Results of a multicenter phase I dose-finding trial of hyperthermic intraperitoneal cisplatin after neoadjuvant chemotherapy and complete cytoreductive surgery and followed by maintenance bevacizumab in initially unresectable ovarian cancer

Purpose Hyperthermic intraperitoneal chemotherapy (HIPEC) may improve the outcome of patients with initially unresectable ovarian cancer who are eligible for complete cytoreductive surgery (CCRS) after neoadjuvant chemotherapy. The main objective of this multicenter phase-I study was to identify the recommended dose of cisplatin for HIPEC at CCRS after neoadjuvant carboplatin and paclitaxel (CP). Methods Patients were treated with 6 cycles of CP followed by CCRS and HIPEC using cisplatin heated for one hour at 42 °C +/− 1 °C. Four cisplatin dose-levels were evaluated: 50, 60, 70, 80 mg/m². Dose-limiting toxicities (DLTs) were defined as a grade ≥ IIIb adverse event (Dindo classification). The Continual Reassessment Method was used for this dose-finding study, with a target percentage of DLT set at 20%. Twenty-two cycles (15 mg/kg/cycle) of maintenance bevacizumab therapy were planned after surgery. Results Between June-2011 and September-2012, 30 patients were recruited. No DLT occurred at the first three dose-levels (4, 4 and 5 patients at 50, 60 and 70 mg/m² respectively). At dose-level 4 (80 mg/m², 17 patients), four DLTs occurred: renal failure (n = 2), peritonitis (n = 1) and hemorrhage (n = 1). Eight weeks after surgery, creatinine clearance was reduced to < 30 mL/min in 3 patients, all treated at 80 mg/m², and between 30 and 60 mL/min in 6 patients (2, 1, 1 and 2 at the four dose-levels respectively). Twenty patients started maintenance bevacizumab, and 7 received the 22 courses initially planned. Conclusions Based on the observed DLTs and prolonged impairment of renal function, we recommend a dose of 70 mg/m² of cisplatin for HIPEC.