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.

Figure 1

Efficacy of HIPEC perioperative regimen. In this treatment plan, 5-FU is given twice. Thirty minutes prior to the initiation of HIPEC an intravenous bolus of 500 mg/m² of 5-fluorouracil with leucovorin 25 mg/m² is infused. After the abdomen is closed, 650 mg/m² of EPIC 5-FU is instilled into the peritoneal space. The HIPEC is for 30 minutes. The chemotherapy solution contains oxaliplatin 360 mg/m² and irinotecan 360 mg/m². *, exact dose to be determined in a phase I trial.

Figure 2

Perioperative FOLFOX as a HIPEC regimen. In this treatment plan, 5-FU is administered at 3 different time points. In order to saturate body tissues with 5-FU, a bolus of 400 mg/m² is administered approximately 30 minutes prior to the initiation of HIPEC. As HIPEC is started, a continuous intravenous infusion for 12 hours of 800 mg/m² of 5-fluorouracil is started. Then, after the abdomen is closed early postoperative intraperitoneal chemotherapy with 5-FU at 400 mg/m² in 2 L of peritoneal dialysis solution is instilled into the peritoneal space to remain for 24 hours. The HIPEC oxaliplatin is 200 mg/m² and the peritoneal lavage is continued for 120 minutes.