A phase I dose-escalation study of oxaliplatin delivered via a laparoscopic approach using pressurised intraperitoneal aerosol chemotherapy for advanced peritoneal metastases of gastrointestinal tract cancers.

Abstract

The objectives were to define the maximum tolerated dose (MTD), safety profile and pharmacokinetics (PKs) of intraperitoneal oxaliplatin delivered by pressurised intraperitoneal aerosol chemotherapy (PIPAC) in patients with advanced peritoneal carcinomatosis from gastrointestinal tract cancers. PIPAC was applied every 4-6 weeks, for 5 cycles, in a phase I dose-escalation study using a 3+3 design. The first dose level was 90mg/m2 with planned increases of 50mg/m2 per level. Platinum concentration was measured in plasma, tissues and intraperitoneal fluid samples. The trial was registered at ClinicalTrials.gov (NCT03294252). Ten patients with 33 PIPAC sessions were included. No dose limiting toxicity (DLT) occurred at 90mg/m2 and two at 140mg/m2. The MTD was therefore set at 90mg/m2. Overall treatment included a median number of three PIPAC sessions (range: 1-5) and secondary complete cytoreductive surgery for two patients. Overall safety showed 67 grade I-II and 11 grade III-IV toxicities, usually haematologic, digestive (nausea/vomiting, abdominal pain), and fatigue. Oxaliplatin concentrations were three- to four-fold higher in tissue in contact with aerosol than in muscle without contact. At 140mg/m2, the plasma oxaliplatin concentration was high with Cmax and area under the curve (AUC)0-48h of 1035μg/l and 9028μgh/L, respectively. The MTD of oxaliplatin during PIPAC is 90mg/m2. PK data demonstrate a high tumour concentration and a significant systemic absorption.