Feasibility study of intraperitoneal docetaxel combined with intravenous cisplatin and oral S-1 for gastric cancer patients with peritoneal carcinomatosis

Abstract

Introduction: Peritoneal carcinomatosis (PC) is common in advanced gastric cancer. Systemic therapy has been the mainstay of treatment but the outcomes remain poor. The V325 study demonstrated superior efficacy for the triplet regimen of IV docetaxel, cisplatin and 5FU at the cost of increased toxicity. Emerging evidence supports the role of intraperitoneal chemotherapy with potentially less systemic toxicity. The current phase I study evaluated the feasibility of a triplet regimen of intraperitoneal docetaxel, IV cisplatin and oral S-1 in gastric cancer patients with peritoneal carcinomatosis. (NCT02024841). Methods: Patients with histologic confirmed gastric adenocarcinoma and peritoneal metastasis were enrolled. Those with prior systemic treatment in the palliative setting or other distant metastasis, except lymph node metastasis, were excluded. Intraperitoneal docetaxel was given over 1 hour on day 1 every 3 weeks. The dose of docetaxel was escalated from 40mg/m2(level I) to 50mg/m2(level II) and 60mg/m2(level III) according to phase I classical '3 + 3' protocol. DLT was determined in cycle I. IV cisplatin was administered at a fixed dose of 60mg/m2 on day 1 and oral S-1 was administered twice daily according to BSA on day 1-14 every 3 weeks. Patients were treated for three cycles unless unacceptable toxicities or patient withdrawal. Reassessment upper endoscopy and CT scan was performed 3 weeks after completion of chemotherapy. Staging laparoscopy was performed for all patients unless disease progression. In cases of no macroscopic residual PC, gastrectomy with D2 lymph node dissection was performed. Cases with residual PC continued chemotherapy and gastrectomy would not be performed. The primary objective was to determine the maximum-tolerated dose (MTD) and the recommended dose (RD) of intraperitoneal docetaxel in gastric cancer patients with PC. Results: Twelve patients were enrolled from Dec 2013 to Mar 2017. Eight patients were female and the median age was 57.5 years. 3 patients were treated at level I and no DLT was observed. One patient treated at level II was hospitalised for syncopy. Although this was determined to be unlikely treatment-related, additional three more patients were treated at level II and confirmed no DLT. Three patients were treated at level III and no DLT was observed. All but one patients completed 3 cycles of treatment. In cycle II and III, four patients had delay of treatment cycle and one patient had dose reduction. The commonest > =G3 hematological toxicity was leucopenia and non-hematological toxicity was hyponatraemia. No treatment-related death was observed. Five out of 11 patients (45.5%) who have completed 3 cycles of treatment had no gross PC seen at re-staging diagnostic laparoscopy and they had gastrectomy with D2 LND done. The median PFS and OS for the overall population was 11 and 15 months, respectively. Patients who had gastrectomy done has significantly prolonged PFS (21 vs 6 months, p = 0.025) and a trend towards improved OS (26 vs 13 months, p = 0.052). Conclusion: Intraperitoneal docetaxel, IV cisplatin and oral TS1 were well-tolerated with promising efficacy for gastric cancer with PC. The maximum tolerated dose is not reached in this phase I dose-escalation study and recommend dose of intraperitoneal docetaxel at 60mg/m2 every 3 weeks is suggested.