Radiotherapy and Oncology xxx (2014) xxx–xxx

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Radiotherapy and Oncology

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Original article

The importance of actual tumor growth rate on disease free survival

and overall survival in laryngeal squamous cell carcinoma
Liselotte W. van Bockel a,⇑, Gerda M. Verduijn b, Evelyn M. Monninkhof c, Frank A. Pameijer d,
Chris H.J. Terhaard a
a
University Medical Centre Utrecht, Department of Radiation Oncology; b Erasmus Medical Centre, Department of Radiation Oncology, Rotterdam; c University Medical Centre
Utrecht, Julius Center for Health Sciences and Primary Care; and d University Medical Centre Utrecht, Department of Radiology, The Netherlands

a r t i c l e i n f o a b s t r a c t

Article history: Background and purpose: Evaluation of the variation in tumor growth rate and the influence of tumor
Received 11 July 2012 growth rate on disease free survival (DFS) and overall survival (OS) in laryngeal squamous cell carcinoma
Received in revised form 30 May 2014 (LSCC).
Accepted 2 June 2014
Material and methods: We delineated tumor volume on a diagnostic and planning CT scan in 131 patients
Available online xxxx
with laryngeal squamous cell carcinoma and calculated the tumor growth rate. Primary endpoint was
DFS. Follow up data were collected retrospectively.
Keywords:
Results: A large variation in tumor growth rate was seen. When dichotomized with a cut-off point of
Growth rate
Doubling time
0.3 ln(cc/day), we found a significant association between high growth rate and worse DFS
Laryngeal carcinoma (p = 0.008) and OS (p = 0.013). After stepwise adjustment for potential confounders (age, differentiation
Outcome and tumor volume) this significant association persisted. However, after adjustment of N-stage associa-
DFS tion disappeared. Exploratory analyses suggested a strong association between N-stage and tumor
OS growth rate.
Conclusions: In laryngeal squamous cell carcinoma, there is a large variation in tumor growth rate. This
tumor growth rate seems to be an important factor in disease free survival and OS. This tumor growth
rate is independent of age, differentiation and tumor volume associated with DFS, but N-stage seems
to be a more important risk factor.
Ó 2014 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology xxx (2014) xxx–xxx

The incidence rate of laryngeal cancer in Europe is almost treatment delay is due to an increasing number of patients and lack
40,000 patients (International agency for research on cancer, of capacity in the past [6,7].
EUCAN, website). There are several prognostic factors for outcome Whether a tumor will proceed to a higher stage or a larger vol-
in patients with laryngeal carcinoma. For instance, it is commonly ume will depend on the tumor growth rate and the waiting time.
known that prognosis declines with more advanced tumor stage To determine this growth rate, a potential doubling time (Tpot),
(T-stage) [1–5]. When treatment is delayed, tumors may grow based on a BrdU-labeling index and the duration of the S-phase,
and proceed to a more advanced stage with formation of meta- has been used in previous studies. One study showed an associa-
static clones [5]. In the Netherlands, the preferred time between tion between Tpot and outcome [8]. However, several other studies
diagnosis and start of treatment is 30 days or less, as stated by could not find a correlation between Tpot and locoregional control
the Dutch Cooperative Head and Neck Group. Although recent or survival in head and neck cancers [2–4].
years have shown some improvement, these 30 days are often In two different retrospective studies concerning head and neck
not achieved. As seen in other countries, the unacceptable squamous cell carcinoma (SCC), growth rate was based on the
increase in tumor volume between a diagnostic and a planning
CT-scan. Within these studies, a wide variation in tumor growth
rate and a loss in tumor control probability, due to treatment delay,
⇑ Corresponding author. Address: University Medical Centre Utrecht, Department were found [9–11].
of Radiation Oncology, HP Q00.118, Postbus 85500, 3508 GA Utrecht, The
Based on this knowledge, we wanted to investigate if the same
Netherlands.
variation in tumor growth rate is present in a homogeneous group
E-mail addresses: l.w.vanbockel@umcutrecht.nl (L.W. van Bockel), g.verduijn@
erasmusmc.nl (G.M. Verduijn), e.monninkhof@umcutrecht.nl (E.M. Monninkhof), of patients with laryngeal carcinoma. Therefore, the aim of the
f.a.pameijer@umcutrecht.nl (F.A. Pameijer), c.h.j.terhaard@umcutrecht.nl study was to evaluate the variation in tumor growth rate and the
(C.H.J. Terhaard).

http://dx.doi.org/10.1016/j.radonc.2014.06.004
0167-8140/Ó 2014 Elsevier Ireland Ltd. All rights reserved.

Please cite this article in press as: van Bockel LW et al. The importance of actual tumor growth rate on disease free survival and overall survival in laryngeal
squamous cell carcinoma. Radiother Oncol (2014), http://dx.doi.org/10.1016/j.radonc.2014.06.004
2 Tumor growth rate in laryngeal SCC

influence of tumor growth rate on disease free survival (DFS) and the time of analysis. DFS was measured from the start of treatment
overall survival (OS) in laryngeal SCC. until an event occurred. Events were defined as a local or regional
recurrence or a distant metastasis.
Methods and materials

Statistical analysis
Patients
Descriptive statistics were used to characterize the study popu-
Between 1996 and 2009, 700 patients were treated for laryn-
lation and to describe growth rate.
geal SCC at the Radiation Oncology department of our hospital. For
Cox proportional hazard regression analysis was used to evalu-
this study, we included patients with laryngeal SCC and who were
ate the influence of tumor growth rate on DFS. We evaluated tumor
primarily treated with radiotherapy. Also a diagnostic (dCT) and
growth rate as both a continuous and a dichotomous parameter,
planning CT-scan (pCT) had to be available. Patients with a medical
with a threshold of 0.3 ln(cc/day) between fast and slow growth.
history of previous radiotherapy treatment in the head and neck
The considered factors for further analysis on DFS were: age, sex,
area were excluded. These criteria were met in 159 patients. Dur-
smoking, alcohol, location, differentiation, volume on diagnostic
ing analysis, 28 patients were excluded, because the tumor was not
CT scan, mobility of the vocal cord, T-stage and N-stage. Age and
visible on the CT-scan, partly due to artifacts. Therefore, 131
volume were analyzed as continuous variables. To obtain sufficient
patients were included in the final analysis. While the patients
data in the categories for the analyses, we combined poor, undiffer-
were treated with different treatment schedules, most patients
entiated and basaloid differentiation in one category and we also
received an accelerated radiotherapy schedule (92.4%).
combined micro-invasive and unknown differentiation in one
category. Four categories were used for N-stage: 0, 1, 2a–b, 2c–3.
Measurements: volume The T-stage parameter includes both stages T2a and T2b. This is
because two studies have shown that, for stage T2 laryngeal SCC,
Visible primary tumor mass (lymfnode volume excluded) was
the presence of impaired vocal cord mobility was associated with
delineated manually on the axial slices of the contrast-enhanced
worse ultimate local control (LC), when treated with a conven-
dCT and pCT. In the majority of the CT-scans, a single-slice
tional radiotherapy schedule. The studies suggested a division of
technique was used. Most dCT scans had a slice thickness of
stage T2 into stage T2a, with normal vocal cord mobility and stage
1.5–2 mm and most pCT scans a slice thickness of 2–3 mm (range
T2b, with impaired vocal cord mobility. Since LC of stage T2a laryn-
1–5 mm). CT-scans that showed severe motion artifacts at the level
geal carcinoma showed a comparable LC to stage T1 laryngeal SCC,
of the larynx were excluded. Delineation was performed by the
these two stages were combined in our analysis [13,14]. Further-
first author and consensus was reached with an experienced radi-
more, we investigated the primary location of the laryngeal
ation-oncologist (CHJT). In difficult cases, an experienced head and
tumors, supraglottic, glottic or subglottic.
neck radiologist (FAP) was consulted. Criteria for tumor involve-
In multivariate Cox regression analysis, we adjusted stepwise
ment were: abnormal contrast enhancement, soft tissue thicken-
for potential confounding and intermediate factors. The parame-
ing, presence of a mass lesion, infiltration of fatty tissue, or a
ters volume, mobility and T-stage are highly correlated. Therefore,
combination of these. Delineation on both scans was performed
we only adjusted for one of these parameters in the multivariate
using 3-D delineation software (in-house developed). This soft-
Cox regression analyses. First, the hazard ratio (HR) of tumor
ware package (VolumeTool) includes image quantification tools
growth rate was adjusted for age (continuous). Next, differentia-
such as volumetry and 3D visualization. The delineation package
tion (four categories) was added to the model. After this, volume
is based on a combined Java/C+ library and includes a (in-house
(continuous) was added. Finally, HR’s were adjusted for N-stage
developed) DICOM server for storing image data-sets as well as
(four categories).
delineated structures sets [12].
To explore the association between tumor growth rate and
N-stage, we used cross-tabulation. The statistical software SPSS
Growth and growth rate 16 was used for the analysis.

The interval (in days) between the two CT scans was recorded.
Tumor growth was based on the volume difference between the Results
diagnostic and planning CT-scans. Exponential growth was
assumed. Sixty-four glottic, sixty-six supraglottic and 1 subglottic laryn-
geal squamous cell carcinoma were analyzed. Table 1 gives an out-
Tumor growth rateðTGRÞ ¼ lnðVplan  VdiagnÞ=T
line of the patient characteristics for these 131 patients. There was
a significant difference between fast and slow growing tumors in
ðVdiagn ¼ tumor volume on dCT; Vplan location (v2 = 10.5 p = 0.005) and N-stage (v2 = 19.4 p = 0.002).
¼ tumor volume on pCT; T Location and N-stage are significantly associated (v2 = 20.7
¼ days between dCT and pCTÞ p = 0.024).
The follow-up time ranged from 1 to 149 months with a mean
follow-up of 50 months. These data were retrospectively and
partly prospectively collected.
Outcome
The mean time between the dCT- and pCTscans was 25.7 days
The primary objective in this study was disease free survival (SD 11.6). The mean tumor growth rate was 0.3 ln(cc/day) and,
(DFS). We chose DFS as our primary endpoint since we hypothe- therefore, this was used as cut-off point (Fig. 1).
sized that fast growing tumors will not only result in a larger vol- For 39 of the patients, 48 events took place. Of these 27 were
ume locally but also metastasize earlier to regional and distant local recurrences, 5 were regional recurrences and 16 were distant
locations. Follow-up data were collected retrospectively by chart metastases.
control. If the patients were lost to follow-up in the Radiation In crude Cox regression analysis (Table 2), no significant associ-
Oncology department, follow-up data were retrieved from other ation between tumor growth rate as a continuous parameter and
hospitals, general practitioners or municipal databases, up until LC, DFS and overall survival (OS) could be found. However, when

Please cite this article in press as: van Bockel LW et al. The importance of actual tumor growth rate on disease free survival and overall survival in laryngeal
squamous cell carcinoma. Radiother Oncol (2014), http://dx.doi.org/10.1016/j.radonc.2014.06.004
 L.W. van Bockel et al. / Radiotherapy and Oncology xxx (2014) xxx–xxx 3

Table 1
Patient characteristics.

N = 131 N N (%) Slow growth rate Fast growth rate

Gender Male 110 84 73 37
Female 21 16 10 11
Differentiation Well 6 4.6 4 2
Moderate 81 61.8 49 32
P/B/Ua 14 10.7 7 7
Microinvasive/unknown 30 22.9 23 7
Age Mean age at start of treatment 63 years (range 40–87 years) 65 years 60 years
Location Glottic 64 48.9 49 15
Supraglottic 66 50.4 34 32
Subglottic 1 0.7 0 1

T-stage (UICC TNM classification) 1 2 1.6 2 0

200 a00 37 28.2 27 10
200 b00 38 29.0 26 12
3 42 32.1 23 19
4 12 9.2 5 7
N-stage (UICC TNM classification) 0 104 79.4 75 29
1 8 6.1 1 7
2a 1 0.8 0 1
2b 7 5.3 3 4
2c 10 7.6 4 6
3 1 0.8 0 1
Mobility vocal cord Normal 49 37.4 35 14
Impaired 54 41.2 34 20
Immobile 28 21.4 14 14
Smokingb Ceased 25 19.1 20 5
0 5 3.8 5 0
1–15 sig/day 30 22.9 19 11
16–25 sig/day 46 35.1 27 19
>25 sig/day 25 19.1 12 13
a
P/B/U: poor, indifferent and basaloid.
b
Smoking ceased: smoking ceased more than 1 year before diagnosis.

dichotomized with a cut-off point of 0.3 ln(cc/day), we did find a (p = 0.002) showed a significant association with DFS. We further
significant association with DFS (HR 2.4; 95% Confidence Interval evaluated sex, age, location, smoking, alcohol and T-stage, but none
(CI) 1.3–4.4) and OS (HR 1.9; CI 1.2–3.2). of these showed a significant association. Mobility of the vocal cord
Fast growing tumors (n = 48) had a 5 year DFS and OS of 56% (p = 0.06) was borderline significantly associated. In OS analysis,
resp. 40% compared with 78% resp. 65% in slow growing tumors smoking and age were significantly associated, which was to be
(n = 83). expected, as patients who smoke and are older are more
For further analysis, we also adjusted for pre-treatment charac- vulnerable.
teristics in DFS analysis. In crude Cox regression analysis, differen- In the multivariate Cox regression analysis, adjustments were
tiation (p = 0.005), N-stage (p 6 0.001) and primary tumor volume made step-wise for the selected potential confounder (age) and
intermediate factors (differentiation, location, primary tumor vol-
ume and N-stage) (Table 3). We also performed the multivariate
analysis with mobility of the vocal cord or T-stage, instead of
volume, which did not affect the results.
When we performed the analysis with the 121 patients who
received accelerated radiotherapy, the conclusions did not change.
Adjusted for age, growth rate showed a positive association
with DFS (HR 2.2 CI 1.2–4.3), i.e. tumors with a fast growth rate
had a worse DFS. Further adjustment for differentiation did not
affect this association (model 2). Adding differentiation and diag-
nostic tumor volume in model 3, hardly weakened the association
between growth rate and DFS and was still significant.
However, the effect of tumor growth rate on DFS disappeared
after further adjustment for N-stage in model 4. We repeated the
analysis for a patient group with an N0 stage at diagnosis, but no
significant associations were seen.
When further exploring the association between tumor growth
rate and N-stage, a significant association was found (v2 6 0.000)
(Table 4). Of the slow growing tumors, 90% of patients had an N0
stage at time of diagnosis and 10% had an N+ stage. Of the fast
growing tumors, 60% of the tumors had an N0-stage and 40% had
Fig. 1. Distribution of tumor growth rate. an N+-stage.

Please cite this article in press as: van Bockel LW et al. The importance of actual tumor growth rate on disease free survival and overall survival in laryngeal
squamous cell carcinoma. Radiother Oncol (2014), http://dx.doi.org/10.1016/j.radonc.2014.06.004
4 Tumor growth rate in laryngeal SCC

Table 2
Results of different univariate Cox regression analyses on DFS and OS for the main determinant and several potential confounding factors.

Crude analysis DFS OS

p-Value HR CI p-Value HR CI
Continuous variables
Tumor growth rate 0.465 1.33 0.62–2.85 0.997 1.00 0.58–1.72
Age 0.217 0.007
Tumor volume 0.002 0.018
Alcohol 0.333 0.544
Dichotomous variables
Tumor growth rate 0.008 2.35 1.25–4.42 0.013 1.93 1.15–3.24
Differentiation 0.005 0.015
Location 0.318 0.061
Smoking 0.549 0.022
T-stage 0.143 0.589
N-stage <0.001 <0.001
Mobility of vocal cord 0.063 0.368

HR: hazard ratio. 95% CI: 95% confidence interval.

Table 3
Results of the different multivariate Cox regressions models on DFS and OS.

Disease free survival Overall survival

HR 95% CI p-Value HR 95% CI p-Value
Model 1
Growth rate 2.24 1.17–4.28 0.015 2.37 1.39–4.03 0.001
Age 0.503 0.001
Model 2
Growth rate 2.47 1.25–4.89 0.009 2.47 1.42–4.29 0.001
Age 0.824 0.000
Differentiation 0.005 0.004
Model 3
Growth rate 2.45 1.21–4.97 0.013 2.39 1.35–4.23 0.003
Age 1.0 0.97–1.03 0.876 0.000
Differentiation 0.009 0.009
Location 0.969 0.416
Model 4
Growth rate 2.27 1.11–4.65 0.025 2.25 1.26–4.03 0.006
Age 0.810 0.000
Differentiation 0.028 0.032
Location 0.991 0.377
Diagnostic tumor volume 0.160 0.370
Model 5
Growth rate 1.59 0.74–3.39 0.233 1.55 0.81–2.97 0.184
Age 0.946 0.000
Differentiation 0.039 0.040
Location 0.622 0.081
Diagnostic tumor volume 0.702 0.385
N-stage 0.000 0.000

HR: hazard ratio. 95% CI: 95% confidence interval.

Table 4 diagnostic CT scan with a planning CT scan and noting the time
The association between tumor growth rate and N-stage.
interval in days between the two. The results revealed a large var-
N-stage iation in actual tumor growth rate over the total patient group.
0 1 2a + b 2c + 3 Total Independent of age, differentiation and volume, the tumor growth
Tumor growth rate Slow 75 1 3 4 83
rate was significantly associated with DFS and OS. However, after
90.4% 1.2% 3.6% 4.8% adjustment of N-stage the association between tumor growth rate
Fast 29 7 5 7 48 and DFS diminished and lost significance. This might be explained
60.4% 14.6% 10.4% 14.6% by the finding that fast growing tumors had significantly more
Total 104 8 8 11 131
metastasis in the regional lymph nodes at diagnosis than that of
Slow: <0.3 ln(cc/day); fast: >0.3 ln(cc/day). slow growing tumors. This implies that fast growing tumors will
lead to metastasis to the regional lymph nodes earlier than slow
growing tumors.
Discussion The fact that we did not find any significant association of
growth rate and outcome when we did a subgroup analysis in N0
To the best of our knowledge, this is the first study assessing the patients, might be explained by insufficient power in this subgroup
association between measured tumor growth rate and outcome for analysis.
laryngeal squamous cell carcinoma. Tumor growth rate was In a previous study, we analyzed the tumor growth rate in oro-
measured by comparing the primary tumor volume based on a pharyngeal carcinoma. The mean tumor volume of these tumors

Please cite this article in press as: van Bockel LW et al. The importance of actual tumor growth rate on disease free survival and overall survival in laryngeal
squamous cell carcinoma. Radiother Oncol (2014), http://dx.doi.org/10.1016/j.radonc.2014.06.004
 L.W. van Bockel et al. / Radiotherapy and Oncology xxx (2014) xxx–xxx 5

was 23.6 cc and there was a large variation in tumor growth rate conventional radiotherapy. Accelerated radiotherapy was associ-
[10]. In the current study, a large variation in tumor growth rate ated with a better locoregional control, but a difference in survival
was also seen for laryngeal SCC. The mean tumor volume of the lar- between the two therapy regimens was not found. They did not
yngeal SCC group was smaller than the mean tumor volume of the find Tpot to be an independent predictor of treatment outcome.
oropharyngeal SCC group (4.6 cc vs. 23.6 cc resp.). In spite of this However, a cut-off point was used to make a distinction between
difference, also laryngeal SCC showed a large range in growth fast and slow growing tumors. In the fast growing tumor group
potential. Since the volume of laryngeal tumors is very small, there was a significant difference in 3 year local control between
intra-observer variability is expected to be quite high relatively. the accelerated and the conventional regimens. This difference
We delineated 11 patients again and we confirmed this high vari- could not be seen in slow growing tumors [18].
ability (not reported). All parameters such as volume and tumor In our study, most patients were treated with an accelerated
growth rate were highly correlated and we did find that none of schedule. Therefore, we could not study the influence of tumor
these patients would be assigned to another group of fast or slow growth rate on outcome after conventional or accelerated radio-
growing tumors. It seems that dichotomized growth rate is a good therapy. Further prospective studies of the association between
prognosticator for outcome and continuous tumor growth rate is tumor growth rate and treatment schedule are warranted.
not, because of the small tumor volumes and consequently However, before initiation of these studies, it is important to be
relatively high intra-observer variability. able to reliably predict the growth rate of the primary tumor on
An important question remains: what is the impact of this the diagnostic biopsy. Unfortunately, at present a reliable marker
variable tumor growth rate on outcome? In crude analysis, a signif- predicting high versus low tumor growth rate in squamous cell
icant association was found between tumor growth rate, dichoto- cancer is not available.
mized at 0.3 ln(cc/day), and DFS and OS. According to past Furthermore, it is also obvious that tumors, which progress dur-
literature, it is known that T-stage, tumor volume and mobility ing their waiting time, will have a worse prognosis than if they
of the vocal cord are associated with outcome [1–5,14,15]. We con- would have been treated at the time of diagnosis. Consequently,
firmed in our data that T-stage, volume and mobility are mutually tumors with a rapid tumor growth rate will progress faster to a
inter-related factors. Therefore, we did not incorporate these worse prognosis.
parameters simultaneously in the multivariate models. Since we In conclusion, tumor growth rate may be an important factor for
found only volume to be independently associated with DFS in this DFS and OS, but N-stage is still more important. It does seem that
analysis, we decided to use this parameter in the multivariate patients with a high tumor growth rate are prone to develop lymph
analysis. In a sensitivity analysis, we also evaluated the model with node metastases. For treatment decisions, tumor growth rate could
T-stage and mobility of the vocal cord as confounders, but the be of importance according to literature. Therefore, more data on
results did not change. Smoking and alcohol data were collected the impact of tumor growth rate on outcome are needed. Further
retrospectively and without questionnaires and were therefore research should be aimed at identification of reliable markers
maybe not reliable. predicting tumor growth rate.
In multivariate analysis, tumor growth rate also appears to be
an important factor in prediction of DFS and OS. As is seen in Conflict of interest statement
models 1 and 2, the effect of tumor growth rate on DFS and OS is
independent of age and differentiation. No conflicts of interest by any author.
When volume is added to the model this only has a borderline
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squamous cell carcinoma. Radiother Oncol (2014), http://dx.doi.org/10.1016/j.radonc.2014.06.004