Clinical Trial| Volume 130, P114-125, May 2020

Download started.


Comparison of survival between primary debulking surgery and neoadjuvant chemotherapy for stage III/IV ovarian, tubal and peritoneal cancers in phase III randomised trial

Published:March 13, 2020DOI:


      • Survival noninferiority of NACT compared to PDS was not confirmed in this study.
      • Noninferiority of the previous studies cannot be denied because of smaller numbers.
      • There seems to be diversity in the efficacy of PDS/NACT among subgroups of patients.



      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).


      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.


      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) 0·835–1·326], 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 0·75–1·23]). 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.


      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.


      Ministry of Health, Labour and Welfare, Japan and the National Cancer Center, Japan.

      Clinical trial information



      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to European Journal of Cancer
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Heintz A.P.
        • Odicino F.
        • Maisonneuve P.
        • Quinn M.A.
        • Benedet J.L.
        • Creasman W.T.
        • et al.
        Carcinoma of the ovary. FIGO 26th Annual Report on the Results of Treatment in Gynecological Cancer.
        Int J Gynaecol Obstet. 2006; 95: S161-S192
        • Dauplat J.
        • Le Bouedec G.
        • Pomel C.
        • Scherer C.
        Cytoreductive surgery for advanced stages of ovarian cancer.
        Semin Surg Oncol. 2000; 19: 42-48
        • Jacob J.H.
        • Gershenson D.M.
        • Morris M.
        • Copeland L.J.
        • Burke T.W.
        • Wharton J.T.
        Neoadjuvant chemotherapy and interval debulking for advanced epithelial ovarian cancer.
        Gynecol Oncol. 1991; 42: 146-150
        • Kayikçioḡlu F.
        • Köse M.F.
        • Boran N.
        • Çalişkan E.
        • Tulunay G.
        Neoadjuvant chemotherapy or primary surgery in advanced epithelial ovarian carcinoma.
        Int J Gynecol Cancer. 2001; 11: 466-470
        • Vrščaj M.U.
        • Rakar S.
        Neoadjuvant chemotherapy for advanced epithelial ovarian carcinoma: a retrospective case-control study.
        Eur J Gynaecol Oncol. 2002; 23: 405-410
        • Everett E.N.
        • French A.E.
        • Stone R.L.
        • Pastore L.M.
        • Jazaeri A.A.
        • Andersen W.A.
        • et al.
        Initial chemotherapy followed by surgical cytoreduction for the treatment of stage III/IV epithelial ovarian cancer.
        Am J Obstet Gynecol. 2006; 195 (discussion 74-6): 568-574
        • Schwartz P.E.
        • Rutherford T.J.
        • Chambers J.T.
        • Kohorn E.I.
        • Thiel R.P.
        Neoadjuvant chemotherapy for advanced ovarian cancer: long-term survival.
        Gynecol Oncol. 1999; 72: 93-99
        • Morice P.
        • Brehier-Ollive D.
        • Rey A.
        • Atallah D.
        • Lhommé C.
        • Pautier P.
        • et al.
        Results of interval debulking surgery in advanced stage ovarian cancer: an exposed-non-exposed study.
        Ann Oncol. 2003; 14: 74-77
        • Hou J.Y.
        • Kelly M.G.
        • Yu H.
        • McAlpine J.N.
        • Azodi M.
        • Rutherford T.J.
        • et al.
        Neoadjuvant chemotherapy lessens surgical morbidity in advanced ovarian cancer and leads to improved survival in stage IV disease.
        Gynecol Oncol. 2007; 105: 211-217
        • Vergote I.
        • Tropé C.G.
        • Amant F.
        • Kristensen G.B.
        • Ehlen T.
        • Johnson N.
        • et al.
        Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer.
        N Engl J Med. 2010; 363: 943-953
        • Kehoe S.
        • Hook J.
        • Nankivell M.
        • Jayson G.C.
        • Kitchener H.
        • Lopes T.
        • et al.
        Primary chemotherapy versus primary surgery for newly diagnosed advanced ovarian cancer (CHORUS): an open-label, randomised, controlled, non-inferiority trial.
        Lancet. 2015; 386: 249-257
        • Onda T.
        • Matsumoto K.
        • Shibata T.
        • Sato A.
        • Fukuda H.
        • Konishi I.
        • et al.
        Phase III trial of upfront debulking surgery versus neoadjuvant chemotherapy for stage III/IV ovarian, tubal and peritoneal cancers: Japan Clinical Oncology Group Study JCOG0602.
        Jpn J Clin Oncol. 2008; 38: 74-77
        • Onda T.
        • Satoh T.
        • Saito T.
        • Kasamatsu T.
        • Nakanishi T.
        • Nakamura K.
        • et al.
        Comparison of treatment invasiveness between upfront debulking surgery versus interval debulking surgery following neoadjuvant chemotherapy for stage III/IV ovarian, tubal, and peritoneal cancers in a phase III randomised trial: Japan Clinical Oncology Group Study JCOG0602.
        Eur J Cancer. 2016; 64: 22-31
        • Onda T.
        • Kobayashi H.
        • Nakanishi T.
        • Hatae M.
        • Iwasaka T.
        • Konishi I.
        • et al.
        Feasibility study of neoadjuvant chemotherapy followed by interval debulking surgery for stage III/IV ovarian, tubal, and peritoneal cancers: Japan Clinical Oncology Group Study JCOG0206.
        Gynecol Oncol. 2009; 113: 57-62
        • Pocock S.J.
        • Simon R.
        Sequential treatment assignment with balancing for prognostic factors in the controlled clinical trial.
        Biometrics. 1975; 31: 103-115
        • van der Burg M.E.
        • van Lent M.
        • Buyse M.
        • Kobierska A.
        • Colombo N.
        • Favalli G.
        • et al.
        The effect of debulking surgery after induction chemotherapy on the prognosis in advanced epithelial ovarian cancer. Gynecological Cancer Cooperative Group of the European Organization for Research and Treatment of Cancer.
        N Engl J Med. 1995; 332: 629-634
        • Rose P.G.
        • Nerenstone S.
        • Brady M.F.
        • Clarke-Pearson D.
        • Olt G.
        • Rubin S.C.
        • et al.
        Secondary surgical cytoreduction for advanced ovarian carcinoma.
        N Engl J Med. 2004; 351: 2489-2497
        • Tangjitgamol S.
        • Manusirivithaya S.
        • Laopaiboon M.
        • Lumbiganon P.
        • Bryant A.
        Interval debulking surgery for advanced epithelial ovarian cancer (Review).
        Cochran Database Syst Rev. 2010; 10
        • Vergote I.
        • Coens C.
        • Nankivell M.
        • Kristensen G.B.
        • Parmar M.K.B.
        • Ehlen T.
        • et al.
        Neoadjuvant chemotherapy versus debulking surgery in advanced tubo-ovarian cancers: pooled analysis of individual patient data from the EORTC 55971 and CHORUS trials.
        Lancet Oncol. 2018; 19: 1680-1687
        • Petrillo M.
        • Ferrandina G.
        • Fagotti A.
        • Vizzielli G.
        • Margariti P.A.
        • Pedone A.L.
        • et al.
        Timing and pattern of recurrence in ovarian cancer patients with high tumor dissemination treated with primary debulking surgery versus neoadjuvant chemotherapy.
        Ann Surg Oncol. 2013; 20: 3955-3960
        • da Costa A.A.
        • Valadares C.V.
        • Baiocchi G.
        • Mantoan H.
        • Saito A.
        • Sanches S.
        • et al.
        Neoadjuvant Chemotherapy Followed by Interval Debulking Surgery and the Risk of Platinum Resistance in Epithelial Ovarian Cancer.
        Ann Surg Oncol. 2015; 22: S971-S978
        • Rauh-Hain J.A.
        • Nitschmann C.C.
        • Worley Jr., M.J.
        • Bradford L.S.
        • Berkowitz R.S.
        • Schorge J.O.
        • et al.
        Platinum resistance after neoadjuvant chemotherapy compared to primary surgery in patients with advanced epithelial ovarian carcinoma.
        Gynecol Oncol. 2013; 129: 63-68
        • Aletti G.D.
        • Eisenhauer E.L.
        • Santillan A.
        • Axtell A.
        • Aletti G.
        • Holschneider C.
        • et al.
        Identification of patient groups at highest risk from traditional approach to ovarian cancer treatment.
        Gynecol Oncol. 2011; 120: 23-28
        • Glasgow M.A.
        • Yu H.
        • Rutherford T.J.
        • Azodi M.
        • Silasi D.A.
        • Santin A.D.
        • et al.
        Neoadjuvant chemotherapy (NACT) is an effective way of managing elderly women with advanced stage ovarian cancer (FIGO Stage IIIC and IV).
        J Surg Oncol. 2013; 107: 195-200
        • Suidan R.S.
        • Ramirez P.T.
        • Sarasohn D.M.
        • Teitcher J.B.
        • Mironov S.
        • Iyer R.B.
        • et al.
        A multicenter prospective trial evaluating the ability of preoperative computed tomography scan and serum CA-125 to predict suboptimal cytoreduction at primary debulking surgery for advanced ovarian, fallopian tube, and peritoneal cancer.
        Gynecol Oncol. 2014; 134: 455-461
        • Fagotti A.
        • Ferrandina G.
        • Vizzielli G.
        • Fanfani F.
        • Gallotta V.
        • Chiantera V.
        • et al.
        Phase III randomised clinical trial comparing primary surgery versus neoadjuvant chemotherapy in advanced epithelial ovarian cancer with high tumour load (SCORPION trial): Final analysis of peri-operative outcome.
        Eur J Cancer. 2016; 59: 22-33
        • Wright A.A.
        • Bohlke K.
        • Armstrong D.K.
        • Bookman M.A.
        • Cliby W.A.
        • Coleman R.L.
        • et al.
        Neoadjuvant Chemotherapy for Newly Diagnosed, Advanced Ovarian Cancer: Society of Gynecologic Oncology and American Society of Clinical Oncology Clinical Practice Guideline.
        J Clin Oncol. 2016; 34: 3460-3473
        • Wright A.A.
        • Bohlke K.
        • Armstrong D.K.
        • Bookman M.A.
        • Cliby W.A.
        • Coleman R.L.
        • et al.
        Neoadjuvant chemotherapy for newly diagnosed, advanced ovarian cancer: Society of Gynecologic Oncology and American Society of Clinical Oncology Clinical Practice Guideline.
        Gynecol Oncol. 2016; 143: 3-15
        • Meyer L.A.
        • Cronin A.M.
        • Sun C.C.
        • Bixel K.
        • Bookman M.A.
        • Cristea M.C.
        • et al.
        Use and Effectiveness of Neoadjuvant Chemotherapy for Treatment of Ovarian Cancer.
        J Clin Oncol. 2016; 34: 3854-3863
        • Melamed A.
        • Hinchcliff E.M.
        • Clemmer J.T.
        • Bregar A.J.
        • Uppal S.
        • Bostock I.
        • et al.
        Trends in the use of neoadjuvant chemotherapy for advanced ovarian cancer in the United States.
        Gynecol Oncol. 2016; 143: 236-240