SCLC Lancet

Seminar
Small-cell lung cancer

Jan P van Meerbeeck, Dean A Fennell, Dirk K M De Ruysscher
The incidence and mortality of small-cell lung cancer worldwide make this disease a notable health-care issue. Diagnosis
relies on histology, with the use of immunohistochemical studies to conrm dicult cases. Typical patients are men
older than 70 years who are current or past heavy smokers and who have pulmonary and cardiovascular comorbidities.
Patients often present with rapid-onset symptoms due to local intrathoracic tumour growth, extrapulmonary distant
spread, paraneoplastic syndromes, or a combination of these features. Staging aims ultimately to dene disease as
metastatic or non-metastatic. Combination chemotherapy, generally platinum-based plus etoposide or irinotecan, is the
mainstay rst-line treatment for metastatic small-cell lung cancer. For non-metastatic disease, evidence supports early
concurrent thoracic radiotherapy. Prophylactic cranial irradiation should be considered for patients with or without
metastases whose disease does not progress after induction chemotherapy and radiotherapy. Despite high initial
response rates, most patients eventually relapse. Except for topotecan, few treatment options then remain. Signalling
pathways have been identied that might yield new drug targets.
Introduction
Small-cell lung cancer (SCLC) is a distinct clinical and
histological entity within the range of lung cancers. Its
management has followed the major developments of
modern cancer treatment through the integration of
biology, imaging, chemotherapy, and radiotherapy.
SCLC was originally thought to originate from the
lymphatic system because of microscopic similarities
between SCLC and lymphoma cells. In 1879, Hrting and
Hesse1 described an arsenic-induced lymphosarcoma in
miners. The term SCLC was rst coined in 1926, when
its epithelial origin was recognised.2 In this and ensuing
classications, phenotypical variants were described as
oat cell or mixed subtypes. These terms are no longer
used in WHOs classication.3
Here we address the scientic advances that have been
made in dening the biology of SCLC and that have
increased our ability to manage this cancer. We also
consolidate the evidence on the usefulness of current
therapeutic and prophylactic methods, and suggest ways
they can be further improved by new developments in
targeted therapy.
as NSCLC.3,8 An increase in incidence is expected in

countries where smoking prevalence remains high, such
as those in eastern Europe and Asia.
Diagnosis
SCLC is dened as a malignant epithelial tumour
consisting of small cells with scant cytoplasm, ill-dened
cell borders, nely granular nuclear chromatin, and
absent or inconspicuous nucleoli (gure 1).3 Typical
SCLC involves only small cells and accounts for around
90% of cases. The remaining cases are classied as
combined disease, in which the tumour contains largecell components.3,9
Molecular biology
Lancet 2011; 378: 174155

Published Online
May 11, 2011
DOI:10.1016/S01406736(11)60165-7
See Editorial page 1678
Department of Respiratory
Medicine and Lung Oncological
Network, Ghent University
Hospital, Ghent, Belgium
(Prof J P van Meerbeeck CMO);
Belfast Cancer Research UK
Centre, Queens University
Belfast, Belfast, UK
(D A Fennell FRCP); and
Department of Radiation
Oncology (Maastro Clinic),
Maastricht University Medical
Centre, GROWSchool for
Oncology and Developmental
Biology, Maastricht,
Netherlands
(Prof D K M De Ruysscher MD)
Correspondence to:
Prof Jan P van Meerbeeck,
Department of Respiratory
Medicine and Lung Oncological
Network Ghent University
Hospital (LONG),
De Pintelaan 185, B-9000 Ghent,
Belgium
jan.vanmeerbeeck@ugent.be
Cytogenetically, SCLC has several distinguishing

abnormalities in DNA copy number. In virtually all
expression microarray analyses, SCLC has shown many
specic gene expression features.10 Several important
genetic and molecular characteristics have been
recorded, including the identication of autocrine
growth loops, proto-oncogene activation, and loss or
Epidemiology
Lung cancer accounts for 12% of all new cases of cancers
worldwide, it is the second most common cancer in men
and women, and it is the leading cause of cancer-related
death in the USA.4 SCLC represents 13% of all newly
diagnosed cases of lung cancer worldwide, or more than
180 000 cases per year. More than 90% of patients with
SCLC are elderly current or past heavy smokers, and risk
rises with increasing duration and intensity of smoking.5
Although rare cases have been reported in people who
have never smoked,6 SCLC, by contrast with non-smallcell lung cancer (NSCLC), is not associated with a specic
somatic mutation.7 In industrialised countries the annual
incidence of SCLC has decreased over the past 30 years,
probably owing to changes in smoking patterns. A shift
in the WHO classication of lung cancers might also
have contributed, as some borderline cases that were
previously described as mixed subtypes are now classied
www.thelancet.com Vol 378 November 12, 2011
Search strategy and selection criteria

We searched PubMed with the following keywords used in
various combinations: carcinoma, small cell lung,
epidemiology, pathology, biology, diagnosis,
staging, treatment, management, antineoplastic
agents, targeted agent, radiotherapy, and surgery. The
search was limited to articles published in peer-reviewed,
journals published from 2005 onwards. For the management
section we searched all publications and for the other
sections we only searched journals published in English.
Some classic papers were also selected according to the
authors knowledge. We consulted the latest guidelines of the
National Institute for Health and Clinical Excellence in the UK,
the American College of Chest Physicians, the National
Comprehensive Cancer Network, and the European Society of
Medical Oncology.
1741
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Figure 1: Microscopic features of SCLC

(A) In typical SCLC, cells are small (generally less than the size of three small resting lymphocytes) with scant
cytoplasm, nuclear moulding, and nely granular nuclei with inconspicuous nucleoli (Di-Quick staining, 200).
(B) Cells can be round, oval, or spindle-shaped and cell borders are rarely seen. Architectural patterns include
nesting, trabeculae, peripheral palisading, and rosette formation, as seen in other neuroendocrine-tumour cells
(haematoxylin and eosin staining, 200). Immunohistochemistry shows strongly positive results for (C) CK-7, the
neuroendocrine markers (D) CD56 and (E) synaptophysin, and (F) TTF-1 along plasma membranes and in the
nuclei. SCLC=small-cell lung cancer. All pictures reproduced by permission of M Praet and L Ferdinande,
N Goormaghtigh Institute of Pathology, Ghent, Belgium.
inactivation of tumour-suppressor genes.9 The

deletion 3p(1423) in the region containing the tumoursuppressor gene FHIT is seen in virtually all SCLC
tumours.9 Another common nding is a copy-number
gain in 7p22.3, which encompasses MAD1L1, which
encodes the mitotic spindle assembly checkpoint
protein MAD1.11 Nearly all patients with SCLC also have
loss of the tumour-suppressor retinoblastoma gene RB1
and have more frequent mutations in TP53 than do
patients with NSCLC. These mutations decrease
proapoptotic activity during SCLC tumorigenesis,
which encourages agressive growth and increases the
survival advantage of carcinogenic cells.12 Tyrosinekinase signalling genes, including KRAS and EGFR,
are rarely mutated.9 Information on the molecular
features of SCLC is, however, not yet sucient to aect
diagnostic methods.
Histopathology
Although SCLC is often suspected on the basis of
presenting symptoms and signs, pathological and
cytopathological studies are typically required to conrm
the diagnosis. Samples from the primary tumour, lymph
nodes, or other metastatic sites should be obtained by
bronchoscopic biopsy or ne-needle aspiration. The
tumour grows under the bronchial mucosa and,
therefore, bronchial biopsy, cytological brush, or sputum
samples might be negative. Necrosis or crush artifacts
by the bronchoscopic forceps sometimes hamper
1742
diagnosis, but good interobserver agreement has been

reported between pathologists for dierentiation of
SCLC from NSCLC.3,9 Immunohistochemical studies
can be used to conrm dicult cases. Testing for
neuroendocrine markers, such as chromogranin,
synaptophysin, and CD56, can be useful (gure 1); less
than 10% of SCLC tumours are negative for all
neuroendocrine markers. SCLC is also positive for TTF-1
in up to 90% of cases. Epithelial markers, such as
cytokeratins, are seen in many SCLC tumours and help
to distinguish them from lymphomas and other small
round tumours.
Presentation
Watson and Berg13 were the rst to describe distinct
clinical features of SCLC, especially the predominantly
central and bulky location on chest radiography, the
tendency for early dissemination, the high initial
response rates to chemotherapy, and the high frequency
of metastases at autopsy. Patients are typically men
older than 70 years who are heavy current or ex-smokers
and have various pulmonary, cardiovascular, and
metabolic comorbidities.14 Onset of symptoms is rapid,
with the duration before presentation generally being
812 weeks. The most frequent symptoms are cough,
wheeze, dyspnoea, haemoptysis caused by local
intrapulmonary tumour growth, symptoms due to
intrathoracic spread to the chest wall, superior vena
cava, or oesophagus, recurrent nerve, pain, fatigue,
anorexia, and neurological complaints caused by distant
spread, and paraneoplastic syndromes.15,16 Preferential
metastatic sites are the brain, liver, adrenal glands,
bone, and bone marrow.
SCLC is the most frequent cause of paraneoplastic
syndromes (table 1).28 These syndromes should be actively
excluded whenever a patient presents with any of their
associated features. The most frequent endocrine
syndromes are the syndrome of inappropriate antidiuresis17,18 and Cushings syndrome.19,20 Subclinical
presentations of both have been reported. Dermatological abnormalities specically associated with SCLC
include acquired tylosis, trip palms, and erythema
gyratum repens.15
Rarer manifestations are dermatomyositis, hyperglycaemia, hypoglycaemia, hypercalcaemia, and gynaecomastia. SCLC elicits various serum antibody responses.
Among these, neurological syndromes are of special
interest, owing to the generation of autoantibodies and
T lymphocytes specic for common epitopes in the
tumour and components of the nervous system.21 These
syndromes can antedate a diagnosis of SCLC by several
months. Lambert-Eaton syndrome is a disease of the
neuromuscular junction and is caused by antibodies
directed against the P/Q-type voltage-gated calcium
channels in the presynaptic nerve terminal that are
expressed by SCLC cells. This complication suggests
autoimmunisation by the tumour is the cause of the
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Main symptoms, signs, and ndings
Cause
Proportion of SCLC Proportion of patients

with the syndrome that
patients with
have SCLC (%)
syndrome (%)
Prognosis
Syndrome of
inappropriate
antidiuresis17,18
Weakness, dysgeusia, and clinical euvolaemia

(osmolality <275 mOsmol/kg water, urinary
osmolality >100 mOsmol/kg water during
hypotonicity, urinary sodium >40 mmol/L with
normal dietary salt intake)
Arginine vasopressin or atrial

natriuretic peptide
1540
..
Frequently normalises with

treatment but precedes
relapse
Cushings syndrome19,20
Hypercorticism
Ectopic corticotropin
311
Poor owing to high rate of

infections during
chemotherapy
Lambert-Eaton
syndrome2124
Antibodies to voltage-gated
Muscle weakness and fatiguability, mostly in
proximal muscles of lower extremities, abnormal calcium channels of nerve
terminal and to SOX
gait, hyporeexia, increased deep-tendon
reexes after facilitation, autonomic dysfunction,
and paraesthesia
Limbic encephalitis and

encephalomyelitis21,2527
Personality and psychiatric changes, seizures,

short-term memory loss, and space and time
disorientation, with or without dementia
Paraneoplastic cerebellar
degeneration or Hu
syndrome21,2527
Superior vena cava

syndrome16
25
50
50% of patients improve

during treatment, 50%
refractory
<1
50
Neurological symptoms not

reversible
Antibodies to Hu family
Truncal, limb, and gait ataxia, dysarthria; ocular
ndings, and vertigo with inability to stand, walk, proteins, YO, CRMP-5, Pca-2,
MA1, voltage-gated calcium
or sit
channels of nerve terminal,
and RI
<1
Neurological symptoms not

reversible
Oedema of upper body
50
25
Antibodies to Hu family
proteins
Obstruction of superior vena

cava by primary tumour,
enlarged mediastinal lymph
nodes, or thrombus
Resolves rapidly with

chemotherapy or
radiotherapy
SCLC=small-cell lung cancer.
Table 1: Paraneoplastic and other syndromes frequently associated with SCLC
Number of
patients
Cerny et al
35
Albain et al36
Origin of patients
details
Factors associated with improved outcomes

Patient
Tumour
Biology
407
Manchester Group
clinical trials
Karnofsky performance
status >80
Limited stage
Normal baseline concentrations of LDH, sodium,

alkaline phosphatase, or bicarbonate in serum
1137
SWOG clinical trials
Age <70 years
Limited stage, no
pleural eusion
Normal baseline concentration of LDH in serum
Sagman et al37
614
Clinical trials
ECOG performance
status 01; female sex
Limited stage, no
liver metastasis
Normal baseline concentrations of LDH or alkaline

phosphatises in serum or normal baseline WBCC
Paesmans et
al38
763
ELCWP clinical trials
Karnofsky performance
status >80; female sex;
age <60 years
Limited stage
Baseline neutrophil rate <75%
Sculier et al39
4359
IASLC database
Performance score <1,

female sex, age <65 years
Limited stage
..
Foster et al40
910
(ES only)
NCCTG clinical trials
Performance status <1,

female sex
Low number of
metastatic sites
Normal baseline creatinine concentration
SCLC=small-cell lung cancer. LDH=lactate dehydrogenase. SWOG=South West Oncology Group. ECOG=Eastern Cooperative Oncology Group. WBCC=white-blood-cell count.
ELCWP=European Lung Cancer Working Party. IASLC=International Association for the Study of Lung Cancer. ES=extensive stage SCLC. NCCTG=North Central Cancer
Treatment Group Trials.
Table 2: Prognostic factors in reported in SCLC database studies
syndrome. In one series, ve of 63 unselected SCLC

patients had raised concentrations in serum of antibodies
against P/Q-type voltage-gated calcium channels,
although only two had Lambert-Eaton syndrome.22
Antibodies against SOX family proteins have diagnostic
value in discriminating Lambert-Eaton syndrome
associated with SCLC from other non-tumorous forms.29
Lambert-Eaton syndrome should be dierentiated from
myasthenia gravis, which is not frequently associated

with SCLC.
Patients with SCLC might have raised concentrations
of antibodies against other antigens, such as the
Hu family of DNA-binding proteins. Paraneoplastic
encephalomyelitis and paraneoplastic sensory neuronopathy have been associated with raised titres of
antibodies to Hu family proteins.25 Low titres in serum,
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94 mm
74 mm
Figure 2: Radiological imaging of SCLC at presentation and after treatment in a patient presenting with
dyspnoea, stridor, and superior vena cava syndrome
(A) Radiography showed a left lower lobe tumour (asterisk) with multiple enlarged mediastinal lymph nodes
(arrows). (B) On CT the superior caval vein and the trachea were compressed (arrow), multiple lymph nodes were
enlarged in the para-aortic (asterisk) and both paratracheal zones (arrowheads), and (C) left adrenal metastasis
could be seen (asterisk). (D) MRI showed diuse vertebral metastases with medullar compression at the level of
T9T10 (arrowhead). After two cycles of etoposide and cisplatin a partial response was seen (E) on radiography and
(F) on CT, with shrinkage of 20% in the primary tumour and reduction in size of the mediastinal lymph nodes.
without accompanying clinical paraneoplastic syndrome,

have been found in 16% of neurologically asymptomatic
patients with SCLC.30
Staging and prognosis

The aggressive early locoregional and distant spread of
SCLC led the Veterans Administration Lung Study
1744
Group, in 1957, to create a dichotomised staging system:

limited stage was characterised by a tumour volume
encompassed in one radiation portal; all other disease
spread was classied as extensive stage.31 50 years later,
the International Association for the Study of Lung
Cancer recommended that the TNM classication
system should be used for SCLC as well as for NSCLC.32
This recommendation was based on a retrospective
analysis of data from 8000 patients with SCLC, which
showed signicantly worse survival for patients with
limited-stage disease and mediastinal lymph node
involvement (TNM stage III) than for those with no
lymph node involvement (stage I) or with N1 lymph
node involvement (stage II).33 Intermediate prognosis
was assigned to patients with pleural eusion, between
that for patients in stage III and those with
haematogenous spread (stage IV). Thus, patients with
cytologically negative eusions are now classied as
having stage III disease. Although its simplicity makes
the Veterans Administration Lung Study Group
classication attractive for use in routine practice,
clinicians and cancer registrars are nevertheless strongly
encouraged to use TNM staging. This classication can
be easily converted to limited stage (TNM stages IIII)
and extensive stage (TNM stage IV).
Prognosis in SCLC is poor. Median survival without
treatment has been reported as 24 months.34 The most
reproducible prognostic factor is disease extent,
although a few other prognostic factors have been
identied: performance status, sex, and some routine
laboratory tests show some merit.3540 No histological or
molecular features are prognostically useful.41 Several
algorithms have been validated for predicting survival
(table 2).3540 The individual value of these tools, however,
remains poor.42 Paraneoplastic syndromes are more
frequently seen in patients with limited-stage SCLC
than in those with extensive-stage disease, but their
presence is not unequivocally prognostically favourable
(table 1).23,24,26,27
As disease extent is the major prognostic factor, staging
aims to identify whether the tumour has metastasised
(gure 2). The number and sequence of staging tests
should be guided by the patients signs and symptoms at
presentation, the most likely sites of metastatic
involvement at diagnosis, and the availability and
accuracy of the diagnostic tests. Around two-thirds of
patients present with clinically obvious metastatic
disease, although unequivocal proof can be challenging.
Even in patients whose history and clinical examination
suggest that disease is limited to the hemithorax, a full
assessment should be planned because identication of
occult dissemination spares patients from unnecessary
chest radiotherapy.
In view of the rapid growth of SCLC tumours, staging
should be done quickly and include at least full history,
physical examination, chest radiography, complete blood
count (including dierential counts), liver and renal
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function tests, assay of lactate dehydrogenase and sodium

concentrations, and contrast-enhanced CT of the chest
and upper abdomen. Bone scintigraphy is optional. CT
or MRI of the brain with intravenous contrast are
recommended in patients being considered for chemoradiation with curative intent,43 or are mandatory44,45 to
exclude asymptomatic brain metastases. In one series,
the prevalence of brain metastases was 10% with CT and
24% with MRI.46 All CT-detected brain metastases were
symptomatic, whereas 11% of those detected by MRI
were asymptomatic. Bone-marrow inltration should be
suspected if an isolated rise in lactate dehydrogenase
concentration or blood counts indicating otherwise
unexplained anaemia or a leucoerythroblastic response
are seen.
Once metastatic spread is detected by one test, further
staging can be omitted in the absence of symptoms that
require intervention. Routine use of pulmonary function
tests is not necessary, other than to exclude or assess
comorbid pulmonary disease.47 Use of combined
uorodeoxyglucose PET (FDG-PET) and CT notably
improves the accuracy of staging in NSCLC by the
detection of mediastinal nodal and occult metastatic
spread, but its routine use in SCLC remains
controversial. PET is, however, being used for fast-track
diagnosis or to plan radiotherapy in some countries.
Evidence that it changes the planning target volume is
limited,48 and wider implementation will probably
increase the proportion of patients who are identied as
having metastatic patients, which could improve stagespecic survival because of stage migration.49 Most
chemoradiation trials were done, however, before PET
was available.
Management
Early treatments for SCLC were nitrogen mustard,50
surgery (which was rst used in 1948), radical
radiotherapy,51 and cyclophosphamide; treatment with
cyclophosphamide signicantly favoured survival.52 In the
mid-1970s, the possibility of cure seemed feasible as new
drugs were developed and combination chemotherapy
became possible and led to better results than did singleagent treatments.53 Although no cure has emerged,
combined chemotherapy remains the cornerstone for all
stages of SCLC.54 Median survival for patients with
limited-stage disease is currently 1520 months,
with 2040% surviving to 2 years, and for those with
extensive-stage disease the values are 813 months and
5%, respectively.55 Since the mid-1980s, increases in
survival have slowed56 although stage migration, platinumbased chemotherapy, and radiotherapy have all exerted
benecial eects. A simplied treatment algorithm of
SCLC is given in gure 3.
Identication of the best drug combinations and
scheduling have been the focus of much investigation for
the past 30 years. Anthracycline-based treatment in
combination with cyclophosphamide and vincristine
Clinical TNM stage
I (very limited)
Resection
Adjuvant chemotherapy
Prophylactic cranial irradiation?
IIIII (limited)
IV (extensive)
Fit for concurrent chemoradiotherapy?
Fit for chemotherapy?
Yes
No
Yes
Concurrent
chemoradiotherapy
Sequential
chemoradiotherapy
Supportive care+
palliative chemotherapy
Prophylactic cranial
irradiation*
irradiation*
irradiation*
No
Supportive care
palliative radiotherapy
Figure 3: Simplied algorithm for the management of SCLC

SCLC=small-cell lung cancer. *If not progressive after induction treatment
became standard therapy during the 1970s,57 followed by

etoposide-containing regimens,58 Cisplatin-based regimens became rst-line treatment in the 1980s.59,60
Extensive-stage disease
SCLC is very chemosensitive and, therefore, chemotherapy can produce rapid responses with sometimes
striking improvements in symptoms and outcomes.
First-line treatment is also useful in patients with poor
performance status,61 by contrast with the situation in
NSCLC, albeit at the risk of serious toxic eects.
The rst-line treatment of choice in extensive-stage
SCLC remains four to six cycles of etoposide combined
with a platinum salt (cisplatin or carboplatin). In two
meta-analyses such a combination was better than other
combined treatments,62,63 although a third analysis did
not support the ndings (table 3).64 Dierences in design
probably explain the discrepancy. All three analyses
included patients with extensive-stage and limited-stage
disease, but one did not include trials involving any
regimen containing carboplatin,62 and in another the
study regimens had to include etoposide, cisplatin, or
both, and the same drug or drugs had to be omitted from
the control groups.63 The third meta-analysis included
trials comparing any platinum agent at any dose or for
any number of cycles compared with any other
chemotherapy regimen.64 The substitution of cisplatin
by carboplatin to avoid the side-eects of cisplatin is
unlikely, however, to have contributed to the discrepancy
between the meta-analyses because survival was not
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Regimens
Number of
Response
trials/patients
Outcome
Toxic eects
Pujol et al62
Etoposide and
cisplatin vs nonplatinum-basedchemotherapy*
19/4054
Increased response rate with

cisplatin (OR 135, 95% CI 118155;
p<1105)
Reduced risk of death at

1 year (OR 080 [95% CI
069093], p<0002)
No dierence in mortality
related to toxic eects
Mascaux et al63
Etoposide,
cisplatin, or both
vs one or neither
drug
36/7173
NR
Survival benet in favour of

etoposide alone or in
combination with cisplatin
NR
Amarasena et al64
Platinum-based 29/5530
vs non-platinumbased
Signicantly higher rate of complete

response with platinum-based
regimen, no signicant dierence in
overall tumour response
No signicant dierence in
survival at 6, 12, and
24 months; risk ratios
numerically favour
platinum-based regimens
Signicantly higher rates of

nausea, vomiting, anaemia,
and thrombocytopenia with
platinum-based regimen
SCLC=small-cell lung cancer. OR=odds ratio. NR=not reported. *Etoposide was administered in some comparison groups.
Table 3: Meta-analyses of platinum-based compared with non-platinum-based chemotherapy in SCLC
altered, even with the use of split doses of both drugs in

elderly patients or those with poor outlook.65 Many
clinicians already deem carboplatin to be an acceptable
palliative option for extensive-stage SCLC when the
tolerability of full-dose etoposide with cisplatin is of
concern.43 In one review toxic eects were increased with
regimens containing platinum,64 although the eects on
quality of life could not be assessed because of a lack of
data. Major dierences in quality-of-life outcomes
between an anthracycline and platinum-based regimen
are, however, not expected, and use of modern
antiemetics and growth factor transfusions will probably
be able to counteract these toxic eects. Large
comparative studies of quality of life are, therefore,
unlikely to be done in the near future.
In a pooled meta-analysis of six trials involving
1476 previously untreated Asian and white patients with
extensive-stage SCLC, irinotecan and platinum
combination regimens were associated with higher
response rates and better overall survival than was
etoposide and cisplatin.66 The irinotecan-containing
regimens led to less severe anaemia, neutropenia, and
thrombocytopenia but more severe vomiting and
diarrhoea than those containing etoposide and cisplatin;
treatment-related mortality was similar. Whether the
results of this meta-analysis apply to white patients is
debatable, as rates of toxic eects and death have been
lower in Asian than in European or US trials.6770
Dierences between Japanese and white patients in the
frequency of variant alleles that encode topoisomerase I
enzymes, which are involved in DNA repair and aect
irinotecan metabolism, might explain this discrepancy.71
Amrubicin is a synthetic anthracycline that inhibits
topoisomerase I and has shown promising rst-line
activity when used alone or in combination with
platinum,72 and might provide an alternative to irinotecan.
Thus, in patients with extensive-stage SCLC who are
otherwise t, four to six cycles of etoposide and cisplatin
(in non-Asian patients) or irinotecan and cisplatin (in
1746
Asian patients) should result in a complete response rate

of more than 20% and keep treatment-related mortality
below 5%.
Strategies that have alternated non-cross-resistant drugs
and increased total dose, dose intensity, number of courses,
or number of drugs have been unsuccessful. These
approaches are not recommended outside clinical trials.73
Preliminary evidence suggests that adding thoracic
radiotherapy to chemotherapy improves survival in
patients with extensive-stage SCLC who have a complete
response outside the thorax and at least a partial response
within the thorax after three cycles of etoposide and
cisplatin.74 This nding, however, was from a singlecentre trial, and the results of a larger, multicentre Dutch
randomised trial (CREST) and a US trial (NCT01055197)
are awaited.
Immediate whole-brain radiotherapy is indicated in
patients with brain metastases and intracranial
hypertension, pending lock-in syndrome, or other
neurological emergencies. In some series in patients
with SCLC and NSCLC and brain metastases wholebrain radiotherapy combined with dierent chemotherapy regimens seemed to increase the risk of
neurological toxic eects, but also to increase response
rates and lengthen the time to progression of brain
metastasis.7578 This increase in toxic eects was probably
related to the use of anthracyclines and high doses of
radiation per fraction. On the basis of this evidence
whole-brain radiotherapy should be started after the
completion of chemotherapy in patients with brain
metastases, with or without symptoms, but not delivered
concomitantly with cytotoxic treatment.
Limited-stage disease
Although SCLC is deemed a systemic disease, local
treatments might have a role in certain patients with
limited-stage disease. Immediate surgery should be
considered for individuals who have biopsy-proven
T1N0M0 tumours, but only after node negativity has been
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conrmed by endoscopic ultrasonographic or mediastinoscopic staging. These patients typically present with
a pulmonary nodule, the nature of which can only be
ascertained after resection. The role of postinduction
surgery has never been greatly explored because most
patients with non-metastatic SCLC present with
unresectable stage III tumours. Two phase 3 trials of
surgery alone or in combination with chest radiotherapy
showed no survival advantage compared with radiotherapy alone.51,79 A review of the data from these studies,
however, suggests that the usefulness of surgery was
underestimated because resection was not complete in all
patients assigned surgery.51,79 Retrospective reports suggest
that surgery led to good local control and favourable
long-term survival in highly selected patients with
stage IIII SCLC.80,81 A formal randomised trial, however,
has never started.82 Adjuvant chemotherapy is recommended in patients who undergo surgery, followed by
prophylactic cranial irradiation. This approach yields
5-year survival rates up to 57%.41
Meta-analyses indicate that chemotherapy combined
with chest irradiation improves survival.83,84 An improvement of around 54% in the absolute survival at 3 years
was observed in patients who received chest radiotherapy
after induction chemotherapy, compared with that in
patients receiving chemotherapy alone. The 5-year
survival rate, however, remained disappointingly low at
1015%. Among chemotherapy regimens some had
better eects than others. For instance, survival was
signicantly better in patients who received etoposide
and cisplatin than among those given a cyclophosphamide,
etoposide, and vincristine regimen.60 In a small,
randomised study, chest radiotherapy plus cisplatin
instead of carboplatin, alone and in combination with
etoposide, resulted in similar survival.85 New drugs added
to etoposide and cisplatin or tested as new regimens have
not improved outcomes.8690
Data on the optimum radiotherapy dose and
fractionation come mostly from retrospective and
phase 2 prospective studies. The results from nonrandomised studies of patients receiving sequential or
alternating schedules of chemotherapy and radiotherapy
indicate a notable increase in local control when the dose
is increased from 35 to 40 Gy and a possible slight further
gain with 50 Gy.91 Whether dose escalation to higher than
4550 Gy is benecial in patients receiving concurrent
chemotherapy and radiotherapy, however, is unclear.
The current standard regimen of a 45 Gy dose
administered in 15 Gy fractions twice daily for 30 days
is being compared with higher-dose regimens in two
phase 3 trials, one in the USA (NCT00433563) and one
in Europe (NCT00632853).
The denition of the target volumes is important to
keep irradiation of normal tissues and side-eects to a
minimum. In NSCLC, elective irradiation of the
mediastinum has gradually been replaced by treatment
limited to mediastinal nodes identied by CT or
FDG-PET as being involved. Little evidence to support

this approach in SCLC is, however, available. In a
prospective study in which only CT-positive mediastinal
lymph nodes in patients with limited-stage SCLC were
included in the target volume, the isolated recurrence
rate was 11%, which was higher than expected.92
Irradiation of only nodes positive on FDG-PET was
tested in a phase 2 study.48 Among 60 patients isolated
nodal failures were seen in only two (3%). Conrmation
of this nding is awaited. Elective nodal irradiation,
therefore, remains the recommended approach outside
clinical studies.
Many phase 3 studies have been done to investigate the
optimum timing of chest irradiation.93,94 At 5 years,
survival was signicantly higher when chest radiotherapy
was given within 30 days of starting platinum-based
chemotherapy than when it was started after 30 days
(20% vs 14%). In a pivotal phase 3 study, shortening the
duration of radiotherapy also increased survival: 45 Gy
administered in 18 Gy fractions once daily in
25 treatments over 5 weeks yielded 16% survival,
compared with 26% after 15 Gy fractions twice daily for
3 weeks.95 All patients received concurrent etoposide and
cisplatin. Grade 3 acute esophagitis was reported in
56 (27%) of 211 patients who received accelerated
radiotherapy and in 22 (11%) of 206 who received nonaccelerated radiotherapy. In this trial, elective mediastinal
radiotherapy was used. Importantly, toxic eects to the
lungs did not dier between groups. A time interaction
was suspected between chest irradiation and
chemotherapy and, therefore, accelerated repopulation
was postulated to be triggered by the rst dose of any
eective cytotoxic agent.96 Thus, to obtain local tumour
control, the last tumour clonogen should be killed by the
end of radiotherapy. Long-term survival, therefore,
decreases with increasing time between the start of any
treatment to the end of radiotherapy (gure 4). A metaanalysis showed better long-term survival if time from
the start to the end of radiotherapy was shorter than
30 days.96 These results are consistent with the hypothesis
that accelerated proliferation of tumour clonal cells is
triggered by radiotherapy, chemotherapy, or both.
In summary, for limited-stage SCLC, current evidence
supports early administration of 45 Gy with concurrent
etoposide and cisplatin at systemic doses. If for reasons of
tness or availability this regimen cannot be oered, chest
radiotherapy should follow induction chemotherapy.
Prophylactic cranial irradiation

The response rate and a median survival after wholebrain radiotherapy in SCLC patients with recurrence in
the brain alone are 50% and 45 months, respectively.97
Several randomised studies have been done, therefore,
to investigate the usefulness of prophylactic cranial
irradiation against microscopic brain involvement in
limited-stage disease. Prophylactic cranial irradiation
could indeed kill small tumour deposits with low
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40
35
5-year survival (%)
30
25
20
15
10
5
20
40
60
80
100
120
Duration of treatment (days)
140
160
180
Figure 4: Survival at 5 years as a function of the time from the start of any treatment to the end of radiotherapy
Each dot represents one trial with and error bars show SE. Reproduced from reference 96 by permission of the
American Society of Clinical Oncology.
radiation doses, thus resulting in increased long-term

survival if all extracranial cancer is controlled. In an
update of a meta-analysis of studies involving patients in
radiographically conrmed remission, the addition of
prophylactic cranial irradiation was signicantly associated with higher 3-year survival than no cranial
irradiation (21% vs 15%, p=001).98 Furthermore, diseasefree survival was higher and cumulative incidence of
subsequent brain metastases was lower for patients who
received prophylactic cranial irradation. A signicant
trend was seen for eect on prevention of brain
metastases, which seemed to increase with decreasing
time between induction therapy and irradiation, although
the relative risk of death was not altered.
Radiological assessment of response after radiotherapy
is notoriously inaccurate because changes cannot be
distinguished from active tumour.91 In current phase 3
trials, therefore, patients without progressive disease
are being oered prophylactic cranial irradiation
(NCT00433453 and NCT00632853). After this metaanalysis a 25 Gy dose delivered in 25 Gy fractions once
daily for 10 days became standard. In a large phase 3 trial,
patients with limited-stage SCLC in remission after
induction chemotherapy were randomly assigned this
standard or a higher radiation dose of 36 Gy.99 No survival
benet was seen with the higher dose and the risk of
neurotoxic eects was increased.100 On the basis of these
results, this standard regimen remains recommended.
In patients with extensive-stage (stage IV) SCLC,
symptomatic brain metastases occur in up to 50% and,
therefore, the use of prophylactic cranial irradiation
seems justied. In a phase 3 trial, patients who received
prophylactic cranial irradiation had a lower risk of
symptomatic brain metastases at 1 year than did controls
(15% vs 41%) and 1-year survival was almost twice as
high (27% vs 13%).101
1748
Little investigation has been done into the neurotoxic

eects of prophylactic cranial irradiation.102104 Neurocognitive testing before irradiation has shown impaired
cognitive function in 47% of patients.102104 Some transient
and early decline is seen in executive function and
language performance after prophylactic cranial
irradiation.102104 Large daily fractions and concomitant
chemotherapy should be avoided. Furthermore,
competing risk factors for neurocognitive decline
(eg, mental stress, paraneoplastic syndromes, smallvessel CNS thrombosis, and age-related predisposition)
should be carefully assessed before administration.105
Overall, prophylactic cranial irradiation should be
planned for all patients with SCLC but no comorbidities
and with no disease progression after induction therapy.
Caution should be exercised when treating patients with
severe medical comorbidities, poor performance status,
or impaired neurocognitive function.
Relapsing and refractory disease

Despite high initial response rates, relapse is frequent
after combined etoposide and cisplatin, probably because
of rapid selection of a small number of residual tumourinsensitive cells or stem cells.96 Patients are classied as
having relapsed if disease returns after treatment. Patients
are classied as being sensitive to treatment if recurrence
is seen 90 days or more after the end of rst-line treatment,
or resistant if disease recurs within 90 days. If disease
progresses during rst-line treatment, SCLC is classied
as refractory (gure 5). Only sensitive patients benet
from rechallenge with rst-line treatment.
Second-line treatment is an option in only a few
patients, owing to rapid disease progression and poor
performance status. When used, the response rate is low
and, although a signicant benet is seen, the duration
of survival is only a few months longer than best
supportive care.106 Third-line treatment for SCLC is very
rarely used.
Topotecan is currently the only approved drug for the
treatment of patients with SCLC who relapse after rstline chemotherapy.107,108 Administration of 15 mg/m in
30 min infusions given daily for 5 days in cycles with
21 day intervals leads to outcomes similar to those
achieved with a cyclophosphamide, doxorubicin, and
vincristine regimen after rst-line treatment with
etoposide and cisplatin.109
Owing to the frequency of relapse, several new drugs
have been assessed, including anthracyclines, camptothecins, antifolates, and taxanes.73,110 A randomised,
phase 2 trial of amrubicin compared with topotecan
indicated ecacy of amrubicin in sensitive and resistant
patients.111 This drug is being assessed further in trials in
rst-line and second-line regimens (NCT00547651,
NCT00388960, NCT00660504).
The ecacy of picoplatin, a platinum compound
designed to overcome platinum resistance and toxic
eects, is being investigated.112,113
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Non-tumour treatment targets

Several targeted therapies have been assessed in SCLC,
but, unlike for advanced-stage NSCLC, none has made
their way into daily practice.73,110,114 Various small-molecule
inhibitors of dierent receptor tyrosine kinases
(eg, EGFR, c-Kit, and VEGFR) have been studied in
phase 2 trials, with or without chemotherapy, but did not
show the expected activity, probably because patients
were not selected according to target expression. Two
large, randomised, phase 3 trials showed no signicant
benets from adding thalidomide, a broadly targeted,
antiangiogenic agent, to standard chemotherapy.
Similarly, the addition of two dierent matrix metalloproteinase inhibitors to standard chemotherapy did not
improve survival and adversely aected quality of life. A
vaccine against the ganglioside family of antigens on the
SCLC surface has shown no benet.
Results with systemic treatments and therapies used to
treat the symptoms of paraneoplastic syndromes have
varied (table 1). Endocrine and dermatological abnormalities
have often resolved, but neurological symptoms have
generally remained refractory. Changes in concentrations
of biochemical markers or antibodies can precede relapse.
Treatment with anticoagulants has been proposed for
cancer owing to an antitumour eect. In a meta-analysis
warfarin has been associated with lower mortality at
6 months in SCLC, particularly in patients with extensivestage disease, but the risk of major and minor bleeding
was increased and the advantage was not sustained at
1 year.115 Heparin was associated with a survival benet in
cancer patients in general, and in particular in patients
with limited-stage SCLC, but not in those with extensivestage disease.116 Randomised trials to investigate the use
of low-molecular-weight heparins in SCLC are currently
recruiting patients in Sweden (NCT00717938) and the
UK (NCT00519805).
In preclinical studies, simvastatin suppressed tumour
growth, induced apoptosis of SCLC cells, and increased
tumour sensitivity to etoposide.117 Pravastatin might stop
the growth of tumour cells by blocking some of the
enzymes needed for cell growth and increasing tumour
cells sensitivity to chemotherapy.118 A randomised,
controlled, phase 3 trial to investigate the addition of
pravastatin to standard rst-line treatment in SCLC is
currently accruing in the UK (NCT00433498).
Smoking cessation
Smoking cessation should be an integral part of the
management of patients with SCLC. Patients who cannot
quit alone should be referred for specialist help, such as
in smoking clinics.119 Tobacco smoke exacerbates oral
mucositis and leads to loss of taste, xerostomia, weight
loss, and fatigue.120 Patients with lung cancer who stop
smoking report decreases in fatigue and dyspnoea, and
improvements in activity level, sleep, and mood.121
Smoking during radiotherapy has been associated in
some studies with an increase in the probability of
Progression
During rst-line therapy

Refractory
Consider palliative radiotherapy or clinical trial
<90 days after end of rst-line therapy
>90 days after end of rst-line therapy
Resistant
Sensitive
Topotecan or CAV or clinical trial
Rechallenge with rst-line chemotherapy regimen
Figure 5: Simplied algorithm for the management of relapsing SCLC

SCLC=small-cell lung cancer. CAV= cyclophosphamide, doxorubicin, and vincristine.
radiation pneumonitis,122 but not in others.123 Finally,

continuing or relapsing smokers are at increased risk of
second primary tumours124 and prognosis is poorer than
that in patients who stop smoking altogether.125
Novel biological targets

Evasion of apoptosis is a hallmark of cancer and is a
major factor underlying drug resistance in SCLC. The
mechanisms are complex and incompletely understood,
but, similarly to other cancers, SCLC cells seem to
suppress apoptosis by at least three mechanisms:
increase in stimulation of antiapoptopic pathways via
extracellular signals, desensitisation of the intrinsic cell
death machinery via addiction to antiapoptosis proteins,
and mutational burden leading to the loss of
proapoptotic tumour suppressors. These mechanisms
might oer targets for new treatments. Insights into
genetics might also lead to the discovery of treatment
biomarkers and targets.
SCLC cells are surrounded by an extensive extracellular
matrix that includes collagen IV, tenascin, bronectin,
and laminin (gure 6). High expression of these
components is associated with a poor prognosis.
Adhesion of SCLC cells to the extracellular matrix
requires 1-integrins and results in suppression of
chemotherapy-induced apoptosis by stimulation of
PI3K.126 The cell cycle arrest and apoptosis normally
induced by etoposide is, therefore, prevented.
Several growth factors have been implicated as
mediators of autocrine signalling in SCLC, including
growth hormone releasing hormone,127 insulin like
growth factor I (IGF-I),128 bombesin,129 hepatocyte growth
factor,130 and broblast growth factor 2 (FGF2).131
Inhibitors of several of these growth factor pathways are
in clinical development (NCT00896752). For example,
FGF2 drives the proliferation of SCLC cells, and confers
resistance to etoposide in vitro by upregulation of
1749
Seminar
ECM
B1
integrin
FAK
HGF
IGF
c-Met
IGFR
GHRH
FGF2
c-Met
inhibitors
SHh
PD173074
PI3K
IGFR
inhibitors
PKC
RAF
Itraconazole
SHh inhibitors
S6K2
AKT
BAD
Patched
GHRHR FGF1/2R
ABT-263
obatoclax
MEK
Apoptosis
BCl-2/BclxL BAX/BAK
Mcl-1
Nucleus
Tumour
suppressor
Oncogene
DNA loss 3p (1423)
FHIT
Mitochondria
Figure 6: Suppression of apoptosis in SCLC cells and interaction with targeted agents
SCLC cells can suppress apoptosis by increase in stimulation of antiapoptopic pathways via extracellular signals, by
desensitisation of the intrinsic cell death machinery via addiction to antiapoptosis proteins, and by mutational
burden in genes capable of inducing apoptosis, leading to the loss of proapoptotic tumour suppressors. The pink
boxes indicate where investigational targeted agents interact with the the relevant pathways. SCLC=small-cell lung
cancer. ECM=extracellular matrix. SHh: sonic hedgehog homologue.
antiapoptotic proteins (Bcl-XL, Bcl-2, and X-linked IAP)

and suppression of the proapoptotic protein BAD. This
activity depends on the mitogen-activated protein kinase
pathway in a regulatory protein complex comprising
RAF, protein kinase C type, and S6K.132 Inhibition of
FGF2 signalling by the compound PD173074 impairs
SCLC proliferation and chemoresistance, and induces
apoptosis in vitro and in vivo. Clinical evaluation of FGF2
inhibitors, therefore, seems warranted.133 Monoclonal
antibodies against IGF-I and hepatocyte growth factor
are in clinical development (NCT00940225).
SCLC cells activate the hedgehog signalling pathway,
which is involved in embryonic development of the
airway epithelium by regulation of morphogenesis and
stem-cell fate. In SCLC the hedgehog pathway is
abnormal. Activation of the pathway is required to
sustain SCLC cells in vitro and in vivo.134 Mutations of
the pathway receptor, however, have not been associated
with SCLC. Itraconazole inhibits the hedgehog pathway,
by a mechanism distinct from those used by prototype
compounds, such as cyclopamine,135 and might, therefore, become a useful treatment for SCLC tumours that
show dependence on hedgehog signalling.
Targeting of the mitochondrial apoptosis pathway is
currently being explored as a therapeutic strategy for
SCLC. The Bcl-2 family proteins are crucial regulators of
apoptosis and have proapoptotic and antiapoptotic roles.
The antiapoptotic protein Bcl-2 is overexpressed in SCLC
cell lines and primary tissue136138 and inhibits the
proapoptotic proteins BAX and BAK. These two proteins
1750
initiate apoptosis by forming pores in the outer

membrane of mitochondria, which leads to the release of
other proapoptotic factors, and thereby to activation of
caspase enzymes. Activation of BAX requires interaction
with other proteins in the Bcl-2 family, such as BID, that
harbour the Bcl-2 homology domain BH3, either directly
or by the release of bound proapoptotic members (eg,
BAD). BAD blocks the antiapoptotic actions of Bcl-2,
Bcl-XL, and Bcl-W.
Study of the interaction between the BAD BH3 domain
and Bcl-XL has led to the discovery of a highly potent
small-molecule BAD mimetic called ABT-737 (oral
formulation ABT-263). This agent is currently being
tested in patients with SCLC (NCT00445198).139 Although
SCLC cell lines have been sensitive to ABT-737 in
preclinical studies, resistance to this agent is conferred
by expression of the prosurvival Bcl-2 family member
Mcl-1.140 Studies of SCLC cell lines and primary xenograft
models established with samples from patients with
SCLC suggest that resistance also arises via other
mechanisms, such as raised concentrations of
proapoptotic BAX, BIM, and NOXA, and reduced
concentrations of Mcl-1. A gene expression prole
associated with sensitivity indicates involvement of
multiple genes linked to apoptosis.141 Copy number gains
at 18q lead to increased expression of Bcl-2 and NOXA,
which correlates with sensitivity.142 These mechanisms of
resistance will probably be relevant to studies with
ABT-263 and other drug regimens that selectively target
Bcl-2, such as antisense oligonucleotides.143
Another Bcl-2 inhibitor, obatoclax, is in clinical
development as a treatment for SCLC (NCT00682981).
By contrast with ABT-737, obatoclax and another
compound AT-101 target all antiapoptopic members of
the Bcl-2 family, including Mcl-1 (NCT00773955).144 These
agents, but not ABT-737, however, exhibit toxic eects
independent of BAX and BAK.
High-throughput sequencing of SCLC samples, coupled
with clinical phenotyping, has the potential to reveal
information crucial to decyphering chemoresistance.
Such knowledge should help to focus development of
targeted treatments, especially for relapse. Several smallmolecule inhibitors of Src kinase, an enzyme involved in
cell migration and adhesion, are in development for
relapsing and refractory SCLC (NCT00528645).145,146
SCLC is also one of the most hypoxic tumours; more
than 60% of patients develop severe hypoxia.147 This
complication is associated with resistance to chemotherapy and radiotherapy and with a raised risk of
metastasis. Prevention of hypoxia tolerance has,
therefore, become of interest in SCLC.148 Methods
investigated include inhibition of hypoxia-induced
factor-1 and autophagy.149,150
The advent of next-generation DNA sequencing will
enable detailed interrogation of somatic gene alterations
and their roles in SCLC. The mutational range of an
SCLC cell line, H209, has been established with
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massively parallel sequencing technology and revealed

22 910 somatic mutations, of which 134 were in the
exome and revealed signatures of tobacco exposure.151
Specic gene rearrangement in CHD-7, a member of
the chromodomain helicase DNA binding domain
family of ATP-dependent chromatin remodelling
enzymes, has been reported.151 Comprehensive mapping
of other somatic mutations in SCLC might, therefore,
lead to identication of crucial gene networks involved
in tumorigenesis and reveal potential targets for therapeutic intervention.
The tailoring of therapy with novel agents to individual
patients needs will become the most benecial approach
to treatment of SCLC. In addition to new agents,
biomarkers of chemosensitivity will need to be identied
to ecaciously assess single agents for relapse after rstline therapy or as maintenance therapy in placebocontrolled, randomised designs.
Conclusions and additional issues

SCLC remains a frustrating disease to research and to
treat. In extensive-stage disease new drug combinations
and approaches have made little dierence to overall
survival. Improved survival remains the ultimate goal as,
unlike in other chemosensitive cancers, second-line
treatment is not an option for most patients.
Although most patients with limited-stage SCLC will
also succumb, long-term survival has been improved by
good integration of chemotherapy with early, accelerated
chest radiotherapy and prophylactic cranial irradiation. A
small but notable proportion of patients with SCLC
survive long term. After 2 years, the risk of death from
the initial disease begins to decrease.125 The risk of a
second primary cancer, however, is 210% per patient per
year, which is higher than in adult male smokers who
have never developed lung cancer. Patients should,
therefore, be monitored and refrain from smoking for
life.121 Any new lung mass should undergo biopsy and be
tested for early stage NSCLC.152
Etoposide and cisplatin remain the mainstays of rstline SCLC treatment. Although the decreasing
prevalence of smoking in industrialised countries will
be associated with decreasing incidence of SCLC, the
burden of disease is shifting to developing countries.
Further investment in research for this disease is,
therefore, warranted. Many phase 1 and 2 studies of
drugs with potential activity in SCLC and phase 2 and 3
trials to improve radiotherapy are underway. Inclusion
of patients with SCLC in such trials should be
encouraged, especially otherwise healthy patients with
relapsing or refractory SCLC, for whom treatment
options are limited. A new, eective, and active
combination for extensive-stage SCLC would be quickly
moved up as a treatment priority.
Contributors
All authors were involved in the literature searches, writing, review,
and correction of drafts.
Conicts of interest
JvM has received money for consultancy from AstraZeneca, Amgen,
Pzer, Hospira, Eli Lilly, Sano-Aventis, and GlaxoSmithKline, and for
speaking from Eli Lilly, and his institution has received educational
grants from Eli Lilly. DAF has received money for consultancy from
Merck, Astellas, Genentech, Boehringer Ingelheim, AstraZeneca,
Amgen, and Daiichi Sankyo, and for speaking from Merck, Genentech,
and Roche. DDR declares that he has no conicts of interest.
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Seminar

Small-cell lung cancer

as NSCLC.3,8 An increase in incidence is expected in

Lancet 2011; 378: 174155

Cytogenetically, SCLC has several distinguishing

Search strategy and selection criteria

Figure 1: Microscopic features of SCLC

inactivation of tumour-suppressor genes.9 The

diagnosis, but good interobserver agreement has been

Main symptoms, signs, and ndings

Proportion of SCLC Proportion of patients

Weakness, dysgeusia, and clinical euvolaemia

Arginine vasopressin or atrial

Frequently normalises with

Poor owing to high rate of

Limbic encephalitis and

Personality and psychiatric changes, seizures,

Superior vena cava

50% of patients improve

Neurological symptoms not

Neurological symptoms not

Oedema of upper body

Obstruction of superior vena

Resolves rapidly with

SCLC=small-cell lung cancer.

Table 1: Paraneoplastic and other syndromes frequently associated with SCLC

Factors associated with improved outcomes

Normal baseline concentrations of LDH, sodium,

SWOG clinical trials

Age <70 years

Normal baseline concentration of LDH in serum

Normal baseline concentrations of LDH or alkaline

ELCWP clinical trials

Baseline neutrophil rate <75%

Performance score <1,

NCCTG clinical trials

Performance status <1,

Normal baseline creatinine concentration

Table 2: Prognostic factors in reported in SCLC database studies

syndrome. In one series, ve of 63 unselected SCLC

myasthenia gravis, which is not frequently associated

without accompanying clinical paraneoplastic syndrome,

Staging and prognosis

Group, in 1957, to create a dichotomised staging system:

function tests, assay of lactate dehydrogenase and sodium

Clinical TNM stage

Fit for concurrent chemoradiotherapy?

Fit for chemotherapy?

Figure 3: Simplied algorithm for the management of SCLC

became standard therapy during the 1970s,57 followed by

Increased response rate with

Reduced risk of death at

Survival benet in favour of

Signicantly higher rate of complete

Signicantly higher rates of

Table 3: Meta-analyses of platinum-based compared with non-platinum-based chemotherapy in SCLC

altered, even with the use of split doses of both drugs in

Asian patients) should result in a complete response rate