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Central radiology assessment of the randomized phase III open-label OVHIPEC-1 trial in ovarian cancer
  1. Simone N. Koole1,2,
  2. Leigh Bruijs3,
  3. Cristina Fabris4,5,
  4. Karolina Sikorska6,
  5. Maurits Engbersen4,
  6. Jules H. Schagen van Leeuwen7,
  7. Henk W.R. Schreuder8,
  8. Ralph H. Hermans9,
  9. Jacobus van der Velden10,
  10. Henriette J.G. Arts11,
  11. Maaike van Ham12,
  12. Peter Van Dam13,
  13. Peter Vuylsteke14,15,
  14. Max Lahaye4,
  15. Gabe Sonke2,16 and
  16. Willemien van Driel1,17
  1. 1Department of Gynaecology, Netherlands Cancer Institute, Amsterdam, The Netherlands
  2. 2Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands
  3. 3Amsterdam University Medical Center, University of Amsterdam Faculty of Medicine, Amsterdam, The Netherlands
  4. 4Department of Radiology, Netherlands Cancer Institute, Amsterdam, The Netherlands
  5. 5Department of Radiology, University of Verona, Verona, Italy
  6. 6Department of Biostatistics, Netherlands Cancer Institute, Amsterdam, The Netherlands
  7. 7Department of Obstetrics & Gynecology, Sint Antonius Hospital, Nieuwegein, The Netherlands
  8. 8Department of Gynecological Oncology, Universitair Medisch Centrum Utrecht, Utrecht, The Netherlands
  9. 9Department of Gynaecology, Catharina Hospital, Eindhoven, The Netherlands
  10. 10Gynecological Oncology, Amsterdam University Medical Centres, Amsterdam, The Netherlands
  11. 11Department of Gynecological Oncology, University Medical Centre Groningen, Groningen, The Netherlands
  12. 12Obstetrics and Gynecology, University Medical Center Nijmegen, Nijmegen, The Netherlands
  13. 13Department of Gynaecologic Oncology, University Hospital Antwerp, Edegem, Belgium
  14. 14Department of Medical Oncology, CHU UCL Namur, Namur, Belgium
  15. 15Department of Internal Medicine, University of Botswana, Gaborone, Botswana
  16. 16The Dutch Gynecological Oncology Group, Amsterdam, Netherlands
  17. 17(similar as affilitation 16), The Dutch Gynecological Oncology Group, Amsterdam, Netherlands
  1. Correspondence to Dr Willemien van Driel, Department of Gynaecology, Netherlands Cancer Institute, Amsterdam 1066 CX, The Netherlands; w.v.driel{at}nki.nl

Abstract

Introduction Hyperthermic intraperitoneal chemotherapy (HIPEC) improved investigator-assessed recurrence-free survival and overall survival in patients with stage III ovarian cancer in the phase III OVHIPEC-1 trial. We analyzed whether an open-label design affected the results of the trial by central blinded assessment of recurrence-free survival, and tested whether HIPEC specifically targets the peritoneal surface by analyzing the site of disease recurrence.

Methods OVHIPEC-1 was an open-label, multicenter, phase III trial that randomized 245 patients after three cycles of neoadjuvant chemotherapy to interval cytoreduction with or without HIPEC using cisplatin (100 mg/m2). Patients received three additional cycles of chemotherapy after surgery. Computed tomography (CT) scans and serum cancer antigen 125 (CA125) measurements were performed during chemotherapy, and during follow-up. Two expert radiologists reviewed all available CT scans. They were blinded for treatment allocation and clinical outcome. Central revision included Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 measurements and peritoneal cancer index scorings at baseline, during treatment, and during follow-up. Time to centrally-revised recurrence was compared between study arms using Cox proportional hazard models. Subdistribution models compared time to peritoneal recurrence between arms, accounting for competing risks.

Results CT scans for central revision were available for 231 patients (94%) during neoadjuvant treatment and 212 patients (87%) during follow-up. Centrally-assessed median recurrence-free survival was 9.9 months in the surgery group and 13.2 months in the surgery+HIPEC group (HR for disease recurrence or death 0.72, 95% CI 0.55 to 0.94; p=0.015). The improved recurrence-free survival and overall survival associated with HIPEC were irrespective of response to neoadjuvant chemotherapy and baseline peritoneal cancer index. Cumulative incidence of peritoneal recurrence was lower after surgery+HIPEC, but there was no difference in extraperitoneal recurrences.

Conclusion Centrally-assessed recurrence-free survival analysis confirms the benefit of adding HIPEC to interval cytoreductive surgery in patients with stage III ovarian cancer, with fewer peritoneal recurrences. These results rule out radiological bias caused by the open-label nature of the study.

  • ovarian cancer
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Footnotes

  • GS and WvD are joint senior authors.

  • Twitter @MPEngbersen

  • GS and WvD contributed equally.

  • Collaborators The Dutch OVHIPEC group (in alphabetical order): L Aronson, HJG Arts, I Boere, GJ Creemers, WJ van Driel, KN Gaarenstroom, M van Gent, M van Ham, B Hellebrekers, R Hermans, I de Hingh, SN Koole, JR Kroep, CD de Kroon, R Lalisang, S Lambrechts, P Ottevanger, N Reesink, V Retel, AKL Reyners, EM Roes, HWR Schreuder, GS Sonke, RM van Stein, A Thijs, A Westermann, PO Witteveen, A Wymenga, R Yigit.

  • Contributors SK wrote the initial drafts of the manuscript and performed data curation and formal analysis. ML and CF were responsible for central CT scan review. SK and LB were responsible for central data collection. JSvL, HS, RH, JvV, HA, MvH, PvD, PV and WvD were responsible for patient acquisition and data collection. LB, KS, ME, GS, ML and WvD contributed clinical or statistical expertise to the analysis and manuscript. All authors read and commented on the manuscript and approved the final version.

  • Competing interests GS reports institutional research support outside the submitted work, from AstraZeneca, Merck, Novartis, and Roche, during the conduct of the study.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data are available upon reasonable request. In accordance with the journal’s guidelines, we will provide our data for the reproducibility of this study in other centers if requested.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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