A phase I–II trial of intraperitoneal cisplatin and α-lnterferon in patients with persistent epithelial ovarian cancer

Abstract

A toxicity, dose, and schedule study of intraperitoneal (ip) cisplatin and α-interferon was conducted as a salvage therapy for patients with persistent, advanced epithelial ovarian cancer after primary systemic therapy with cisplatin-combination chemotherapy. Twenty-four patients were entered into this prospective, nonrandomized phase I–II trial conducted at two institutions following a uniform protocol. Cisplatin doses were escalated from 45 to 90 mg/m 2, and α-interferon doses were escalated from 10 to 50 × 10 6 IU. At protocol entry, 4 (16%) patients had microscopic residual disease at second-look laparotomy, 5 (21%) had minimal residual disease <5 mm, 7 (30%) had residual disease 5–20 mm, and 8 (33%) had bulky residual disease >20 mm. Toxicity was acceptable overall. Hematopoietic toxicity included a grade 3 total white cell count in 12% of courses when the cisplatin dose was equal to or >60 mg/m 2. Renal toxicity was modest with grade 2 toxicity in 20% of courses with a cisplatin dose >60 mg/m 2. Gastrointestinal toxicity, especially nausea and vomiting was seen in most courses; however, it was grade 3 and dose-limiting in >30% of courses with cisplatin 75–90 mg/m 2. General malaise, fever, flu-like symptoms, chills, and myalgias were seen in most courses, but it was dose-limiting (grade 3) toxicity in 6–11% of cycles when the dose of interferon was 25–50 × 10 6 IU. There was no grade 4 toxicity. Thus, the maximum tolerated dose (MTD) of the combination is 60 mg/m 2 cisplatin and 25 × 10 6 IU interferon. Eighteen patients were evaluable for response, 15 of whom had responded to prior cisplatin therapy and 3 had not. Of the 10 patients evaluable for clinical response, one patient (10%) achieved a complete response (CCR), and one (10%) had a partial response (PCR). The progression free interval (PFI) and survival were 11 months and 19 months, respectively, for the CCR patient, 6 and 11 months, respectively, for the PCR patient, and the mean survival for nonresponders was 8 months. The other 8 patients underwent a reassessment laparotomy: 2 (25%) achieved a complete pathologic response (CPR), and 3 (38%) had a partial pathologic response (PPR). Both pathologic responses were in patients with minimal residual disease <5 mm. Mean PFI for patients with CPR was 17 months, one patient died at 24 months, and one is alive at 38 months; PFI and survival for PPR patients was 9 and 18 months, respectively, and the mean survival of nonresponders was 12 months. These data justify a phase II trial using an intraperitoneal regimen with the MTD of 25 × 10 6 IU of α-interferon and 60 mg/m 2 cisplatin.