Abstract
BackgroundThe annual incidence of gastrointestinal carcinomas (stomach, small bowel, colon and rectum) is increasing in Western countries, reaching 50,000 new cases each year in France. Peritoneal carcinomatosis (PC) is diagnosed in 15% of these patients. Complete cytoreductive surgery (CCS) plus Hyperthermic IntraPeritoneal Chemotherapy (HIPEC) is the only therapy that can offer patients with PC a chance for long-term survival with a 5 year overall survival (OS) rate of 30–60% versus 0–5% with systemic chemotherapy alone. However, CCS plus HIPEC still presents serious limitations and very few patients (10%) are candidates for these radical treatments. PC remains a palliative setting for 90% of patients with a median survival ranging from 15 to 25 months. Innovative surgical therapies such as Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) therefore need to be developed to improve the prognosis. Potential benefits were obtained after intraperitoneal nebulization of oxaliplatin in patients with advanced PC from colorectal cancer. Innovative surgical therapies such as pressurized intraperitoneal aerosol chemotherapy (PIPAC) have been proposed as palliative locoregional treatment with some promising results. The dose of oxaliplatin currently established by nebulization (PIPAC) is really low at 92 mg/m2. However, the peritoneum acts as a barrier limiting the systemic passage of intraperitoneal drug. Oxaliplatin used at higher doses during PIPAC procedures could be a safe option and allow better intratumoral penetration of chemotherapy.Method and designThe proposed study is a multicenter phase I/II trial of oxaliplatin dose escalation during PIPAC. The aim is to determine the maximum tolerated dose of pressurized oxaliplatin administered by the intraperitoneal route (PIPAC) during two consecutive procedures at a 4–6 week interval for patients with extended peritoneal carcinomatosis from the gastrointestinal tract. Dose started at 90 mg/m2 and escalation was in 50 mg/m2 steps up to a maximum of 300 mg/m2.DiscussionOxaliplatin is an effective drug in gastrointestinal cancer and high doses given by the intraperitoneal route during HIPEC are well tolerated. In this phase I trial, we hypothesized that high-dose oxaliplatin during PIPAC is feasible and safe. The repeated local administration of high doses of oxaliplatin could improve tumor response and prognosis.Trial registrationProspective study. ClinicalTrials.gov: NCT03294252. EudraCT: 2016-003666-49
Highlights
The annual incidence of gastrointestinal carcinomas is increasing in Western countries, reaching 50,000 new cases each year in France
The aim is to determine the maximum tolerated dose of pressurized oxaliplatin administered by the intraperitoneal route (PIPAC) during two consecutive procedures at a 4–6 week interval for patients with extended peritoneal carcinomatosis from the gastrointestinal tract
The primary objective of the PIPOX study in patients with extended or nonresectable Peritoneal carcinomatosis (PC) arising from digestive carcinoma, is to determine the maximum tolerated dose (MTD) of pressurized oxaliplatin administered by the intraperitoneal route (PIPAC) and the recommended dose for Phase-II during two consecutive procedures performed 4 to 6 weeks apart
Summary
The annual incidence of colorectal and gastric carcinomas is increasing in Western countries [1], with 40,000 and 7,000 new cases, respectively, each year in France [2]. The median survival rate for patients with PCI higher than 17 is low and close to that obtained with current systemic chemotherapy alone [18] These results do not justify the morbidity and mortality risks inherent to this procedure [18]. Due to the many inherent limitations of CCS plus HIPEC, very few patients (10%) radical treatments of PC from gastric, bowel or colorectal carcinomas and most (90%) are treated with systemic palliative chemotherapy. Demtröder reported 17 patients in good general condition [23] with extended PC (mean PCI score = 16) from colorectal carcinoma at time of relapse following a modern systemic chemotherapy (FOLFOX or FOLFIRI, and/or Cetuximab, and/or Bevacizumab): 48 PIPAC procedures were performed using oxaliplatin at a mean dose of 92 mg/m2. – overall tolerance after a total of three to five procedures. – tumor response rate. – overall and progression-free survival. – secondary resection rate
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