Hyperthermic intraperitoneal chemotherapy (HIPEC) for colorectal and appendiceal peritoneal metastases: lessons learned from PRODIGE 7

Abstract

The treatment for peritoneal metastases from appendiceal, colon and rectal cancer (MO1) has relied on cytoreductive surgery (CRS) to remove all visible evidence of disease plus a perioperative chemotherapy for the entire abdomen to eliminate microscopic residual disease. Using the results obtained from the PRODIGE 7 randomized controlled trial, methodological issues were discussed and possible improvements to the hyperthermic intraperitoneal chemotherapy (HIPEC) with oxaliplatin were sought. Possible methodological and pharmacologic flaws were identified. Several methodological flaws included the sample size, cross-over option, neoadjuvant chemotherapy use and timing of the peritoneal disease evaluation. The sample size issue raised the question of what the minimal clinically relevant benefit we want in future trials. Neoadjuvant FOLFOX may have induced acquired drug resistance to oxaliplatin. Several pharmacological issues were identified including limited 5-fluorouracil exposure as well as limited oxaliplatin peritoneal exposure time. Insufficient 5-fluorouracil accompanied the oxaliplatin as only a bolus dose was used and continuous 5-FU infusion has previously been an integral part of oxaliplatin treatment. Finally, only approximately one-half of the oxaliplatin entered body tissues or tumor. Three suggestions from the lessons learned from a critique of PRODIGE 7 were offered as adjustments to the HIPEC protocol. The Efficacy of HIPEC, a perioperative FOLFOX or a return to HIPEC with mitomycin C were described.

Keywords: 5-fluorouracil; Intraperitoneal chemotherapy; cytoreductive surgery (CRS); early postoperative intraperitoneal chemotherapy (EPIC); hyperthermia; irinotecan.