European Journal of Cancer 130 (2020) 114e125

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Clinical Trial

Comparison of survival between primary debulking
surgery and neoadjuvant chemotherapy for stage III/IV
ovarian, tubal and peritoneal cancers in phase III
randomised trial
Takashi Onda a,*, Toyomi Satoh b, Gakuto Ogawa c, Toshiaki Saito d,
Takahiro Kasamatsu e, Toru Nakanishi f, Tomonori Mizutani c,
Kazuhiro Takehara g, Aikou Okamoto h, Kimio Ushijima i,
Hiroaki Kobayashi j, Kei Kawana k, Harushige Yokota l,
Masashi Takano m, Hiroyuki Kanao n, Yoh Watanabe o,Kaichiro Yamamoto p, Nobuo Yaegashi q, Toshiharu Kamura r,
Hiroyuki Yoshikawa s on behalf of Japan Clinical Oncology Groupa

Department of Gynecology, Kitasato University School of Medicine, Sagamihara, Japan
Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japanc
JCOG Data Center/Operations Office, National Cancer Center Hospital, Tokyo, Japand
Gynecology Service, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japane
Department of Gynecologic Oncology, National Cancer Center Hospital, Tokyo, Japanf
Department of Gynecologic Oncology, Aichi Cancer Center Hospital, Nagoya, Japang
Department of Gynecologic Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japanh
Department of Obstetrics and Gynecology, The Jikei University School of Medicine, Tokyo, Japani
Department of Obstetrics and Gynecology, Kurume University School of Medicine, Kurume, Japanj
Department of Gynecology and Obstetrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japank
Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japanl
Department of Gynecology, Saitama Cancer Center, Kita Adachi Gun, Japanm
Department of Clinical Oncology, National Defense Medical College Hospital, Tokorozawa, Japann
Department of Gynecological Oncology, Cancer Institute Hospital, Tokyo, Japano
Department of Obstetrics and Gynecology, Kindai University Faculty of Medicine, Osakasayama, Japanp
Department of Obstetrics and Gynecology, Faculty of Medicine, Kindai University, Sakai Hospital, Sakai, Japanq
Department of Obstetrics and Gynecology, Tohoku University Graduate School of Medicine, Sendai, Japanr
Medical Care Education Research Foundation, Yanagawa Hospital, Yanagawa, Japans
Ibaraki Prefectural Central Hospital, Kasama, Japanb

Received 2 August 2019; received in revised form 5 February 2020; accepted 9 February 2020

* Corresponding author. Takashi Onda, Department of Gynecology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku,
Sagamihara, Kanagawa, 252-0374, Japan. Fax: þ81 42 778 9433.
E-mail address: takashi-tky@umin.ac.jp (T. Onda).
https://doi.org/10.1016/j.ejca.2020.02.020
0959-8049/ª 2020 Elsevier Ltd. All rights reserved.

T. Onda et al. / European Journal of Cancer 130 (2020) 114e125

KEYWORDS
Ovarian neoplasms;
Neoadjuvant
chemotherapy;
Interval debulking
surgery;
Primary debulking
surgery

115

Abstract Background: Regarding the comparison between primary debulking surgery (PDS)
and neoadjuvant chemotherapy (NACT) for stage III/IV ovarian, tubal and peritoneal cancers, EORTC55971 and CHORUS studies demonstrated noninferiority of NACT. Previously,
we reported reduced invasiveness of NACT in JCOG0602. This is a final analysis including the
primary endpoint of overall survival (OS).
Methods: Patients were randomised to PDS (PDS followed by 8x paclitaxel and carboplatin,
i.e. TC regimen) or NACT (4x TC, interval debulking surgery [IDS], 4x TC). The primary
endpoint was OS. The noninferiority hazard ratio (HR) margin for NACT compared with
PDS was 1$161. The planned sample size was 300.
Findings: Between 2006 and 2011, 301 patients were randomised, 149 to PDS and 152 to
NACT. The median OS was 49$0 and 44$3 months in the PDS and NACT. HR for NACT
was 1$052 [90$8% confidence interval (CI) 0$835e1$326], and one-sided noninferiority p-value
was 0$24. Median progression-free survival was 15$1 and 16$4 months in the PDS and NACT
(HR: 0$96 [95%CI 0$75e1$23]). In the PDS arm, 147/149 underwent PDS and 49/147 underwent IDS. In the NACT arm 130/152 underwent IDS. Complete resection was achieved in 12%(17/147) of PDS and 31% (45/147) of PDS  IDS in the PDS arm and in 64% (83/130) of IDS
in the NACT arm. Optimal surgery (residual tumour <1 cm) was achieved in 37% (55/147),
63% (92/147), and 82% (107/130 respectively. In the NACT, PS 2/3, serum albumin 2$5,
CA125 > 2000 an institution with low study activity was advantageous, whereas clear/mucinous histology was disadvantageous for OS.
Interpretation: The noninferiority of NACT was not confirmed. NACT may not always be a
substitute for PDS. However, as our study had smaller numbers, the noninferiority of the previous studies cannot be denied.
Funding: Ministry of Health, Labour and Welfare, Japan and the National Cancer Center,
Japan.
Clinical trial information: UMIN000000523.
ª 2020 Elsevier Ltd. All rights reserved.

1. Introduction
Epithelial ovarian, tubal, or peritoneal cancer isacknowledged to have the worst prognosis among major
gynecologic malignancies. One of the reasons for this isthat most cases present in advanced stages (about twothirds at stage III/IV [1]). The prognosis of advanced
disease is very poor, with 5-year survival rates lower
than 35% [1]. The standard treatment for advanced tumours is primary debulking surgery (PDS), followed byplatinum and taxane chemotherapy. Although optimal
debulking (less than 1 cm in maximum diameter of residual tumour) or complete resection (no residual
tumour) is desirable, optimal surgery is only achieved in
25%e40% of cases undergoing PDS in the vast majority
of institutions [2].
Patients with apparently unresectable tumours by imaging study or laparoscopic inspection and patients withlow performance status (PS) or medical complications
often receive neoadjuvant chemotherapy (NACT), followed by interval debulking surgery (IDS) and subsequentchemotherapy as an alternative approach. The results ofseveral retrospective analyses comparing NACT with PDS
have shown a higher proportion of optimal surgery [3e6],
comparable overall survival (OS) [3e6], and reduced surgical invasiveness [4,7e9] with NACT.

To further investigate the favourable outcomes
associated with NACT, at least three randomised trials
comparing PDS and NACT were conducted in Europe[10,11] and Japan [12]. Two previous studiesdthe
EORTC55971 study [10], conducted by the European
Organization for Research and Treatment of Cancer(EORTC) and the CHORUS study [11], conducted by
the Medical Research Council Clinical Trials Unit
(MRC-CTU)ddemonstrated the noninferior OS(EORTC hazard ratio [HR] 0$98 [90% confidence interval [CI] 0$84e1$13], noninferiority margin 1$25;
CHORUS HR 0$87 [95% CI 0$72e1$05], noninferiority
margin 1$18) and reduced invasiveness of NACT.
The Japan Clinical Oncology Group (JCOG) phase III
randomised clinical trial (JCOG0602) previously clearly
demonstrated the reduced invasiveness of NACT
compared with PDS, in terms of the number of surgeries,
operation time, blood/ascites loss and transfusions, perioperative morbidity and extent of surgery [13]. Now, theauthors report the results of the study’s final analysis,
including the primary endpoint of OS and the major secondary endpoint of progression-free survival (PFS).

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T. Onda et al. / European Journal of Cancer 130 (2020) 114e125

2. Patients and methods

2.4. Procedures

2.1. Study design

Patients assigned to PDS arm were submitted to PDS
and subsequently received eight cycles of postoperative
chemotherapy. IDS after the fourth cycle of chemotherapy was allowed for residual tumours >1 cm indiameter after PDS; IDS was mandatory in cases inwhich the uterus, adnexa or omentum was not removed
by PDS, unless disease progression was noted.
Patients assigned to the NACT arm received fourcycles of NACT and were subsequently submitted to
IDS (unless disease progression was noted), followed byfour cycles of postoperative chemotherapy.
The standard procedures for PDS in PDS arm and
IDS in the NACT arm consisted of total abdominal
hysterectomy,
bilateralsalpingo-oophorectomy,
omentectomy and maximum debulking of metastatic
tumours. Systematic pelvic lymphadenectomy (PLA)
and/or para-aortic lymphadenectomy (PALA) wereallowed but excluded from standard procedures. All
surgeries were performed under the responsibility ofgynecologic oncologists certified by the Japan Society of
Gynecologic Oncology. IDS during PDS treatment was
performed to complete the aforementioned standard
procedures. Maximum debulking of metastatic tumours
and lymphadenectomies were allowed. Minimally invasive surgery, such as laparoscopic or robotic surgery,
was not allowed.
Both NACT and postoperative chemotherapy
comprised a combination of paclitaxel (175 mg/m2, day
1) and carboplatin (AUC 6, day 1), namely, the TC
regimen. These agents were administered every three
weeks.
Detailed treatment schedules are provided in the
Supplementary protocol.
Physical examination, subjective or objective
symptoms and tumour marker should be evaluatedevery one month for two years after the protocoltreatment, every two months in the third year, every
three months in the fourth year and every six months
thereafter. Chest X-rays and upper abdominal and pelvic imaging were performed every six months for one
year, then annually along with routine examinations.

This study was a randomised open-label phase III
noninferiority trial in 34 Japanese centres or hospitals,
for which the planned accrual period of three years was
extended to nearly five years because of the slow accrual
pace. The follow-up period after accrual completion was
extended from five to six years because of the low
number of events.
The trial was conducted in accordance with the
Declaration of Helsinki. The study protocol wasapproved by the JCOG Protocol Review Committee andthe institutional review board of each participating
institution before patient enrolment. This study isregistered in UMIN-CTR (www.umin.ac.jp/ctr/) underidentification number UMIN000000523.

2.2. Patients
This study included subjects with presumed International Federation of Gynecology and Obstetrics (FIGO,
1988) stages III or IV ovarian, tubal and peritoneal
cancers diagnosed using clinical findings, including imaging studies (CT, MRI and chest radiography) andcytology of ascites, pleural effusions or tumour cyst
fluids obtained by tumour centesis. Diagnostic laparoscopy or laparotomy was not performed as the previous
feasibility JCOG0206 study confirmed that the target
disease could be diagnosed with >90% accuracy (positive predictive value) by imaging analysis only [14].
Malignancies of different origins, e.g. breast and digestive tract, were excluded by mammography, ultrasonography, endoscopy or opaque enema whenever they
were suspected from symptoms, physical examination or
imaging exams. For ruling out malignancies of thedigestive tract, the criteria for tumour markers were set
at CA125 > 200 U/mL and CEA <20 ng/ml. Other inclusion criteria included (1) age, 20e75 years; (2)Eastern Cooperative Oncology Group (ECOG) PS,
0e3; (3) adequate bone marrow, hepatic, renal,
cardiac and respiratory functions; and (4) written
informed consent. The details for further inclusion andexclusion criteria are shown in the Supplementary
protocol and described in previous reports [13].

2.5. Outcomes
2.3. Randomisation and masking
Patients were randomised to PDS or NACT arm by aminimization method with a random element [15] at the
JCOG Data Center. Allocation factors for minimization
were an institution, stage (III vs. IV), PS (0e1 vs. 2e3)
and age (<60 vs. 60). Participants and investigators
were not masked to treatment allocation.

The study primary endpoint was OS for all randomised
patients, measured from the date of registration to thedate of death from any cause. The major secondary efficacy endpoint was progression-free survival (PFS),
which was calculated from the date of registration to theearliest date of progression, recurrence, or death fromany cause.

T. Onda et al. / European Journal of Cancer 130 (2020) 114e125

117

Fig. 1. CONSORT flowchart of patient selection. The number of enrolled and randomised patients who received treatment and were
included in the analysis. Tx: treatment, CTx: chemotherapy, AE: adverse event.

2.6. Statistical analysis
After the follow-up period, the primary analysis using a
Cox proportional hazard model stratified by stage,
PS and age was specified to test NACT noninferiority
for OS in all randomised patients. A required total event
number of 276 would provide an 80% statistical powerwith a one-sided alpha of 0$05 to confirm the noninferiority of NACT, with a noninferiority HR marginof 1$161. A HR of 1$161 corresponds to a 5% decreasein 3-year survival with PDS. Taking into account theaccrual and follow-up periods, a sample size of 298
patients was calculated, estimating a 3-year survival of
25% with PDS and an expected 3-year survival of 30$3%

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T. Onda et al. / European Journal of Cancer 130 (2020) 114e125

with NACT. Thus, a target sample size of 300 patients(150 patients per group) was defined. For the primary
analysis of OS, the null hypothesis was “NACT isinferior to PDS (HR > 1$161)” and the alternative hypothesis was “NACT is not inferior to PDS(HR  1$161)”. In the planned settings, HR of 0$953
was the boundary to reject the null hypothesis when 276
events were observed. The interim analysis was planned
after enrolment of 150 patients, and additional interim
analysis was planned at 2$5 years after patient assignment because of extended accrual and follow-up periods. The O’BrieneFleming-type alpha-spending
function was used to adjust multiplicity for OS.
The OS and PFS curves were calculated using the
KaplaneMeier method, and HRs and respective CIs
were estimated using the Cox proportional hazard
model. The total number of events observed was 226,
even after extended follow-up periods. Actual statisticalpower became 73%. Adverse events and surgical invasiveness had already been shown in a previous report[13]. All analyses were conducted in the statistical program SAS Release 9$4 (SAS Institute, Cary, NC).

noninferiority HR for OS of NACT compared with
PDS was 1$052 (90$8% CI 0$8351$326; P Z 0$24).
The proportional hazard assumption was checked using
a logelog plot, and no serious problem was observed.
The median PFS values were 15$1 and 16$4 M in the
PDS and NACT arms, respectively (Fig. 2B), with a HR
of 0$96 (95% CI 0$751$23) for noninferiority of
NACT.
Fig. 3 shows the OS according to treatment arm anddebulking results. The median OS values for patientswith 0, <1, and 1 cm residual tumours were following;
not estimable, 54$9 M, and 43$0 M in the PDS arm and
67$0, 34$0, and 32$0 M in the NACT arm, respectively.
Adverse events and surgical invasiveness had alreadybeen shown in a previous report [13].
To identify subgroups of patients or institutions with
better OS associated with either of the study arms, forest
plots were shown according to different prognostic
factors (Fig. 4). Considering patients’ characteristics, theHR of NACT was considerably lower in subgroups withpoor PS (2 or 3), low albumin (2$5 g/dL), and highCA125 (>2000 U/mL), whereas it was considerably
higher in subgroups with chemo-resistant histology(pathologically clear and mucinous). Concerning

3. Results
Table 1

From November 2006 to October 2011, 301 patientswere enrolled in the study. All patients were randomly
assigned to PDS or NACT (Fig. 1). A total of 149 patients were assigned to the PDS arm; 147 of these patients underwent PDS, 49 of which underwent IDS. A
total of 152 patients were assigned to the NACT arm,
150 of whom received NACT and 130 of them underwent IDS. All randomised 301 patients were included in
the primary analysis. Patients’ characteristics and thenumber of chemotherapy cycles received are listed inTable 1. Over 30% of patients had stage IV disease, andapproximately 13% had PS 2/3 in each treatment arm.
All adjustment factors were equally distributed. The
median number of chemotherapy cycles was eight for
both arms.
Histological diagnosis, median operation time, andfrequency of surgical procedures are listed in Table 2.
Serous histology was observed in nearly 80% of patientsin each arm, and chemo-resistant histology (clear andmucinous adenocarcinoma) was observed in 9$5% and
4$6% of patients in the PDS and NACT arms, respectively. Both complete and optimal surgeries were more
frequently achieved with IDS in the NACT arm thanwith PDS or PDS  IDS in the PDS arm (63$8% vs.
11$6% or 30$6%, and 82$3% vs. 37$4% or 62$6%,
respectively).
The median OS values for all patients randomised
were 49$0 and 44$3 months (M) in the PDS and NACT
arms, respectively (Fig. 2A). For the primary analysis,
the significance level of 0$046 was used for adjusting
multiplicity owing to interim analyses. The

Baseline patient characteristics (for all patients enrolled).
Treatment arm

PDS (N Z 149)

Median age (range)
59 (30e75)Age<60
75 (50$3%)
60
74 (49$7%)PS
0e1
130 (87$2%)
2e3
19 (12$8%)
Stage
III
100 (67$1%)
IV
49 (32$9%)
Primary tumoura
Ovary
131 (87$9%)
Fallopian tube
1 (0$7%)Peritoneum23 (15$4%)
Measurable lesions
present
140 (94$0%)
absent9 (6$0%)CA125(U/mL)
500
24 (16$1%)
1000
25 (16$8%)
2000
26 (17$4%)>2000
74 (49$7%)
Size of upper abdominal tumour2 cm
32 (21$5%)5 cm
42 (28$2%)
10 cm40 (26$8%)>10 cm35 (23$5%)
Chemotherapy cycles
Median (25%e75%)
8 (6e8)Average  SD
6$7  2$5

NACT (N Z 152)
60$5 (36e75)
72 (47$4%)
80 (52$6%)
131 (86$2%)
21 (13$8%)
105 (69$1%)
47 (30$9%)
125 (82$2%)
1 (0$7%)34 (22$4%)
142 (93$4%)
10 (6$6%)
29 (19$1%)
34 (22$4%)
24 (15$8%)
65 (42$8%)
42 (27$6%)51 (33$6%)
35 (23$0%)
24 (15$8%)
8 (7e8)6$8  2$2

PDS, primary debulking surgery; NACT, neoadjuvant chemotherapy;
PS; performance status; SD, standard deviation.
a
Selection of multiple sites was allowed if it was difficult to specify
one primary site.

T. Onda et al. / European Journal of Cancer 130 (2020) 114e125

119

Table 2
Histology diagnosed from surgical specimens and surgery-related factors.
Treatment arm

PDS (N Z 149)

Surgery

PDS (N Z 147)

Histology
SerousEndometrioid
Mucinous
Clear
Mixed
Others115 (78$2%)
6 (4$1%)2 (1$4%)12 (8$2%)
4 (2$7%)8 (5$4%)

Median operation time (min)Surgical outcome
RT Z 0RT < 1 cm
RT  1 cm
Surgical procedures
Pelvic lymphadenectomy
Para-aortic lymphadenectomy
Abdominal organ resection

NACT (N Z 152)
IDS (N Z 49)

PDS  IDS (N Z 147)

IDS (N Z 130)102 (78$5%)
4 (3$1%)2 (1$5%)4 (3$1%)
1 (0$8%)17 (13$1%)

240

270

347

302

17 (11$6%)
38 (25$9%)
92 (62$6%)

28 (57$1%)
9 (18$4%)
12 (24$5%)

45 (30$6%)
47 (32$0%)55 (37$4%)

83 (63$8%)
24 (18$5%)
23 (17$7%)40 (27$2%)
17 (11$6%)
40 (27$2%)

19 (38$8%)
12 (24$5%)
17 (34$7%)

59 (40$1%)
29 (19$7%)
56 (38$1%)

94 (72$3%)
64 (49$2%)
36 (27$7%)

PDS, primary debulking surgery; NACT, neoadjuvant chemotherapy; IDS, interval debulking surgery; RT, residual tumour.

institution features, the HR of NACT was lower in thesubgroup with low study activity (<20 total patient accruals) and higher in the subgroup with high study activity (20 total patient accruals). A similar HR was
found for subgroups with high (>60%) and low (<60%)
proportions of optimal debulking in PDS (HR Z 1$12
vs. 1$05).
4. Discussion
Compared with PDS, a survival noninferiority of NACT
was not confirmed in this study. This disagrees withprevious phase III randomised studies (EORTC55971[10] and CHORUS [11]), which showed noninferior OS
of NACT compared with PDS. The results of these twostudies and the present one are summarised in Table 3.
The possible reasons for the disparate results aredifferent study designs, treatment protocols and surgicaloutcomes along with the lower statistical power in ourstudy.
Compared with previous studies, in this study, IDS
was more frequently performed in PDS arm (33% vs.
17% and not described [probably less frequent] in
EORTC [10] and CHORUS[11], respectively). One
reason for the higher incidence of IDS was lower rates ofcomplete and optimal debulking at PDS compared withprevious studies. Another reason was a wide indicationof IDS in our study; it allowed for patients with suboptimal PDS and mandatory in cases the uterus,
adnexa, or omentum was not removed by PDS.
Although the treatment efficacy of IDS following suboptimal PDS was demonstrated by another EORTC
phase III trial [16], a randomised trial conducted after
the EORTC study by Gynecologic Oncology Group did
not corroborate this efficacy benefit [17]. Owing to theseresults, EORTC 55971 institutions may hesitate toperform IDS, although it is recommended in theirtreatment protocol following nonoptimal PDS. In the
CHORUS trial, institutions had to specify patients
before randomisation to perform IDS. The protocol
setting in CHORUS might preclude the IDS. However,a Cochran systematic review with meta-analysis
concluded that IDS yields benefit only for women witha primary surgery not performed by gynecologic oncologists or less extensive [18]. This means that patientswith insufficient PDS may benefit from IDS. Considering the highly suboptimal rate of PDS in the present
study, more patients in the PDS arm may benefit from
IDS. A higher percentage of IDS might have improved
OS associated with PDS in the present study.
Conversely, 20 patients (13%) did not undergo IDS in
the NACT arm; this may have worsened the outcome of
NACT; however, the frequency in our study was notmuch higher than in previous studies (11% in EORTC
and 20% in CHORUS).
Although NACT had an apparent advantage in stage
IV patients [19] in the pooled analysis of the two previous studies, this was not confirmed in this study.
Although the HR for NACT was similar in both analyses for stage III patients (1$04 and 1$04, respectively),
it was much lower in the pooled analysis than in thepresent study for stage IV patients (0$76 [median OS,
21$2 and 23$2 M in PDS and NACT, respectively] vs.
1$15 [median OS, 45$7 and 46$0 M in PDS and NACT,
respectively]). The outcomes of patients with stage IV
ovarian cancer receiving PDS were poorer in the two
previous studies, which may be due to two disparate
reasons. On the one hand, there was a higher frequencyof postoperative deaths with PDS in those studies (2$5%in EORTC and 6% in CHORUS) compared to ours
(0$7%), potentially worsening the PDS outcomes. The
lower incidence may be related to less aggressive PDS in

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T. Onda et al. / European Journal of Cancer 130 (2020) 114e125

A

B

Fig. 2. Prognosis of patients enrolled. Overall survival. (A) and progression-free survival (B) of patients who were enrolled in the study. HR
for death with NACT compared with PDS was 1$052 (90$8% CI, 0$8351$326; P Z 0$24 for noninferiority calculated using the Cox
proportional hazard model stratified by FIGO stage, PS and age) (A). HR for progression with NACT compared with PDS was 0$96 (95%CI, 0$751$23 calculated by the Cox proportional hazard model stratified by theFIGO stage, PS and age) (B).

the present study. On the other hand, there may be somereluctance by clinicians to perform aggressive maximum
debulking surgery, especially in stage IV patients. In thepresent study, the opportunity to perform IDS as second
surgery in the PDS arm may have given a safe andrather aggressive treatment option for stage IV patientsin that treatment arm. The absence of an advantage of
NACT in stage IV patients in the present study may also
explain why our results did not match those from previous studies.
Regarding chemotherapy cycle numbers in NACT,
four cycles used in this study were larger than threecycles used in the previous two studies. NACT may
more frequently induce chemo-resistance because of thelarger tumour volume at the initiation of chemotherapy[20e22]. Possibly, our four-cycle NACT regimen may
have induced a higher frequency of chemo-resistancebecause post-progression survival in NACT was 6
months shorter than that in PDS in this study; however,the survivals were almost the same in the previous twostudies.
As for the age, our study limited the age to 75 years
old in contrast to previous studies, those made no age
limitation. Advanced age is known to be an important
prognostic factor for ovarian cancer [23], and NACT is
proposed as an effective way of managing elderly patients [24]. The age limitation in the present study may
contribute to better OS in both arms and worse NACT
efficacy compared with previous studies.
The present study showed that institutions with highsurgical activity (proportion of optimal surgery in
PDS > 60% [mean; 74%]) achieved better OS than thosewith low surgical activity (mean; 24%) in both PDS and
NACT (56$9 M and 49$5 M vs. 46$8 M and 42$4 M,
Supplementary Table 1). As a result, a similar HR for
NACT (HR Z 1$12 vs. HR Z 1$05) was observed between institutions with high and low surgical activity(Fig. 4), because institutions with high and low surgical

T. Onda et al. / European Journal of Cancer 130 (2020) 114e125

121

A

B

Fig. 3. Overall survival, according to the residual tumour size at debulking surgery. Overall survival for patients treated with PDS (A) and
NACT (B) according to residual tumour size at debulking surgery. In PDS, 49 patients who underwent both PDS and IDS were classified
according to the residual tumour size at PDS without considering IDS results. In NACT, 20 patients who did not undergo IDS were
excluded from this analysis.

activity in PDS had similar high and low surgical activity also in IDS in NACT (proportion of complete
surgery; 80% vs. 59%). Although our data suggest thatsurgical activity is not so related to superiority or inferiority of NACT compared with PDS, we must expect
the results of new phase III studies comparing PDS and
NACT among institutions achieving complete resectionin 50% PDS dTRUST and SUNNY (ClinicalTrials.
gov NCT02859038 and NCT02828618) dconductedby Arbeitsgemeinschaft Gynäkologische Onkologie(AGO) and the Shanghai Gynecologic Oncology
Group (SGOG).
Concerning the other subset analyses, patients withpoor PS (2 or 3), low albumin (2$5 g/dL), and highCA125 (>2000 U/mL) showed favourable treatment
outcomes with NACT in this study’s subgroup analyses.
These findings are in line with previous studies showing
these features as unfavourable prognostic factors or

predictors for suboptimal debulking with PDS [23,25].
High CA125 (>2000 U/mL) indicates serous histology
or chemo-sensitivity. In previous studies, a higher frequency of PS 2 (CHORUS) or undifferentiated histology (CHORUS and EORTC) may have improved
treatment results with NACT. In this study, although
the number of patients was small, PDS was associatedwith relatively better treatment outcomes in patientswith clear-cell or mucinous histology. These results
suggest that there is diversity in the efficacy of PDS and
NACT among various subgroups of advanced ovariancancer.
On the basis of the results from the CHORUS andEORTC trials [10,11], our preceding study concerning
treatment invasiveness [13], and another phase III trial[26], the American Society of Clinical Oncology (ASCO)[27] and the Society of Gynecologic Oncology (SGO)[28] copublished guidelines for the treatment of

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T. Onda et al. / European Journal of Cancer 130 (2020) 114e125

Fig. 4. Treatment effect for NACT on overall survival in subgroups. Treatment effect with NACT compared with PDS in several subgroups.
UAT: upper abdominal tumour.

advanced ovarian cancer in 2016. The guidelines
generally recommend NACT for all patients, except for
those with optimally resectable tumours and a generalcondition suitable for surgery. Concurrently (or previously), NACT had become more widely accepted as oneof the standard treatment options for such advanced
ovarian cancer patients [29,30]. In fact, the results fromthree randomised studies, including ours, suggest that
NACT is a safer treatment for ovarian cancer. However,regarding the efficacy results, our results demonstrated
that NACT may not always be a good substitute for

PDS in advanced ovarian tumours, suggesting that patients who are candidates for NACT should be selectedon the basis of resectability, general condition, nutritionand supposed chemo-sensitivity. This study’s results
were generally in line with the guidelines.
This study has some limitations. First, the sample sizein our study was rather small than that in previous
studies. Further, the reduction of statistical power to
73% owing to fewer events than expected was also ashortcoming of our study. However, even if the numberof events was 276 as planned, noninferiority could not

Table 3Comparison of treatment results of three phase III studies.
Study

EORTC

CHORUSJCOG

Treatment arm

PDS (N Z 336) NACT (N Z 334) PDS (N Z 276) NACT (N Z 274) PDS (N Z 149) NACT (N Z 152)

Surgery

PDS (N Z 310) IDS (N Z 322)

PDS (N Z 251) IDS (N Z 217)

PDS (N Z 147) IDS (N Z 130)

Surgical outcome and procedures
Operation time165
RT Z 061 (19%)RT < 1 cm
70 (22%)RT  1 cm
167 (53%)180
151 (51%)
87 (30%)52 (18%)120
39 (17%)57 (24%)137 (59%)120
79 (39%)68 (34%)54 (27%)240
17 (12%)38 (26%)92 (63%)302
83 (64%)24 (18%)23 (18%)Survival outcomesPFS (Months)
OS (Months)

12
29

12
30

10$7
22$6

12$0
24$1

15$1
49$0

16$4
44$3

Statistical factors
HR for NACT in OS
Confidence Interval (CI)
Noninferiority margin
P value for noninferiority

0$98
90% CI 0$84e1$13
1$25
0$01

0$87
95% CI 0$72e1$05
1$18
NA

1$05
90$8% CI 0$83e1$33
1$161
0$24

PDS, primary debulking surgery; NACT, neoadjuvant chemotherapy; IDS, interval debulking surgery; RT, residual tumour; PFS, progression-freesurvival; OS, overall survival; PLA, pelvic lymphadenectomy; PALA, para-aortic lymphadenectomy; HR, hazard ratio; NA, not available.

T. Onda et al. / European Journal of Cancer 130 (2020) 114e125

be confirmed because observed HR of 1$052 exceeded
the boundary of 0$953 in planned settings. Second,although the HR for NACT was rather higher in subgroups with clear and mucinous histology, the study
protocol did not require histological confirmation bysurgery at the start of treatment in NACT arm.
Consequently, it may be inappropriate to discuss thehistological diagnosis in NACT in this study.
In conclusion, the OS noninferiority of NACT was
not confirmed. The data suggest that NACT may notalways be a substitute for PDS. Our study had a smaller
sample size; therefore, we cannot deny the noninferiority
evidence of NACT confirmed by the previous twostudies. There seems to be diversity in the efficacy of
PDS or NACT among subgroups of advanced ovariancancer.
Contribution of authors
TO1 and HY19 were involved in the conception,
design and management of the study. TO1 and HY19
were also involved in patient recruitment, data collection, data analysis, interpretation and manuscript
writing. TS2, TS4, TK5, TN6, KT7, AO8, KU9, HK10,
KK11, HY12, MT13, HK14, YW15, KY16, NY17, TK18
were involved in patient recruitment, data collection andcontributed to manuscript writing. TM3 was involved indata collection, analysis, interpretation and contributed
to manuscript writing. GO3 was responsible for statistical analysis and interpretation, and contributed tomanuscript writing. All authors reviewed the final
version of the manuscript.
Conflict of interest statement
TO1 received grant and personal fee from Chugai,
grants from Kaken, Taiho, Daiichi-Sankyo, Mochida,
and Meiji Yasuda Health Development Foundation,and personal fees from AstraZeneca and Ono outside
the submitted work. TS2 reported personal fees from
Mochida, Nippon Kayaku, Chugai, Daiichi-Sankyo,
Kyowa Kirin, AstraZeneca, Kaken, Eisai, Tsumura,
Beyer, and Aska outside the submitted work. TS4 reported grants and personal fees from Chugai andNippon Kayaku, and grants from Taiho and Yakult
outside the submitted work. KT7 reported otherfinancial activities from AstraZeneca, Daiichi Sankyo,
Chugai, and Eisai outside the submitted work. AO8
reported other financial activities from Taiho, Meiji,
Fuji, Nippon Shinyaku, Novartis, Mochida, Chugai,
Tsumura, Pfizer, Kissei, Shionogi, Daiichi Sankyo,
Kaken, GenoDive, CMIC, and Shinnihonseiyaku, andpersonal fee from AstraZeneca outside the submitted
work. KU9 received grants and personal fees from
AstraZeneca, MSD, Chugai, Kaken, Takeda, Nippon
Kayaku, Mochida, and Tsumura, and grants from123

Abbvie, Ono, and Eisai, and personal fees from Taiho,
Yakult, Kyowa Kirin, Bayer, and Aska outside thesubmitted work. HY12 received grants from MSD and
Zeria, and personal fees from Kaken, Ono, AstraZeneca and Chugai, and Pfizer outside the submitted
work. TK18 reported a personal fee from BrightPath
Biotherapeutics outside the submitted work. HY19 reported personal fees from Ono, Taiho, MSD, and GSK
outside the submitted work. GO3, TK5, TM3, TN6,
HK10, KK11, MT13, HK14, YW15, KY16, NY17 reported no competing interests.

Acknowledgments
Participating institutions:
Hokkaido University Hospital; Sapporo Medical
University; Iwate Medical University; Tohoku University Hospital; Faculty of Medicine, University of Tsukuba; National Defense Medical College; Saitama
Cancer Center; Saitama Medical Center, Saitama
Medical University; Jikei Kashiwa Hospital; National
Cancer Center Hospital; Jikei University Hospital;
Cancer Institute Hospital of Japanese Foundation forCancer Research; The University of Tokyo Hospital;
Juntendo University Hospital; Kitasato University
School of Medicine; Niigata Cancer Center Hospital;
Shinshu University School of Medicine; Aichi Cancer
Center Hospital; Nagoya University School of Medicine; Kyoto University Hospital; Osaka City University
Hospital; Kindai University Faculty of Medicine; Osaka
Prefectural Hospital Organization Osaka Medical Center for Cancer and Cardiovascular Diseases; Osaka City
General Hospital; Sakai Hospital, Kindai University
Faculty of Medicine; Faculty of Medicine, Tottori
University; National Hospital Organization Kure
Medical Center Chugoku Cancer Center; National
Hospital Organization Shikoku Cancer Center; National Kyushu Cancer Center; Kurume University
School of Medicine; Kyushu University Hospital; Faculty of Medicine, Saga University; Kagoshima City
Hospital; University of the Ryukyus Hospital.
JCOG Data Center and Operations Office:H. Fukuda (Data Center Director), J. Mizusawa(Statistical Section), K. Kubota (Data Management
Section), J. Eba, (Operations Office).
Funding source
The study was supported by Health Sciences
Research Grants for the Third-Term Comprehensive
Control Research for Cancer (H16-035), Health Sciences Research Grants for Clinical Cancer Research(H19e028, H22-020), Grants-in Aid for Cancer
Research (17S-1, 17S-5, 18-06, 20S-1, 20S-6) from the
Ministry of Health, Labour and Welfare, Japan, and the
National Cancer Center Research and Development
Funds (23-A-16, 23-A-17, 26-A-4, and 29-A-3).
Role of the funding source

124

T. Onda et al. / European Journal of Cancer 130 (2020) 114e125

The funders had no role in study design, datacollection, data analysis, data interpretation, or writingof the report.
Appendix A. Supplementary data
Supplementary data to this article can be found online
at https://doi.org/10.1016/j.ejca.2020.02.020.

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