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Jco 2017 75 9985
Jco 2017 75 9985
definitive radiotherapy improved survival compared with only determined 1994 FIGO stage IB2, IIA, or IIB disease before random as-
radiation.3-7 Although one trial8 failed to demonstrate its benefit, signment. Study investigators and patients were not blinded to treatment
based on cumulative evidence,9,10 concomitant platinum-based allocation.
chemotherapy and radiotherapy has been the standard treatment
of locally advanced cervical cancer since 1999. However, 25% to Study Procedures
40% of patients still experience relapse, and some experience All patients underwent punch biopsy to establish diagnosis and
distant failure despite local control after chemoradiation10; in a detailed clinical examination, including a pelvic examination by two
addition, this treatment is associated with early and long-term clinicians, to determine initial stage. Patients underwent examination
under anesthesia, if required. Patients also underwent blood tests and
toxicity. Thus, there is a need for further improvement in out-
either computed tomography scan or ultrasonography of the abdomen and
comes, but few definitive studies of new therapeutic strategies have pelvis before random assignment.
been reported in the past two decades. Patients randomly assigned to the neoadjuvant chemotherapy plus
The use of neoadjuvant chemotherapy followed by radical surgery group received three cycles of paclitaxel (175 mg/m2) and car-
hysterectomy has been considered an attractive approach to im- boplatin (dosed to an area under curve of 5 to 6) once every 3 weeks.
prove disease control and reduce toxicity. Cervical cancer has Patients underwent clinical response assessment after the second and third
a high response rate to modern chemotherapy including taxane cycles of chemotherapy. Patients who had no response or disease pro-
gression at these time points were crossed over to receive definitive
and platinum agents.11 Neoadjuvant chemotherapy has the po-
concomitant chemotherapy and radiotherapy, whereas responders un-
tential to eradicate micrometastases and could reduce systemic derwent surgery 3 to 4 weeks after the third cycle of chemotherapy.
failures, in addition to facilitating local control by surgical re- Patients assigned to the neoadjuvant chemotherapy plus surgery
section. Some studies and a meta-analysis suggested that neo- group underwent Piver-Rutledge class III radical abdominal hysterectomy,
adjuvant chemotherapy followed by surgery could improve bilateral pelvic lymphadenectomy, and lower para-aortic lymph node
survival outcomes compared with radiotherapy.12-14 However, sampling by expert gynecologic oncologists. Surgery was abandoned in
radiotherapy without concomitant chemotherapy became an patients with intraoperative findings of either unresectable primary tumor
or lymph node disease, and these patients were treated with definitive
obsolete standard, and the chemotherapy regimens used in these concomitant chemoradiation.
studies were not contemporary. Neoadjuvant chemotherapy before Patients assigned to the concomitant chemoradiation group and
definitive radiotherapy failed to show benefit,15,16 possibly because those who were crossed over from the neoadjuvant chemotherapy plus
of selection of radiotherapy-resistant clones, but there is potentially surgery group received standard external-beam radiation to the whole
no such interaction between chemotherapy and surgery. Although pelvis and brachytherapy. They received an external radiation dose of 40 Gy
promising, the neoadjuvant chemotherapy plus surgery approach in 20 fractions with 2 Gy per fraction and a midline shield at 20 Gy,
followed by intracavitary radiation to point A as follows: either two ap-
lacks adequate evidence but continues to be practiced in many
plications of a low dose rate of 30 Gy each or five applications of a high dose
parts of the world.17,18 rate of 7 Gy each. Radiation doses were modified to respect tumor, rectal,
Therefore, we conducted a randomized controlled trial to and bladder constraints. These patients also received five cycles of cisplatin
compare neoadjuvant chemotherapy, using a contemporary reg- (40 mg/m2), administered once every week starting with external-beam
imen of paclitaxel and carboplatin, followed by radical surgery radiotherapy.
versus concomitant chemoradiation in patients with stage IB2, IIA, Patients in the neoadjuvant chemotherapy plus surgery group who
or IIB squamous cervical cancer. underwent radical hysterectomy were given adjuvant therapy (radio-
therapy or concomitant chemotherapy and radiotherapy) as per protocol-
defined criteria, in accordance with published evidence.7,19 On the basis of
histopathologic evaluation of the surgical specimen, adjuvant chemo-
PATIENTS AND METHODS radiation was given in the presence of any one of the following features:
lymph node metastasis, positive surgical margins, or parametrial in-
Study Design and Patients volvement. Adjuvant radiotherapy alone was given based on the presence
This study was designed as a prospective, single-center, two-group, of any two of the following features: deep cervical stromal invasion,
open-label, phase III, randomized controlled trial. Women between 18 and lymphovascular invasion, or tumor size . 4 cm. Patients in both groups
65 years of age with newly diagnosed, previously untreated, histopatho- were evaluated at protocol-defined time points to evaluate response,
logically proven squamous cell carcinoma of the uterine cervix with 1994 monitor for relapse, and assess toxicity.
FIGO stage IB2, IIA, or IIB disease were included in the study. In addition,
the Eastern Cooperative Oncology Group performance status was # 1,
there was no evidence of distant metastases, and hematologic and bio- Outcomes
chemical parameters, including renal function, were adequate. The primary end point of the study was disease-free survival (DFS),
The study was designed by faculty member investigators belonging to which was defined as the time interval between the date of random as-
the Gynecologic Oncology Disease Management Group of Tata Memorial signment and the date of the first documented evidence of relapse at any
Centre (Mumbai, India) and approved by the institutional human ethics site (local, distant, or both) or second primary cancer or death related to
committee. Written informed consent was obtained from all patients cancer (including toxicity), whichever occurred first. Patients who died of
before inclusion in the study. The study protocol and amendments are causes unrelated to cancer or of unknown cause were censored at the time
available in the Data Supplement. of their death in the analysis of primary end point. An additional analysis
that included death as a result of any cause (if it was the first event) in the
definition of a DFS event was also performed. The secondary end points of
Random Assignment the study were overall survival (OS), which was defined as the time interval
Eligible patients were randomly assigned to either study group in a 1:1 between the date of random assignment and the date of death from any
ratio with the use of a computerized block design with a block size of 4. cause, and toxicity, which was defined according to Common Terminology
Random assignment was performed by the Clinical Trials Unit of Tata Criteria for Adverse Events (version 2.0). First recurrences were catego-
Memorial Centre. Patients were stratified according to clinically rized as local if they were confined to the pelvic region including the vagina,
pelvic lymph nodes, and/or other pelvic tissues; as distant if they were
located outside the pelvis; or as local plus distant if they occurred in both RESULTS
regions simultaneously.
Patients
From September 2003 through February 2015, we evaluated
Statistical Analysis 1,713 patients for potential participation in the study, of whom 635
The study was planned based on an expected 5-year DFS rate of 65% were randomly assigned (Fig 1). After excluding two patients with
in the concomitant chemoradiation group with an absolute increase of 10
eligibility violations, the present analysis reports the findings in the
percentage points in the neoadjuvant chemotherapy plus surgery group at
an a level of .05 and statistical power of 80%, using a two-sided test. The remaining 633 patients (316 in the neoadjuvant chemotherapy plus
final sample size was 730 patients, which accounted for a 10% rate of surgery group and 317 in the concomitant chemoradiation group).
patients lost to follow-up. Because of the long recruitment period and At the data cutoff point of March 2017, the median follow-up time
slower than anticipated recruitment, the study team, with the approval of in surviving patients was 58.5 months (interquartile range, 39.3 to
the institutional ethics committee, decided to close study accrual as of 79.7 months). The number of patients lost to follow-up were 16
February 2015 and analyze the study for its primary end point after follow- (5.1%) in the neoadjuvant chemotherapy plus surgery group and 13
up of at least 2 years for the last randomly assigned patient. The final
(4.1%) in concomitant chemoradiation group. The two study groups
accrued patient population constitutes 87% of the planned sample size.
The current report is the first analysis of this study. were well balanced with respect to baseline characteristics (Table 1).
The primary and secondary end points related to survival were The majority of patients had 1994 FIGO stage IIB disease (57.2%).
assessed in the intent-to-treat population, estimated using the Kaplan-
Meier method, and tested by means of a two-sided log-rank test. Analysis
of DFS was performed in subgroups that were defined according to the Treatment
stratification factor of 1994 FIGO stage (IB2, IIA, or IIB), as well as other There was good compliance to planned treatment in both
prognostic factors (hemoglobin level . or # 11 g/dL, Eastern Cooperative arms, including doses and duration of chemotherapy and radio-
Oncology Group performance status of 0 or 1, and radiologic pelvic lymph
node status [negative or positive]), using univariable Cox analysis. A Cox
therapy (Table 2). In the neoadjuvant chemotherapy plus surgery
proportional hazards model was used to perform multivariable analysis of group, two patients (0.63%) received concomitant chemotherapy
various factors affecting DFS and OS, including study intervention. All and radiotherapy, and in the concomitant chemotherapy and ra-
analyses were performed using SPSS Statistics for Windows software, diotherapy group, two patients (0.63%) underwent surgical resection
version 20.0 (SPSS, Chicago, IL). (protocol nonadherence). In the neoadjuvant chemotherapy plus
Patients with
stage IB2, IIA, or IIB
cervical cancer were
assessed for eligibility
(N = 1,713)
Excluded (n = 1,078)
Not eligible (n = 432)
Declined to participate (n = 310)
Enrolled onto other trials (n = 203)
Unreliable for follow-up (n = 133)
Patients with
squamous carcinoma
randomly assigned
(n = 635)
Eligibility Eligibility
violations violations
(adenocarcinoma; n = 1) (stage IIIB; n = 1)
1.70; P = .086; Appendix Fig A1, online only). NOTE. Data presented as No. (%) unless otherwise indicated.
In subgroup analyses, the DFS detriment in the neoadjuvant Abbreviations: CTRT, concomitant chemotherapy and radiotherapy; ICRU, In-
ternational Commission on Radiation Units and Measurements; IQR, interquartile
chemotherapy plus surgery group was statistically significant in range; NA, not applicable; NACT, neoadjuvant chemotherapy; RT, radiotherapy.
patients with FIGO stage IIB disease, with a significant test of *Figures calculated in delivered chemotherapy cycles.
†Low dose rate–equivalent doses calculated using high dose rate to low dose
interaction between treatment effect and stages IIA and IIB disease rate conversion factor of 1/0.54.
(Fig 3 and Appendix Fig A2, online only). In patients with stage IIB
disease, the 5-year DFS rates in the neoadjuvant chemotherapy plus
A B
1.0
1.0
0.8
OS (probability)
DFS (probability)
0.8
0.6
0.6
0.4 0.4
HR for relapse or death as a result of cancer: HR for death: 1.025 (95% CI, 0.752 to 1.398);
1.38 (95% CI, 1.02 to 1.87); log-rank P = .038 log-rank P = .87
0.2 0.2
NACT plus surgery 5-year DFS, 69.3% (95% CI, 63.8 to 74.8) NACT plus surgery 5-year OS, 75.4% (95% CI, 70.1 to 80.7)
CTRT 5-year DFS, 76.7% (95% CI, 71.6 to 81.8) CTRT 5-year OS, 74.7% (95% CI, 69.4 to 80.0)
0 12 24 36 48 60 72 84 0 12 24 36 48 60 72 84
Times Since Random Assignment (months) Times Since Random Assignment (months)
No. at risk: No. at risk:
NACT plus surgery 316 266 233 192 152 114 84 54 NACT plus surgery 316 286 264 215 171 127 95 58
CTRT 317 282 261 210 167 116 85 60 CTRT 317 297 277 223 176 120 86 60
Fig 2. Kaplan-Meier plots for (A) disease-free survival (DFS) and (B) overall survival (OS) in the intent-to-treat population by study group. CTRT, concomitant che-
moradiation; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; NACT, neoadjuvant chemotherapy.
surgery group and 13.56% of patients (43 of 317 patients) in the surgery group, grade 3 or 4 thrombocytopenia occurred at a higher
concomitant chemoradiation group experienced local (with or rate than in the concomitant chemoradiation group (3.5% v 0.3%,
without distant) first recurrences. Treatment at relapse, by study respectively; P = .003), but there was no significant difference
group, in patients with DFS events is listed in Appendix Table A5 between the two study groups with respect to grade 3 or 4 GI and
(online only). bladder toxicities. In the neoadjuvant chemotherapy plus surgery
group, perioperative hemorrhage with . 1,000 mL of blood loss
occurred in 7.9% of patients.
Toxicity The cumulative late adverse events of any grade are listed in
The early adverse events during or within 42 days of treatment Table 4. In the neoadjuvant chemotherapy plus surgery group,
completion are listed in Table 3. Treatment in both study groups compared with the concomitant chemoradiation group, there was
was generally well tolerated. In the neoadjuvant chemotherapy plus a lower rate of rectal (5.7% v 13.3%, respectively; P = .002), bladder
0.1 1 10
Table 3. Adverse Events Reported During Treatment or Within 42 Days After Completion of Treatment
No. of Patients (%)
NACT Plus Surgery (n = 316) CTRT (n = 317)
Toxicity All Grades Grade 3 or 4 All Grades Grade 3 or 4
Hematologic
Anemia 28 (8.8) 8 (2.5) 17 (5.3) 2 (0.6)
Thrombocytopenia 24 (7.6) 11 (3.5) 7 (2.2) 1 (0.3)
Neutropenia 23 (7.3) 6 (1.9) 15 (4.7) 3 (0.9)
Nonhematologic
Abdominal pain 77 (24.4) 6 (1.9) 67 (21.1) 1 (0.3)
Vomiting 163 (51.6) 6 (1.9) 164 (51.7) 3 (0.9)
Diarrhea 68 (21.6) 5 (1.6) 113 (35.6) 9 (2.8)
GI bleeding 6 (1.9) 0 3 (0.9) 0
Renal failure 1 (0.3) 0 7 (2.2) 0
Dysuria 27 (8.5) 1 (0.3) 69 (21.8) 0
Skin toxicity 58 (18.4) 4 (1.3) 109 (34.3) 3 (0.9)
Perioperative hemorrhage (. 1,000 mL) 25 (7.9) NA NA
Postoperative wound complications (any grade) 10 (3.2) NA NA
Postoperative infection (any grade) 3 (0.9) NA NA
Other postoperative complications (any grade) 7 (2.2) NA NA
NOTE. Adverse events were assessed using the National Cancer Institute Common Toxicity Criteria Version 2.0. Some patients had more than one adverse event.
Abbreviations: CTRT, concomitant chemotherapy and radiotherapy; NA, not applicable; NACT, neoadjuvant chemotherapy.
(2.8% v 7.3%, respectively; P = .017), and vaginal (19.9% v 36.9%, stage IIB disease. There was no difference in OS between the two
respectively; P , .001) toxicity occurring or persisting 90 days after groups, although the study was not powered to make a definitive
treatment completion. However, 24 months after treatment com- conclusion with respect to this end point.
pletion, there was no difference in rectal and bladder toxicities This study was based on the presumption that neoadjuvant
between the two groups, whereas vaginal toxicity continued to occur taxane plus platinum chemotherapy will substantially reduce the
at a lower rate in the neoadjuvant chemotherapy plus surgery group risk of distant recurrence and facilitate local control with surgery
(12.0% v 25.6% in the concomitant chemoradiation group; P , .001). compared with chemoradiation. However, our results do not fulfill
the promise that the neoadjuvant chemotherapy plus surgical
strategy showed when it was compared with radiotherapy
DISCUSSION alone.12-14 It is worth noting that the control group in our study
included concomitant cisplatin chemotherapy at a cumulative dose
We report here the outcomes of, to our knowledge, the first of up to 200 mg/m2, which is likely to have provided a level of
randomized study that has compared neoadjuvant chemotherapy systemic control that could not be further improved by the
followed by radical surgery with the current standard treatment of neoadjuvant chemotherapy regimen. The results suggest that it is
concomitant chemoradiation in patients with locally advanced unlikely that addition of more chemotherapy, over and above that
squamous cervical cancer. Treatment was delivered by expert used in concomitant chemoradiation, will further improve sur-
gynecologic, medical, and radiation oncologists at a single tertiary vival in patients with locally advanced cervical cancer. In this
cancer center in India. Concomitant chemoradiation resulted in an context, results of three ongoing studies evaluating the role of
increased 5-year DFS rate compared with neoadjuvant chemo- chemotherapy will be of interest (ClinicalTrials.gov identifiers:
therapy and surgery, with an absolute difference of 7.4 percentage NCT00039338, NCT01414608, and NCT01566240). A European
points between the groups. Subgroup analysis suggests that the Organisation for Research and Treatment of Cancer study
main benefit of concomitant chemoradiation was in patients with (ClinicalTrials.gov identifier: NCT00039338) is testing the same
Table 4. Adverse Events of Any Grade Occurring or Persisting . 90 Days or . 24 Months After Completion of Treatment
. 90 Days . 24 Months
Site NACT Plus Surgery, No. (%) CTRT, No. (%) P NACT Plus Surgery, No. (%) CTRT, No. (%) P
Rectal 18 (5.7) 42 (13.3) .002 7 (2.2) 11 (3.5) .474
Bladder 9 (2.8) 23 (7.3) .017 5 (1.6) 11 (3.5) .204
Vaginal* 63 (19.9) 117 (36.9) , .001 38 (12) 81 (25.6) , .001
Other† 30 (9.5) 17 (5.4) .068 17 (5.4) 11 (3.5) .334
NOTE. Adverse events were assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events version 2.0. Some patients had more than
one adverse event.
Abbreviations: CTRT, concomitant chemotherapy and radiotherapy; NACT, neoadjuvant chemotherapy.
*Vaginal adverse events included synechiae, stenosis, and fibrosis.
†Other adverse events included lymphedema, hernia, and intestinal obstruction.
question of neoadjuvant chemotherapy followed by surgery versus a critical factor in the outcome of our study. An ongoing ran-
concomitant chemoradiation in patients with stage IB and II disease domized study (ClinicalTrials.gov identifier: NCT01414608) is also
using cisplatin-based neoadjuvant chemotherapy regimens. A second using paclitaxel plus carboplatin as the adjuvant regimen.
study (ClinicalTrials.gov identifier: NCT01414608) is testing four Treatment in both groups was well tolerated, and adverse
cycles of paclitaxel plus carboplatin as adjuvant treatment after con- events were within acceptable limits. Of note, the rates of severe
comitant chemoradiation. Another previously reported randomized grades of nonhematologic early toxicities were not significantly
study has reported improvements in DFS and OS with the use of different between the two study groups. Although late toxicities
concomitant and adjuvant gemcitabine and cisplatin chemotherapy,20 beyond 3 months involving the bladder and rectum were higher in
but this has not become standard practice because of excessive toxicity. the concomitant chemoradiation group, there was no significant
In our study, the majority of first recurrences (102 of 162 re- difference at 24 months or later, indicating their resolution in most
currences, 62.96%) were local (with or without distant; Appendix patients. Only vaginal toxicity continued to be significantly higher
Table A4), attesting to the importance of good local control. There has in the concomitant chemoradiation group at 24 months or later.
been continuing interest in the use of surgery in patients with locally This study has some limitations. We included patients with
advanced cervical cancer.14,17,18,21,22 Despite adequate neoadjuvant different disease stages, and the analysis is not powered to definitely
chemotherapy, surgery was possible in only 227 patients (72.15%) in answer the question in patients with operable cervical cancer
the neoadjuvant chemotherapy plus surgery group, similar to the (stages IB2 and IIA). Quality of life was not prospectively measured
ongoing European Organisation for Research and Treatment of and could have elucidated the relative effect of two treatment
Cancer randomized study,23 which has reported a 76% surgical re- strategies on this outcome.
section rate. Our study results indicate that the surgical strategy does Our study has answered a long-standing and important
not improve the local control rate compared with concomitant clinical question in the treatment of patients with locally advanced
chemoradiation. Moreover, many surgical patients (32.2%) required cervical cancer. Concomitant chemoradiation using single-agent
adjuvant radiation or chemoradiation, resulting in trimodality weekly cisplatin results in a significantly increased DFS rate
treatment in a considerable fraction of patients in this group. compared with neoadjuvant chemotherapy followed by radical
A number of reasons could explain the outcomes of our study. surgery in this patient population.
A post hoc analysis of our data suggests that DFS in patients who
were unable to undergo surgery and crossed over to concomitant
chemoradiation is inferior compared with patients who could AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
undergo surgery (HR, 1.49; 95% CI, 0.94 to 2.38; P = .089; Ap- OF INTEREST
pendix Fig A3, online only). Another post hoc analysis in the
neoadjuvant chemotherapy plus surgery group patients who were Disclosures provided by the authors are available with this article at
able to undergo surgery (227 of 316 patients) suggests that patients jco.org.
who received adjuvant radiation or concomitant chemoradiation
had inferior DFS compared with patients who did not (HR, 1.69;
95% CI, 1.02 to 2.80; P = .04; Appendix Fig A4, online only). AUTHOR CONTRIBUTIONS
Although prognostically poor by selection, it is possible that
delaying definitive chemoradiation and/or induction of cross- Conception and design: Sudeep Gupta, Amita Maheshwari, Umesh
Mahantshetty, Rohini Hawaldar, Hemant Tongaonkar, Shyam Shrivastava,
resistance between chemotherapy and radiation were detrimen-
Rajendra Badwe
tal for disease control in these patient subgroups. It could be argued Administrative support: Yogesh Kembhavi
that cisplatin may have been more efficacious than carboplatin Collection and assembly of data: Sudeep Gupta, Pallavi Parab, Rajendra
when combined with paclitaxel. In a Japanese study in the re- Kerkar, Reena Engineer, Jaya Ghosh, Seema Gulia, Neha Kumar,
current or metastatic setting,24 paclitaxel plus carboplatin was T. Surappa Shylasree, Renuka Gawade, Yogesh Kembhavi, Madhuri Gaikar,
noninferior to paclitaxel plus cisplatin in the full population, but Santosh Menon, Meenakshi Thakur, Shyam Shrivastava
the latter regimen resulted in higher OS in the platinum-naı̈ve Data analysis and interpretation: Sudeep Gupta, Amita Maheshwari,
Pallavi Parab, Umesh Mahantshetty, Rohini Hawaldar, Supriya Sastri
subgroup. However, a subgroup analysis cannot be considered (Chopra)
definitive. Moreover, the two regimens were different not only with Manuscript writing: All authors
respect to platinum but also paclitaxel dose and administration Final approval of manuscript: All authors
schedule. Thus, the choice of platinum drug is unlikely to be Accountable for all aspects of the work: All authors
3. Morris M, Eifel PJ, Lu J, et al: Pelvic radiation for locally advanced cervical cancer. N Engl J Med 340:
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Affiliations
All authors: Tata Memorial Centre, Mumbai, India.
Support
Supported by an intramural research grant from the Tata Memorial Centre, Government of India.
Prior Presentation
Presented in part at the European Society for Medical Oncology 2017 Congress, Madrid, Spain, September 8-12, 2017.
nnn
Appendix
1.0
0.8
DFS (probability)
0.6
0.4
0 12 24 36 48 60 72 84
Time Since Random Assignment (months)
No. at risk:
NACT plus surgery 317 268 234 193 153 115 85 54
CTRT 318 283 262 210 167 117 85 60
Fig A1. Kaplan-Meier plot for disease-free survival (DFS), including death as
a result of any cause as a DFS event, in all randomly assigned patients (N 5 635) by
study group (sensitivity analysis). DFS was defined as the interval between the
date of random assignment and the date of the first documented evidence of relapse
at any site (local, distant, or both) or second primary cancer or death as a result of any
cause, whichever occurred first. CTRT, concomitant chemoradiation; HR, hazard
ratio; NACT, neoadjuvant chemotherapy.
A B
DFS (probability)
0.8 0.8
0.6 0.6
0.4 0.4
HR for relapse or death as a result of cancer: HR for relapse or death as a result of cancer:
1.03 (95% CI, 0.51 to 2.08); log-rank P = .94 0.90 (95% CI, 0.50 to 1.62); log-rank P = .73
0.2 0.2
NACT plus surgery 5-year DFS, 74.0% (95% CI, 62.2 to 85.8) NACT plus surgery 5-year DFS, 74.0% (95% CI, 62.2 to 85.8)
CTRT 5-year DFS, 72.6% (95% CI, 59.3 to 85.9) CTRT 5-year DFS, 72.6% (95% CI, 59.3 to 85.9)
0 12 24 36 48 60 72 84 0 12 24 36 48 60 72 84
Time Since Random Assignment (months) Time Since Random Assignment (months)
No. at risk: No. at risk:
NACT plus surgery 57 45 42 35 31 25 21 13 NACT plus surgery 80 69 60 51 40 26 21 16
CTRT 56 45 40 33 25 18 14 13 CTRT 78 66 59 46 39 23 17 13
1.0
DFS (probability)
0.8
0.6
0.4
HR for relapse or death as a result of cancer:
1.90 (95% CI, 1.25 to 2.89); log-rank P = .003
0.2
NACT plus surgery 5-year DFS, 67.2% (95% CI, 59.8 to 74.7)
CTRT 5-year DFS, 79.3% (95% CI, 72.8 to 85.8)
0 12 24 36 48 60 72 84
Time Since Random Assignment (months)
No. at risk:
NACT plus surgery 179 152 131 106 81 63 42 25
CTRT 183 171 162 131 103 75 54 34
Fig A2. Kaplan-Meier plots for disease-free survival (DFS) in patients with (A) stage IB2, (B) stage IIA, and (C) stage IIB disease by study group. CTRT, concomitant
chemoradiation; HR, hazard ratio; NACT, neoadjuvant chemotherapy.
1.0
0.8
DFS (probability)
0.6
0 12 24 36 48 60 72 84
Time Since Random Assignment (months)
No. at risk:
Surgery 227 200 179 148 121 89 67 44
Crossed over 68 56 47 39 29 23 15 10
to CTRT
Fig A3. Kaplan-Meier plot for disease-free survival (DFS) in the neoadjuvant
chemotherapy plus surgery group by surgical resection versus crossover to
concomitant chemotherapy and radiotherapy (CTRT). Surgically resected indicates
patients who underwent radical surgery. HR, hazard ratio.
Probability of Disease-Free Survival
1.0
0.8
0.6
0 12 24 36 48 60 72 84
Fig A4. Kaplan-Meier plot for disease-free survival in the neoadjuvant chemo-
therapy plus surgery group by receipt of adjuvant treatment after surgical re-
section. Surgical resection only denotes patients who did not receive adjuvant
radiation (RT) or chemoradiation (CTRT).
Table A1. Univariable and Multivariable Analysis for Disease-Free Survival by Prognostic Factors
Univariable Analysis Multivariable Analysis
Variable HR (95% CI) P HR (95% CI) P
Treatment (NACT plus surgery v CTRT) 1.378 (1.017 to 1.868) .038 1.46 (1.077 to 1.988) .015
FIGO stage
IB2 v IIB 1.11 (0.739 to 1.667) .616 0.837 (0.549 to 1.276) .408
IIA v IIB 1.138 (0.797 to 1.625) .478 1.074 (0.75 to 1.539) .697
Age (continuous variable) — — 0.960 (0.942 to 0.979) , .001
Hemoglobin (continuous variable) — — 0.929 (0.829 to 1.040) .201
Radiologic pelvic lymph node (negative v positive) 0.676 (0.453 to 1.009) .055 0.699 (0.467 to 1.047) .082
Eastern Cooperative Oncology Group performance status (0 v 1) 1.225 (0.599 to 2.506) .578 1.102 (0.537 to 2.261) .791
Abbreviations: CTRT, concomitant chemoradiation; FIGO, International Federation of Gynecology and Obstetrics; HR, hazard ratio; NACT, neoadjuvant chemotherapy.
Table A3. Univariable and Multivariable Analysis for Overall Survival by Prognostic Factors
Univariable Analysis Multivariable Analysis
Variable HR (95% CI) P HR (95% CI) P
Treatment (NACT plus surgery v CTRT) 1.025 (0.752 to 1.398) .874 1.056 (0.773 to 1.442) .732
FIGO stage
IB2 v IIB 1.310 (0.874 to 1.965) .191 1.066 (0.699 to 1.624) .767
IIA v IIB 1.348 (0.938 to 1.936) .107 1.287 (0.893 to 1.856) .176
Age (continuous variable) — — 0.977 (0.958 to 0.996) .017
Hemoglobin (continuous variable) — — 0.881 (0.783 to 0.991) .035
Radiologic pelvic lymph node (negative v positive) 0.748 (0.488 to 1.148) .184 0.800 (0.519 to 1.232) .311
Eastern Cooperative Oncology Group performance status (0 v 1) 1.000 (0.464 to 2.154) .999 0.877 (0.405 to 1.898) .739
Abbreviations: CTRT, concomitant chemoradiation; FIGO, International Federation of Gynecology and Obstetrics; HR, hazard ratio; NACT, neoadjuvant chemotherapy.
NOTE. Recurrence was classified as local if first detected in the pelvic region
including vaginal or pelvic lymph nodes, as distant if first detected outside the
pelvis, or as local plus distant if first detected simultaneously within and outside
the pelvis.
Abbreviations: CTRT, concomitant chemotherapy and radiotherapy; NACT,
neoadjuvant chemotherapy.
*These patients have experienced disease recurrence, but their exact pattern of
first recurrence is not available.
Table A5. Treatment at Relapse, by Study Group, in Patients With DFS Events
No. of Patients (%)
NACT Plus Surgery CTRT
Treatment (n = 95) (n = 74)
Chemotherapy 27 (28.4) 33 (44.6)
Radiotherapy 11 (11.6) 07 (9.5)
Chemotherapy and radiotherapy 19 (20.0) 04 (5.4)
Other 03 (3.2) 02 (2.7)
No treatment 35 (36.8) 28 (37.8)
Total with DFS events 95 74