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

Abstract

Purpose: 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 92 mg/m2. We conducted a phase I study to establish safety and tolerability. Patients and Methods: 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 120 mg/m2. Results: 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 45 mg/m2, necessitating cohort expansion. Another patient developed grade 2 pancreatitis at 90 mg/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 AUC (r2 = 0.99). On the basis of RECIST, 62.5% and 50% had stable disease after one and two PIPAC procedures, respectively. A total of 8 patients underwent two 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 II dose is 120 mg/m2. Future studies should further delineate the efficacy and role of PIPAC oxaliplatin for peritoneal metastases. See related commentary by de Jong et al., p. 1830

A Phase I Dose Escalation Study of Oxaliplatin, Cisplatin and Doxorubicin Applied as PIPAC in Patients with Peritoneal Carcinomatosis

“…As reported in the two phase I studies [ 22 , 23 ], we did not register any liver and renal function alteration and no systemic hematologic toxicity was observed.…”

“…The choice to perform a single PIPAC administration was based on two considerations: the number of PIPACs that can be performed in a patient is variable and the possibility of performing further procedures often decreases over time. This is evident in both phase I trials: in the study by Tempfer [ 22 ], eight patients (53.3%) were submitted to three PIPAC procedures, three patients (20%) to two PIPACs and four patients (26.7%) to one PIPAC; this aspect is even more evident in the study by Kim [ 23 ], in which 50% of the patients underwent only one PIPAC procedure.…”

“…Similarly to PIPAC with CDDP and DXR, the administration of oxaliplatin as pressurized intraperitoneal aerosol was also the subject of only one phase I study, reporting that the recommended phase II dose should be 120 mg/m 2 [ 23 ].…”

“…In the PIPAC-OX trial, three cases of acute pancreatitis (of which one G3 complication) are reported; in our case history, neither analogous cases nor cases of serum amylase and/or lipase elevation were recorded [ 23 ]. As reported by the authors themselves, acute pancreatitis is not a complication typically related to the administration of OXA as PIPAC.…”

“…So far, the drugs used in PIPAC include cisplatin (CDDP), doxorubicin (DXR) and oxaliplatin (OXA), but there are few data comparing different dosage schedules: a phase I study in patients with recurrent ovarian cancer reported that PIPAC with CDDP and DXR may be safely used at a dose of 10.5 mg/m 2 and 2.1 mg/m 2 , respectively, with low systemic toxicity [ 22 ]; a recent dose-escalation study described that the recommended phase II dose of PIPAC with OXA is 120 mg/m 2 [ 23 ]. Therefore, we designed a phase I study with three cytotoxic substances: oxaliplatin in PC of intestinal origin and pseudomyxoma peritonei (PMP), and cisplatin plus doxorubicin in peritoneal mesothelioma, ovarian and gastric cancer; aim of the study was to identify dose-limiting toxicities and the maximum-tolerable dose (MTD) of the treatment.…”