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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GS and WvD are joint senior authors.
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.
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