Phase I Study of Intraperitoneal Administration of Paclitaxel Combined with S-1 Plus Cisplatin for Gastric Cancer with Peritoneal Metastasis

<b><i>Introduction:</i></b> Intraperitoneal (IP) chemotherapy is a promising treatment option for gastric cancer (GC) with peritoneal metastasis (PM). Recently, superiority of IP administration of paclitaxel (PTX) combined with S-1 and intravenous PTX over conventional systemic chemotherapy was suggested in a phase III study, although the difference in overall survival did not reach statistical significance in the primary analysis. Thus, 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 plus cisplatin (SP), which is regarded as the standard first-line treatment for metastatic GC in Japan, and subsequently carried out a dose-escalation study. <b><i>Methods:</i></b> The combination was a 5-weekly 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 b.i.d. 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. Dose-limiting toxicities (DLTs) were defined as grade 4 leukopenia, grade 3 (G3) febrile neutropenia, G3 thrombocytopenia, and G3 nonhematological toxicity. <b><i>Results:</i></b> 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. No adverse events or technical problems associated with the IP administration were observed. Consequently, the maximum-tolerated dose was not reached, and the dose for further clinical trials of IP PTX was determined as 20 mg/m². As for efficacy, peritoneal lavage cytology turned negative after the first course in 4 of 7 patients who had positive cytology before treatment. <b><i>Conclusion:</i></b> The present study determined the dose for further clinical trials of IP PTX to be 20 mg/m², when combined with the 5-weekly SP regimen.