VOLUME 36 • NUMBER 16
JOURNAL OF CLINICAL ONCOLOGY
Author affiliations and support information
(if applicable) appear at the end of this
article.
Published at jco.org on February 12, 2018.
Clinical trial information: NCT00193739.
Corresponding author: Sudeep Gupta, MD,
Department of Medical Oncology, Tata
Memorial Centre, Parel, Mumbai 400012,
India; e-mail: sudeepgupta04@yahoo.
com.
© 2018 by American Society of Clinical
Oncology
0732-183X/18/3616w-1548w/$20.00
ASSOCIATED CONTENT
See accompanying Oncology
Grand Rounds on page 1543
Appendix
DOI: https://doi.org/10.1200/JCO.
2017.75.9985
Data Supplements
DOI: https://doi.org/10.1200/JCO.
2017.75.9985
DOI: https://doi.org/10.1200/JCO.2017.
75.9985
1548 © 2018 by American Society of Clinical Oncology
• JUNE 1, 2018
O R I G I N A L R E P O R T
Neoadjuvant Chemotherapy Followed by Radical Surgery
Versus Concomitant Chemotherapy and Radiotherapy in
Patients With Stage IB2, IIA, or IIB Squamous Cervical
Cancer: A Randomized Controlled Trial
Sudeep Gupta, Amita Maheshwari, Pallavi Parab, Umesh Mahantshetty, Rohini Hawaldar, Supriya Sastri
(Chopra), Rajendra Kerkar, Reena Engineer, Hemant Tongaonkar, Jaya Ghosh, Seema Gulia, Neha Kumar,
T. Surappa Shylasree, Renuka Gawade, Yogesh Kembhavi, Madhuri Gaikar, Santosh Menon, Meenakshi Thakur,
Shyam Shrivastava, and Rajendra Badwe
A B S T R A C T
Purpose
We compared the efficacy and toxicity of neoadjuvant chemotherapy followed by radical surgery
versus standard cisplatin-based chemoradiation in patients with locally advanced squamous cervical
cancer.
Patients and Methods
This was a single-center, phase III, randomized controlled trial (ClinicalTrials.gov identifier:
NCT00193739). Eligible patients were between 18 and 65 years old and had stage IB2, IIA, or IIB
squamous cervical cancer. They were randomly assigned, after stratification by stage, to receive
either three cycles of neoadjuvant chemotherapy using paclitaxel and carboplatin once every
3 weeks followed by radical hysterectomy or standard radiotherapy with concomitant cisplatin once
every week for 5 weeks. Patients in the neoadjuvant group received postoperative adjuvant radiation
or concomitant chemotherapy and radiotherapy, if indicated. The primary end point was disease-free
survival (DFS), defined as survival without relapse or death related to cancer, and secondary end
points included overall survival and toxicity.
Results
Between September 2003 and February 2015, 635 patients were randomly assigned, of whom 633
(316 patients in the neoadjuvant chemotherapy plus surgery group and 317 patients in the con-
comitant chemoradiation group) were included in the final analysis, with a median follow-up time of
58.5 months. The 5-year DFS in the neoadjuvant chemotherapy plus surgery group was 69.3%
compared with 76.7% in the concomitant chemoradiation group (hazard ratio, 1.38; 95% CI, 1.02 to
1.87; P = .038), whereas the corresponding 5-year OS rates were 75.4% and 74.7%, respectively
(hazard ratio, 1.025; 95% CI, 0.752 to 1.398; P = .87). The delayed toxicities at 24 months or later
after treatment completion in the neoadjuvant chemotherapy plus surgery group versus the con-
comitant chemoradiation group were rectal (2.2% v 3.5%, respectively), bladder (1.6% v 3.5%,
respectively), and vaginal (12.0% v 25.6%, respectively).
Conclusion
Cisplatin-based concomitant chemoradiation resulted in superior DFS compared with neoadjuvant
chemotherapy followed by radical surgery in locally advanced cervical cancer.
J Clin Oncol 36:1548-1555. © 2018 by American Society of Clinical Oncology
locally advanced cancer. Radiotherapy is the primary
INTRODUCTION
modality of treatment, although definitive surgery
Cervical cancer is a major public health problem can also be performed in patients with stage IB2 or
worldwide,1 and squamous carcinoma is the most IIA disease.2
common subtype. Patients with International The treatment of cervical cancer underwent
Federation of Gynecology and Obstetrics (FIGO) a paradigm shift when several trials proved that
stages IB2 to IVA disease are considered to have administration of concomitant chemotherapy with
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Copyright © 2023 American Society of Clinical Oncology. All rights reserved.
 Neoadjuvant Chemotherapy Followed by Surgery in Cervical Cancer
definitive radiotherapy improved survival compared with only
radiation.3-7 Although one trial8 failed to demonstrate its benefit,
based on cumulative evidence,9,10 concomitant platinum-based
chemotherapy and radiotherapy has been the standard treatment
of locally advanced cervical cancer since 1999. However, 25% to
40% of patients still experience relapse, and some experience
distant failure despite local control after chemoradiation10; in
addition, this treatment is associated with early and long-term
toxicity. Thus, there is a need for further improvement in out-
comes, but few definitive studies of new therapeutic strategies have
been reported in the past two decades.
The use of neoadjuvant chemotherapy followed by radical
hysterectomy has been considered an attractive approach to im-
prove disease control and reduce toxicity. Cervical cancer has
a high response rate to modern chemotherapy including taxane
and platinum agents.11 Neoadjuvant chemotherapy has the po-
tential to eradicate micrometastases and could reduce systemic
failures, in addition to facilitating local control by surgical re-
section. Some studies and a meta-analysis suggested that neo-
adjuvant chemotherapy followed by surgery could improve
survival outcomes compared with radiotherapy.12-14 However,
radiotherapy without concomitant chemotherapy became an
obsolete standard, and the chemotherapy regimens used in these
studies were not contemporary. Neoadjuvant chemotherapy before
definitive radiotherapy failed to show benefit,15,16 possibly because
of selection of radiotherapy-resistant clones, but there is potentially
no such interaction between chemotherapy and surgery. Although
promising, the neoadjuvant chemotherapy plus surgery approach
lacks adequate evidence but continues to be practiced in many
parts of the world.17,18
Therefore, we conducted a randomized controlled trial to
compare neoadjuvant chemotherapy, using a contemporary reg-
imen of paclitaxel and carboplatin, followed by radical surgery
versus concomitant chemoradiation in patients with stage IB2, IIA,
or IIB squamous cervical cancer.
PATIENTS AND METHODS
Study Design and Patients
This study was designed as a prospective, single-center, two-group,
open-label, phase III, randomized controlled trial. Women between 18 and
65 years of age with newly diagnosed, previously untreated, histopatho-
logically proven squamous cell carcinoma of the uterine cervix with 1994
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-
chemical parameters, including renal function, were adequate.
The study was designed by faculty member investigators belonging to
the Gynecologic Oncology Disease Management Group of Tata Memorial
Centre (Mumbai, India) and approved by the institutional human ethics
committee. Written informed consent was obtained from all patients
before inclusion in the study. The study protocol and amendments are
available in the Data Supplement.
Random Assignment
Eligible patients were randomly assigned to either study group in a 1:1
ratio with the use of a computerized block design with a block size of 4.
Random assignment was performed by the Clinical Trials Unit of Tata
Memorial Centre. Patients were stratified according to clinically
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determined 1994 FIGO stage IB2, IIA, or IIB disease before random as-
signment. Study investigators and patients were not blinded to treatment
allocation.
Study Procedures
All patients underwent punch biopsy to establish diagnosis and
a detailed clinical examination, including a pelvic examination by two
clinicians, to determine initial stage. Patients underwent examination
under anesthesia, if required. Patients also underwent blood tests and
either computed tomography scan or ultrasonography of the abdomen and
pelvis before random assignment.
Patients randomly assigned to the neoadjuvant chemotherapy plus
surgery group received three cycles of paclitaxel (175 mg/m2) and car-
boplatin (dosed to an area under curve of 5 to 6) once every 3 weeks.
Patients underwent clinical response assessment after the second and third
cycles of chemotherapy. Patients who had no response or disease pro-
gression at these time points were crossed over to receive definitive
concomitant chemotherapy and radiotherapy, whereas responders un-
derwent surgery 3 to 4 weeks after the third cycle of chemotherapy.
Patients assigned to the neoadjuvant chemotherapy plus surgery
group underwent Piver-Rutledge class III radical abdominal hysterectomy,
bilateral pelvic lymphadenectomy, and lower para-aortic lymph node
sampling by expert gynecologic oncologists. Surgery was abandoned in
patients with intraoperative findings of either unresectable primary tumor
or lymph node disease, and these patients were treated with definitive
concomitant chemoradiation.
Patients assigned to the concomitant chemoradiation group and
those who were crossed over from the neoadjuvant chemotherapy plus
surgery group received standard external-beam radiation to the whole
pelvis and brachytherapy. They received an external radiation dose of 40 Gy
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-
plications of a low dose rate of 30 Gy each or five applications of a high dose
rate of 7 Gy each. Radiation doses were modified to respect tumor, rectal,
and bladder constraints. These patients also received five cycles of cisplatin
(40 mg/m2), administered once every week starting with external-beam
radiotherapy.
Patients in the neoadjuvant chemotherapy plus surgery group who
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-
radiation was given in the presence of any one of the following features:
lymph node metastasis, positive surgical margins, or parametrial in-
volvement. Adjuvant radiotherapy alone was given based on the presence
of any two of the following features: deep cervical stromal invasion,
lymphovascular invasion, or tumor size . 4 cm. Patients in both groups
were evaluated at protocol-defined time points to evaluate response,
monitor for relapse, and assess toxicity.
Outcomes
The primary end point of the study was disease-free survival (DFS),
which was defined as the time interval between the date of random as-
signment and the date of the first documented evidence of relapse at any
site (local, distant, or both) or second primary cancer or death related to
cancer (including toxicity), whichever occurred first. Patients who died of
causes unrelated to cancer or of unknown cause were censored at the time
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
the study were overall survival (OS), which was defined as the time interval
between the date of random assignment and the date of death from any
cause, and toxicity, which was defined according to Common Terminology
Criteria for Adverse Events (version 2.0). First recurrences were catego-
rized as local if they were confined to the pelvic region including the vagina,
© 2018 by American Society of Clinical Oncology 1549
 Gupta et al

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
regions simultaneously.
Statistical Analysis
The study was planned based on an expected 5-year DFS rate of 65%
in the concomitant chemoradiation group with an absolute increase of 10
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
final sample size was 730 patients, which accounted for a 10% rate of
patients lost to follow-up. Because of the long recruitment period and
slower than anticipated recruitment, the study team, with the approval of
the institutional ethics committee, decided to close study accrual as of
February 2015 and analyze the study for its primary end point after follow-
up of at least 2 years for the last randomly assigned patient. The final
accrued patient population constitutes 87% of the planned sample size.
The current report is the first analysis of this study.
The primary and secondary end points related to survival were
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
stratification factor of 1994 FIGO stage (IB2, IIA, or IIB), as well as other
prognostic factors (hemoglobin level . or # 11 g/dL, Eastern Cooperative
Oncology Group performance status of 0 or 1, and radiologic pelvic lymph
node status [negative or positive]), using univariable Cox analysis. A Cox
proportional hazards model was used to perform multivariable analysis of
various factors affecting DFS and OS, including study intervention. All
analyses were performed using SPSS Statistics for Windows software,
version 20.0 (SPSS, Chicago, IL).
RESULTS
Patients
From September 2003 through February 2015, we evaluated
1,713 patients for potential participation in the study, of whom 635
were randomly assigned (Fig 1). After excluding two patients with
eligibility violations, the present analysis reports the findings in the
remaining 633 patients (316 in the neoadjuvant chemotherapy plus
surgery group and 317 in the concomitant chemoradiation group).
At the data cutoff point of March 2017, the median follow-up time
in surviving patients was 58.5 months (interquartile range, 39.3 to
79.7 months). The number of patients lost to follow-up were 16
(5.1%) in the neoadjuvant chemotherapy plus surgery group and 13
(4.1%) in concomitant chemoradiation group. The two study groups
were well balanced with respect to baseline characteristics (Table 1).
The majority of patients had 1994 FIGO stage IIB disease (57.2%).
Treatment
There was good compliance to planned treatment in both
arms, including doses and duration of chemotherapy and radio-
therapy (Table 2). In the neoadjuvant chemotherapy plus surgery
group, two patients (0.63%) received concomitant chemotherapy
and radiotherapy, and in the concomitant chemotherapy and ra-
diotherapy group, two patients (0.63%) underwent surgical resection
(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)

Fig 1. CONSORT diagram.

Assigned to
Assigned to
undergo neoadjuvant
undergo concomitant
chemotherapy
chemoradiation
followed by surgery
(n = 318)
(n = 317)

Eligibility Eligibility
violations violations
(adenocarcinoma; n = 1) (stage IIIB; n = 1)

Lost to follow-up Lost to follow-up

(n = 16) (n = 13)

Patients included Patients included

in the analysis in the analysis
(n = 316) (n = 317)

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 Neoadjuvant Chemotherapy Followed by Surgery in Cervical Cancer

surgery and concomitant chemoradiation groups were 67.2% and

Table 1. Baseline Patients Characteristics
79.3%, respectively (unadjusted HR for DFS in the neoadjuvant
NACT Plus Surgery chemotherapy plus surgery group, 1.90; 95% CI, 1.25 to 2.89; P = .003).
Characteristic (n = 316) CTRT (n = 317)
Eighty patients (25.32%) died in the neoadjuvant chemo-
Median age, years (range) 50 (27-65) 48 (26-65)
therapy plus surgery group, and 80 patients (25.24%) died in the
Median hemoglobin, g/dL (range) 11.5 (7.6-15.6) 11.5 (7.4-15.5)
Median body mass index, kg/m2 22.6 (12.8-44.2) 22.5 (14.5-38.4) concomitant chemotherapy plus radiotherapy group, with cor-
(range) responding 5-year OS rates of 75.4% and 74.7%, respectively
Comorbidities (unadjusted HR for death in the neoadjuvant chemotherapy plus
Yes 67 (21.2) 61 (19.2)
No 249 (78.8) 256 (80.8)
surgery group, 1.025; 95% CI, 0.752 to 1.398; P = .87; Fig 2;
Eastern Cooperative Oncology Group Appendix Table A2, online only). There was no difference in OS
performance status between the two groups after adjusting for stage, pelvic lymph node
0 290 (91.8) 293 (92.4)
1 26 (8.2) 24 (7.6)
status, age, hemoglobin level, and performance status (adjusted
FIGO stage HR, 1.06; 95% CI, 0.77 to 1.44; Appendix Table A3, online only).
IB2 57 (18.0) 56 (17.7) The pattern of first recurrence in the two study groups is
IIA 80 (25.3) 78 (24.6) provided in Appendix Table A4 (online only). Overall, 18.67% of
IIB 179 (56.7) 183 (57.7)
Radiologic pelvic lymph node status
patients (59 in 316 patients) in the neoadjuvant chemotherapy plus
Positive 46 (14.6) 45 (14.2)
Negative 270 (85.4) 272 (85.8)

NOTE. Data presented as No. (%) unless otherwise indicated.

Abbreviations: CTRT, concomitant chemotherapy and radiotherapy; FIGO, Table 2. Treatment Details in Both Groups
International Federation of Gynecology and Obstetrics; NACT, neoadjuvant
chemotherapy. NACT Plus Surgery
Treatment (n = 316) CTRT (n = 317)
Concurrent cisplatin cycles
#3 NA 50 (15.7)
4-5 NA 267 (84.2)
surgery group, 68 patients (21.5%) crossed over (presurgery Neoadjuvant paclitaxel plus
carboplatin cycles
crossover and intraoperative unresectable disease) to receive de-
0 19 (6) NA
finitive concomitant chemoradiation, 42 patients (13.3%) received 1 5 (1.6) NA
postoperative adjuvant chemoradiation, and 31 patients (9.8%) 2 26 (8.2) NA
received postoperative adjuvant radiotherapy, according to 3 266 (84.2) NA
Neoadjuvant chemotherapy dose
protocol-defined criteria. reduction*
Yes 24 (7.6) NA
No 273 (86.4) NA
Efficacy Information not available 19 (6.0) NA
Ninety-five DFS events (30.06%) occurred in the neoadjuvant Concurrent cisplatin dose reduction*
Yes NA 35 (11.0)
chemotherapy plus surgery group, and 74 events (23.34%) oc-
No NA 269 (84.9)
curred in the concomitant chemoradiation group; the corre- Information not available NA 13 (4.1)
sponding 5-year DFS rates were 69.3% and 76.7%, respectively Chemotherapy cycle delay
(unadjusted hazard ratio [HR] for DFS in the neoadjuvant che- by $ 7 days*
No delay 272 (86.1) 281 (88.6)
motherapy plus surgery group, 1.38; 95% CI, 1.02 to 1.87; P = .038; Delay 25 (7.9) 17 (5.4)
Fig 2). DFS was also significantly inferior in the neoadjuvant Information not available 19 (6.0) 19 (6.0)
chemotherapy plus surgery group after adjusting for stage, pelvic Median paclitaxel dose per cycle, 174.6 (172.9-175.5) NA
mg/m2 (IQR)*
lymph node status, age, hemoglobin level, and performance status Median cisplatin dose per cycle, NA 39.4 (37.4-40.1)
(adjusted HR, 1.46; 95% CI, 1.08 to 1.99; P = .015; Appendix Table mg/m2 (IQR)*
A1, online only). When the definition of a DFS event included Median total dose to point A, Gy NA 88.8 (86.9-88.8)
(IQR)†
death as a result of any cause and all randomly assigned patients Median ICRU rectum (IQR)† NA 60.7 (54.8-66.2)
(N = 635) were analyzed (sensitivity analysis), DFS showed a trend Median ICRU bladder (IQR)† NA 60.0 (53.5-68.0)
of being inferior in the neoadjuvant chemotherapy plus surgery Median duration of radiotherapy, days NA 48 (43-56)
(IQR)
group compared with the concomitant chemoradiation group Surgical resection
(5-year DFS, 67.6% v 72.0%, respectively), although this comparison Resection only 154 (48.7) NA
did not reach statistical significance (unadjusted HR in the neo- Resection followed by RT 42 (13.3) NA
adjuvant chemotherapy plus surgery group, 1.28; 95% CI, 0.97 to Resection followed by CTRT 31 (09.8) NA

1.70; P = .086; Appendix Fig A1, online only).
In subgroup analyses, the DFS detriment in the neoadjuvant
chemotherapy plus surgery group was statistically significant in
patients with FIGO stage IIB disease, with a significant test of
interaction between treatment effect and stages IIA and IIB disease
(Fig 3 and Appendix Fig A2, online only). In patients with stage IIB
disease, the 5-year DFS rates in the neoadjuvant chemotherapy plus
NOTE. Data presented as No. (%) unless otherwise indicated.
Abbreviations: CTRT, concomitant chemotherapy and radiotherapy; ICRU, In-
ternational Commission on Radiation Units and Measurements; IQR, interquartile
range; NA, not applicable; NACT, neoadjuvant chemotherapy; RT, radiotherapy.
*Figures calculated in delivered chemotherapy cycles.
†Low dose rate–equivalent doses calculated using high dose rate to low dose
rate conversion factor of 1/0.54.

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 Gupta et al

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
concomitant chemoradiation group experienced local (with or
without distant) first recurrences. Treatment at relapse, by study
group, in patients with DFS events is listed in Appendix Table A5
(online only).
Toxicity
The early adverse events during or within 42 days of treatment
completion are listed in Table 3. Treatment in both study groups
was generally well tolerated. In the neoadjuvant chemotherapy plus
surgery group, grade 3 or 4 thrombocytopenia occurred at a higher
rate than in the concomitant chemoradiation group (3.5% v 0.3%,
respectively; P = .003), but there was no significant difference
between the two study groups with respect to grade 3 or 4 GI and
bladder toxicities. In the neoadjuvant chemotherapy plus surgery
group, perioperative hemorrhage with . 1,000 mL of blood loss
occurred in 7.9% of patients.
The cumulative late adverse events of any grade are listed in
Table 4. In the neoadjuvant chemotherapy plus surgery group,
compared with the concomitant chemoradiation group, there was
a lower rate of rectal (5.7% v 13.3%, respectively; P = .002), bladder

No. of Events/No. of Patients

P for
NACT Plus Surgery CTRT HR (95% CI)
Interaction
Stage
IB2 16/57 15/56 .14
IIA 22/80 23/78 .04
IIB 57/179 36/183
Fig 3. Disease-free survival (DFS) of sub-
Hemoglobin .78 groups. P values are for the interaction term
> 11 g/dL 60/206 44/203 from a model with study arm, the subgroup
≤ 11 g/dL 35/110 30/114 variable, and arm 3 subgroup interaction term.
DFS hazard ratios are indicated by diamonds,
Pelvic lymph node status .15 and 95% CIs are indicated by the crossing
Negative 82/270 58/272 horizontal lines. Diamond size is proportional to
each patient subgroup population size. All haz-
Positive 13/46 16/45
ard ratios (HR) are unadjusted. CTRT, con-
comitant chemoradiation; NACT, neoadjuvant
ECOG performance status .79 chemotherapy.
0 90/290 71/293
1 5/26 3/24

All patients 95/316 74/317

0.1 1 10

NACT Plus Surgery Better CTRT Better

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 Neoadjuvant Chemotherapy Followed by Surgery in Cervical Cancer

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%,
respectively; P , .001) toxicity occurring or persisting 90 days after
treatment completion. However, 24 months after treatment com-
pletion, there was no difference in rectal and bladder toxicities
between the two groups, whereas vaginal toxicity continued to occur
at a lower rate in the neoadjuvant chemotherapy plus surgery group
(12.0% v 25.6% in the concomitant chemoradiation group; P , .001).
DISCUSSION
We report here the outcomes of, to our knowledge, the first
randomized study that has compared neoadjuvant chemotherapy
followed by radical surgery with the current standard treatment of
concomitant chemoradiation in patients with locally advanced
squamous cervical cancer. Treatment was delivered by expert
gynecologic, medical, and radiation oncologists at a single tertiary
cancer center in India. Concomitant chemoradiation resulted in an
increased 5-year DFS rate compared with neoadjuvant chemo-
therapy and surgery, with an absolute difference of 7.4 percentage
points between the groups. Subgroup analysis suggests that the
main benefit of concomitant chemoradiation was in patients with
stage IIB disease. There was no difference in OS between the two
groups, although the study was not powered to make a definitive
conclusion with respect to this end point.
This study was based on the presumption that neoadjuvant
taxane plus platinum chemotherapy will substantially reduce the
risk of distant recurrence and facilitate local control with surgery
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
alone.12-14 It is worth noting that the control group in our study
included concomitant cisplatin chemotherapy at a cumulative dose
of up to 200 mg/m2, which is likely to have provided a level of
systemic control that could not be further improved by the
neoadjuvant chemotherapy regimen. The results suggest that it is
unlikely that addition of more chemotherapy, over and above that
used in concomitant chemoradiation, will further improve sur-
vival in patients with locally advanced cervical cancer. In this
context, results of three ongoing studies evaluating the role of
chemotherapy will be of interest (ClinicalTrials.gov identifiers:
NCT00039338, NCT01414608, and NCT01566240). A European
Organisation for Research and Treatment of Cancer study
(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.

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 Gupta et al

question of neoadjuvant chemotherapy followed by surgery versus
concomitant chemoradiation in patients with stage IB and II disease
using cisplatin-based neoadjuvant chemotherapy regimens. A second
study (ClinicalTrials.gov identifier: NCT01414608) is testing four
cycles of paclitaxel plus carboplatin as adjuvant treatment after con-
comitant chemoradiation. Another previously reported randomized
study has reported improvements in DFS and OS with the use of
concomitant and adjuvant gemcitabine and cisplatin chemotherapy,20
but this has not become standard practice because of excessive toxicity.
In our study, the majority of first recurrences (102 of 162 re-
currences, 62.96%) were local (with or without distant; Appendix
Table A4), attesting to the importance of good local control. There has
been continuing interest in the use of surgery in patients with locally
advanced cervical cancer.14,17,18,21,22 Despite adequate neoadjuvant
chemotherapy, surgery was possible in only 227 patients (72.15%) in
the neoadjuvant chemotherapy plus surgery group, similar to the
ongoing European Organisation for Research and Treatment of
Cancer randomized study,23 which has reported a 76% surgical re-
section rate. Our study results indicate that the surgical strategy does
not improve the local control rate compared with concomitant
chemoradiation. Moreover, many surgical patients (32.2%) required
adjuvant radiation or chemoradiation, resulting in trimodality
treatment in a considerable fraction of patients in this group.
A number of reasons could explain the outcomes of our study.
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
undergo surgery (HR, 1.49; 95% CI, 0.94 to 2.38; P = .089; Ap-
pendix Fig A3, online only). Another post hoc analysis in the
neoadjuvant chemotherapy plus surgery group patients who were
able to undergo surgery (227 of 316 patients) suggests that patients
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).
Although prognostically poor by selection, it is possible that
delaying definitive chemoradiation and/or induction of cross-
resistance between chemotherapy and radiation were detrimen-
tal for disease control in these patient subgroups. It could be argued
that cisplatin may have been more efficacious than carboplatin
when combined with paclitaxel. In a Japanese study in the re-
current or metastatic setting,24 paclitaxel plus carboplatin was
noninferior to paclitaxel plus cisplatin in the full population, but
the latter regimen resulted in higher OS in the platinum-naı̈ve
subgroup. However, a subgroup analysis cannot be considered
definitive. Moreover, the two regimens were different not only with
respect to platinum but also paclitaxel dose and administration
schedule. Thus, the choice of platinum drug is unlikely to be
a critical factor in the outcome of our study. An ongoing ran-
domized study (ClinicalTrials.gov identifier: NCT01414608) is also
using paclitaxel plus carboplatin as the adjuvant regimen.
Treatment in both groups was well tolerated, and adverse
events were within acceptable limits. Of note, the rates of severe
grades of nonhematologic early toxicities were not significantly
different between the two study groups. Although late toxicities
beyond 3 months involving the bladder and rectum were higher in
the concomitant chemoradiation group, there was no significant
difference at 24 months or later, indicating their resolution in most
patients. Only vaginal toxicity continued to be significantly higher
in the concomitant chemoradiation group at 24 months or later.
This study has some limitations. We included patients with
different disease stages, and the analysis is not powered to definitely
answer the question in patients with operable cervical cancer
(stages IB2 and IIA). Quality of life was not prospectively measured
and could have elucidated the relative effect of two treatment
strategies on this outcome.
Our study has answered a long-standing and important
clinical question in the treatment of patients with locally advanced
cervical cancer. Concomitant chemoradiation using single-agent
weekly cisplatin results in a significantly increased DFS rate
compared with neoadjuvant chemotherapy followed by radical
surgery in this patient population.
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
OF INTEREST
Disclosures provided by the authors are available with this article at
jco.org.
AUTHOR CONTRIBUTIONS
Conception and design: Sudeep Gupta, Amita Maheshwari, Umesh
Mahantshetty, Rohini Hawaldar, Hemant Tongaonkar, Shyam Shrivastava,
Rajendra Badwe
Administrative support: Yogesh Kembhavi
Collection and assembly of data: Sudeep Gupta, Pallavi Parab, Rajendra
Kerkar, Reena Engineer, Jaya Ghosh, Seema Gulia, Neha Kumar,
T. Surappa Shylasree, Renuka Gawade, Yogesh Kembhavi, Madhuri Gaikar,
Santosh Menon, Meenakshi Thakur, Shyam Shrivastava
Data analysis and interpretation: Sudeep Gupta, Amita Maheshwari,
Pallavi Parab, Umesh Mahantshetty, Rohini Hawaldar, Supriya Sastri
(Chopra)
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors

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11. Moore DH, Blessing JA, McQuellon RP, et al:
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12. Sardi JE, Sananes CE, Giaroli A, et al: Neo-
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Cancer 8:441-450, 1998
13. Benedetti-Panici P, Greggi S, Colombo A, et al:
Neoadjuvant chemotherapy and radical surgery
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Italian multicenter randomized study. J Clin Oncol 20:
179-188, 2002
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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

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 Gupta et al

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Neoadjuvant Chemotherapy Followed by Radical Surgery Versus Concomitant Chemotherapy and Radiotherapy in Patients With Stage IB2, IIA, or
IIB Squamous Cervical Cancer: A Randomized Controlled Trial
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are
self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more
information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc.
Sudeep Gupta Seema Gulia
Research Funding: Roche (Inst), Sanofi (Inst), Johnson & Johnson (Inst), Research Funding: Pfizer (Inst)
Amgen (Inst), Celltrion (Inst), Oncostem Diagnostics (Inst), Novartis
(Inst) Neha Kumar
No relationship to disclose
Amita Maheshwari
No relationship to disclose T. Surappa Shylasree
No relationship to disclose
Pallavi Parab
Travel, Accommodations, Expenses: BIOCON Renuka Gawade
No relationship to disclose
Umesh Mahantshetty
Research Funding: Varian Medical Systems (Inst) Yogesh Kembhavi
No relationship to disclose
Rohini Hawaldar
No relationship to disclose Madhuri Gaikar
No relationship to disclose
Supriya Sastri (Chopra)
Research Funding: Varian Medical Systems (Inst) Santosh Menon
No relationship to disclose
Rajendra Kerkar
No relationship to disclose Meenakshi Thakur
No relationship to disclose
Reena Engineer
No relationship to disclose Shyam Shrivastava
No relationship to disclose
Hemant Tongaonkar
No relationship to disclose Rajendra Badwe
Research Funding: Pfizer (Inst)
Jaya Ghosh
No relationship to disclose

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 Neoadjuvant Chemotherapy Followed by Surgery in Cervical Cancer

Appendix

1.0

0.8

DFS (probability)
0.6

0.4

HR for relapse or death as a result of cancer:

1.28 (95% CI, 0.97 to 1.70); log-rank P = .086
0.2
NACT plus surgery 5-year DFS, 67.6% (95% CI, 62.1 to 73.1)
CTRT 5-year DFS, 72.0% (95% CI, 66.5 to 77.5)

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.

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 Gupta et al

A B

DFS (probability) 1.0 1.0

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.

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 Neoadjuvant Chemotherapy Followed by Surgery in Cervical Cancer

1.0

0.8

DFS (probability)
0.6

0.4 HR for relapse or death as a result of cancer:

1.49 (95% CI, 0.94 to 2.38); log-rank P = .089

Surgically resected 5-year DFS, 73.4%

0.2 (95% CI, 67.3 to 79.5)
Crossed over to CTRT 5-year DFS, 59.6%
(95% CI, 46.7 to 72.5)

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

0.4 HR for relapse or death as a result of cancer:

1.69 (95% CI, 1.02 to 2.80); log-rank P = .04

Surgical resection only 5-year disease-free survival, 77.5%

0.2 (95% CI, 70.4 to 84.6)
Adjuvant RT or CTRT 5-year disease-free survival, 64.6%
(95% CI, 53.0 to 76.2)

0 12 24 36 48 60 72 84

Time Since Random Assignment (months)

No. at risk:
Surgery 154 138 128 106 87 63 48 32
Adjuvant RT 73 62 51 42 34 26 19 12
or CTRT

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).

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 Gupta et al

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 A2. Cause of Death

No. of Patients (%)
NACT Plus Surgery CTRT
Cause of Death (n = 316) (n = 317)
Disease 66 (20.9) 64 (20.2)
Toxicity 02 (0.6) 02 (0.6)
Other cause 09 (2.8) 10 (3.2)
Unknown cause 03 (0.9) 04 (1.3)

Abbreviations: CTRT, concomitant chemoradiation; NACT, neoadjuvant

chemotherapy.

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 Neoadjuvant Chemotherapy Followed by Surgery in Cervical Cancer

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.

Table A4. Pattern of Recurrence

No. of Patients (%)
NACT Plus Surgery CTRT
Recurrence Site (n = 316) (n = 317)
Local 39 (12.3) 19 (6.0)
Distant 11 (3.5) 22 (6.9)
Local plus distant 20 (6.3) 24 (7.6)
Unknown* 19 (6.0) 8 (2.5)

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

Abbreviations: CTRT, concomitant chemotherapy and radiotherapy; DFS,

disease-free survival; NACT, neoadjuvant chemotherapy.

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