy of NO inhalation during general anesthesia
in surgical treatment for lung cancer with respiratory P1.246 ADJUVANT CHEMOTHERAPY
distress syndrome. FOLLOWING RADICAL SURGERY FOR
Methods: We retrospectively investigated patients NON-SMALL-CELL LUNG CANCER: A
with respiratory distress syndrome from the 91 cases RANDOMIZED STUDY ON 70 PATIENTS
performed surgical treatment for lung cancer from Shiying Zheng1, Dong Jiang1, Hong Li2
1
January 2009 to December 2010. Twelve patients Department Of Cardio-thoracic Surgery, The First
(6 males and 6 females) were enrolled in this study, AfÀliated Hospital Of Soochow University/China,
2
with a mean age of 75 years (71-80 years). Patients Department Of Geriatrics, The First AfÀliated
with a documented history of uncompensated Hospital Of Soochow University/China
Background: Surgery is a major treatment approach NSCLC.

for non-small-cell lung cancer (NSCLC). The Keywords: non-small-cell lung cancer (NSCLC),
5-year survival rate following surgical resection is Adjuvant chemotherapy, survival rate
60%-80% for patients with stage disease, 25%-50%
for patients with stage , and 10%-40% for stage a. A revised/updated abstract may be included in
Surgery has rarely been used alone in the treatment the Late Breaking Abstract Supplement, available
of patients with stage b disease. We performed this at the 14th World Conference on Lung Cancer.
prospective randomized study to assess the effect of
adjuvant chemotherapy in NSCLC patients who had
undergone radical resections using the regimen of Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15
cyclophosphamide, vincristine, adriamycin, cisplatin,
lomustine and ftorafur (FT-207). P1.247 ANALYSIS OF MINIMALLY
Methods: Seventy patients who underwent radical INVASIVE SURGICAL TECHNIQUES IN
surgery for NSCLC in the Department of Cardio- THE TREATMENT OF LUNG CANCER
Thoracic Surgery, The First AfÀliated Hospital You B. Cui, Yong X. Wang, Xue Shan, Qi C. Cui,
of Soochow University from January 2003 to Yong Zhao
July 2008 were selected for the study. Seventy Thoracic Surgery, The First AfÀliated Hospital Of
patients with NSCLC (stages) undergoing radical Jilin University/China
surgery were randomized into two groups. Group
1 (n=35): combination group, which received Background: To analyze three minimally invasive
adjuvant chemotherapy with cyclophosphamide surgeries for lung cancer comparatively,and to Ànd
300 mg/m2, vincristine 1.4 mg/m2, adriamycin some clues for selection of the three minimally
50 mg/m2, and lomustine 50 mg/m2on day 1, and invasive surgical technique in the treatment of Lung
cisplatin 20 mg/m2on days 1-5. The treatment was Cancer.
repeated every 4-6 weeks for 4 cycles, followed by Methods: The cases of 131 hospitalized
oral administration of ftorafur (FT-207) 600-900 patients with lung cancer in the First AfÀliated
mg/d for 1 year. Group 2 (n=35): surgery group, Hospital of JiLin University were analyzed
which received surgical treatment only. Follow-up retrospectively,incluing 44 treated by video-
was scheduled monthly for 6 months, then every assisted thoracoscopic surgery(VATS), 43 by
3 months for the Àrst year and every 6 months Video-assisted mini-thoracotomy(VAMT) and 44
thereafter. Routine follow-up consisted of physical by Mini-thoracotomy(MT). The comparison of
examination, chest X-ray, ultrasound scan of the the feasible and safe, the operative duration, the
abdomen, electrocardiogram, routine blood tests, number of lymph node resected,the blood loss, the
liver and renal function tests, and tumor marker tests. pain,the complication and the time returning to full
Further testing was performed as clinically indicated. preoperative activities were analyzed.
Follow-up examinations were sometimes performed Results: The operative duration of VATS group was
in a local hospital, with the results provided by letter shorter than those of VAMT and MT groups,but there
or telephone. was not signiÀcant difference(P>0.05). The blood
Results: The overall 5-year survival rate was 48.6% loss and the pain in MT group were more than those
in the combination group versus 31.4% in the surgery of VATS and VAMT groups(P<0.05).There was no
group, and difference between the two groups signiÀcant difference in the complication and the
was not statistically signiÀcant (Ƶ2=3.09,P>0.05). time returning to full preoperative activities in three
The 5-year survival rate for patients with stage groups,however,the complications in MT group were
disease was 44% and 20.8% in the combination and more than the other two groups,such as the morbidity
surgery groups, respectively, showing a statistically of shoulder function limitation.
signiÀcant difference (Ƶ2=5.28,P<0.025). The 5-year Conclusion: Compared with this three minimally
survival rates of patients in stages in the two groups invasive surgical technique, VATS is a safe and
were 60.0% and 54.5%, respectively, and were not effective technique,howere,which surgical technique
signiÀcantly different (Ƶ2=0.03,P>0.75). should be selected Ànally depends on the age,clinical
Conclusion: Postoperative adjuvant chemotherapy stage and pathology of the patient ,and the
provides statistically signiÀcant improvement in indications should be complied with carefully.
the 5-year survival rate only in patients with stage Keyword: lung cancer ;minimally invasive surgery ;
VATS;VAMT;MT rate ; retrospective analysis
P1.248 THE ANALYSIS OF PROGNOSTIC P1.249 ANALYSIS OF THE EFFECTS OF

FACTORS ON 321 CASES OF PATIENTS THE SURGICAL THERAPY FOR AGED
WITH LUNG CANCER PATIENTS WITH LUNG CANCER
You B. Cui, Xue Shan, Yong X. Wang, Tian Y. Lu, You B. Cui, Shi Y. Feng, Yong X. Wang, Wei F.
Yong Zhao Song, Xue Shan
Thoracic Surgery, The First AfÀliated Hospital Of Thoracic Surgery, The First AfÀliated Hospital Of
Jilin University/China Jilin University/China
Background: To analyze prognostic factors of 321 Background: With the aging process an, the old
cases of lung cancer of our hospital over a period age disease incidence was inevitable signiÀcantly
of recent 2 years, and try to Ànd some clues for increased. As for our thoracic surgeon, we have
prevention and treatment of lung cancer in future. more and more elder (> 70 years) or even more elder
Methods: The data of 321 hospitalized patients with (> 80 years) patients with lung cancer. The aim of
primary lung cancer in the First AfÀliated Hospital of this study was to evaluate the surgical treatment of
JiLin University from 2003 to 2005 were reviewed elderly patients with lung cancer and summarizes the
retrospectively, and analyzed their survival rate and clinical experience of surgical treatment, to diminish
explored the factors which inÁuence prognosis and postoperative mortality, improve the surgical effect.
survival rate,such as age,clinical stage,pathology Methods: Retrospective clinical data were analyzed
and treatment.The survival rate was calculated by for 60 lung cancer sufferers over 70 who received
Product-limit method, its signiÀcance was tested by operation.
logrank test. Results: All patients received pneumoectomy
Results: The overall one-,three-andÀve- year lobectomy and other surgical treatment under general
survival rates were 79.31%,35.43%,15.02%.The anesthesia. The surgical resection rate was 93.9 %.
Àve-year survival rate of 40~50 years old patients Postoperative mortality was 3.3 % within 30d. The
was higher than the Àve-year survival rate of post-operative complication was 59.1 %. The follow-
others(P<0.05). The Àve-year survival rate was up rate was 94.3%. Survival rates of radical resection
22.02% for patients whose clinical TNM stage is after 1, 2, and 5 years were 81.6 %, 50.9 % , and34.7
stageI,11.21% in stageII,2.87% in stageIIIa, 0 in % respectively.
stageIIIb andIV(P<0.05).The Àve-year survival rate Conclusion: The age is not an absolute
was 16.34% for patients with squamous carcinoma, contraindication of the surgery , Surgical treatment
10.51% for patients with adenocarcinoma,0 for is still an effective treatment for elderly lung
SCLC patients(P<0.05). The Àve-year survival cancer. The comprehensive evaluation on the
rate was 18.1% in treatment with operation,0.02%, clinical functions is needed. Tumor stage, and
without operation.The 5-year survival rate was cardiopulmonary etc vital organs function status is
found to increase as following order: chemotherapy to determine whether surgery basis. Correct surgical
combined with radiotherapy,radiotherapy and/or methods and preoperative period care are the key to
chemotherapy post-operation and operation only. ensure the surgical treatment effects.
The 5-year survival rate for operation alone(25.13%) Keyword: aged patients；Survival rates；surgical
was higher than those for radiotherapy and/or therapy；
chemotherapy post-operation,but there was not
signiÀcant difference(P>0.05).The 5-year survival
rate was 8.23% for chemotherapy combined with
radiotherapy group (P<0.05).
Conclusion: Age,clinical stage,pathology and
different therapy were important factors affecting
prognosis of lung cancer.
Keyword: lung cancer ; prognostic factor ; survival
Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15 Division Of Thoracic Surgery, Tochigi Cancer
Center/Japan
P1.250 ANALYSIS OF
BRONCHOPLEURAL FISTULA AFTER Background: After lung cancer surgery, we often
LOBECTOMY FOR THE PATIENT WITH experience cases in which an initial recurrence lesion
LUNG CANCER is discovered in the brain. In our institute, brain
You B. Cui, Yong X. Wang, Xue Shan, Wei F. Song, MRI or CT is routinely performed for postoperative
Shi Y. Feng patients at two or three months postoperatively and
Thoracic Surgery, The First AfÀliated Hospital Of at Àve or six months postoperatively. In this study,
Jilin University/China we reviewed whether early diagnosis by regular
brain examination inÁuenced the later course and
Background: This study was to analyze the prognosis.
bronchial stump closure by different methods Methods: We retrospectively analyzed the records
to reduce the incidence of the postoperative of 389 patients with lung cancer who underwent
bronchopleural Àstula in pneumonectomy for lung curative surgery from January 2004 to January 2009
cancer and treatment for bronchopleural Àstulae at the Tochigi Cancer Center. For all patients, the
(BPF) after pneumonectomy for lung cancer. frequency of metastasis, method of brain metastases
Methods: This study was to analyze the bronchial detection, treatment for brain metastases, clinical
stump closure by different methods to reduce the course after treatment, and prognosis were reviewed.
incidence of the postoperative bronchopleural Àstula Results: Of the 389 cases, 258 underwent regular
in pneumonectomy for lung cancer and treatment for brain examination after surgery. Among these 258
bronchopleural Àstulae (BPF) after pneumonectomy patients, brain metastases as initial recurrence lesions
for lung cancer. were detected in 10 (regular group). In addition,
Results: Six BPFs developed postoperatively brain metastases were detected due to symptoms in
among the 276 cases (overall incidence,2.2%): 1 8 cases (symptom group). Six of the patients in the
after manual suturing (2.2%) and four after stapling regular group had solitary metastases and four had
(1.7%), and this difference was not statistically multiple metastases. Regarding the pathological
signiÀcant. Of all the BPF cases , One of 2 cases background of the regular group, 7 patients had
of conservative treatment and one of 2 cases of adenocarcinoma, 2 had large cell carcinoma, and
operation treatment were dead, the total mortality 1 had squamous cell carcinoma. The pathological
rate were 33%. Tow cases sufferance from bronchial tumor stages were stage 1B in 3, stage 2A in 1,
Àstula postoperatively regain. stage 2B in 1, stage 3A in 4, and stage 3B in 1.
Conclusion: The incidence of the postoperative All cases in the regular group were treated with
bronchopleural Àstula was acceptable and was stereotactic radiosurgery. Of the 10 patients in the
not directly associated with the methods of regular group, 9 had local or distant recurrence
bronchial stump closure. The key therapy for 1 to 5 months after the Àrst treatment for brain
postpneumonectomy BPF is to close the stoma metastases. Only one patient was recurrence-free
and thoroughly eliminate infection. Malnutrition, for 30 months. Of the 9 relapse cases, 7 died and 2
lower pulmonary lobectomy, total pneumonectomy, were alive with the disease. In the symptom group,
perioperative chemotherapy and radiontherapy, are 4 patients had solitary brain metastases and 4 had
high risk factors of BPF after pneumonectomy. multiple metastases. Regarding the pathological
Keyword: lobectomy; bronchopleural Àstula; background of the symptom group, 5 patients had
mechanical stapling; lung cancer adenocarcinoma, 1 had squamous cell carcinoma, 1
had adenosquamous cell carcinoma, and 1 had small
cell carcinoma. The pathological tumor stages were
Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15 stage 1B in 3, stage 2B in 1, and stage 3A in 4. Three
of the 8 patients in the symptom group were treated
P1.251 FOLLOW-UP EXAMINATION with stereotactic radiosurgery and the remaining
FOR DETECTING BRAIN METASTASES cases were treated with surgery or whole brain
AFTER LUNG CANCER SURGERY radiotherapy. Seven patients in the symptom group
Rie Nakahara, Akiko Ui, Norihisa Oohata, Haruhisa relapsed after the Àrst treatment for brain metastases,
Matsuguma of whom 5 died and 2 were alive with the disease.
One of the 8 patients in the symptom group was octogenarians made up 6.1%; 5.6% and 2.5% of
recurrence-free for 8 months. No signiÀcant lobectomies each year whereas in the Ànal year they
correlation was observed between the clinical course, comprised 14.6% (p=0.004 Fisher’s). Co morbidities
prognosis and method of detection. were commoner in the control group 58% [11
Conclusion: Regular brain examination in the cardiovascular (CV) and 13 non-CV] compared to
early postoperative period identiÀed silent early 27% in the octogenarian group [8 CV; 3 non-CV]
metastasis to the brain, which allowed us to choose a p=0.007. There were no in hospital deaths in either
minimally aggressive treatment, such as stereotactic group. Lung function was signiÀcantly poorer in the
radiosurgery. However, because of the limited control group (table). Twelve (29%) octogenarians
number of cases, these results do not suggest that had post operative complications, six were admitted
regular follow-up radiological examinations of the to intensive care (2 unplanned) compared to 16
brain should be performed after lung cancer surgery. (39%) (p=0.4) controls who suffered complications,
four of which were admitted to intensive care (3
unplanned). Hospital stay was similar in the two
Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15 groups (table) In the octogenarian group histology
revealed two typical carcinoid tumours; 14
P1.252 IS LOBECTOMY FOR PRIMARY adenocarcinomas; 24 squamous cell carcinomas and
LUNG TUMOUR IN OCTOGENARIANS one large cell carcinoma. Pathological staging of the
WORTH THE RISK? A CASE CONTROL NSCLC was IA 12, IB 17, IIA 1, IIB 6, IIIA 2, IIIB
STUDY 1. Over a median follow up of 637 days (range 22-
Marco A. Scarci, Saina Attaran, Lewis Haywood, 1720) seven octogenarians have died; the controls
Loic Lang-Lazdunski, Juliet King, Tom Routledge, have been followed for a median 1023 days (range
Karen Harrison-Phipps, John Pilling 170 - 1722) with nine deaths. Log rank test, Kaplan
Thoracic Department, Guy’s Hospital/United Meier method shows no signiÀcant difference
Kingdom between the two groups (p=0.89).
Conclusion: Lobectomy for primary lung tumour in
Background: For early stage non small cell lung octogenarians is feasible with similar morbidity and
cancer (NSCLC) surgery is the treatment of choice. mortality to younger patients whom undergo surgery
The aging population will lead to increasing requests despite a greater number of co-morbidities. The
for surgical intervention in octogenarians. There post operative survival of octogenarians justiÀes an
are some reservations that this may be excessively aggressive surgical approach.
dangerous for the survival gained. Keyword: lung surrgery in octogenarians
Methods: We reviewed 41 consecutive
octogenarians [24 male, median age 82 years (range
80 - 88)] who underwent lobectomy via thoracotomy Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15
(36) or VATS (5) for suspected NSCLC over 48
months. These were compared to 41 younger P1.253 THE EXTENT OF LUNG
controls [median age 65 years (range 34 -78)] PARENCHYMA RESECTION
matched for incision, lobe resected, histology, TNM SIGNIFICANTLY IMPACTS LONG-TERM
stage and sex. QUALITY OF LIFE IN PATIENTS WITH
Results: Comparison between octogenarians and NON SMALL CELL LUNG CANCER
controls Tobias Rose1, Roland Kurdow2, Peter Dohrmann1,
Thomas Küchler1, Bodo Schniewind1
Octagenarians Controls p value
1
Median Range Median Range
General And Thoracic Surgery, University Hospital
FEV1(L) 1.98 1.14-3.3 1.78 0.9-4.57 0.2 Of Schleswig-holstein Campus Kiel/Germany,
2
FEV1%(predicted) 93 51-136 78 37-131 0.02 General And Thoracic Surgery, St. Marien Hospital/
FVC(L) 2.7 1.4-4.8 2.8 1.8-6.1 0.08
Germany
TLCO % (predicated) 78 43-119 60 30-96 0.01
Hospital Stay 8 5-42 6 3-67 0.16
Background: Secondary to clinical outcome,
Octogenarians made up 7.5% of the 545 patients health-related quality of life (QOL) after resection
who underwent lobectomy for suspected NSCLC of NSCLC is of particular interest. However, few
during the study. In the Àrst three years of the study studies have explored QOL following lung resection.
Methods: Between January 1998 and December 2004, Background: We observe a great number of cases
a total of 159 patients with NSCLC underwent surgical with lung cancer and coronary artery disease as
resection and were enrolled in this prospective study. their development is caused with common risk
QOL and clinical data were assessed prior to resection factors: age, smoking and improper way of living.
and for up to 24 months after surgery by applying the Methods: From December 2002 to December
EORTC QLQ C-30 questionnaire and the lung-speciÀc 2009 we performed 112 operations for combined
questionnaire, QLQ-LC13. QOL was calculated and the pulmonary, chest, cardiac and esophageal
QOL following bi-/lobectomy was compared with QOL pathologies. In 89 cases (79.4%) we carried
after pneumonectomy. out simultaneous operations for cardiac and
Results: Overall, the 5 year survival rate was pulmonary diseases. In others, in 18 cases we
42%. Mean survival of the pneumonectomy group performed transcutaneous angioplasties before the
was slightly lower than that of the bi-/lobectomy pulmonary resections and in 2 (1.8%) - myocardial
group, although the difference was not statistically revascularization on a beating heart via the lateral
signiÀcant (p=0.058). The rate of complications was thoracotomy and in 3 – staged cardiac and then
not signiÀcantly different between the two groups. pulmonary operations. All simultaneous operations
After a postoperative drop, most QOL indicators were carried through the same anesthesia with
remained near baseline for up to 24 months, with CPB.
the exception of physical function (p<0.001), pain Results: We performed lobectomies – 91% of all
(p=0.034), and dyspnoea (p<0.001), which remained operations, of those 54% right-sided procedures.
signiÀcantly impaired. QOL was signiÀcantly better There were seven bronchoplastic operations –
(difference >10 points) after bi-/lobectomy than lobectomies with circular bronchial resections.
after pneumonectomy. However, differences were Six patients (86%) had upper lobectomies and
statistically signiÀcant only with regards to physical only one patient had a lower lobectomy with
function (at 3 months), social function (at 3 and 6 anastomosed upper lobar bronchus and left main
months), role function (at 3, 6 and 12 months), global bronchus. Comparing mortality and morbidity
health (at 3 and 6 months), and pain (at 6 months). rates in groups with staged and simultaneous
Conclusion: Patients who underwent lung resection operations we did not observe authentic
for NSCLC failed to make a complete recovery after differences: a morbidity rate was 20% (staged
24 months. Patients who underwent pneumonectomy procedures) versus 14% (simultaneous operations)
had signiÀcantly worse QOL values and a decreased and a mortality rate was 5% (staged procedures)
tendency to recover, compared with patients who versus 5.4% (simultaneous). Overall 5-year
underwent bi-/lobectomy. Therefore, major lung survival rate among patients with lung cancer was
resection has a much more serious impact on the QOL 35%, median survival was 41 months.
of affected patients than does major visceral surgery. Conclusion: Thus, we state that simultaneous
Keywords: Lung cancer, Quality of Life, EORTC surgery for cardiac and pulmonary pathologies
QLQ performed through the sternotomy with CPB is
an effective surgical technique as it improves life
A revised/updated abstract may be included in quality in patients with lung cancer and decreases
the Late Breaking Abstract Supplement, available mortality rates in patients with severe cardiac
at the 14th World Conference on Lung Cancer. pathology.

Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15 the Late Breaking Abstract Supplement, available
P1.254 SIMULTANEOUS OPERATION
FOR MALIGNANT PATHOLOGY
OF HEART AND LUNG THROUGH
STERNOTOMY
Vladimir Porhanov1, Igor Polyakov2, Kirill Barbukhatti1
1
Cardiothoracic Surgery Center/Russian Federation,
2
Oncological Department, Cardiothoracic Surgery
Center/Russian Federation
Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15 Keywords: pulmonary resection, metastatic lung
tumors, colorectal carcinoma
P1.255 RADIOLOGICAL PROGNOSTIC A revised/updated abstract may be included in
FACTORS IN PATIENTS WITH the Late Breaking Abstract Supplement, available
RESECTED METASTATIC LUNG at the 14th World Conference on Lung Cancer.
TUMORS IN PATIENTS WITH
COLORECTAL CARCINOMA
Takeshi Matsunaga1, Yoshikazu Miyasaka2, Kazuya Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15
Takamochi2, Shiaki Oh2, Kenji Suzuki2
1
Division Of General Thoracic Surgery, Juntendo P1.256 COMPLICATIONS FOLLOWING
University School Of Medicine/Japan, 2Division Of LUNG SURGERY IN THE NELSON
Thoracic Surgery, Juntendo University School Of LUNG CANCER SCREENING TRIAL: A
Medicine/Japan COMPARISON WITH THE LITERATURE
Susan V.’. Westeinde1, Harry J. De Koning2, Paul De
Background: Metastasectomy is performed as Leyn3, Nanda Horeweg1, Frederik B. Thunnissen4,
one of treatment strategy for pulmonary metastasis Matthijs Oudkerk5, Harry J.M. Groen6, Jan-Willem
of colorectal carcinoma. However, the indication J. Lammers7, Carla Weenink8, Rene Vernhout1,
remains controversial. Kristiaan Nackaerts9, Willem Mali10, Rob J. Van
Methods: A retrospective study was conducted Klaveren1
1
on 108 patients (126 resections) with pulmonary Pulmonary Medicine, Erasmus MC/Netherlands,
2
metastases of colorectal cancer, resected between Public Health, Erasmus MC/Netherlands,
3
January 2000 and October 2010. We reviewed University Hospital Leuven/Belgium, 4VUMC/
radiological Àndings of computed tomography in Netherlands, 5Radiology, UMC Groningen/
all cases, and classiÀed as follows; Type 1; solitary Netherlands, 6Pulmonary Medicine, UMC
big tumor (>3cm), type 2; solitary small tumor Groningen/Netherlands, 7Pulmonary Medicine,
(3cm), type 3; solitary big tumor and other small UMC Utrecht/Netherlands, 8Pulmonary Medicine,
multiple tumors, and type 4; multiple small tumors. Kennemer Gasthuis/Netherlands, 9Respiratory
We analyzed the following preoperative prognostic Oncology Unit, University Hospitals Leuven/
factors: gender, age, CEA, tumor size, numbers Belgium, 10Radiology, UMC Utrecht/Netherlands
of tumors, presence of metastases at other sites,
DFI (disease-free interval) and the classiÀcation of Background: Lung cancer screening populations
type1-4. Survival was estimated with Kaplan-Meyer usually consist of heavy current and former smokers
method and multivariate analysis was performed by at an advanced age and at high risk for co-morbid
the Cox proportional hazards regression. disease. The objective was to assess the complication
Results: There were 62 men and 46 women and rate in participants of the screen arm of the NELSON
age ranged 35 to 81 with median of 64. The actual lung cancer screening trial who underwent surgical
5-year survival of over all patients was 49.3%. That resection and to investigate, based on a literature
of type 3 was 28.1% less than type 1 (61.1%), 2 review, whether the complication rate, length of
(51.9%) and 4 (52.9%). In multivariate analysis, the hospital stay, re-thoracotomy and mortality rates
signiÀcant prognostic factors were type 3 (risk ratio: after a surgical procedure were different from non-
7.75, 95% CI: 2.31-25.97, p-value: <0.001), DFI(risk screening series.
ratio: 0.23, 95% CI: 0.06-0.87, p-value: 0.031) Methods: Between April 2004 and December 2008
and females(risk ratio: 5.16, 95% CI: 1.64-16.26, 198 subjects underwent thoracic surgery. Co-morbid
p-value: 0.005). conditions were retrieved from the medical records
Conclusion: Radiological classiÀcation of metastatic and scaled according to the Charlson-Co-morbidity
lung tumors of colorectal carcinoma was one of the Index. Post-operative complications were classiÀed
signiÀcant prognostic predictors. Recently outcome as minor and major.
of chemotherapy for colorectal carcinoma continues Results: In total, 182 thoracotomies, 5 thoracotomies
to be improving. Thus prognosis of resected after Video Assisted Thoracoscopic Surgery (VATS)
metastatic lung tumor of colorectal carcinoma and 11 VATS procedures were performed. In these
could be improved and the indication should be re- patients, 36% had chronic obstructive lung disease,
considered based of those prognostic factors. 16% coronary artery disease, 14% diabetes mellitus
and 11% peripheral vascular disease. Following CI: 15;35). The median hospitalization was 9 days
thoracotomy, 48% (90/187) had 1 minor and (5-28) and drainage time was 5 days (0-17). In 19
10% (18/187) 1 major complication; following (36,5%) patients complications occurred. Pulmonary
VATS, 38% (6/16) had 1 minor complication, but complications occurred in 8 (15,4%) patients: 1 with
no major complications. Seventeen percent (3/18) bronchialstump-insufÀcieny, 1 with hemothorax,
of major complications and, 21% (20/96) of minor 1 with prolonged air leak and 5 with pneumonia.
complications were seen in subjects operated for Reoperation was necessary in 3 patients. In 12
benign disease. The re-thoracotomy rate was 3% and (23.1%) patients cardiovascular morbidity occurred
there was no 30-day mortality after thoracotomy or requiring medical and antiarrhytmic treatment, 6
VATS. (11.5%) had other complications (cerebrovascular
Conclusion: Mortality and major complication rates incident, urinary tract infection).
after surgical procedures are lower in the screen arm Conclusion: Lung resections in selected
of the NELSON lung cancer screening trial than in octogenarians can be performed safely and without
non-screening series. a higher risk of perioperative mortality. The
Keywords: Early detection of lung cancer, perioperative morbidity does not differ from other
Postoperative complications, Thoracotomy, Thoracic patients. Long term survival justiÀes an active
Surgery, Video-assisted approach.
Keyword: lung cancer, surgery, octogenarians

P1.257 PERIOPERATIVE MORBIDITY,
MORTALITY AND SURVIVAL P1.258 PPOFEV1.0% FOR THE
AFTER LUNG RESECTIONS IN PREOPERATIVE RISK ASSESSMENT
OCTOGENARIANS IS BETTER THAN PPOFEV1.0 IN LUNG
Michaela Tutic, Dagmar Paredes, Peter Kestenholz, CANCER RESECTION.
Isabelle Opitz, Didier Schneiter, Walter Weder Keita Tokuishi, Shinichi Yamashita, Takafumi
Thoracic Surgery, University Hospital Zurich/ Hashimoto, Toshihiko Moroga, Michiyo Miyawaki,
Switzerland Masao Chujo, Satoshi Yamamoto, Katsunobu
Kawahara
Background: Due to a rapid aging population and Surgery ɉ, Oita University Faculty Of Medicine/
increased life expectancy in octogenarians, lung Japan
surgeries are more commonly being performed in
elderly patients. The purpose of the present study Background: The purpose of this study is to asses
was to evaluate our current mortality, morbidity and the outcome of the patients after VATS lung resection
long term survival in this patient population. by preoperative lung function test.
Methods: Retrospective analysis of 52 patients Methods: We retrospectively reviewed the results
(13 females) who were 80 years or older (80-88) of 324 patients who underwent VATS or open lung
who underwent surgery for Non-Small-Cell-Lunger resection between January 2003 and November
Cancer (NSCLC) over the past 10 years. 2009.Predicted postoperative FEV1.0(ppo FEV1.0)
Results: The histology revealed squamous cell was calculated by FEV1.0×(1- number of resected
carcinoma in 21, adenocarcinoma in 22, large cell subsegments /42). Four groups according to ppo
carcinoma in 5, and 4 patients with other histological FEV1.0, such as less than 0.8L, 0.8-1.0L, 1.0-
types. Tumor staging of the 49 patients with NSCLC 1.2L, and more than 1.2L were compared. In
showed 29 patients with stage I, 8 with stage II, 9 %ppoFEV1.0, three groups were divided to less than
with stage IIIA, 2 with stage IIIB, 1 with stage IV. 40%, 40-60%, and more than 60%.
Lobectomy was performed in 32, bilobectomy in 10, Results: Postoperative pulmonary complication
sleeve-lobectomy in 1, pneumonectomy in 4, and were 3 cases in ppoFEV1.0 less than 0.8L (n:10),
segmental-/wedge resections in 5 patients. There 4 in 0.8-1.0L(n:14), 6 in 1.0-1.2L (n:25) and 54
was no in-hospital or 90-day mortality. Out of the in more than 1.2L (n:270). These results were not
52 patients 9 patients died, the Àrst after 16 months. statistically signiÀcant (p=0.74). Mortality was only
The median survival time was 25 months (95% 2 cases (0.6%). However, postoperative complication
was signiÀcantly related to ppoFEV1.0%, which the for pulmonary resection.

complication rates were 50% (9 out of 18 cases) in Results: It took 18.3 ± 9.4 seconds for patients with
less than 40% group, 27% (38 out of 141) in 40-60% artiÀcial pneumothorax to be initiated the surgery,
group, and 12.5% (20 out of 160). (p <0.01) on the other hand it took about 300 seconds for those
Conclusion: These results suggested that without artiÀcial pneumothorax. The reduction in the
ppoFEV1.0% should be used for the preoperative blood Áow from the whole body to heart leaded to
risk assessment rather than ppoFEV1.0. decrease in blood pressure, approximately 20mmHg
during artiÀcial pneumothorax, which had no effect
A revised/updated abstract may be included in on the initiation of the pulmonary resection. There
the Late Breaking Abstract Supplement, available were some patients who had pulmonary adhesion.
at the 14th World Conference on Lung Cancer. But if it was mild adhesion, it was possible to
separates the lung from the wall of the chest using
the way of the artiÀcial pneumothorax .
Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15 Conclusion: When there was only single port hole
for a thoracoscope in chest wall, a conÀned space
P1.259 A PILOT STUDY OF THE can be maintained and artiÀcial pneumothorax can
ARTIFICIAL PNEUMOTHORAX be created with relative ease. It induces no serious
FOR A VATS LOBECTOMY AND side effects and needs little costs. This method
SEGMENTECTOMY. shortens deÁating time of lung,that solves decrease
Masami Morimoto, Takanori Miyoshi, Hisashi in SpO2 from ventilation-perfusion mismatch during
Matsuoka, Naoki Hino, Masaru Tsuyuguchi the differential lung ventilation. In this way it is
Surgery, Tokushima Municipal Hospital/Japan suggested that artiÀcial pneumothorax is becoming a
useful option intra VATS.
Background: Video-assisted thoracoscopic (VATS) Keywords: artiÀcial pneumothorax, VATS
lobectomy remains controversial. Recently, VATS
lobectomy and segmentectomy for malignancies A revised/updated abstract may be included in
has spread slowly. It is necessary to deÁate the the Late Breaking Abstract Supplement, available
illness side lung under the single-lung ventilation at the 14th World Conference on Lung Cancer.
for VATS lobectomy, and then the deÁation of
lung is an important factor to its feasibility and
safety. As problems, the single-lung ventilation Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15
causes ventilation perfusion ratio inequality, which
decreases in SpO2. Thus, the purpose of this study P1.260 WHAT IS THE PROGNOSIS
was to be given the lung collapse in a short time, OF SURGICALLY RESECTED NON
and to be given enough operative Àelds of vision. SMALL CELL LUNG CANCER WITH
We have developed the method by the artiÀcial UNEXPECTED PATHOLOGICAL N2
pneumothorax. DISEASE?
Methods: Of the 27 patients who underwent Andrea Billie1, Saina Attaran1, Lewis Haywood2,
pulmonary resections with the artiÀcial Loic Lang-Lazdunski2, Juliet King1, Tom Routledge2,
pneumothorax at Tokushima Municipal Hospital Karen Harrison-Phipps1, John Pilling2
1
from May 2010 to February 2011, these patients Thoracic Surgery, Guys Hospital/United Kingdom,
2
were reviewed retrospectively. At Àrst, under Thoracic Department, Guy’s Hospital/United
single-lung anesthesia, the patient was placed in Kingdom
the lateral decubitus position. A 5-mm, 30-degree
thoracoscope was placed through the seventh Background: The prognosis of non-small cell
intercostal space in the midaxillary line. Then lung cancer (NSCLC) is stage related. Staging
the artiÀcial pneumothorax was produced at 8-10 investigations are used to exclude patients with
cmH2O using the pneumoperitoneum apparatus. mediastinal nodal disease from surgical resection.
And a 2-cm incision was then made in the seventh Due to limitations in these tests a number of N2
intercostal space in the auscultatory triangle. An positive patients undergo resection. The aim of this
access thoracotomy was always located in the fourth study was to investigate the outcome after lung
intercostal space in the anterior axillary line (3 cm) resection in patients with N2 involvement.
Methods: We reviewed all patients (n=663) Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15
undergoing anatomical lung resection for NSCLC at
our institution over a 48 month period from January P1.261 FEV1 IS NOT A PROGNOSTIC
2006. Patients underwent staging by CT and PET, MARKER IN OPERATED PATIENTS
if indicated, by mediastinoscopy or EBUS. Patients WITH STAGE I OR II NON-SMALL CELL
without clinical mediastinal nodal disease were LUNG CANCER (NSCLC)
subjected to anatomical resection. Anouschka Cogen1, Yanina Dockx1, Annelies
Results: Of all the patients who had lung resection, Janssens2, Joost Weyler3, Paul Van Schil1
1
58 (8.7%) were pN2 [38 male, median age 66 Thoracic And Vascular Surgery, Antwerp University
years (range 43 - 82)]. The majority, 49 underwent Hospital/Belgium, 2Pulmonary Medicine, Antwerp
lobectomy, 9 pneumonectomy and 3 sleeve resection; University Hospital/Belgium, 3Epidemiology And
5 patients had concomitant chest wall resection There Social Medicine, University Of Antwerp/Belgium
was one death within 30 days of operation (1.7%).
Postoperative staging showed seven T1, n=38 T2 and Background: Prognosis of patients with NSCLC
n=13 T3. All patients were referred to oncologists depends on stage, histology, gender and is also
for consideration of adjuvant therapy. Follow up is determined by other tumor and patient related
complete for all patients. The median follow up for the factors. In retrospective studies lung cancer mortality
surviving patients is 818 days. The median survival was found to be higher in patients with chronic
(Kaplan Meier method) was 859 days. Survival at obstructive pulmonary disease (COPD) and a forced
one, two and three years being 73%, 51% and 44% , expiratory volume in one second (FEV1) < 70%
respectively. Histology; presence of N1 disease; single (Sekine et all. Association of chronic obstructive
versus multiple, station or zone N2 disease; resection pulmonary disease and tumor recurrence in patients
margins and extent of resection were not signiÀcantly with stage IA lung cancer after complete resection.
associated with altered survival. Increasing T stage was Ann Thorac Surg 2007; 84: 946-51). In the Cher@
signiÀcantly associated with poorer survival (p=0.009). Nostrial and the Paccora trials a strong relationship
was observed between FEV1 and overall survival
(OS) (Germonpré P et al. J Thor Oncol 2007; 2:
S640. Germonpré P et al. Chicago multisdisciplinary
symposium in thoracic oncology 2010). These
studies were based on patients with clinical stage
III with unresectable disease. In a smaller Japanese
study FEV1 was a prognostic factor for OS in
operated patients (Nakaljima T, Sekine Y, Yamada
Y et all. Long-term surgical outcome in patients
with lung cancer and coexisting severe COPD.
Thorac Cardiovasc Surg 2009; 57: 339-342). In the
present study we investigate whether the presence
of moderate COPD deÀned as a FEV1 70% of the
predictive value, is a prognostic marker in patients
with resectable stage I and II NSCLC.
Methods: Study population:
• All relevant clinical information was gathered
retrospectively from 77 consecutive patients
undergoing complete resection between January
2003 and January 2006.
Conclusion: While these data need to mature further • All patients were staged according to the 7th TNM-
it seems that surgery can make a contribution to the classiÀcation.
multimodality treatment of low volume mediastinal • Primary endpoints were OS and progression-free
nodal disease. It is time to study the place of surgery survival (PFS).
in the treatment of clinically apparent mediastinal • Patients dying within 30 days after the operation
nodal disease, especially with an early T stage. were excluded (5 patients).
Keyword: surgery in N2 disease • None of the patients received systemic
chemotherapy or radiotherapy before the operation. Methods: 53 lung cancer patients (15 females, 38
• Follow-up information was complete for all males), without pleural adhesions were enrolled and
patients and ended in July 2010. eligible for the study. Three pneumonectomies, 3
Patients were classiÀed as having a FEV1 70% or a bilobectomies, 47 lobectomies (including 6 VATS
FEV1 > 70%. lobectomies) and 1 anatomical segmentectomy
Results: According to the Kaplan Meier analysis were performed. Patients were randomized after
(log rank test) FEV1 was not a signiÀcant prognostic completion of lung resection and lymphadenectomy.
factor for OS [p=0.461] (Àg.1) or PFS [p=0.530]. In 29 patients from the Tachosil® group 1 to 3
In a Cox multiple regression analysis the adjusted large pieces of Tachosil (mean 1.8, SD±0.7) were
hazard ratio for FEV1 (measured on a continuous applied, while in 24 patients from the control group
scale) was 1.632 (p= 0.458) after adjustment for only coagulation was allowed. Clinical data were
stage and age. collected, and pleural concentrations of IL-6, IL-
1ra and IL-8 on postoperative days 1, 2 and 3 were
measured, with ELISA method.
Results: Both groups were well balanced according
to sex, age, number of packyears of cigarettes,
time from smoking cessation, pulmonary function
test results, concomitant diseases, BMI index and
perioperative serum concentrations of IL-6, IL-1ra
and L-8. Postoperative complications occurred in
8/29 and 12/24 patients from each group (p=0.3),
respectively, with no mortality. No differences
in time of surgery, intraoperative blood loss,
Conclusion: In contrast to other studies our data amount of drainage and drainage hemoglobin
show that FEV1 is not a prognostic factor in patients concentration on postoperative days 1, 2 and 3,
with resectable stage I and II NSCLC. Precise time to drainage removal and number of blood units
selection criteria regarding cardiopulmonary function transfused between the groups were observed. The
excluding patients with a very poor cardiopulmonary total postoperative pleural drainage was lower in
function for surgical therapy, could be responsible Tachosil® group (1289.1±641.39, vs. 1987±1462mL,
for this Ànding. p=0.025). There was a positive correlation between
Keywords: FEV1, prognostic factor, non-small cell poor performance status (PS) and the volume of
lung cancer (NSCLC), Overall survival postoperative drainage on postoperative days 2 and
3, as well as total postoperative drainage. Decreased
IL-6 concentrations in pleural Áuid on the Àrst
Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15 postoperative day correlated with increased drainage
on the 2nd and the 3rd postoperative days, as well
P1.262 THE ROLE OF TACHOSIL® IN as with total postoperative drainage in the whole
LYMPHOSTASIS AFTER MEDIASTINAL group and in the non-Tachosil® group, but not in
LYMPHADENECTOMY IN LUNG the Tachosil® group. No signiÀcant differences of
CANCER PATIENTS. IL-1ra and IL-8 in pleural Áuid on postoperative
Tomasz Szczĕsny1, Izabela Kubiszewska2, days 1, 2 and 3 between the groups were observed.
Agnieszka Rybak3, Jacek Michaãkiewicz2, Maria Concentration of IL-6 in pleural drainage was higher
Szymankiewicz3, Janusz Kowalewski1 in the Tachosil® group on the Àrst (188790 (119135-
1
Department Of Thoracic Surgery, Oncology Center 290380) vs 104052.5(80286.25-176356.3)pg/mL,
In Bydgoszcz/Poland, 2Department Of Immunology, p=0.01) and the second (117155 (75505-184670) vs
Nicolaus Copernicus University In Torun, Collegium 68205 (43268-113625)pg/mL, p=0.03) postoperative
Medicum In Bydgoszcz/Poland, 3Oncology Center In days.
Bydgoszcz/Poland Conclusion: This study did not show any serious
impact of application of Tachosil® on mediastinum
Background: Final results of prospective randomized after lymphadenectomy on clinical outcome, except
study to assess the inÁuence of Tachosil® applied on decreased amount of total postoperative drainage.
mediastinum after lymphadenectomy are presented. It also showed a signiÀcantly higher concentration
of IL-6 in pleural Áuid on postoperative day 1 65.4% and 44.6%, respectively.

and 2, which may be the result of local immune Conclusion: ASC was found more frequently in older
response to Tachosil®, without signiÀcant impact on patients. Compared with AC patients, ASC patients
postoperative complications. had worse pathological stage and poor prognosis.
Keywords: Lung cancer, Tachosil, mediastinal Keyword: adenosquamous cell carcinoma
lymphadenectomy
A revised/updated abstract may be included in the Late Breaking Abstract Supplement, available
the Late Breaking Abstract Supplement, available at the 14th World Conference on Lung Cancer.

P1.264 NEW SURGICAL STRATEGY FOR
P1.263 CLINICOPATHOLOGICAL STAGE III THYMOMA COMBINED WITH
FEATURES OF RESECTED VIDEO-ASSISTED THORACIC SURGERY
ADENOSQUAMOUS CELL CARCINOMA Kyoji Hirai
OF THE LUNG. Division Of Thoracic Surgery, Nippon Medical
Yoshinori Shitara1, Kouhei Tajima2, Masatoshi School Chiba Hokusou Hospital/Japan
Ishizaki2, Toshiki Yajima3, Shigebumi Tanaka3,
Hiroyuki Kuwano4 Background: Whether thoracoscopic surgical
1
Surgery, Fujioka General Hospital/Japan, 2Fujioka treatment is acceptable for invasive thymoma
General Hospital/Japan, 3Isesaki Municipal remains to be still controversial. We performed the
Hospital/Japan, 4General Surgical Science, Gunma video-assisted thoracoscopic surgery for Masaoka
University/Japan stage III thymoma invaded to adjacent organs
after acquisition of the patient permission. We
Background: Primary adenosquamous cell examined the feasibility of modiÀed video-assissted
carcinoma(ASC) of the lung is a rare disease. The thoracoscopic thymectomy (MVAT-T) with lateral
purpose of this retrospective study is to investigate thoracotomy for Masaoka stage III thymoma. We
the clinicopathological features of resected ASC lung demonstrate the outcomes of the resected cases and
cancer patients. introduce our representative operations.
Methods: From September 1997 to December 2010, Methods: We evaluated the short-term outcomes of
20 patients with ASC of the lung underwent pulmonary 8 cases undergoing surgery for stage III thymomas
resection. ASC represented 3.1% of the 651 patients. without myasthenia gravis between Jan 2007 and
We investigated the clinicopathological features of ASC Dec 2010. A part of stage III thymomas occurred in
patients and compared with 352 adenocarcinoma(AC) lower pole of the thymus, which locally invaded the
patients and 227 squamous cell carcinoma(SC) patients lung, the pericardium and the left brachiocephalic
underwent pulmonary resection. vein was selected for this technique. Of these, 5
Results: ASC patients consisted of 14 male and 6 cases were operated via right thoracic cavity, and 3
female with a mean age of 71 years old. The surgical cases were operated via left thoracic cavity. Lateral
procedures comprised 15 lobectomies and 5 sublober thoracotomy was done at fourth or Àfth intercostal
resections (two segmentectomies, three wedge space. One or two thoracoscopic ports were inserted
resections). Four patients had pathological stage IA, at sixth or seventh intercostal space on the anterior
5 patients had stage IB, 2 patients had stage IIA, 5 axillary line. We inserted unilateral hand into thoracic
patients had stage IIIA, 3 patients had stage IIIB, cavity adequately and touched the tumor directly
and one patient had stage IV. Median tumor size was under thoracoscopic vision. As for surgical treatment
38.1mm in length. Nine patients had lymphnodes of upper pole of thymus, all cases were carried out
metastases. Median follow-up was 30.1 months. using chest wall lifting method by the kirchner wires
The overall 5-year survival rate of ASC patients inserted under the skin on the sternum.
was 38.2%. Mean age of both AC patients and Results: Complete follow-up data were available
SC patients were 67 years old. The overall 5-year in 8 patients (4 females, and ages ranged from 46 to
survival rates of AC patients and SC patients were 74 years with a mean age of 58.5). Mean operative
duration was 212 minutes (range, 160 to 265 Methods: Retrospective analyses were performed
minutes) . The median postoperative hospital stay of all patients who underwent surgical resection
was 7.5 days. The pathological examinaton showed after neoadjuvant chemoradiation therapy for stage
that type AB was in two cases, type B1 in three IIIA-N2 non-small cell lung cancer from 1998 to
cases, and type B2 in three cases. In all cases tumor 2007. The chemotherapy regimens consisted of
cells at surgical margin and in postoperative pleural weekly paclitaxel plus cisplatin or weekly paclitaxel
effusion could not be found. Postoperative radiation plus carboplatin for 5 weeks. Concurrent thoracic
therapy was carried out in four cases. At a median radiotherapy dose was 45 Gy over 5 weeks. Surgical
follow-up of 2.1 ± 0.7 years (range, 0.6-3.8 years) resection was planned at around 4 weeks following
, there was no recurrence on enhanced CTor PET/ the completion of neoadjuvant therapy.
CT. No patient in this group underwent conversion to Results: Of 186 patients who underwent
median sternotomy. No severe surgical complications neoadjuvant therapy, 23 bilobectomies, 28
and postoperative complications were detected. pneumonectomies, and 135 lobectomies were
Conclusion: The operative wound and postoperative performed. Early postoperative mortality rate (within
ADL was very satisfactory to all patients. For 30 days after operation) was 7.1%, 8.7%, and 1.5%
females, compared with median sternotomy, this in pneumonectomy, bilobectomy, and lobectomy,
technique decreases mental stress of operation and respectively. In addition to, late postoperative
gives superior cosmesis. These results suggest that mortality rate (within 90 days) of lobectomy,
MVAT-T for a part of stage III thymomas is safe bilobectomy, and pneumonectomy were 5.9%,
and may confer some advantages over conventional 13% and 10.7%, respectively. Overall survival
methods of standard median sternotomy. However, was signiÀcantly higher among patients treated by
this technique requires further investigation in a large lobectomy than among those treated by bilobectomy
series with a long-term follow-up data. (p=.041) or pneumonectomy (p=.010) (Fig 1).
Keywords: video-assisted thoracic surgery, Recurrence was signiÀcantly lower among patients
Thymoma treated by lobectomy than among those treated by
pneumonectomy (p=.034) (Fig 2).
A revised/updated abstract may be included in Conclusion: Bilobectomy carries high operative
the Late Breaking Abstract Supplement, available mortality and poor longterm survival after
at the 14th World Conference on Lung Cancer. neoadjuvant concurrent chemoradiotherapy for stage
IIIA-N2 non-small cell lung cancer. Outcomes of
bilobectomy were similar as pneumonectomy in
Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15 terms of overall survival, disease-free survival, and
postoperative mortality
P1.265 RISK OF BILOBECTOMY Keywords: Lung cancer, Surgery, Neoadjuvant
AFTER NEOADJUVANT CONCURRENT Treatment
CHEMORADIOTHERAPY FOR STAGE
IIIA-N2 NON-SMALL CELL LUNG
CANCER Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15
Jong Ho Cho1, Hong Kwan Kim2, Jhingook Kim2,
Yong Soo Choi2, Kwhanmien Kim2, Young Mog P1.266 OBSERVATION ON EFFECT OF
Shim2, Keunchil Park3, Yong Chan Ahn4 INTERCOSTAL NERVES FREEZING
1
Thoracic And Cardiovascular Surgery, Samsung FOR ELDERLY PATIENTS UNDERGONE
Medical Center/Korea, 2Department Of Thoracic CHEST OPERATION
And Cardiovascular Surgery, Samsung Medical Lei Liu
Center/Korea, 3Division Of Hematology-oncology, Thoracic Surgery, China Capital University
Department Of Medicine, Samsung Medical Center/ Hospital/China
Korea, 4Department Of Radiation Oncology,
Samsung Medical Center/Korea Background: To investigate the clinical effect
of intercostal nerves freezing for elderly patients
Background: The aim of this study was to evaluate undergone chest operation
the outcomes of surgical resection, especially Methods: Collect and analyze the postoperative
bilobectomy, after chemoradiation therapy. pain situation and complications of more than 200
cases of elderly patients ,who have received chest Results: 12 patients were converted to thoracotomy,
operation in our hospital since 2006. thoracotomy rate was 2.5% (12/475). The operation
Results: Among all the cases ,the patients who time was 80 to 410mins, the average was 195mins;
received intercostal nerves freezing feel pain relief intraoperative bleeding was 50ml to 1600ml, average
the ratio of total 86% .Received routine methods was 356ml, and intraoperative blood transfusion
including taking analgesic drugs or muscle and were taken in 64 patients. Postoperative drainage
intravenous anesthesia class analgesics the patients was 70ml to 2100ml, average was 420ml. Extubation
feel pain relief the ratio of total 68%.And the Àrst time was 1 day to 10 days, average was 4.3 days.
group’s adverse effects and complications have The number of stapple was 3 to 16, average was 6.5.
signiÀcantly reduced . Intraoperative lymph node dissection was 3 groups
Conclusion: For elderly patients open-chest surgery to 7 groups and 3 nodes to 34 nodes, average was 5.4
is concerned, intercostal nerves freezing technology groups and 12.8 nodes respectively. Serious air leak
in alleviate postoperative pain, curative effect really, of bronchial stump was found and sutured during
simple operation, post-operative fewer adverse operation in 2 cases.Patients started to walk on the
effects, the proposal is in thoracic Àeld widely used. Àrst day after surgery,and the postoperative hospital
Keyword: intercostal nerves freezing stay was 3 days to 25 days, 9.7 days on average.
No patient died during the surgery. Cardiovascular-
A revised/updated abstract may be included in related complications occurred within Àrst week
the Late Breaking Abstract Supplement, available in 17 cases, Àberoptic bronchoscopy sputum
at the 14th World Conference on Lung Cancer. suction in 23 cases, pulmonary infection in 12
cases, chylothorax in 4 cases, 1 patient underwent
thoracoscopic repair after 8 days of surgery due to
Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15 bronchopleural Àstula,and two cases of right upper
lobectomy had implemented middle lobectomy
P1.267 CLINICAL ANALYSIS OF 475 due to the middle lobe reverse within 2 weeks after
CASES OF VATS LOBECTOMY FOR operation, pumping pleural effusion in 11 cases,
LUNG CANCER postoperative complication rate was 15% (70/475).
Li Wen-Tao One case with bilateral VATS died of respiratory
Department Of Thoracic Surgery, Shanghai failure owing to pulmonary hemorrhage on 21 day
Pulmonary Hospital,tongji University/China after surgery, and perioperative mortality was 0.2%
(1/475); one case underwent radiotherapy because of
Background: To evaluate the feasibility of the wound tumor recurrence 3 months later and made an
implementation of complete resection by VATS improvement. Patients with pathological TNM stage
for lung cancer, analysising of issues such as their II and above were treated by conventional adjuvant
surgical procedure, indications, intraoperative lymph chemotherapy.
node dissection, operative time, blood loss and Conclusion: VATS lobectomy for lung cancer with
postoperative complications, etc. less trauma and faster recovery, fewer complications,
Methods: From July 2007 to February 2010, 475 can be applied to patients with stage I, II or part
cases of VATS complete resection for lung cancer of stage III,and even some stage IV patients
were implemented, of which 250 male cases, 225 with isolated brain metastases after gamma knife
female cases, aged from 27 to 89 years old, mean treatment.
59.42 years old. Surgical procedure: right upper lobe Keyword: VATS; Lobectomy; Lymph Node
resection of 143 cases, right lower lung resection of Dissection; Lung Cancer
103 cases, right middle lobe resection of 32 cases,
right middle-upper lobe resection of 2 cases, right A revised/updated abstract may be included in
middle-lower of 7 cases, left upper lobe resection of the Late Breaking Abstract Supplement, available
101 cases, lingular lobectomy of 2 cases, left lower at the 14th World Conference on Lung Cancer.
lobe resection of 81 cases, bilateral lobectomy of 4
cases. All patients were treated with routine systemic
mediastinal lymph node dissection which including
level 2,3a,3p,4,7,8 9,10,11 in the right side and level
4,5,6,7,8,9,10,11 in the left side.
Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15 were no differences in the risk of having a metastasis
vs a new primary tumor (OR 0,2000, CI 1,8609 to
P1.268 SOLITARY PULMONARY 0,0215, p = 0,1573). Prevalence of malignant SPN
NODULES IN PATIENTS WITH A according to the antecedent of a previous malignancy
HISTORY OF PREVIOUS MALIGNANCY
Gustavo A. Lyons1, Silvia Quadrelli2, Domingo J. No previous Previous lung
Previous
extrapulmonary Total
Chimondeguy1, Felipe Chertcoff2, Carlos Silva3, malignancy cancer
malignancy
Pablo Jordan2, Karina Vera3 Benign SPN 120 (29%) 6 (50%) 15 (36,3%) 141 (29,2%)
1
Thoracic Surgery, Buenos Aires British Hospital/ Malignant SPN 294 (71.0%) 6 (50%) 42 (73,6%) 342 (70,8%)
Total 414 12 57 483
Argentina, 2Respiratory Medicine, Buenos Aires
British Hospital/Argentina, 3Oncology, Buenos Aires
British Hospital/Argentina Conclusion: The occurrence of an SPN in the setting
of a patient with a history of extrapulmonary cancer
Background: The Ànding of nodules in patients cannot be automatically considered a lung metastasis
already diagnosed with cancer poses a clinical as often represents a primary lung tumor rather than
dilemma. Such nodules may represent scarring, a metastasis.
metastatic disease, or new previously unknown Keywords: Solitary pulmonary nodule, Lung cancer,
primary tumours. The objectives of this study were LUNG METASTASIS
to determine the probability of malignancy in a
pulmonary nodule in the setting of a history of
previous cancer and identify factors that may alter Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15
such probability.
Methods: All patients undergoing pulmonary P1.269 APPROACH TO METASTASIS-
resection with of a solitary pulmonary nodule (SPN) SUSPECTED NODULE IN OTHERWISE
in the British Hospital in Buenos Aires between OPERABLE NON-SMALL CELL LUNG
January 1986 and January 2007 were eligible for CANCER
inclusion in this retrospective study. Based on cancer Sumin Shin1, Joon Suk Park2, Hong Kwan Kim1,
history, patients were grouped as having no history Yong Soo Choi1, Kwhanmien Kim1, Young Mog
of malignancy; history of lung cancer; or history of Shim1, Jhingook Kim1
1
extrapulmonary cancer. Departement Of Thoracic And Cardiovascular
Results: Four hundred and eighty three patients Surgery, Samsung Medical Center/Korea,
2
(483) with SPN were included. Sixty nine (14.2%) Department Of Thoracic And Cardiovascular
had a history of a previous malignancy. Among Surgery, Samsung Medical Center/Korea
all the 483 patients (age 52,2 ± 18,9 years, 37,1%
female) 70,8% were malignant. Lung was the Background: Although the seventh edition of
most prevalent malignancy among the malignant the lung cancer staging system draws attention to
SPN (n = 305, 89,2%). Patients with a malignant the synchronous additional pulmonary nodules in
SPN were slightly older (55,4 ±19,3 vs 51,4 ± patients with non-small cell lung cancer (NSCLC),
17,8 year-old, p = 0,035) and had a larger SPN ( it doesn’t clarify how to approach to these patients.
2,18 ±1,8 vs 1,39 ± 0,7cm , p =0,001 ) In a logistic We retrospectively reviewed radiologic features and
regression model the antecedent of a previous pathologic diagnoses of additional solid pulmonary
malignancy did not increase the risk of having a nodule with otherwise operable non-small cell lung
malignant SPN (OR 0,8638, CI 0,4887 to 1,5269, p cancer.
= 0,6144). However, being older than 60 (OR 1,634 Methods: From January 2003 to December 2007,
CI 1,0909 to 2,4485, p = 0,017) and a SPN 2 cm 77 patients who had operable NSCLC, only except
(OR 2,4196, CI 1,3920 to 4,2059, p = 0,00171) had suspected pulmonary metastasis in non-primary
a signiÀcantly higher risk of Ànding a malignant lobe, underwent lung resections. We retrospectively
SPN. Forty-two of the 57 patients with a previous reviewed radiologic features and pathologic
extrapulmonary malignancy had a malignant SPN, diagnoses, clinical results.
21 (50%) of them were new primaries. If patients Results: In 45 patients, suspected nodules were
with a previous lung cancer were compared with any pathologically conÀrmed by lung resection with
other previous extrapulmonary malignancy there or without curative intent. In 32 patients in whom
pathologic diagnosis was unavailable, curative Results: Histologic analysis revealed lung cancers
resection for primary tumor was performed and in 65 patients (including adenocarcinoma in 33
suspected lesion was carefully monitored by regular patients, squamous cell carcinoma in 19, carcinoid
follow-up CT scan. As a result, 13 patients were in 5 small cell lung cancer in 3, adeno-squamous
Ànally diagnosed to have had true metastasis. The carcinoma in 3, large cell lung cancer in 2), benign
accuracy of radiologic diagnosis of pulmonary lesions in 19 patients ( includeing tuberculoma in
metastasis was 16.9%. Tumors were located in 6 , inÁammatory pseudotumor in 5, harmatoma
the ipsilateral different lobe in 10 patients and in 5, sclerosing hemangioma in 3). The accuracy,
contralateral in 2, and bilateral in 1 patient. The sensitivity, speciÀcity of PET/CT for diagnosing
overall survival rate in patients with true metastasis lung cancer were 83.3% 70/84‰, 86.2% 56/65
was 38.5% and mean survival was 32.6 months(1.7 ‰and 73.7% 14/19 ‰, respectively; compared with
months ~ 68.4 months). 75.0%(63/84 ‰, 78.5% 51/65 ‰, 63.1% 12/19 ‰for
Conclusion: The radiologic diagnosis of pulmonary CT (P=0.55, 0.12, 0.63, respectively); No signiÀcant
metastasis was not always reliable, and can deprive difference was seen between PET/CT and CT. The
patients of the opportunity of curative resection. sensitivity, speciï¬city, accuracy of PET/CT for
When an additional nodule is detected in otherwise lymph nodes were 80.3%(57/71), 83.7%(297/355),
operable lung cancer, aggressive approach for 83.1%(354/426), respectively; compared with
pathological assessment should be considered. 62.0%(297/355), 70.4%(250/355), 69.0%(294/426)
Keywords: Non-small cell lung cancer, Radiologic for CT (P= 0.03, 0.000, 0.005, respectively.
features, Pathologic diagnoses, Surgery Preoperative nodal staging was compared with
postoperative histopathological staging, 81.5% (53
of 65) of patients correctly staged, 12.3% (8 of 65)
Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15 of patients were overstaged, and 6.2% (4 of 65)
were understaged by PET/CT, while those values for
P1.270 VALUE OF 11C-CHOLINE PET/CT CT were 58.5% (38 of 65), 24.6% (16 of 65), and
IN THE EVALUATION OF DIAGNOSIS 6.2% (11 of 65), respectively. Eight patients being
AND STAGING IN LUNG CANCER. overstaged and 10 petients being understaged on
Zhongmin Peng1, Meng Li2, Qi Liu2, Sun Jian2, Qi CT were corrected by PET/CT. One patients being
Liu3 overstaged and 2 petients being understaged on
1
Thoracic Surgery, Provincial Hospital AfÀliated PET/CT were corrected by CT. Seven patient being
To Shandong University/China, 2Department Of overstaged and 1 petient being understaged both on
Thoracic Surgery, Provincial Hospital AfÀliated CT and PET/CT. The SUVmax for the 65 NSCLC
To Shandong University/China, 3Cancer Center, was 4.12± 2.05 0.52-8.46 ‰, and the Ki67 were
Provincial Hospital AfÀliated To Shandong 41.29±15.59% 16%-83%. The 11C-CH uptakes
University/China showed a signiÀcant correlation with Ki-67 staining
scores (r=0.505 p=0.002).
Background: The aim of this study was to Conclusion: The value of diagnosing pulmonary
evaluate the value of diagnosis and staging of leision by CH PET/CT was not signiÀcant high
11
C-choline(CH) PET/CT images in the patients with than enhanced CT;however, CH PET/CT improves
lung cancer, and evaluating its tumor aggressiveness. the value in the assessment of locoregional lymph
11C
-CH-PET and enhanced CT were compared. nodes, and provides more accurate nodal staging.
Methods: From June 2007 to Feb 2010, 84 SUV-indexed CH metabolic activity correlated
potentially operable patients with proven or signiÀcantly with proliferative activity (Ki67
suspected non-small cell lung cancer underwent expression).
integrated PET/CT and CT scans followed by Keyword: Keywords: 11C-choline PET; CT; lung
surgical nodal staging. The results of reviewing PET/ cancer; Lymph node metastasis; Ki67
CT and enhanced CT images for the locoregional
lymph node metastasis were compared in relation
to pathologic ï¬ndings. The 11C-CH uptakes were
examined to determine the relationship with the
proliferative activity determined by Ki-67 staining
score.
Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15 suture line of the bronchus (sutured with tantalum
staples or synthetic sutures). This prevents infectious
P1.271 BRONCHIAL STUMP spreading into peribronchial tissues and pleural
INSUFFICIENCY FOLLOWING cavity, improves bronchial stump healing due to
PNEUMONECTOMY FOR LUNG omentum plastic properties and thus, is an effective
CANCER for prevention of Àstulae development following
Vladimir Porhanov1, Igor Polyakov2, Nikolay pneumonectomy.
Naryzhny2
1
Cardiothoracic Surgery Center/Russian Federation, A revised/updated abstract may be included in
2
Oncological Department, Cardiothoracic Surgery the Late Breaking Abstract Supplement, available
Center/Russian Federation at the 14th World Conference on Lung Cancer.
Background: Fistula development following lobar

resections and pneumonectomies accounts for Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15
0,5 - 3% and 1-20%, respectively. One of the most
common and severe complications is bronchial P1.272 CLINICAL OUTCOMES IN
stump insufÀciency (8-20%). We analyzed different COMPLETION PNEUMONECTOMY
methods of treatment and preventive care for main FOR CANCER: A RETROSPECTIVE
bronchus stump following pneumonectomy. MULTICENTRIC STUDY ABOUT 46
Methods: We studied history reports of 484 patients, CASES.
treated from 2002 to 2009, all of them were operated Mayeul Tabutin1, Sebastien Couraud2, Benoit
on for pneumonectomy. Age range was 18 - 75 Guibert2, Pierre Mulsant2, Pierre Jean Souquet2,
years, mean age was 56 years. In 169 cases we François Tronc3
1
performed right-sided pneumonectomies (34,9%), Chirurgie Thoracique, Hopital Louis Pradel/
left pneumonectomies were performed in 314 France, 2Hôpital Lyon-sud/France, 3Hôpital Louis
(65,1%) patients. Pneumonectomies were performed Pradel/France
via thoracotomy approach in 454 and in 30 cases
via sternotomy. All patients underwent systematic Background: Aims of the study are to describe
lymph node dissection. And in patients operated via postoperative complications and long term results
transsternal approach we performed bilateral lymph of completion pneumonectomy and to highlight
node dissection. In all cases with thoracotomy, right prognostic factors.
main bronchus stump was covered with a pericardial Methods: We retrospectively reviewed 46 patients
Áap with a vascular pedicle. In patients operated operated of completion pneumonectomy for cancer
on via transsternal approach with bilateral lymph between 1995 and 2009, in two thoracic surgery
node dissection and high risk of development of departments (38 men, 8 women). 89% were current
main bronchus stump insufÀciency (21 patients) we or former smokers. Among those, 57% quit smoking
carried out covering of main bronchus with omentum at least one year before completion surgery. At
(pedicled vascular Áaps). After the main surgical surgery, mean age was 59years (ranged 38 to 79).
stage completion, we performed superior-median Most of patients did not undergo chemotherapy
laparotomy with retrosternal omentum carrying and (76%) or radiotherapy (83%) before surgery. Surgery
covering of main bronchus stump or anastomosis. was performed mainly on the right lung (61%).
This technique was applied in 9 cases for BPF with Bronchial stump was covered for 17 patients, 59%
transsternal occlusion, left in 7 cases and right in two underwent an intrapericardic technique, and none
cases. had parietal or vascular resection.
Results: Main bronchial stump Àstula developed Results: Complications after surgery were
in 23 of 484 patients (4,7%), of those 13 had right- respiratory failure (15%), bronchopleural Àstula
sided Àstulae and 5 were found to have left-sided (13%, with no preference according to the side) and
Àstulae. This technique showed deÀnite beneÀt as a empyema (13%). Blood transfusion (preoperative or
rate of BPF development was reduced to 3,3%. Total post-operative) was necessary for 45% (average of
mortality rate was 4,3%. 2 blood packs). Day30 death rate was 13% (n = 6).
Conclusion: While performing this technique we Postoperative staging showed mostly limited disease:
safely cover a line of bronchial transsection and a 79.5% T2 or less and 87% N1 or less. Twenty eight
patients (61%) were operated for a second or primary patients (84.3%), Bilobectomy in 14 (5.6%) and
cancer, 16 for local recurrence (35%), including pneumonectomy in 25 (10.1%). The most common
4 for microscopically incomplete resection, 2 for histology was squamous cell carcinoma (117 patients,
metastases (4%). After completion, 31% patients 47.2%). Adenocarcinoma was in 96 patients (38.7%)
had adjuvant treatment. Median overall survival and other type of histology was in 35 patients
after completion surgery is 30,4months. Among 15 (14.1%). Thirty three patients (71.7%) of 46 pN2
patients alive (33%), 11 are free of disease (24%). In patients had the single zone metastasis, 13 patients
a Cox regression model, factors inÁuencing overall (28.3%) had multiple zone metastases over two nodal
survival are age up to 65 years old (OR = 2,47 [1,1- zone metastasis. The 5-year disease free survival
5,4], p=.012) and being a current smoker (OR=2,285 rates were 58% in pN0, 39% in pN1, and 30% in
[1,07-4,88], p=.033). There was no signiÀcant pN2. The disease free survival was signiÀcantly
inÁuence on prognosis of demographical data, co better in pN0 compared with pN1 or pN2 (p = 0.030
morbidities, disease stage, or technical used. and p = 0.000). However, there was no statistically
Conclusion: Despite increased postoperative signiÀcant differences between pN1 and pN2 (p =
complications and mortality, compared to standard 0.326). The 5-year disease free survival rates was
pneumonectomy, completion pneumonectomy has 29% in the single zone metastasis and 30% in the
encouraging long term results. Two main factors multiple zone metastasis group (p = 0.635). There
appear predictive of better overall survival: age less were no statistically differences between two groups.
than 65 years, having quit smoking since at least one Recurrences occurred in 91 patients (36.7%). Loco-
year before surgery. regional recurrences were in 46 patients (18.5%), and
Keywords: completion pneumonectomy, Cancer, distant recurrences were in 45 patients (18.1%). Loco-
Surgery, Morbidity regional recurrence most commonly occurred in post
operative pathologic N1 patient’s group (20 (37.0%)
of 54 patients), and distant recurrence most commonly
Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15 occurred in post operative pathologic N2 patient’s
group (22 (47.8%) of 46 patients).
P1.273 SURVIVAL OF PATIENTS WITH Conclusion: The 5 year disease free survival of
UNSUSPECTED N2 (STAGE IIIA) NON- patients of unsuspected N2 disease who underwent
SMALL CELL LUNG CANCER complete resection was statistically similar with
Chang Kwon Park1, Deok Heon Lee2 pathological N1 disease in this study. The beneÀt of
1
Thoracic Surgery, Dongsan Medical Center, chemotherapy in these patients was still unproven.
Keimyung University/Korea, 2Thoracic Surgery, Therefore, a prospective randomized analysis for
Donsan Medical Center Keimyung University/Korea conÀrming the beneÀt of surgery or chemotherapy in
patients with unsuspected N2 disease is needed
Background: The aim of this study was to determine Keywords: Non-small cell lung cancer, unsuspected
the survival of patients (unsuspected N2 disease) N2 disease
who were preoperatively diagnosed with negative
N2 lymph node, but postoperatively conÀrmed as N2 A revised/updated abstract may be included in
node positive by pathological evaluation the Late Breaking Abstract Supplement, available
Methods: Between May 1994 and December 2009, at the 14th World Conference on Lung Cancer.
we retrospectively reviewed the hospital records of
248 patients with primary non-small cell lung cancer
who underwent pulmonary resection and mediastinal Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15
lymphadenectomy at our hospital. All patients were
preoperatively diagnosed with negative of N2 lymph P1.274 CLINICAL EXAMINATION
node. 148 (59.7%) patients were in pathological N0, OF PRIMARY LUNG CANCER IN
54 (21.8%) were in pathological N1 and 46 (18.5%) OCTOGENARIAN
were in pathological N2 after the surgery. Satoshi Yamamoto1, Katsunobu Kawahara2, Shinichi
Results: There were 175 males (70.6%) and 73 Yamashita2, Michiyo Miyawaki2, Keita Tokuishi2
1
females (29.4%) and, with mean age of 62.3 ± Sergery Ii, Oita University Faculty Of Medicine/
9.4 years. The mean follow-up period was 36.1 ± Japan, 2Surgery Ii, Oita University Faculty Of
31.5 months. Lobectomy was performed in 209 Medicine/Japan
Background: The high age population has been Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15
increase in Japan. We have performed lung
resection for the octogenarian patients. In this P1.275 INTRAOPERATIVE INJECTION
study, we try to exam of clinical outcome in the OF 99MTC-NEOMANNOSYL HUMAN
population. SERUM ALBUMIN (99MTC-MSA) FOR
Methods: In 2004 – 2010, we performed lung SENTINEL NODE IDENTIFICATION IN
resection for 466 primary lung cancer patients. LUNG CANCER: COMPARISON WITH
In those patients, 46(9.9%) were octogenarian 99MTC-PHYTATE
population. Hyun Koo Kim1, Sungeun Kim2, Jae Min Jeong3,
Results: The range of age is 80-90 year old, the Young Ho Choi1
1
average is 82.5 year old. Performance status of Thoracic And Cardiovascular Surgery, College Of
all ectogenarian patients is 0-I. The each clinical Medicine, Korea University Guro Hospital/Korea,
2
stage of those patients were c-IA: 20 cases (43.4%), Nuclear Medicine, College Of Medicine, Korea
IIA: 16 cases (34.8%), IIB: 5 cases (10.9%), IIIA: University Guro Hospital/Korea, 3Nuclear Medicine,
5 cases (10.9%). The performed operations were College Of Medicine, Seoul National University
lobectomy for 26 cases (56.5%), bi-lobectomy Hospital/Korea
for one case (2.2%), segmentectomy for 9 cases
(19.6%), partial resection for 10 cases (21.7%). Background: A novel radiotracer (Technetium-99m
The eight patients of those 46 patients had any neomannosyl human serum albumin, 99mTc-MSA)
preoperative complication. 6 patients had Chronic can pass quickly through lymphatics and stay longer
Obstructive Lung Disease (COLD), one patient in sentinel lymph node due to its small size and
had pneumoconiosis, one patient had heart failure. receptor-binding property. The aim of this study was
The seven patients had postoperative complication. to compare the intraoperative injection of 99mTc-MSA
Pulmonary complication occurred for four patients, between 99mTc-phytate for sentinel node mapping in
thoracic hematoma, Interstitial pneumonia (IP) patients with early stage non-small cell lung cancer.
and prolonged thoracic effusion (8days) were Methods: One-hundred and six patients (73 men,
occurred each one patient. Four patients were died 33 women; mean age 63.0±9.3 years) that were
without primary disease on 1504, 1001, 449, 330 candidates for lobectomy with mediastinal lymph
postoperative days. The remaining patients are Àne node dissection for clinical stage I non-small cell
without lung cancer recurrence. lung cancer were enrolled. 99mTc- MSA or 99mTc-
Conclusion: The lung resection for the good phytate was administered at the peri-tumor region
performance octogenarian primary lung cancer soon after thoracotomy. The radioactive lymph nodes
patients is safety operation and the oncological were identiÀed with a handheld gamma probe after
outcome is feasible. However, the preoperative lymph node dissection (ex vivo).
complication rate in the octogenarian is gradually Results: The patient’s age and the sex ratio of both
high, so there is careful observation after surgical groups were similar. The tumor size, pathology,
treatment in long term. clinical stage, and tumor location did not differ.
Keywords: Octogenarian, Complication, lung The total number of dissected lymph nodes was not
resection different (22.5±10.65 in MSA group, 20.2±12.28
in phytate group, p=NS). The sentinel nodes were
A revised/updated abstract may be included in detected in 56 of the 57 patients (98.2%) in MSA
the Late Breaking Abstract Supplement, available group and 44 of the 49 patients (89.8%) in phytate
at the 14th World Conference on Lung Cancer. group (p<0.05). The number of sentinel nodes per
patient did not differ (2.2±1.21 in MSA group,
2.1±1.41 in phytate group, p=NS). False-negative
sentinel lymph nodes were not detected (0/13, 0%)
among the 13 patients with pathologic N1 or N2
disease in MSA group and two (2/12, 16.7%) of
the 12 patients with pathologic N1 or N2 disease in
phytate group (p<0.05).
Conclusion: Intraoperative injection of 99mTc-MSA can
be a better choice than 99mTc-phytate for identiÀcation
of the sentinel node in lung cancer patients. Background: Surgical criteria for pulmonary
Keywords: Lung cancer, Mediastinal lymph node metastasectomy of colorectal cancer have been
dissection, Sentinel lymph node extended nowadays by the development of surgical
and anesthetic technique. We have also expanded
the surgical criteria, case with bilateral pulmonary
Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15 metastases, multiple metastases(more than 3 lesions),
with concomitant extra-thoracic metastasis, or
P1.276 MAJOR LUNG RESECTION FOR with local recurrence, which were contraindication
THE TREATMENT OF LUNG CANCER IN historically, were all indication if all lesions will be
OCTOGENARIAN PATIENTS resected by planned procedure, or all extra-thoracic
Donghong Chen or local disease will be resected another procedure or
Thoracic Surgery, Beijing Lung Cancer Center, controlled another modality in our rule. However, the
Capital Medical University/China signiÀcance of extension of surgical criteria has not
been well discussed.
Background: To explore the clinical characteristics of Methods: This study was retrospective analysis
bronchial carcinoma in elder patients and determine from our clinical data base and clinical charts.
the operative indication, surgical technique, and From January 2003 to June 2010, a total of 132
management in the perioperative period. patients underwent pulmonary metastasectomy
Methods: From January 2005 to July 2010, 16 of colorectal cancer in our hospital. We reviewed
patients with bronchial carcinoma aged 80 and over the results of surgical resection, and analyzed the
received major pulmonary resection through muscle results of overall survival, disease free survival
sparing mini-thoracotomy. The operative procedures and the pattern of recurrence. Overall and disease
were lobectomy(8 cases), bilobectomy(3cases), free survival were calculated from the date of
sleeve lobectomy(2cases), pneumonectomy(1 pulmonary metastasectomy. Median follow-up
cases),and lobectomy plus wedge resection(2cases). period was 32.9 months. We divided patients in 3
Clinical data were analyzed retrospectively. subgroups for comparison of surgical criteria. Group
Results: Of the 16 patients, 6 with stage I disease, A: standard criteria, classical Thomford’s criteria,
3 with stage II and 7 with stage III disease. There Group B: Extended criteria, more than 3 pulmonary
were no perioperative death occurred. The most metastases, with extra-thoracic lesion or with local
popular postoperative complications were cardiac recurrence which will be controlled by surgery or
arrhythmia, pulmonary infection and hypoxemia. another treatment, Group C: convert case, a case
Conclusion: Major pulmonary resection is a rational of initially in-operable and conversion to surgery
choice for part of the octogenarian patients with lung after chemotherapy. The statistical analysis was
cancer. performed by SPSS software and survival estimates
Keywords: aged, 80 and over, Lung neoplasms, were achieved using the Kaplan-Meier method.
Surgical Procedures, opetative The signiÀcant differences between subgroup were
calculated using the log-rank test.
A revised/updated abstract may be included in Results: There were 81 men and 51 women, median
the Late Breaking Abstract Supplement, available age was 64-year old. There were 105 patients in
at the 14th World Conference on Lung Cancer. Group A, 11 in Group B, 16 in Group C. In all
patients, 3, 5-year overall survival and disease
free survival were 92.0 %, 64.8%, 51.9 %, 43.6 %
Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15 respectively. In subgroups, 5-year overall survival
of Group A, B, C were 65.8 %, 83.3 %, 47.6 %
P1.277 OUTCOMES OF EXTENDED respectively (p=0.2655). 5-year disease free survival
SURGICAL CRITERIA FOR of Group A, B, C were 46.0 %, 48.0 %, 22.2 %
PULMONARY METASTASECTOMY OF respectively (p=0.0016). There was signiÀcant
COLORECTAL CANCER difference between Group A / B and C, but not
Yasuhisa Ohde, Shinsuke Saisho, Mitsuhiro Isaka, between Group A and B. In Group C, recurrence rate
Tomohiro Maniwa, Kazuo Nakagawa, Takehiro was relative high, however, overall median survival
Okumura, Haruhiko Kondo was 54.3 months. This result is not inferior to that of
Thoracic Surgery, Shizuoka Cancer Center/Japan conversion surgery of liver metastases.
Conclusion: Overall survival in recent extended is at the poorest level and mostly manual. VATS is
criteria is acceptable, not inferior to that in classical present at one of the units but mostly being used for
criteria. In conversion surgery with initially non- diagnostic purposes due to lack of expertise. Even
resectable case, although recurrence rate is high, diagnostic pathological services are unreliable except
recurrent disease was well controlled by systemic in few of private diagnostic laboratories. There is
therapy, overall survival is similar to that of no prevention program at both hospital & media
conversion surgery of hepatic metastasis from level except a general warning on packs stressing on
colorectal cancer. mouth cancer rather than carcinoma lungs.
Keywords: Surgery, pulmonary metastasis, Conclusion: It is concluded that Role of surgery in
Colorectal Cancer, Surgical Criteria carcinoma lung is at very low level. Professional
medical bodies as well as government should follow
A revised/updated abstract may be included in standard guidelines to improve this service and take
the Late Breaking Abstract Supplement, available into consideration the largest killing cancer in the
at the 14th World Conference on Lung Cancer. world for such a big population.
Keywords: Lahore, Surgery, Lungs

P1.278 ROLE OF SURGERY IN
MANAGEMENT OF CARCINOMA LUNG P1.279 FACTORS INFLUENCING
IN PAKISTAN. SURVIVAL OF PATIENT WITH
Imran Javed PATHOLOGICAL PROVEN N1 NON-
Surgery, Private Medical College/Pakistan SMALL CELL LUNG CANCER
Hirohiko Shinohara, Takehisa Hashimoto, Masanori
Background: Surgical treatment of carcinoma of Tsuchida
the lung is not an option for the management of Thoracic And Cardiovascular Surgery, Niigata
the disease due to many factors like: - Advanced University Graduate School Of Medical And Dental
carcinoma of the lung. _ Lack of expertise of the Sciences/Japan
surgeons. - Financial reasons. - Non awareness
of medical community about importance of early Background: The population of patients with
diagnosis. - Non existence of screening programs pathological (p-) N1 disease is small among non-
- Limited scope for thoracic surgery units. - An small cell lung cancer (NSCLC) and limited data
extremely small number of trained Thoracic regarding prognosis is available in this group. We
surgeons. _ Non- Availability of Thoracic Surgical analyzed patients with pN1 disease to identify
Oncologists. _ No referral collaboration between factors inÁuencing survival.
chest physicians & surgeons. - Ignorance of Public Methods: From January 1983 to November 2010,
health deptt of local & federal governments. we performed 1446 anatomic resections in patients
Methods: Standard methods of data collection with primary lung cancer in our institution. Of
between various units of thoracic surgery in the city these, 110 patients had N1 nodal metastases, and a
of Lahore, Pakistan is used. Data is analyzed by total of 86 consecutive patients with pathological
SPSS. N1 NSCLC who underwent lobectomy or
Results: There are only 3 units of Thoracic surgery pneumonectomy with systematic lymph node
for a city 12 million people which is also 2nd largest dissection were retrospectively reviewed using the
city of the 6th largest nation in the world. No unit seventh edition of the TNM classiÀcation system.
in the city of Lahore is recognized for postgraduate The pN1 NSCLC patients in this study included 71
training in Thoracic surgery even by local body i.e. men and 15 women with their mean age 65.0±7.9
College of Physicians & Surgeons Pakistan. There is years (range, 33 to 80). A total of 50 patients (58.8%)
no special emphasis on Thoracic surgery oncology. had tumors on the right side, whereas 35 patients
Most of the people working there are not even (41.2%) had tumors on the left side. Histopathologic
formally trained in thoracic surgery but in general tumor types included squamous cell carcinoma (Sq)
surgery and then they started practicing specialty. in 44 cases (51.1%), adenocarcinoma (Ad) in 33
Record keeping with reference to Carcinoma lung cases (38.4%), and others in 9 cases (10.5%). Of
the 86 patients, 16 had pT1, 47 had pT2, 19 had Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15
pT3, and 4 had pT4 disease. According to the TNM
classiÀcation system, 54 were stage IIA, 9 were P1.280 PREDICTING POSTOPERATIVE
stage IIB, and 23 were stage IIIA. PULMONARY FUNCTION IN PATIENTS
Results: For completely resected patients, the UNDERGOING LUNG RESECTION
5-year survival rate was 42.0%, respectively. Yohei Yatagai1, Takefumi Saito1, Yasuhiro Umetsu2,
The 5-year survival rate for patients with hilar Shimao Fukai1, Kenji Hayashihara1, Masa Shiina2
1
N1 (station 10), interlobar (station 11), and Respiratory Medicine, Ibarakihigashi National
intrapulmonary N1 (stations 12 to 13) involvement Hospital/Japan, 2Clinical Research, Ibarakihigashi
were 33.9%, 35.6%, and 49.8%, respectively (Fig.) National Hospital/Japan
Background: The inÁuence of pulmonary resection

on functional capacity can be assessed in different
ways. The aim of our study was to determine the
effect of lung resection on spirometric lung function
and to evaluate the accuracy of simple calculation
in predicting postoperative pulmonary function in
patients undergoing lung resection.
Methods: We reviewed preoperative and
postoperative pulmonary function test results on
. patients who underwent lung resection for lung
Although patients with hilar and interlobar N1 cancer between January and December 2008. In
(stations 10 and 11) involvement tended to show lobectomies, the predicted postoperative forced
poorer survival than patients with intrapulmonary expiratory volume in one second (ppo FEV1)
N1 (station 12 to 13), no statistically signiÀcant and predicted postoperative forced vital capacity
difference was observed. The 5-year survival rates (ppo FVC) were calculated based on the number
for patients with Sq and Ad were 55.8% and 30.3%. of segments resected and were compared with
Patients with Sq had a signiÀcantly better prognosis the actual postoperative FEV1 and FVC. The ppo
than those with Ad (p=0.034). The 5-year survival FEV1 (or FVC) were calculated using the following
rates for patients with right-sided cancer tended to formula: ppo FEV1 (or FVC) = [1-(b-n) / (42-n)]
show better prognosis than those with left-sided x preoperative FEV1 (or FVC), where n and b are
cancer (49.9% and 27.1%, respectively; p=0.088), the number of obstructed subsegments and total
but no statistically signiÀcant differences were subsegments respectively, in the resected lobe. In
observed. wedge resections, we investigated the association of
Conclusion: Squamous cell carcinoma was pulmonary function (preoperative and postoperative
signiÀcant factors to predict a better prognosis than FVC, preoperative and postoperative FEV1) with
adonocarcinoma, and involvement of the hilar and smoking index, histological type (adenocarcinoma or
interlobar N1 and left-sided cancer tended to be a squamous cell carcinoma), size of tumor, underlying
worse prognosis in resected pN1 NSCLC. lung disease (with or without emphysema) and
Keywords: pathological N1, Prognosis, Lung location of cancerous lesions.
cancer Results: Sixty-Àve patients underwent functional
assessment with pulmonary function test before
A revised/updated abstract may be included in and 6 months after lung resection. In 45 (29 males
the Late Breaking Abstract Supplement, available and 16 females; mean age 72 yrs), a lobectomy was
at the 14th World Conference on Lung Cancer. performed and in 20 (14 males and 6 females; mean
age 74 yrs), a wedge resection was performed. After
lobectomy, in 22 patients, the actual postoperative
FEV1 was greater than 120% of ppo FEV1 (Group
A). In the other 23 patients, the FEV1 decreased
under 120% of ppo FEV1 (Group B). In four
patients of Group A, the FEV1 was improved after
lobectomy. In Group A, there were more patients
with male-sex, upper lobe resection, squamous cell or bilateral disease. Complete resection is the goal
carcinoma and heavy smoking, compared to Group and the most important prognostic factor in survival.
B. The difference of FVC between before and after The minimally invasive approach is the alternative
wedge resection (ƋFVC) was signiÀcantly smaller of choice in selected patient in lieu of thoracotomy
in patients with heavy smoking (smoking index 30 and sternotomy. Its application is both diagnostic
pack years) (p=0.001), adenocarcinoma (p=0.013), and therapeutic. Despite advances in prevention and
larger size of tumor (major axis 11mm) (p=0.030) multi-modality therapy, metastatic disease remains
and underlying lung disease (emphysema) (p=0.048). the leading cause of cancer mortality and further
There was, however, no factor inÁuencing the research is warranted.
difference of FEV1 between before and after wedge Methods: We carried out a retrospective review
resection (ƋFEV1). of the main characteristics of patients undergoing
Conclusion: After lobectomy, the postoperative pulmonary metastasectomies during a 3-year period
FEV1 and FVC tended to be higher than ppo FEV1 (2007-2010) at a single referral center and the type of
and ppo FVC in patients with male-sex, heavy surgical approach used (open vs minimally invasive
smoking, squamous cell carcinoma, upper lobe surgery). A description of our three year experience
resection and with emphysema than with female-sex, is presented.
light smoking, adenocarcinoma, lower lobe resection Results: There were 40 patients that underwent
and without emphysema. After wedge resection, lung resection for metastatic disease between 2007
the postoperative FVC tended to be higher than ppo and 2010. There were 21/40 (53%) female patients
FVC in patients with adenocarcinoma, small size and 19/40 (47%) were men, with an average age
of tumor, light smoking and without emphysema. of 50.8 years. Primary cancers were: 11/40 (27%)
There was, however, no apparent factor inÁuencing had colorectal carcinoma, 10/40 (25%) had renal
postoperative FEV1. carcinoma, there were 8/40 (20%) patients with
Keyword: predicting postoperative pulmonary metastatic germ cell tumors and 11/40 (28%) patients
function with other primary cancers. The treatment for the
primary cancer was surgery in 19/40 patients (47%),
14/40 (35%) underwent surgery plus chemotherapy,
Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15 4/40 (10%) had surgery plus radiotherapy, and 3
patients (8%) had chemotherapy only. The mean
P1.281 PULMONARY overall disease-free period was 33.7 months. More
METASTASECTOMIES: A 3-YEAR patients 25/40 (63%) had disease only in the right
EXPERIENCE AT A QUATERNARY lung, 13/40 (32%) in the left and 2 (5%) had bilateral
REFERRAL CENTER IN MEXICO CITY disease. Three quarters of the patients 29/40 (73%)
Luis M. Argote-Greene1, Patricio Santillan-Doherty2, underwent resection my minimally invasive surgery
Rocio E. Carrera-Cerón2, Said Urbina-Terán1, Ixchel (thoracoscopy or VATS), 10/40 (25%) had an open
Carranza-Martinez2, Juan C. Jacinto-Tinajero2, Jesús resection (thoracotomy or mini-thoracotomy), and
Herrera-Zamora2 1 patient (2%) had a combined approach. In 31/40
1
Thoracic Surgery, Instituto Nacional De Ciencias (78%) of the patients had one or more non-anatomic
Médicas Y Nutrición/Mexico, 2Thoracic Surgery, resections (wedge) , anatomic resection in 6/40
Instituto Nacional De Ciencias Médicas Y Nutrición (15%) and 1/40 (2%), lobectomy and segmentectomy
“salvador Zubirán”/Mexico respectively. Combined, wedge resection and
segmentectomy in 2/40 (5%) patients. Today 34/40
Background: Pulmonary metastases correspond (85%) of patients are alive and 6 (15%) have died.
to secondary deposits of tumor cells in the lung Conclusion: In our experience there is no sex
parenchyma from a known primary neoplasm. difference in the development of lung metastases.
Pulmonary metastasectomy is a potentially curative Colorectal cancer, renal carcinoma and germ cell
surgical procedure and has become standard therapy tumors are the main cause of resectable metastases
in appropriately selected patients. However, the at our institution. The lesions were mainly in the
role of pulmonary metastasectomy treatment is right hemitorax. The most commonly performed
still debated by some oncologic groups. The type procedure at our center was minimally invasive non
of approach for resection of metastases depends anatomic resection. Today most of our patients are
mostly on the patient, and the presence of unilateral still alive, and have not reached median survial.
However, the monitoring of these patients and their patients with unexpected pleuritis carcinomatosis,
speciÀc characteristics should be analyzed in further patients with positive N2 lymph nodes and patients
studies. with unanticipated hilar invasion. Unnecessary
Keywords: metastasectomy, VATS, minimally thoracotomies were avoided in these patients. The
invasive surgery, secondary lung cancer second category consisted of patients considered
not VATS suitable during the preoperative workup,
A revised/updated abstract may be included in that could unexpectedly undergo a radical VATS
the Late Breaking Abstract Supplement, available resection. The third category included patients with
at the 14th World Conference on Lung Cancer. chest wall invasion. VATS offered the opportunity to
dissect the hilum, lymph nodes, and interlobar Àssure
and offered excellent visibility of the extent of chest
Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15 wall invasion. These patients had a VATS lobectomy
combined with a minimally invasive chest wall
P1.282 WHY TO START EVERY resection.
LUNG SURGICAL PROCEDURE Conclusion: An “always VATS” strategy offers
FOR MALIGNANCY WITH great advantages and reduces morbidity in many
THE INTRODUCTION OF A patients. Unnecessary thoracotomies can be avoided
THORACOSCOPE? in unexpected hilar invasion, positive N2 lymph
Niels Smakman, Jan Siebenga, Karel Hulsewé, nodes and pleural metastases. Furthermore, several
Ewald Bollen patients can undergo VATS lobectomy unexpectedly
Surgery, Atrium Medical Center/Netherlands and wide resections can be avoided. Therefore, we
conclude that every lung surgical procedure for
Background: Since the introduction of video- malignancy should be started thoracoscopically.
assisted thoracic surgery (VATS), the morbidity of Keywords: VATS, lobectomy, Lung cancer, Surgery
pulmonary resections for malignancy has improved
dramatically. Furthermore, VATS offers excellent A revised/updated abstract may be included in
visibility and gives the opportunity to assess the the Late Breaking Abstract Supplement, available
pleura, to dissect and sample the N2 lymph nodes at the 14th World Conference on Lung Cancer.
and to determine the extent of hilar and chest wall
invasion in a minimally invasive manner. Therefore,
an “always VATS” strategy may avoid unnecessary Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15
thoracotomies, unnessary wide resections and
may identify patients that can be treated by VATS P1.283 THE PERIOPERATIVE FACTORS
lobectomie unexpectedly. ASSOCIATED WITH POSTOPERATIVE
Methods: Our institution was the Àrst to introduce ACUTE EXACERBATION OF
VATS resections in the Netherlands in 2006. Since INTERSTITIAL PNEUMONIA WITH
the introduction in 2006, we started with VATS in LUNG CANCER.
every patient with resectable lung cancer. Patient Tomohiro Maniwa, Mitsuhiro Isaka, Kazuo
characteristics, preoperative data, operative details Nakagawa, Yasuhisa Ohde, Takehiro Okumura,
and postoperative course were collected in a Haruhiko Kondo
prospective database. The database was analyzed to Thoracic Surgery, Shizuoka Cancer Center/Japan
identify different patient categories that experienced
great beneÀt by the “always VATS” strategy. Background: The relationship between interstitial
Results: From 2006 to 2011 more than three hundred pneumonia (IP) and primary lung cancer has been
patients were operated for lung cancer in our previously reported. The preoperative factors
institution. The procedure was started by VATS in all associated with acute exacerbation (AE) of IP after
cases. By analyzing the data we were able to identify pulmonary resection have often been reported, the
three categories that experienced great beneÀt by postoperative factors rarely. This study investigated
this “always VATS” strategy. The Àrst category the perioperative factors associated with AE of IP
consisted of patients considered resectable by the after pulmonary resection.
preoperative workup, that turned out not resectable Methods: A retrospective chart study was
during thoracoscopy. This category included undertaken of 1309 patients with lung cancer who
underwent pulmonary resection at Shizuoka Cancer Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15
Center Hospital between September 2002 and
January 2011. One hundred Àfteen patients were P1.284 SURVIVAL BENEFIT OF THE
diagnosed with IP by chest computed tomography SURGICAL INTERVENTION FOR THE
or pathological Àndings. Eleven patients (AE TREATMENT OF PATHOLOGICAL N2
group) suffered from AE after surgery while the NON SMALL CELL LUNG CANCER.
remaining 104 patients (non-AE group) did not. We Masanori Kaneda, Katsutoshi Adachi, Tomohito
investigated the clinicopathological Àndings and Tarukawa
postoperative management of the two groups. Thoracic Surgery, Nho Mie Chuo Medical Center/
Results: The two groups did not differ signiÀcantly Japan
in age, sex, Brinkman index, tumor site, histology,
staging, white blood cell count, C-reactive protein Background: Many surgeons had considered that
level, respiratory function, bleeding or operative any patient with superior mediastinal lymph node
time. However serum lactase dehydrogenase (LDH) metastasis is inoperable. But a selected group of
was signiÀcantly higher in the AE group (p=0.0466). patients with N2 disease will beneÀt from complete
Thirty-six patients required chest tube drainage for resection. However, its survival beneÀt has not
more than 5 days after surgery, 23 of these because been established. We have summarized ten years’
of pleural effusion. Of these 23 patients, six suffered experience and analyzed an achieved survival
from AE of IP and 17 did not (p=0.0069). Table. beneÀt.
Patient’s clinico-pathological and postoperative Methods: Among 519 patients who underwent
details of patients with or without postoperative surgical resection from 1998 to 2007, 94 patients
acute exacerbation. were conÀrmed to be a pathological N2 disease.
After excluding the patients with M1 disease and
AE (n=11) non-AE (n=104) P value insufÀcient data description, total 90 patients were
Age 72(63-83) 70(47-83) 0.4080 selected for analysis. Disease-speciÀc survival curve
Sex (Male/Female) 11/0 89/15 0.0717
and disease-free survival curve were generated by
Brinkman index 1000(0-3920) 1060(0-2400) 0.8103
Site (Left/Right) 2/9 45/59 0.0930 the Kaplan-Meier method and 3- and 5-year survival
Histology (Sq/non-Sq) 6/5 59/45 0.8896 rate were estimated. Independent prognostic factors
WBC (/mm3) 6500(4080-8310) 6805(3620-20550) 0.2190 were also retrieved by the multivariate analysis using
LDH (IU/L) 203(174-314) 192(89-323) 0.0466
Cox proportional hazard model with the p value of
CRP (mg/dL) 0.20(0.005-1.42) 0.305(0.001-9.91) 0.1934
PaO2 (mmHg) 86.9(69.7-107.0) 83.1(61.8-120.0) 0.5618
under 0.05.
%VC (%) 93.2(77.3-102.4) 102.75(56.0-133.0) 0.0725 Results: Disease-speciÀc 3- and 5-year survival
FEV1.0% (%) 77.11(55.3-86.3) 74.45(34.6-100.0) 0.8020 rate was 59.9% and 51.7% respectively. Median
FEV1.0 (L) 7.08(7.171-2.56) 2.265(1.06-3.34) 0.3527 survival time was estimated as 68 months. As for
Operative ï½”ime (min) 200(165-713) 251(73-507) 0.6030
the disease-free survival, it was estimated as 43.7%
Blood ï½Œoss (g) 87(13-373) 94(0-961) 0.9069
and 32.4%. The disease-free survival curve reached
Duration of drainage (day) 5(2-8) 4(1-41) 0.8232 its plateau in 74 months after surgery and survival
»More than 5 days 7 29 0.0199 rate at that point was 26.2%. It was considered to be
»»Prolonged air leak 1 8 0.8722
the complete cure rate, which is unusual sequence
»»Pleural effusion 6 17 0.0069
in medical treatment without surgery. According
to the multivariate analysis, pathological T and
Conclusion: Serum LDH is a predictor of AE of IP. number of mediastinal lymph node stations with
In addition, we should pay attention to the volume of metastasis were signiÀcant prognostic factors. But
chest tube drainage after pulmonary resection for IP. age, gender, clinical N2, and affected lobe were
Keywords: Lung cancer, Surgery, interstitial not signiÀcant in our study. 85 patients (83.3%)
pneumonia, Chest tube drainage had an adjuvant chemo- and/or radiation therapy.
But we could not identify the routine regimens
A revised/updated abstract may be included in or methods. Consequently, it was not signiÀcant
the Late Breaking Abstract Supplement, available either. Postoperative recurrence was conÀrmed in 52
at the 14th World Conference on Lung Cancer. patients (57.8%). The recurrence with mediastinal
lymph node enlargement (including lymphangitis
carcinomatosa of the lung) was only 9 cases (17.3%).
The cancer had recurred with distant metastasis in upper lobectomies and one right lower lobectomy.
33 patients (63.5%). These results implied a great Two patients were adenocarcinomas and one was
efÀcacy of the surgical intervention on the local squamous carcinoma. A new and uncommon method
control of the N2 disease. All the patients treated to the problem of postsurgical chylothorax for lung
with ordinary medical treatment after the recurrence cancer with hypertonic glucose (50%) pleurodesis
except one who underwent surgical resection for through the chest drainage tube is presented.
a metastatic pulmonary nodule. Disease-speciÀc Results: All patients were initially treated
survival after the recurrence was estimated as 24.2% conservatively. These three patients needed more
in 3-year survival rate, 12.1% in 5-year survival rate, intervention of hypertonic glucose pleurodesis
and 14months in median survival time. These values through the chest drainage tube. Patients received
were in no way inferior to the medical treatment conservative treatment from initial operation to
without surgery. Then, it could be concluded that the pleurodesis at a median of 4 days (range 3-5days).
time obtained between the surgery and recurrence, Chest tubes were taken out after pleurodesis at
which was estimated as long as 17.8 months in a median of 7 days (range 4-9days).The patients
average, is the survival beneÀt of the surgical underwent initial operation at a median of 12 days
intervention even in the case with recurrence. of chest tube drainage (range 9-14days). All patients
Conclusion: Complete cure rate was estimated as were discharged without recurrent chylothorax.
26.2% of the surgical patients. Survival beneÀt of Conclusion: It is conÀrmed that to try hypertonic
17.8 months in average was a beneÀt of surgical glucose pleurodesis through the chest drainage
intervention also in the case with recurrence. tube to a thoracic duct leak before resort to a
Keywords: N2 NSCLC, survival beneÀt, Surgical thoracoscopic or thoracotomic ligation. This method
Intervention is simple, cheap, rapid recovery, less pain and
effective. The treatment with hypertonic glucose
through the chest tube gives more successful chance
Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15 to conservative management.
Keyword: Chylothorax; Pulmonary Resection; lung
P1.285 TREATMENT OF CHYLOTHORAX cancer; Pleurodesis
COMPLICATING PULMONARY
RESECTION FOR LUNG CANCER WITH
HYPERTONIC GLUCOSE PLEURODESIS Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15
Yang Li1, Chang Y. Li1, You B. Cui1, Jean
Deslauriers2, Yong X. Wang1 P1.286 MODERN MANAGEMENT OF
1
Thoracic Surgery, The First AfÀliated Hospital Of EARLY BRONCHOPLEURAL FISTULA
Jilin University/China, 2Centre De Pneumologie De AFTER PNEUMONECTOMY FOR LUNG
L’hôpital/Canada CANCER
Yang Li1, Chang Y. Li1, You B. Cui1, Jean
Background: Chylothorax following pulmonary Deslauriers2, Yong X. Wang1
1
resection is not a frequent complication, ranging Thoracic Surgery, The First AfÀliated Hospital Of
from 0.25% to 1.0% in modern reports. However, Jilin University/China, 2Centre De Pneumologie De
the mortality rate of this complication can approach Hospital/Canada
50% in untreated patients. The optimal method
of treatment remains controversial, as variable Background: Bronchopleural Àstula remains a
results have been obtained after conservative and devastating complication after pneumonectomy with
operative treatment. It is not very clear that when a reported mortality between 25.0% and 79.2%.
the treatment should be changed from conservative Especially postpneumonectomy bronchopleural
to video-assisted thoracoscopic surgery (VATS) or Àstula occurred in the early postoperative period
thoracotomy. following a high mortality. The aim of this paper
Methods: From January 2006 to December 2008, was to review management of early bronchopleural
3 patients developed chylothorax after pulmonary Àstula within 30 days after pneumonectomy for lung
resection for lung cancer. There are 2 men and one cancer.
woman with a median age 61 years (range 75 to Methods: A 20-years period, thirty cases (2.7%)
52 years). The initial procedures were two right developed a bronchopleural Àstula within 30 days
after 1046 pneumonectomies for lung cancer. pus, early recurred cancer, or some small Àstulas.
These patients were treated by reoperation, closed Some patients, because of poor prognosis of cancer
drainage with or without open thoracic window, or or associated multisystem disorders, are managed
endobronchial glue. best without aggressive surgical intervention and
Results: 20 bronchopleural Àstulas developed discharged with open thoracic window.
within the Àrst two weeks postoperatively (66.7%), Keyword: management; bronchopleural Àstula;
especially 15 bronchopleural Àstulas occurred in 3 pneumonectomy; lung cancer
to 10 days after pneumonectomy (50%). The most
common symptoms of early postpneumonectomy
bronchopleural Àstula are shortness of breath Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15
(65.0%), increased sputum (65.0%), and increased
cough (65.0%). A decrease of pleural Áuid-air level P1.287 NODAL INVOLVEMENT PATTERN
of more than 1 to 2 cm is the most common sign IN CLINICALLY EARLY LUNG CANCER
(50%) to suggesting a bronchopleural Àstula in ACCORDING TO TUMOR LOCATION
chest radiograph. Four (13.3%) of thirty patients Somcharoen Saeteng1, Juntima Euathrongchit2,
who had bronchopleural Àstulas died. In Seventeen Nirush Lertprasertsuke3, Apichat Tantraworasin1,
patients that were returned to the operating room for Sumitra Thongprasert4, Yutthaphun Wannasopha2
1
reclosure of bronchopleural Àstula, one patient died Surgery, Faculty Of Medicine, Chiang Mai
of bronchopleural Àstula and sixteen reoperations University/Thailand, 2Radiology, Faculty Of
were successful. All the repairs of stumps were Medicine, Chiang Mai University/Thailand,
3
all buttressed with vascularized pedicle Áap of Pathology, Faculty Of Medicine, Chiang Mai
intercostal muscle (n=11), pectoralis major muscle University/Thailand, 4Internal Medicine, Faculty Of
(n=4), or pericardial fat (n=1). 12 cases that Medicine, Chiang Mai University/Thailand
were treated by closed drainage with or without
followed open thoracic window. Three cases died Background: A retrospective cohort study was
of bronchopleural Àstula. One patient successfully performed to deÀne the nodal status of the patients
underwent endoscopic glue to close bronchopleural with lung cancer, received surgery, grouped by
Àstula with injection three times. location to evaluate the nodal spreading pattern.
Conclusion: The majority of bronchopleural Methods: From 2006 -2010, 197 patients underwent
Àstulas developed within the Àrst two weeks lobectomy with systemic nodal resection for primary
postoperatively, especially occurred in 3 to 10 days lung cancer in Chiang Mai University. There were
after pneumonectomy. The most common symptoms 123 male and 74 female with age ranging 16 – 85
of early postpneumonectomy bronchopleural Àstula years old, average 61.31 years old. Analysis of tumor
are shortness of breath, increased sputum, and location, histology type and nodal metastasis were
increased cough. A decrease of pleural Áuid-air done.
level of more than 1 to 2 cm is the most common Results: The tumor locations were RUL in 63
sign to suggesting a bronchopleural Àstula in chest (31.98%), RML in 18 (9.14%), RLL in 30 (15.23%),
radiograph. Chest radiograph and bronchoscopy LUL in 55 (27.92%), LLL in 16 (8.12%) and mixed
are the most effective and simple methods to lobes in 15 (7.61%). The mean size was 4.45 cm in
detect and conÀrm an early bronchopleural Àstula. diameter (range 1.2 - 16.5 cm). Adenocarcinoma
Within one month postoperatively, bronchopleural was the most common histological type, which were
Àstula without established empyema with pus 132 cases (67.01%), following by squamous cell
should be reoperated if the patient had enough carcinoma in 41 (20.81%), bronchioloalveolar cell
cardiopulmonary reserve and could therefore tolerate carcinoma in 9 (4.57%), large cell carcinoma in 7
reclosed. Contamination of pleural space is not (3.55%), respectively. Distribution of node in each
the contraindication to reoperation. Reclosure via location was summarized in table 1. Seventeen cases
original thoracotomy and repair the Àstula with (8.63%) had positive mediastinal node without hilar
pedicled intercostal muscle Áap are convenient and node metastasis-also called skip metastasis.
efÀcient. Drainage with or without followed open
thoracic window is appropriate for the patients
with limited cardiopulmonary reserve, impaired
general condition, secondary to empyema with
pathological Àndings showed 15 cases of squamous

cell carcinoma, 34 of adenocarcinoma, 4 of LCNEC
and 1 of small cell carcinoma, and their pathological
stages were 36 patients of stage 1, 11 of stage 2
and 7 of stage 3. Forty-eight patients (89%) had an
underlying disease, and almost all of those were
circulatory system diseases (31 patients). Respiratory
rehabilitation was performed in 42 patients.
Results: 1) Postoperative acute phase progress: All
patients could get out of bed at an early postoperative
day; 36 patients could walk within 2 days. As for
the postoperative complications, 11 patients had a
cardiac arrhythmia, 5 patient had difÀculty in mucus
expectoration, and 5 patients had postoperative
Conclusion: The tumor location cannot predict the disorientation. All of the patients recovered well
pattern of nodal metastasis. Although, there were and were discharged from the hospital, but two
stastistic signiÀcant different between tuor in RUL patient died from pneumonia within 3 months after
and RLL in lower mediastinal node metastasis. discharge. Postoperative complications occurred in
Moreover, we found 8.63% of skip metastasis. 80% in patients with over 3 underlying diseases.
We thus recommend to perform lobectomy with 2) Postoperative chronic stage progress: The
systematic nodal dissection rather than sampling postoperative survival rate by Kaplan-Meyer was
nodal dissection for accurate lung cancer staging in 40% for 3 years and 20% for 5 years. Six patients
spite of the early stage lung cancer. (12%) died of recurrence, and 2 of those 6 patients
Keywords: Lung cancer, Nodal metastasis died within one year. Four patients (8%) died with
other diseases, and 2 patients died with unknown
causes due to loosing our clinical follow-up.
Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15 Conclusion: Postoperative survival of an
octogenarian with stage 1 or stage 2 lung cancer was
P1.288 PULMONARY RESECTION FOR feasible with the control of the underlying disease
LUNG CANCER IN OCTOGENARIANS before surgery. However, surgery had no signiÀcant
Keigo Takagi, Yoshinobu Hata, Shuichi Sasamoto, survival beneÀt, comparing to other treatment
Shoji Takahashi, Fumitomo Sato, Hidenori Goto, options.
Kazuyoshi Tamaki, Hajime Otsuka, Rena Yuasa Keyword: lung cancer, pulmonary resection,
Chest Surgery, Toho University Omori Medical octogenarian
Center/Japan
Background: With an extension of the average Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15
length of life, the number of pulmonary resection for
lung cancer in octogenarians (patients of older than P1.289 SURGICAL PREVENTION
80 years old) has increased. Our objective was to OF DEVELOPMENT OF
analyze their postoperative complications, quality of BRONCHOPLEURAL FISTULA AFTER
life, survival period, and we discussed the beneÀt of PNEUMONECTOMY IN PATIENTS WITH
pulmonary resection for octogenarians. LUNG CANCER
Methods: From 1998 to 2010, there were 54 Otabek Eshonkhodjaev1, Shukhrat Khudaybergenov2,
octogenarians (6.3%) of clinical stage 1 and stage Georgiy Pahomov3, Ortikali Irisov2, Rustem
2 among 855 patients who were operated on lung Hayaliev3
1
cancer. There were 39 males and 15 females; 41 Department Of Surgery Of Lungs And Mediastynum,
patients were aged from 80 to 82 years old, 9 Republican Specialized Centre Of Surgery Named
patients were from 83 to 84 years old and 4 patients After Academician V.vakhidov/Uzbekistan,
2
were over 85 years old. The operative methods Republican Specialized Centre Of Surgery Named
were one pneumonectomy, 43 lobectomies, 4 After Academician V.vakhidov/Uzbekistan, 3Tashkent
segmental resections and 6 partial resections. The Medical Academy/Uzbekistan
Background: Bronchial stump Àstula and

related to it pleural empyema are general causes
of efÀcacy decrease of surgical treatment of
lung cancer and purulent destructive pulmonary
diseases. Development of bronchial stump Àstula
after pneumonectomy (PE) was always related to
bronchial suture failure and unfavorable conditions
of its healing. It allows to determine heterogenicity
of patients’ group in relation to the nearest and
remote prognosis as well as to work out and to
implement optimal volumes of surgical treatment
into practice.
Methods: StratiÀcation data of risk factors of
bronchial stump failure (BSF) development in 575
patients, who underwent pneumonectomy were
presented. Control group (CG) consisted of 477
patients, 390 patients of them had lung cancer and 87
patients had purulent diseases of the lungs. The main
group (MG) consisted from 98 patients, 72 patients
of them had lung cancer and 26 patients had purulent
pulmonary diseases. In CG BSF developed in 52
(10.9%) patients, at the same time an incidence of
this complication in patients of oncologic proÀle was Conclusion: Introduction of tactics of surgical
10.5% (41 patients), and in patients with purulent intervention based on the worked out factor
pulmonary diseases – 12.6% (11 patients). In MG estimation of risk degree of development of BSF
BSF was observed in 3 (3.1%) patients, at the same after PE permitted to decrease an incidence of
time an incidence of this complication in patients of lethality from 7.1% (34 of 477 patients in control
oncologic proÀle was 2.8% (2 patients), and with group) up to 3.1% (3 of 98 patients in main group).
purulent pulmonary diseases – 3.8% (1 patient). To Keywords: bronchial stump Àstula, pneumonectomy
evaluate adequate a retrospective distribution of
patients in risk groups in CG and prospective one in
MG were performed. Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15
Results: The minimal risk of development of this
complication reached 67.9% to the left and only P1.290 MEDIASTINOSCOPY AFTER
6.7% to the right, mean risk was 21.8% and 70.3% NEGATIVE ENDOSONOGRAPHY
respectively, where as maximal degree of risk was IN LUNG CANCER STAGING.
revealed in only 10.3% to the left and in 23.1% to SUBANALYSIS OF ASTER WITH FOCUS
the right. An incidence of BSF after PE in patients ON PET.
of CG accounted for minimal risk 1.3%, at an Kurt G. Tournoy1, Christophe Dooms2, Robert C.
average – 16.0%, and maximal – 32.3%, in its turn, Rintoul3, Ellen Deschepper4, Jouke Annema5
1
an implementation of factor estimation of risk degree Respiratory Medicine - Thoracic Oncology, Ghent
of development of BSF after PE in MG allowed to University Hospital/Belgium, 2Respiratory Oncology
reduce an incidence of this complication until 0.0%, Unit, University Hospitals Leuven/Belgium,
3
2.6% and 9.1% respectively. Department Of Thoracic Oncology, Papworth
Hospital/United Kingdom, 4Biostatistics, Ghent
University Hospital/Belgium, 5Respiratory Medicine
- Thoracic Oncology, Leiden University Medical
Centre/Netherlands
Background: Mediastinal staging in non-small

cell lung cancer with endosonography (EUS-FNA
plus EBUS-TBNA) followed by mediastinoscopy
is more sensitive to detect nodal metastasis as And Allergic Diseases/Japan, 3Department Of

compared to mediastinoscopy alone (ASTER trial, Pathology, Osaka Prefectural Medical Center
JAMA 2010;304:2245). However 11 patients need to For Respiratory And Allergic Diseases/Japan,
4
undergo a mediastinoscopy to detect one with N2/3 Department Of Thoracic Malignancy, Osaka
missed by endosonography. We analysed if FDG- Prefectural Medical Center For Allergic And
PET identiÀes patients in whom the mediastinoscopy Respiratory Diseases/Japan
can be omitted.
Methods: In ASTER, 123 patients were randomized Background: Effective staging systems for lung
to endosonography followed by mediastinoscopy cancer are required to stratify patient survival and
when the former did not show mediastinal assess the treatment results of deÀned the patient
metastasis. Sensitivity, negative predictive value subgroups. This study evaluated the surgical results of
(NPV) and number of mediastinoscopies needed non-small cell lung cancer (NSCLC) with interlobar
to detect one false negative endosonography were pleural invasion (IPI) to investigate whether NSCLC
calculated in the cases with complete data (n=120; with IPI should be classiÀed as either T2 or T3
98%). according to the seventh TNM staging criteria.
Results: With PET, 77 patients had FDG-avid Methods: Nine-hundred and thirty-Àve patients with
mediastinal nodes; the prevalence of N2/3 pathologic T2 and T3 NSCLC (690 males and 245
was 73(62-81)%. The sensitivity and NPV of females; age range 26-87 years, mean, 65.2years)
endosonography was 88 (76-94) and 75 (57-88)%. treated between January 1980 and December 2004
Adding mediastinoscopy increased sensitivity and were retrospectively evaluated. All the medical records,
NPV to 96 (88-99) and 91 (73-98)%. 43 patients including surgical records and pathology reports, were
did not have FDG-avid mediastinal nodes, the retrospectively reviewed to conÀrm the presence of
prevalence of N2/3 was 23 (13-38)%. The sensitivity IPI. The pathological staging was evaluated according
and NPV of endosonography was 70 (40-89)% and to the seventh TNM staging criteria. Among these,
92 (78-97)%. Adding mediastinoscopy increased 682 patients were pathologically staged as T2 without
sensitivity and NPV to 80 (49-94)% and 94 (81- IPI (T2 group), T2 with IPI (IPI group), and 228 as
98)%. In patients with FDG-avid vs. FDG-cold T3 (T3 group). The surgical results of these groups
mediastinal nodes, the number of mediastinoscopies were analyzed using Kaplan-Meier method and the
needed to detect one false negative endosonography log-rank test. A multivariate analysis for prognostic
is 6 vs 36 (p=0.078). factors including T factors (using IPI as a T factor)
Conclusion: A negative endosonography should and N factors was performed by the Cox multivariate
be followed by a mediastinoscopy if PET positive proportional hazard model.
mediastinal nodes are present. In the absence of Results: The median follow-up interval was 47
PET positive nodes, a mediastinoscopy following a months (range 1–301 months). The 5-year survival
negative endosonography can be omitted. rate for the T2 group, IPI group, and T3 group
Keywords: PET-CT scan, Staging, endosonography were 51.9%, 31.1% and 38.8% respectively. There
/ EUS-FNA / EBUS-TBNA, Mediastinoscopy were statistically signiÀcant differences in survival
between the T3 and T2 group (p < 0.001), and
between the IPI and T2 (p = 0.045) group. The
Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15 difference of survival between the IPI group and
T3 group was not signiÀcant (p=0.904). In patients
P1.291 SURGICAL RESULTS AND without nodal involvement, the 5-year survival rate
STAGING OF NON-SMALL CELL LUNG for the T2N0 group, IPI N0group, and T3N0 group
CANCER WITH INTERLOBAR PLEURAL were 61.0%, 40.0% and 45.7% respectively. There
INVASION were statistically signiÀcant differences in survival
Ryu Kanzaki1, Mitsunori Ohta2, Naoki Ikeda2, Eiji between the T3N0 and T2N0 group (p < 0.001), and
Ohkura2, Naoto Kitahara2, Akira Okimura3, Masashi between the IPIN0 and T2N0 (p = 0.026) group. The
Kobayashi4, Kunimitsu Kawahara3 difference of survival between the IPIN0 group and
1
Department Of Thoracic Surgery, Osaka Prefectural T3N0 group was not signiÀcant (p=0.684). The results
Medical Center For Respiratory And Allergic of the multivariate analysis using T and N factors
Diseasefor/Japan, 2Department Of Thoracic Surgery, showed that the hazard ratio for death of the IPI group
Osaka Prefectural Medical Center For Respiratory tend to be higher than that of T2 group, however, the
difference was not signiÀcant (hazard ratio, 1.589; Results: The remaining work-up was normal
95% conÀdence interval, 0.936-2.622; p = 0.070). without any sign of distant relapse. A bronchoscopy
Conclusion: Survival of the IPI group was similar was performed and the pathological showed Àbro-
to that of the T3-group. Therefore, we propose that collagenic tissue without neoplastic cell. The Ànal
NSCLC with IPI be classiÀed into T3 according to diagnosis was therefore a pseudo-tumor after using
the seventh TNM staging system. sleeves for staple-line reinforcement.
Keywords: Lung cancer, Staging, pathology Conclusion: The use of sealant during
pneumonectomies or lobectomies is frequent and
efÀcient to avoid suture dehiscence. These cases
Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15 point a potential cause of mistake for clinicians
as staple-line reinforcement may mimic a tumor
P1.292 TUMOR RELAPSE AFTER relapse. A multidisciplinary team discussion
SURGERY USING A SLEEVE FOR LUNG together with a pathological exam is obviously
STAPLE-LINE REINFORCEMENT: NOT always required to exclude a tumor relapse.
ALWAYS! However, knowing this rare outcome may speed up
Marie-Eve Garcia1, Pascale Tomasini2, Pascal the work up and reinsure patients and physicians
Thomas3, Laurent Greillier4, Fabrice Barlesi2 when following lung cancer patients treated with a
1
Service D’oncologie Multidisciplinaire Et bronchial reinforcement after thoracic surgery.
Innovations Therapeutiques, Chu Nord/France, Keywords: tumor relapse, sleeve, staple-line
2
Oncologie Multidisciplinaire Et Innovations reinforcement, Lung cancer
Thérapeutiques, Hôpital Nord/France, 3Thoracic
Surgery, Hôpital Nord/France, 4Service D’oncologie
Multidisciplinaire Et Innovations Thérapeutiques, Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15
Hôpital Nord, Assistance Publique- Hôpitaux De
Marseille/France P1.293 THE UTILITY OF
ULTRASONICALLY ACTIVATED SHEARS
Background: Standard treatment of early stages IN LYMPH NONE DISSECTION FOR
of non small cell lung cancer (NSCLC) is based on NON-SMALL CELL LUNG CANCER
thoracic surgery and radical lymphadenectomy. Air Hirozo Sakaguchi, Hironori Ishida, Hiroyuki
leaks are one of the most common complications and Nitanda, Nobuhiro Yamazaki, Hiroyoshi Tsubochi,
may occur in up to 28 to 60% of cases. They may be Koichi Kaneko
avoided using a sealant. Department Of General Thoracic Surgery, Saitama
Methods: Our institution participated in a clinical Medical University International Medical Center/
trial of FOREseal® sleeve reinforcement for lung Japan
cancer patients treated (n=66) with a lobectomy.
During the follow-up of these patients, two of them Background: Ultrasonically activated coagulated
(a stage pT2N2M0 adenocarcinoma and a stage shears (UACS) has been reported to be useful for
pT2N1M0 squamous cell carcinoma) presented with lymphadenectomy in patients with gastrointestinal
a CT-scan enlargement and the PET-CT scan showed malignancy. We evaluated the use of UACS
a hyper-metabolic pulmonary lesion at the site of in reducing the operative blood loss and the
the previous bronchial resection. A local relapse was postoperative drained Áuid for NSCLC.
obviously suspected. Methods: We designed retrospective study to
determine the effectiveness of the UACS versus
monopolar electrosurgery in ND2 dissection.
Forty patients, who were treated by same surgeon,
with NSCLC c-Stage I were enrolled. Group
A: 2008-2009,twenty patients were underwent
lymphatic dissection with UACS. Group B:
2004-2006,twenty were underwent lymphatic
dissection with monopolar cautery. BMI,
preoperative serum total protein level, operative
blood loss and postoperative drained Áuid were
compared in two groups. Values represent the mean NSCLC (94). 10 patients underwent induction
± SD, and Mann-Whitney U-test were used. therapy. Median operative time, complication rate,
Results: Right side disease was performed in 8 redo-operation rate, 30 days mortality and length
patients of group A and 11 of group B. No statistical of stay were 190 minutes, 30,2%, 7,9%, 3,2% and
difference were seen for BMI and preoperative 9 days. Lymph nodes from median 5 stations were
serum total protein level. The operative blood loss sampled which led to a pathological upgrading
was 21-170ml (mean 82±47) in group A and 60- in 3 patients. Conversion to open thoracotomy
243ml (mean 125±51) in group B (p=0.01). The was performed in 9 (8%) patients. Reasons for
total amount of drained Áuid was 270-1830ml conversion was pulmonary artery bleeding in 4
(mean 959±352) in group A and 540-2650ml patients (emergency thoracotomy in 2 of them),
(mean1438±384) in group B (p=0.036). clinical mis-staging in 2 patients and technical
Conclusion: UACS is a useful method of Stage I difÀculties in 3 patients, respectively.
lobectomy followed by lymphatic dissection (ND2) Conclusion: A VATS lobectomy program has been
to reduce operative blood loss and postoperative introduced with promising short term results and
lymphorrhea. a reasonable low conversion rate. In this series,
Keywords: Lymph None Dissection, Ultrasonically induction chemotherapy and clinical staging
Activated Shears, Lymph None Dissection higher than IA/B have not been associated with a
higher conversion rate. When introducing a VATS
lobectomy program, safety and oncological accuracy
Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15 rather than a low conversion rate are the main
concerns determining the programs fate.
P1.294 LESSONS LEARNED FROM 8% Keywords: NSCLC, VATS, Conversion
CONVERSION RATE DURING FIRST 111
VATS LOBECTOMIES IN AN ACADEMIC
THORACIC SURGERY CENTER Poster Session 1 – Surgery Monday, 4 July 2011 12:15-14:15
Johannes Bodner1, Herbert Maier2, Thomas Schmid2,
Florian Augustin2 P1.295 RELEVANCE OF
1
Division Of Thoracic Surgery, University Hospital POSTOPERATIVE FOLLOW-UP AFTER
Giessen/Germany, 2Visceral Transplant Thoracic SURGERY FOR NSCLC AND HIGH-
Surgery, Innsbruck University Hospital/Austria GRADE NEUROENDOCRINE TUMOR
(HGNET)
Background: VATS (Video Assisted Thoracic Ryu Nakajima, Makoto Takahama, Ryoji Yamamoto,
Surgery) lobectomy has gained increasing Tada Hirohito
acceptance as an alternative treatment option for General Thoracic Surgery, Osaka City General
early stage NSCLC (non small cell lung cancer). Hospital/Japan
Recently also in Europe, an increasing number
of (academic) centers have introduced a VATS Background: Large Cell Neuroendocrine carcinoma
lobectomy program. Main criterias during the initial (LCNEC) was classiÀed in NSCLC, but clinical
phase of a VATS lobectomy program are patients behaviors of LCNEC were similar to Small Cell
safety and oncologic accuracy. Lung Cancer (SCLC). Several investigators proposed
Methods: From February 2009 to February 2011 LCNEC and SCLC as HGNET. Large numbers
111 patients underwent complete thoracoscopic of post operative lung cancer patients (especially
lobectomy through three non rib-spreading HGNET) were relapsed and periodic clinic visits is
thoracocenteses with individual control of vascular usually recommended after surgery. But there is no
and bronchial structures and oncologic lymph node consensus of ideal visit span, follow up range and
sampling. Retrospective analysis of prospectively modality have not deÀned yet. Objectives of this
collected data was performed. Special attention was retrospective study were to determine the feasibility
given to those patients in who conversion to open of follow-up program of NSCLC (except LCNEC)
thoracotomy was performed. and HGNET.
Results: The median age of 63 men and 48 women Methods: We retrospectively reviewed 265 of
was 62 years. Indications were benign lesions (3), relapsed patients (NSCLC: 238(40%), HGNET:
a neuroendocrine tumor (14) and (stage IA to IIIA) 37(35%)) after surgery in our institution (1994-
2004). In several group, follow up procedure, Background: In terms of morbidities and

detected pattern of recurrence (scheduled / mortalities, lobectomy is safe modality for non-
unscheduled), Àrst relapse site and timing, and small cell lung cancer(NSCLC) patients, if the
survival were analyzed. X2-test and log-rank test postoperative expected (PPO) FEV1 is over 40%.
were used for statistically analysis. In follow up However, effect of moderate pulmonary dysfunction
procedure, scheduled study included physical exam, on longterm survival is not clearly deÀned, and
chest X-ray, blood analysis (within tumor makers) furthermore was not analysed according to stage.
and thoracic CT scan in all patients. In some patients, Because standart treatment strategies are different
periodic brain MRI (17%) and born scan (7%) were between stages, the effect of pulmonary dysfunction
performed. on longterm survival might be assessed by stage.
Results: Seventy-eight of NSCLC patient and 100% We intended to study whether the effect of moderate
of HGNET patient were relapsed within 3 years. pulmonary dysfunction on survival is different
In HGNET, there was no born metastasis after according to stages.
1 year, but NSCLC was featureless. Recurrence Methods: NSCLC patients underwent
was detected by scheduled study in 190 patients lobectomy from Jan, 1992 to Dec, 2009 were
(72%). In both groups, born scan could not detect analysed retrospectively. Demographic data and
recurrence, and 33 % of HGNET patients was clinicopathologic data including pulmonary function
detected brain metastasis by MRI (no patient in tests, pulmonary perfusion scans were obtained from
NSCLC). The Patient that was detected relapse by institutional prospective database with 2100 cases.
scheduled study had signiÀcant superior survival Criteria for moderate pulmonary dysfunction was
(NSCLC; 46 mo. vs. 30mo. and HGNET; 26 mo. vs. PPO FEV1 between 40% and 60%. PPO FEV1 was
12 mo.). calculated with preoperative FEV1 and perfusion
Conclusion: Recurrence was detected over 5years scan data. Survival differences of patients with
in NSCLC patients but 3years in HGNET. Periodic moderate (M) versus mild or no (G) pulmonary
born scan and brain MRI were useless to detect dysfunction were analysed according to pathologic
recurrence in NSCLC patients, but In HGNET stages.
patients, Brain MRI was useful in some patients. Results: Out of 941 eligible patients, 314
Periodic postoperative follow up may improve (33.4%) were female. Mean age was 62.9 years.
survival. Large scale prospective study was needed Adenocarcinoma consisted 59.3% of cases and
to verify the necessity. squamouscarcinoma consisted 34.9%. Patients in
Keywords: post operative follow-up, NSCLC, M group were 129 (13.7%). Operative mortality
HGNET

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Journal of Thoracic Oncology t Volume 6, Number 6, Supplement 2, June 2011 14th World Conference on Lung Cancer

PRS.1 GENOMIC CHARACTERIZATION

Background: Recent advances in the molecular

PRS.3 IMPROVEMENTS IN SURVIVAL PRS.7 THE EFFECTS OF INVESTING

Abstract under Embargo - will be presented in a

Presidential Symposium incl. Best Oral Presentations Wednesday, 6

PRS.5 IN VIVO SELECTION OF NON-

Abstract under Embargo - will be presented in a

PLENARY SESSIONS 5p15.33, 6p21.33 or 15q15.2 inÁuence smoking

are responsible for histology-based differences in cetuximab-containing therapy in colorectal cancer,

MINI SYMPOSIUM SESSIONS growth factor 2 (c-erbB-2)), regulation of cell

Abstract: Studies of the histology, cytology

among metastases. The presentation will also review

Session M04: Issues Surrounding the

Monday, 4 July 2011

Issues Surrounding the Use of PFS as a Primary Endpoint Monday, 4

Tracheal Tumors Monday, 4 July 2011 10:30-12:00

surveyed, lung cancer is thought to be the cancer

on an artiÀcial (electronic) nose, which makes use

Abstract: Randomized phase II studies have become

EMN EMN is a procedure in which a steerable Although further improvement in performance is

Abstract: Positron emission tomography (PET)

M16.2 BIOMARKERS IN CLINICAL

with use of Endobronchial Ultrasound (EBUS) in maneuverability, 3-dimensional visibility and

complications of progressive disease or debilitation, education, pain management, psychosocial support,

lung cancer staging, resection techniques and treatment methods

of the pathologic and molecular preneoplastic academic exercise by pathologists to a dynamic

Abstract: Conceptual preparation to form an

EDUCATIONAL SESSIONS an anti-mesothelin antibody and pseudomonas

Session E03: Borderline Operable non-invasive cardiac testing treatments. If they

(EBUS) or mediastinoscopy. In the present case, differences in their investigation by pathologists,

Abstract: Cytology is often used in the diagnosis E06.2 EUROPE CONCENTRATION OF

E07.2 ASPECTS OF (NURSING) CARE Methods

E08.3 TARGETING GALECTIN-1 IN NON-

Adding radiotherapy to chemotherapy before Better local control might be achieved by

Abstract: Pathologic staging should be performed

E14.3 NURSING ASPECTS OF

routes of administration (nasal, pulmonary) Session E16: Radiotherapy Issues in

if available, should be used to determine tumor

MEET THE EXPERT SESSIONS occult SCLC. Different antibodies involved in

Abstract: The development of agents to prevent

Session MTE16: Radiation Pulmonary 1

Wednesday, 6 July 2011 MTE20.2 HOW TO REPORT PET

antibody-dependent, may be of service too. For results of conventionally fractionated radiotherapy

A CT (computed tomography) or MRI (magnetic Session MTE28: How to Run a Stop

Session MTE29: Second Line Treatment

is presented. He had been investigated years oxyhaemoglobin saturation by pulse oximetry

Thursday, 7 July 2011

Session MTE33: Superior Sulcus Tumor of-care.1 Current surgical standard-of-care

Predicted postoperative FEV1 (ppoFEV1), estimated continuous monitoring of various cardiologic

GRAND ROUNDS SESSIONS COPD is the most common comorbidity (50-60% of

Mesothelioma - Oncological and Supportive Management Session GR04: Intra-Operative Decision

GR03.5 DESTRUCTIVE PAIN SURGERY

PRO-CON SESSIONS eliminates unnecessary passes during the procedure.

SESSION Y: YOUNG or not to pursue a career - and or life - in academic

more complete node dissections, and proving a

The result of advances in survival is that this

ORAL SESSIONS versus zoledronic acid (ZA) for preventing SREs

Background: Denosumab (XGEVA™), a fully