A randomized phase 3 trial of intraperitoneal versus intravenous carboplatin with dose-dense weekly paclitaxel in patients with ovarian, fallopian tube, or primary peritoneal carcinoma (a GOTIC-001/JGOG-3019/GCIG, iPocc Trial) (LBA 3)

Abstract

<b>Objectives:</b> Traditionally, the target of intraperitoneal (IP) chemotherapy for ovarian cancer was patients with minimal residual disease after debulking surgery. However, our pharmacological study suggested that IP carboplatin therapy should also be feasible for patients with larger size residual disease, and our previous phase 2 study demonstrated a satisfactory response rate of IP carboplatin plus dose-dense paclitaxel (ddTCip) regimen in patients with macroscopic residual disease after initial surgery for ovarian (OV), fallopian tube (FT), and primary peritoneal (PP) carcinoma. The purpose of this study is to assess whether IP administration of carboplatin is superior to intravenous (IV) administration of carboplatin (ddTCiv regimen) in OV, FT, and PP carcinoma patients with either minimal or macroscopic residual disease. <b>Methods:</b> Eligible patients were those with newly diagnosed stages II-IV disease. All patients were to undergo an initial laparotomy or laparoscopy with primary debulking surgery if possible. Before abdomen was closed, patients were randomized to either IV or IP arm. An IP port and catheter was placed if the patient was assigned to IP arm. Chemotherapy regimen was either IV paclitaxel plus IV carboplatin (IV arm) or IV paclitaxel plus IP carboplatin (IP arm). Dose of paclitaxel was 80 mg/m² Q1W and dose of carboplatin was at an area under the curve (AUC) of 6 Q3W. Each patient was to receive 6 to 8 cycles of chemotherapy. Patients with bulky residual disease were allowed to undergo interval debulking surgery followed by assigned arm regimen up to 8 cycles total. Primary endpoint was PFS, and secondary endpoints included OS, safety, QOL, and cost/benefit. <b>Results:</b> Total of 655 patients were randomized between 2010 and 2016 from Japan, Singapore, Korea, New Zealand, USA, and Hong Kong. Stage distribution was II (n= 88), III (n=448), and IV (n=119). Size of residual disease at randomization was either 0 cm (n=163), < 1 cm (n=97), 1-2 cm (n=33), or >2 cm (n=362). Histological types were serous (n=420), endometrioid (n=61), clear cell (n=74), and others (n=100). Median follow-up was 55.7 months. IP chemotherapy significantly improved PFS in the ITT population (HR=0.83, 95%CI:0.69-0.99, p=.041) and in the 602 eligible patients (HR=0.78, 95%CI:0.65-0.94, p=.009). Median PFS for ITT population was 20.7 (95%CI: 18.1-22.8) months in the IV arm and 23.5 (95%CI: 20.5-26.9) months in the IP arm. Median PFS for eligible patients was 20.0 (95%CI: 18.0-22.2) months in the IV arm and 22.9 (95%CI:19.6-26.9) months in the IP arm. Subset analysis showed that the survival benefit was greater in patients with larger size residual disease. Toxicity profile was essentially equivalent in both arms except for catheter-related toxicities (11.8%). <b>Conclusions:</b> ddTCip chemotherapy improved the PFS over ddTCiv regimen in patients with OV, FT, and PP carcinoma regardless of the residual tumor size after initial surgery.