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N Engl J Med. 2018 Jan 18;378(3):230-240. doi: 10.1056/NEJMoa1708618.

Hyperthermic Intraperitoneal Chemotherapy in Ovarian Cancer.

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From the Departments of Gynecology (W.J.D., S.N.K.), Biometrics (K.S., H.T.), Surgical Oncology (A.G.J.A.), Pathology (K.K.V.V.), and Medical Oncology (S.N.K., G.S.S.) and the Division of Psychosocial Research and Epidemiology (J.M.K., N.K.A.), the Netherlands Cancer Institute, Amsterdam, the Center for Gynecologic Oncology Amsterdam, Amsterdam (W.J.D., S.N.K., J.V.), the Dutch Gynecologic Oncology Group (W.J.D., J.H.S.L., H.W.R.S., R.H.M.H., J.V., H.J.A., L.F.A.G.M., G.S.S.), the Department of Obstetrics and Gynecology, Academic Medical Center, Amsterdam (J.V.), the Department of Obstetrics and Gynecology, Sint Antonius Hospital, Nieuwegein (J.H.S.L.), the Department of Gynecologic Oncology, UMC Utrecht Cancer Center, University Medical Center Utrecht, Utrecht (H.W.R.S.), the Departments of Gynecology and Obstetrics (R.H.M.H.) and Surgery (I.H.J.T.H.), Catharina Hospital, Eindhoven, the Dutch Peritoneal Oncology Group (I.H.J.T.H., A.G.J.A.), the Department of Gynecologic Oncology, University of Groningen, University Medical Center Groningen, Groningen (H.J.A.), and the Department of Gynecologic Oncology, Radboud University Medical Center, Nijmegen (L.F.A.G.M.) - all in the Netherlands; and the Department of Surgery, Aarhus University Hospital, Aarhus, Denmark (V.J.V.).



Treatment of newly diagnosed advanced-stage ovarian cancer typically involves cytoreductive surgery and systemic chemotherapy. We conducted a trial to investigate whether the addition of hyperthermic intraperitoneal chemotherapy (HIPEC) to interval cytoreductive surgery would improve outcomes among patients who were receiving neoadjuvant chemotherapy for stage III epithelial ovarian cancer.


In a multicenter, open-label, phase 3 trial, we randomly assigned 245 patients who had at least stable disease after three cycles of carboplatin (area under the curve of 5 to 6 mg per milliliter per minute) and paclitaxel (175 mg per square meter of body-surface area) to undergo interval cytoreductive surgery either with or without administration of HIPEC with cisplatin (100 mg per square meter). Randomization was performed at the time of surgery in cases in which surgery that would result in no visible disease (complete cytoreduction) or surgery after which one or more residual tumors measuring 10 mm or less in diameter remain (optimal cytoreduction) was deemed to be feasible. Three additional cycles of carboplatin and paclitaxel were administered postoperatively. The primary end point was recurrence-free survival. Overall survival and the side-effect profile were key secondary end points.


In the intention-to-treat analysis, events of disease recurrence or death occurred in 110 of the 123 patients (89%) who underwent cytoreductive surgery without HIPEC (surgery group) and in 99 of the 122 patients (81%) who underwent cytoreductive surgery with HIPEC (surgery-plus-HIPEC group) (hazard ratio for disease recurrence or death, 0.66; 95% confidence interval [CI], 0.50 to 0.87; P=0.003). The median recurrence-free survival was 10.7 months in the surgery group and 14.2 months in the surgery-plus-HIPEC group. At a median follow-up of 4.7 years, 76 patients (62%) in the surgery group and 61 patients (50%) in the surgery-plus-HIPEC group had died (hazard ratio, 0.67; 95% CI, 0.48 to 0.94; P=0.02). The median overall survival was 33.9 months in the surgery group and 45.7 months in the surgery-plus-HIPEC group. The percentage of patients who had adverse events of grade 3 or 4 was similar in the two groups (25% in the surgery group and 27% in the surgery-plus-HIPEC group, P=0.76).


Among patients with stage III epithelial ovarian cancer, the addition of HIPEC to interval cytoreductive surgery resulted in longer recurrence-free survival and overall survival than surgery alone and did not result in higher rates of side effects. (Funded by the Dutch Cancer Society; number, NCT00426257 ; EudraCT number, 2006-003466-34 .).

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