Phase I study of intraperitoneal paclitaxel combined with S-1 plus cisplatin for gastric cancer with peritoneal metastasis.

Abstract

115 Background: Intraperitoneal (IP) chemotherapy is a promising treatment option for gastric cancer (GC) with peritoneal metastasis (PM). Efficacy of IP paclitaxel (PTX) combined with S-1 and intravenous PTX was reported in a phase II study. Attempts to combine IP PTX with other systemic therapies with higher efficacy are warranted. We designed a new regimen combining IP PTX with S-1/cisplatin (SP) which is regarded as the standard first-line treatment of metastatic GC in Japan. We subsequently carried out a dose-escalation study to determine the maximum-tolerated dose (MTD) and recommended dose (RD). Methods: The combination was a five-week regimen. IP PTX was to be administered on days 1, 8 and 22 with an initial dose of 15 mg/m2 at level 1 and 20 mg/m2 at level 2. S-1 was to be administered orally at a fixed dose of 80 mg/m2 bid for 21 days followed by a 14-day rest. Cisplatin was to be administered intravenously at a dose of 60 mg/m2 on day 8, and was to be decreased to 50 mg/m2 (level 0) if necessary. Since the dosage of S-1 at the fixed dose and cisplatin at level 1 were identical to SP regimen, no further dose-escalation was planned. Dose-limiting toxicities (DLTs) were defined as Grade 4 (G4) leukopenia, G3 febrile neutropenia, G3 thrombocytopenia, and G3 non-hematological toxicity. The MTD was defined as the dose level at which ≥2 of 3 or 6 patients developed DLTs during the first course of treatment. The RD was defined as one level below the MTD. Results: A total of 9 patients with macroscopic PM were enrolled. No DLTs were observed among the 3 patients at level 1 and 6 patients at level 2. Furthermore, no G3 toxicities were observed in any of the patients enrolled. Anemia in 1 patient at level 2 was the only G2 toxicity observed. No adverse events or technical problems associated with the IP administration were observed. Consequently, the MTD was not reached, and the RD of IP PTX was determined as 20 mg/m2 (level 2). As for the efficacy, peritoneal lavage cytology turned negative after the first course in 4 of 7 patients who had positive cytology before treatment. Conclusions: Addition of IP PTX at 20 mg/m2 to the SP regimen at an established dose/schedule was safe and promising, and further evaluation in a phase II trial is underway. Clinical trial information: UMIN000013528.