Heated intra-operative intraperitoneal oxaliplatin plus irinotecan after complete resection of peritoneal carcinomatosis: Pharmacokinetics, tissue distribution and tolerance

Background: The purpose of this study was to report the pharmacokinetics (PK) and tolerance profile of intraoperative intraperitoneal chemo-hyperthermia (IPCH) with oxaliplatin and irinotecan. Patients and methods: Thirty-nine patients with peritoneal carcinomatosis (PC) of either gastrointestinal or peritoneal origin underwent complete cytoreductive surgery followed by IPCH with a stable dose of oxaliplatin (460 mg/m²), plus one among seven escalating doses of irinotecan (from 300 to 700 mg/m²). IPCH was carried out with the abdomen open, for 30 min at 43°C, with 21/m² of a 5% dextrose instillation in a closed continuous circuit. Patients received intravenous leucovorin (20 mg/m²) and 5-fluorouracil (400 mg/m²) just before IPCH to maximize the effect of oxaliplatin and irinotecan. Results: Irinotecan concentration in tumoral tissue increased until 400 mg/m² and then remained stable despite dose escalations. It was 16-23 times higher than in non-bathed tissues. Increasing doses of intraperitoneal irinotecan did not modify the PK of intraperitoneal oxaliplatin, and the drug concentration ratio was 17.8 higher in tumoral tissue (bathed) than in non-bathed tissues. The hospital mortality rate was 2.5% and the non-hematological complication rate was 25%. However, grade 3-4 hematological toxicity rate was 58%. Conclusion: Intraperitoneal heated oxaliplatin (460 mg/m²) plus irinotecan (400 mg/m² presented an advantageous PK profile and was tolerated by patients, despite a high hematological toxicity rate.