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Radiation Oncology
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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
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.
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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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
<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
N/A
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).
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.
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
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Shaverdian et al.
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.
567
Treatment duration and in-field relapse, disease-free survival, and overall survival in radiation therapy patients
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
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
Table 3
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.
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Shaverdian et al.
References
1. Fyles A, Keane TJ, Barton M, et al. The effect of treatment in local
control of cervix cancer. Radiother Oncol 1992;25:273-279.