PIPAC-OX: A Phase I Study of Oxaliplatin-Based Pressurized Intraperitoneal Aerosol Chemotherapy in Patients with Peritoneal Metastases

Abstract

Background: Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) is a novel, laparoscopic intraperitoneal chemotherapy delivery technique aiming to improve drug distribution and tissue penetration to treat peritoneal metastases. Thus far, PIPAC oxaliplatin is conducted at an arbitrary dose of 92mg/m2. We conducted a phase 1 study to establish safety and tolerability. Experimental design: We used a 3+3 dose escalation design of PIPAC oxaliplatin for patients with peritoneal metastases from gastrointestinal tumors, after failure of at least first-line chemotherapy. Dose levels were planned at 45, 60, 90 and 120mg/m2. Findings: This study included 16 patients with 24 PIPAC procedures (8 gastric, 5 colorectal and 1 gallbladder, pancreas and appendix cancer each). Median age and Peritoneal Cancer Index (PCI) score were 62 years and 17, respectively. Two patients developed pancreatitis (grade 2 and 3) at 45mg/m2, necessitating cohort expansion. Another patient developed grade 2 pancreatitis at 90mg/m2. There were no other dose limiting toxicities and the highest dose cohort (120 mg/m2) tolerated PIPAC well. Pharmacokinetic analyses demonstrated good linearity between dose and maximum concentration (r2=0.95) and area under the curve (AUC) (r2=0.99). Based on response evaluation criteria in solid tumors, 62.5% and 50% had stable disease after one and two PIPAC procedures, respectively. 8 patients underwent 2 PIPAC procedures, with improvement of median PCI and Peritoneal Regression Grade Score from 15 to 12 and 2.5 to 2.0, respectively. Conclusions: The recommended phase 2 dose is 120 mg/m2. Future studies should further delineate the efficacy and role of PIPAC oxaliplatin for peritoneal metastases.