International Journal of

Radiation Oncology
biology

physics

www.redjournal.org

Clinical Investigation: Gynecologic Cancer

Effects of Treatment Duration During Concomitant

Chemoradiation Therapy for Cervical Cancer
Narek Shaverdian,* Vinai Gondi, MD,*,y Kathryn L. Sklenar,* Emily F. Dunn, MD,*
Daniel G. Petereit, MD,z Margaret R. Straub, PA-C,* and Kristin A. Bradley, MD*
*Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin;
y
Central Dupage Hospital Cancer Center, Warrenville, Illinois; and zJohn T. Vucurevich Cancer Care Institute, Rapid City
Regional Hospital, Rapid City, South Dakota
Received Nov 15, 2012, and in revised form Jan 15, 2013. Accepted for publication Jan 29, 2013

Summary
Previous studies have
demonstrated adverse effects
from extended treatment
duration in the setting of
radiation therapy alone for
cervical cancer; we report
that in the setting of
concomitant chemoradiation
therapy, extended treatment
duration does not seem to
impact pelvic relapse rates or
disease-free and overall
survival.

Purpose: To determine whether extended treatment duration (TD) impacts in-field relapse and
survival in the setting of concomitant chemoradiation therapy (CRT) for cervical cancer.
Methods and Materials: A total of 480 consecutive cervical cancer patients treated with radiation therapy (RT) alone or concomitant CRT for curative intent were retrospectively analyzed.
Relapse was defined as in-field with respect to external beam radiation therapy fields. The
effects of TD on in-field relapse, disease-free survival (DFS), and overall survival (OS) rates
were assessed continuously and categorically within the separate RT and CRT cohorts. Covariates included age, histology, stage, and cumulative dose to point A. In-field relapse, DFS, and
OS rates were estimated with Kaplan-Meier analysis; comparisons used logerank statistic.
Multivariate analysis used the Cox proportional hazards model.
Results: A total of 372 patients (RT nZ206, CRT nZ166) were evaluable, with a median
follow-up for relapse-free patients of 4.2 years (RT 4.4 years, CRT 4.2 years; PZ.807). Treatment duration was longer in the RT cohort (median 55 days; range 35-99 days) versus the CRT
cohort (median 51 days; range 35-92 days) (PZ.001). In the RT cohort, TD 62 days trended to
significance for predicting inferior DFS (hazard ratio 1.42, 95% confidence interval 0.86-1.98,
PZ.086). However, in the CRT cohort, TD assessed continuously or categorically across
multiple cutoff thresholds did not predict for in-field relapse, DFS, or OS.
Conclusion: With RT alone, extended TD 62 days may adversely impact treatment efficacy.
With the addition of concomitant chemotherapy to RT, however, extended TD has no effect
on treatment efficacy. 2013 Elsevier Inc.

Introduction
Previous studies have reported a detrimental effect of extended
treatment duration (TD) on local control and survival in patients
treated with radiation therapy (RT) alone for squamous cell
Reprint requests to: Kristin A. Bradley, MD, University of Wisconsin
School of Medicine and Public Health, Department of Human Oncology,
Box 0600, Clinical Science Center, 600 Highland Ave, Madison, WI
53792. Tel: (608) 263-8500; E-mail: kabradley@humonc.wisc.edu
Int J Radiation Oncol Biol Phys, Vol. 86, No. 3, pp. 562e568, 2013
0360-3016/$ - see front matter 2013 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.ijrobp.2013.01.037

carcinoma of the cervix (1-5). Accelerated repopulation of

surviving tumor clonogens during the course of RT has been
hypothesized to contribute to the poorer outcomes found in the
setting of extended TD. Recent investigations into tumor repopulation modeling have demonstrated an onset time of
Conflict of interest: none.
AcknowledgmentdThe authors thank Amanda Olson for the helpful
organizational support.

Volume 86  Number 3  2013

approximately 19 days for accelerated repopulation in cervical
cancer (6). Similar findings of accelerated repopulation during RT
have been observed in head-and-neck squamous cell carcinoma
(7, 8), for which accelerated fractionation strategies have resulted
in improved locoregional control as compared with conventional
fractionation (9, 10). In head-and-neck cancer, however, recent
level I evidence has suggested that the concomitant administration of chemotherapy with RT may negate the benefits of accelerated fractionation, and thus the importance of TD during RT
alone (11, 12).
Thus, with the established survival benefit of concomitant
chemotherapy combined with RT for locally advanced cervical
cancer (13, 14), we sought to determine the effects of TD on infield pelvic relapse and survival in patients treated with concomitant chemoradiation therapy (CRT). To provide a historical
control, we also evaluated the effects of TD in the setting of RT
alone. This analysis was based on a published 20-year inter-era
database of consecutively treated cervical cancer patients from
a single academic institution (15).

Methods and Materials

Patient population
The study population consisted of 480 consecutive patients with
cervical cancer who received all or part of their treatment at
a single academic institution from 1989 to 2009 with definitive
RT or CRT for curative intent. All patients underwent brachytherapy at the academic institution, but 21% of patients received
their external beam RT at outside institutions. After approval by
the institutional review board, the charts of patients were
reviewed retrospectively. Patients with planned adjuvant hysterectomies, aborted treatment, sequential chemoradiation therapy,
or histologies other than squamous, adenocarcinoma, or adenosquamous were excluded. Pretreatment evaluation of patients
consisted of a history and complete physical examination
including pelvic examination, routine blood studies, chest x-ray,
and CT of the abdomen and pelvis in the earlier patients and
pelvic MRI and positron emission tomography/CT in patients
treated after 2002.

Radiation therapy
Patients were treated with a combination of pelvic external beam
RT (EBRT) and cervical brachytherapy as previously described
(15). Briefly, pelvic EBRT was delivered using a standard 4-field
technique. Prescription doses of whole-pelvic EBRT varied
between 45 and 50.4 Gy at 1.7 or 1.8 Gy per fraction, according to
clinical factors and the preference of the treating radiation
oncologist. Parametrial boosts, pelvic nodal boosts, and paraaortic nodal irradiation were performed at the discretion of the
radiation oncologist designing the EBRT treatment. Low-dose-rate
(LDR) and high-dose-rate (HDR) brachytherapy were performed
per previously published institutional techniques (16, 17).
Prescription dose of HDR or LDR brachytherapy varied according
to clinical factors and the preference of the treating radiation
oncologist, as previously described (15). For the purpose of this
analysis, combined pelvic EBRT and brachytherapy dose were
assessed by the biological equivalent dose (BED Gy10) (assuming
a/b Z 10) to point A.

Concomitant CRT and treatment duration

563

Chemotherapy
Per institutional protocol, concomitant chemotherapy was
administered as a single agent. Cisplatin was most commonly used
and was delivered once weekly throughout the course of RT at
a dose of 40 mg/m2 (maximum dose of 70 mg weekly). Other
agents included fluorouracil, delivered via protracted venous
infusion, or hydroxyurea, administered orally.

Treatment duration
Treatment duration was calculated from the first day of EBRT to
the last day of brachytherapy or EBRT, whichever was last to
complete. Within the separate RT and CRT treatment cohorts, TD
was evaluated as a continuous variable and categorically across
a range of cutoff thresholds (TD 49-63 days).

Outcome assessment
After completion of treatment, oncologic surveillance was recommended every 3 months for 2 years, every 6 months for years 3
through 5, and annually thereafter. Information on relapse and
survival was obtained through institutional records and records
from referring oncologists. All survival outcomes were verified
using the Social Security Death Index. Relapse was documented
by positive biopsy, clinical examination, or radiographic findings
and classified as in-field (ie, within EBRT fields) or out-of-field
(ie, outside EBRT fields). After first relapse, patients were
censored from analysis of future relapses.

Covariate factors
Covariate factors were assessed as categoric or continuous variables, as documented in Table 1.

Statistical analysis
Chi-squared analysis of covariate factors was used to compare the
RT and CRT cohorts. In-field relapse, disease-free survival (DFS),
and overall survival (OS) rates were estimated with Kaplan-Meier
analysis, with comparisons made using logerank statistic.
Univariate and multivariate analysis used the Cox proportional
hazards model. To prevent inflation of type I error with multiple
categoric comparisons of TD, the Bonferroni correction was
applied, and therefore statistical significance was assigned to
P<.0033 for all univariate categoric analyses of TD. Statistical
significance was assigned to P<.05 for all other analyses. All
statistical analyses were performed using SPSS Statistics 18
(SPSS, Chicago, IL).

Results
After excluding 58 patients who were lost to follow-up and 50
patients who did not meet the aforementioned study criteria, the
final dataset included 372 patients: 206 who received RT alone and
166 who received CRT. The median follow-up of relapse-free
patients was 4.4 years in the RT group and 4.2 years in the CRT
group (PZ.807). Baseline characteristics of both treatment groups
are given in Table 1. Of the 166 patients who received CRT, the

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International Journal of Radiation Oncology  Biology  Physics

Shaverdian et al.

Table 1

Comparison of patients treated with radiation therapy alone and concurrent chemoradiation therapy
Factor

Age
Baseline Karnofsky
performance score
Histology
FIGO stage

BED Gy10 to point A*

Para-aortic nodal EBRT
Brachytherapy dose rate
Brachytherapy applicator
type
Type of chemotherapy

Radiation therapy alone (nZ206)

Chemoradiation therapy (nZ166)

<50 y: 111 (53.9)

50 y: 95 (46.1)
90-100: 160 (83.8)
80: 31 (16.2)
Not available: 15
Squamous cell carcinoma: 177 (85.9)
Adenosquamous or adenocarcinoma: 29 (14.1)
IB: 66 (32.0)
II: 77 (37.4)
III-IVA: 63 (30.6)
Mean: 99
IQR: 96-103
No: 186 (90.3)
Yes: 20 (9.7)
HDR: 202 (98.1)
LDR: 4 (1.9)
Tandem and ovoids: 148 (71.8)
Tandem and cylinders or ringy: 52 (25.2)
Interstitial: 6 (3.0)
N/A

<50 y: 82 (49.4)
50 y: 84 (50.6)
90-100: 84 (88.4)
80: 11(11.6)
Not available: 71
Squamous cell carcinoma: 140 (84.3)
Adenosquamous or adenocarcinoma: 26 (15.7)
IB: 46 (27.7)
II: 86 (51.8)
III-IVA: 34 (20.5)
Mean: 101
IQR: 94-106
No: 140 (84.3)
Yes: 26 (15.7)
HDR: 141 (84.9)
LDR: 25 (15.1)
Tandem and ovoids: 143 (86.1)
Tandem and cylinders or ringy: 6 (3.6)
Interstitial: 17 (10.3)
Cisplatin: 158 (95.2)
5-FU or hydroxyurea: 8 (4.8)
5: 107 (81.1)
<5: 25 (18.9)
Not available: 34
Median: 51
Range: 35-92

No. of weekly cisplatin

cycles

N/A

Treatment duration (d)

Median: 55
Range: 35-99

P
.389
.295

.669
.014

.027
.083
<.001
<.001

N/A

.036

Abbreviations: BED Z biologically equivalent dose; EBRT Z external beam radiation therapy; FIGO Z International Federation of Gynecology and
Oncology; HDR Z high dose rate; IQR Z interquartile range; LDR Z low dose rate; N/A Z not applicable.
Values in parentheses are percentages.
* Assessed by tumor effects model for BED (assuming a/b Z 10).
y
Includes the use of vaginal cylinders (with tandem placement), vaginal ring (with tandem placement).

majority received cisplatin alone (95.2%). Most patients were

treated with HDR brachytherapy (92.2%); of the 29 patients who
received LDR brachytherapy, 25 (86.2%) received CRT and 4
(13.8%) received RT alone (P<.001). Low-dose-rate brachytherapy was most frequently used in patients with stage III-IVA
cervical cancers (62.1% stage III-IVA vs 31.0% stage II vs 6.9%
stage IB) to provide improved tumor coverage via placement of
interstitial needles.
Univariate analyses of covariate factors demonstrated that, in
the RT-alone cohort, advanced stage predicted for inferior in-field
relapse (P<.001), DFS (P<.001), and OS (P<.001), whereas age
>50 years predicted for inferior DFS (PZ.002) and OS (P<.001).
In the CRT cohort, age >50 years, advanced stage, and receipt of
fewer than 5 chemotherapy cycles predicted for inferior DFS
(PZ.018, PZ.029, and PZ.0003, respectively) and OS (PZ.24,
PZ.041, and PZ.003, respectively). All other covariate factors
were not significantly associated with treatment outcomes.
Compared with RT alone, the CRT cohort had an improved
5-year in-field relapse rate (RT alone 30.8%  3.7% vs CRT 14.0%
 3.1%; PZ.006), DFS (RT alone 48.5%  3.7% vs CRT 66.7% 
3.9%; PZ.005), and OS (RT alone 52%  3.7% vs CRT 73% 
3.8%; PZ.004) (Fig. 1). After adjusting for age and stage in
multivariate analysis, the use of concurrent chemotherapy was an
independent predictive factor for lower in-field relapse (hazard ratio
[HR] 1.37, 95% confidence interval [CI] 1.08-1.73, PZ.009),

improved DFS (HR 1.24, 95% CI 1.07-1.45, PZ.004), and

improved OS (HR 1.29, 95% CI 1.09-1.51, PZ.002).
Treatment duration was longer in the RT cohort compared with
the CRT cohort (PZ.036) (Table 1). The distribution of treatment
times varied by stage, with a weak positive correlation for each
treatment cohort (RT: rZ0.25, P<.001; CRT: rZ0.22, PZ.005)
(Fig. 2). The use of LDR versus HDR brachytherapy did not
significantly impact the median total TD (PZ.125).
In the RT-alone cohort, TD evaluated continuously and categorically across multiple cutoff thresholds was predictive of infield relapse, DFS, and/or OS (Table 2). After adjusting for age
and stage in a multivariate model, TD 62 days trended to
significance in predicting inferior DFS (HR 1.42, 95% CI 0.861.98, PZ.086), whereas remaining findings lost statistical
significance. These findings remained consistent when the 4 LDR
brachytherapy-treated patients were excluded from analysis.
In the CRT cohort, TD evaluated continuously and across
multiple cutoff thresholds (TD 49-63 days) was not predictive of
in-field relapse, DFS, or OS (Table 3). Furthermore, within each
age and stage stratum, assessment of TD continuously and categorically by these cutoffs did not demonstrate statistical significance (data not shown). Additionally, because the majority of
patients who received LDR brachytherapy were in the CRT
cohort, a sensitivity analysis excluding patients who received LDR
brachytherapy was conducted but did not alter these findings. In

Volume 86  Number 3  2013

Concomitant CRT and treatment duration

565

Fig. 1. Chemoradiation therapy versus radiation therapy alone on cumulative incidence of (A) in-field relapse rates (PZ.006),
(B) disease-free survival rates (PZ.005), and (C) overall survival rates (PZ.004). Statistical significance was assigned to P<.05.

addition, a separate analysis on patients with squamous histology

alone found no association between TD and in-field relapse,
DFS, or OS.

Discussion
This study is among the first and largest to evaluate the in-field
relapse and survival effects of extended TD in the setting of CRT
for cervical cancer and the only study in which the majority of
patients received HDR brachytherapy. Our findings demonstrate
that during CRT, extended TD is not associated with inferior infield relapse, DFS, or OS. However, during RT alone, TD 62
days may be associated with inferior treatment outcomes in terms

of DFS. These findings support prior observations regarding the

importance of TD during RT alone but offer novel insight that with
the addition of concurrent chemotherapy extended TD may not
impact treatment efficacy for cervical cancer.
The role of TD in patients with cervical cancer has been
extensively studied in the setting of RT alone. These studies have
demonstrated that RT prolongation significantly increases local
relapse rates and decreases survival rates (1-5). Petereit et al (4)
previously reported that extended TD 55 days was adversely
associated with survival and pelvic relapse in a series of 209
patients treated with RT alone consisting of EBRT and LDR
brachytherapy. Similarly, Chen et al (5) observed that TD 63
days was associated with increased pelvic relapse rates and inferior 5-year cause-specific survival. Interestingly, Chen et al (5)

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International Journal of Radiation Oncology  Biology  Physics

Fig. 2. Distribution of treatment times. (A) Frequency of overall treatment times of the concurrent chemoradiation therapy (CRT) and
radiation therapy alone (RT) groups is shown. (B) Frequency of the overall treatment times of the chemoradiation therapy group stratified
by stage IB, II, and III-IVA. (C) Frequency of the overall treatment times of the radiation therapy alone group stratified by stage IB, II, and
III-IVA. FIGO Z International Federation of Gynecology and Oncology.

observed the adverse effects of extended TD later in the treatment

course (ie, 63 days) than previous studies. They attributed this
discrepant finding to their use of HDR brachytherapy and the
potential greater efficacy of HDR, compared with LDR brachytherapy, in counteracting tumor repopulation. In our RT-alone
cohort, in which 98% of patients received HDR brachytherapy,
similar findings of inferior treatment efficacy with TD 62 days
were observed. The summation of these findings emphasizes the
importance of TD in the setting of RT alone, irrespective of brachytherapy dose rate.
Importantly, we observed that in the setting of CRT for
cervical cancer, extended TD has no adverse impact on treatment
efficacy. We present the most comprehensive evaluation of TD
by analyzing TD continuously and categorically across a wide
range of cutoffs. However, through this analysis we found no
signal of association between poor outcomes and extended TD in
the setting of CRT. Furthermore, our database had significant

intrinsic variability, with total TDs ranging from 35 to 92 days

within the CRT cohort; therefore, if there was an association to
be found, we would expect that our database would have allowed
us to do so. Accelerated repopulation by tumor clonogens during
prolonged therapy is the main hypothesis used to explain the
detrimental effects of treatment prolongation on outcomes in
cervical cancer and head-and-neck cancer (6, 18). However, our
findings and similar observations in the setting of head-and-neck
cancers that report no adverse effects from treatment prolongation with CRT suggest that the use of concomitant chemotherapy
with radiation may counteract the adverse effects of prolonged
treatments by possibly further inhibiting the repopulation of
tumor cells (11).
Our findings seem to contrast with those from a recent retrospective study of 113 cervical cancer patients treated with CRT. In
this study, Song et al (19) determined that >56 days of time to
brachytherapy completion from the onset of EBRT independently

Volume 86  Number 3  2013

Table 2

567

Concomitant CRT and treatment duration

Treatment duration and in-field relapse, disease-free survival, and overall survival in radiation therapy patients

Radiation therapy alone

Unadjusted analysis
TD (continuous)
TD 49 vs TD <49
TD 50 vs TD <50
TD 51 vs TD <51
TD 52 vs TD <52
TD 53 vs TD <53
TD 54 vs TD <54
TD 55 vs TD <55
TD 56 vs TD <56
TD 57 vs TD <57
TD 58 vs TD <58
TD 59 vs TD <59
TD 60 vs TD <60
TD 61 vs TD <61
TD 62 vs TD <62
TD 63 vs TD <63
Adjusted analysis
TD (continuous)
TD 55 vs TD <55
TD 56 vs TD <56
TD 57 vs TD <57
TD 58 vs TD <58
TD 59 vs TD <59
TD 62 vs TD <62

d
d
d
d
d
d
d
d
d
d
d
d
d
d
d

d
d
d
d
d
d

In-field relapse
1.027
3.262
2.802
1.856
1.970
1.835
2.150
2.691
2.170
2.095
1.877
1.642
1.577
1.779
1.525
1.405

(0.99-1.055), .056
(1.17-9.06), .023
(1.20-6.55), .018
(0.99-3.46), .052
(1.07-3.62), .029
(1.04-3.23), .035
(1.22-3.78), .008
(1.53-4.73), .001
(1.28-3.69), .004
(1.22-3.59), .007
(1.09-3.24), .024
(0.94-2.87), .082
(0.88-2.83), .127
(0.99-3.20), .054
(0.82-1.53), .187
(0.73-2.72), .314

0.99 (0.95-1.03), .577

0.87 (0.42-1.78), .696
N/A
N/A
N/A
N/A
N/A

Disease-free survival
1.029
1.302
1.807
1.580
1.526
1.513
1.419
1.547
1.737
1.849
1.807
1.735
1.647
1.637
1.818
1.695

Overall survival

(1.01-1.05),
(0.72-2.36),
(1.08-3.01),
(1.01-2.47),
(1.04-2.25),
(1.04-2.20),
(0.99-2.03),
(1.09-2.20),
(1.22-2.47),
(1.30-2.63),
(1.26-2.59),
(1.21-2.50),
(1.14-2.38),
(1.12-2.40),
(1.23-2.69),
(1.13-2.55),

.002
.385
.023
.044
.032
.030
.053
.015
.002
.001
.001
.003
.008
.012
.003
.011

1.025
1.786
1.549
1.608
1.580
1.471
1.557
1.755
1.804
1.653
1.578
1.507
1.502
1.603
1.564
1.656

(1.01-1.05),
(1.06-3.03),
(0.98-2.44),
(1.08-2.40),
(1.07-2.33),
(1.02-2.12),
(1.08-2.23),
(1.23-2.51),
(1.27-2.57),
(1.14-2.39),
(1.09-2.29),
(1.03-2.20),
(1.01-2.23),
(1.07-2.39),
(1.03-2.38),
(1.07-2.56),

.009
.031
.059
.020
.020
.039
.016
.002
.001
.008
.017
.034
.043
.021
.037
.023

1.02 (0.99-1.04),
N/A
1.05 (0.69-1.59),
1.31 (0.89-1.93),
1.36 (0.93-1.99),
1.30 (0.87-1.91),
1.42 (0.86-1.98),

.123

1.01
1.08
1.29
1.31

(0.99-1.03),
(0.70-1.66),
(0.87-1.92),
(0.89-1.93),
N/A
N/A
N/A

.218
.727
.205
.178

.838
.164
.109
.180
.086

Abbreviations: RL Z reference level; TD Z treatment duration. Other abbreviation as in Table 1.

Values are hazard ratio (95% confidence interval), P value. Statistical significance was assigned to P<.0033 for all unadjusted categoric analyses of TD.
Statistical significance was assigned to P<.05 for all other analyses.

predicted for inferior pelvic control. However, our study has

a number of methodologic differences from the Song et al study.
First, the parametrial EBRT boost in the Song et al study was

Table 3

administered after completion of cervical brachytherapy, in

contrast to our institutional practice, whereby no break is
permitted between whole-pelvis EBRT and parametrial boost

Treatment duration and in-field relapse, disease-free survival, and overall survival in chemoradiotherapy patients
Unadjusted

Chemoradiotherapy alone
TD
TD
TD
TD
TD
TD
TD
TD
TD
TD
TD
TD
TD
TD
TD
TD

(continuous)
49 vs TD <49
50 vs TD <50
51 vs TD <51
52 vs TD <52
53 vs TD <53
54 vs TD <54
55 vs TD <55
56 vs TD <56
57 vs TD <57
58 vs TD <58
59 vs TD <59
60 vs TD <60
61 vs TD <61
62 vs TD <62
63 vs TD <63

d
d
d
d
d
d
d
d
d
d
d
d
d
d
d

In-field relapse
1.016
2.032
1.422
1.603
1.643
1.561
1.572
1.388
1.684
1.789
1.681
1.730
1.649
1.474
1.269
1.100

(0.99-1.05),
(0.81-5.08),
(0.64-3.15),
(0.73-3.50),
(0.76-3.56),
(0.72-3.37),
(0.76-3.40),
(0.63-3.06),
(0.76-3.73),
(0.81-3.96),
(0.75-3.78),
(0.77-3.89),
(0.72-3.80),
(0.62-3.51),
(0.51-3.17),
(0.41-2.92),

.299
.108
.385
.237
.208
.257
.251
.417
.199
.151
.209
.185
.240
.381
.609
.848

Disease-free survival
1.009
1.486
1.382
1.219
1.063
1.187
1.156
1.226
1.234
1.453
1.447
1.248
1.282
1.342
1.128
0.988

(0.99-1.03),
(0.81-2.72),
(0.82-2.33),
(0.75-1.97),
(0.66-1.71),
(0.74-1.91),
(0.72-1.86),
(0.76-1.98),
(0.76-2.02),
(0.89-2.38),
(0.88-2.38),
(0.74-2.10),
(0.76-2.16),
(0.79-2.28),
(0.64-1.98),
(0.55-1.78),

.399
.198
.223
.421
.800
.479
.552
.407
.401
.137
.145
.405
.350
.276
.673
.969

Overall survival
1.014
1.621
1.336
1.145
1.340
1.351
1.404
1.472
1.745
1.713
1.533
1.568
1.613
1.319
1.149
1.143

(0.99-1.04),
(0.90-2.92),
(0.79-2.28),
(0.68-1.93),
(0.80-2.26),
(0.80-2.27),
(0.83-2.37),
(0.87-2.50),
(1.03-2.97),
(1.00-2.95),
(0.88-2.66),
(0.90-2.72),
(0.92-2.82),
(0.73-2.38),
(0.62-2.14),
(0.60-2.17),

.188
.109
.288
.611
.270
.257
.204
.152
.040
.049
.130
.111
.094
.359
.661
.681

Abbreviations as in Table 2.
Values are hazard ratio (95% confidence interval), P value. Statistical significance was assigned to P<.0033 for all unadjusted categoric analyses of TD.
Statistical significance was assigned to P<.05 for all other analyses.

568

Shaverdian et al.

EBRT. Second, TD from start of pelvic EBRT to brachytherapy

completion was significantly longer in the Song et al series
(median TD 60 days, range 39-113 days) compared with our series
(median TD 51 days, range 35-92 days). Third, 95% of patients in
the Song et al study were treated with LDR brachytherapy,
whereas 85% of the CRT patients in our study were treated with
HDR brachytherapy. Last, to prevent inflation of type I error due
to multiple testing comparisons, our study a priori assigned
statistical significance to a P value <.0033 for all univariate
categoric analyses of TD. In the Song et al study, the finding of
inferior pelvic control with time to brachytherapy completion >56
days was observed with PZ.04. In our study we observed an
association between inferior OS and TD 56 days; however, the
univariate P value was .040, which did not meet our criterion for
univariate statistical significance. Furthermore, in this report we
present results of TD evaluated continuously and categorically
from 49 to 63 days, data that consistently show no association
between outcomes and TD in the CRT cohort.
Despite multiple phase 3 studies demonstrating improved
treatment efficacy with CRT compared with RT alone for cervical
cancer, 1 phase 3 study conducted by the National Cancer Institute
of Canada (NCIC) did not show such a survival benefit. One
plausible reason for this discrepant finding was the shorter median
TD (51 days) in the NCIC study as compared with other studies
(20). The authors of the NCIC study hypothesized that the addition of concurrent chemotherapy may only be effective when RT is
protracted. In our analysis, in which TDs were comparable to that
in the NCIC study, the CRT cohort had an improved 5-year infield relapse rate, DFS, and OS as compared with the RT-alone
cohort. Thus, these data seem to suggest that even with shorter
TD, the addition of concomitant chemotherapy to RT leads to
improved treatment efficacy.
Given its retrospective design, this study has a number of
limitations. First, this study relied on rigorous reviews of prior
medical records spanning over 20 years. However, throughout the
study period, standardized institutional practices for RT techniques, patient follow-up, and data storage were in place that
likely limited potential bias introduced by a retrospective study.
Although standardized practices were in place at our institution,
21% of the patients received external beam RT at outside institutions, which could have introduced variability in treatment
technique and management of treatment delays. In addition,
although the vast majority of patients in our analysis received
HDR brachytherapy, a small subset was treated with LDR brachytherapy. However, we conducted sensitivity analyses by
excluding the patients who received LDR brachytherapy and
observed no changes to our findings. Furthermore, the use of
relapse as an endpoint may not have been sensitive enough to pick
up associations between TD and treatment efficacy in the setting
of CRT. With the use of targeted therapies or additional adjuvant
chemotherapy, the impact of these treatments on accelerated
repopulation may be best evaluated with more sensitivity
approaches, including serial MRI throughout treatment. We plan
future studies using methods similar to those of Huang et al (6) by
using serial MRI to evaluate tumor responses.

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