Short-term oxaliplatin exposure according to established hyperthermic intraperitoneal chemotherapy (HIPEC) protocols lacks effectiveness in vitro and ex vivo

Cytotoxicity of oxaliplatin-containing solutions (OCS), sampled during patient treatment with hyperthermic intraperitoneal chemotherapy (HIPEC), was assessed by well-established continuous impedance-based real-time cell analysis (RTCA) ex vivo. HIPEC treatment was replicated by exposing OAW-42 cancer cells to OCS for 30 or 60 minutes at 42 °C. In contrast to previous results with continuous exposure, where cytotoxicity was proven, identical OCS obtained during HIPEC did not induce cell death reproducibly and showed strongly attenuated effects after only 30 minutes of application. Based on these unexpected findings, we used spike-ins of oxaliplatin (OX) into peritoneal dialysis solution (PDS) or dextrose 5 % in water (D5W) to replicate HIPEC conditions, as used in either our own protocols or the recently presented randomized controlled PRODIGE 7 trial, where OX HIPEC for 30 minutes failed to produce survival benefits in colorectal carcinoma patients. With OX-spiked into D5W or PDS at identical concentrations as used for PRODIGE 7 or conforming with own HIPEC protocols, we did not observe the expectable cytotoxic effects in RTCA, after replicating OX HIPEC for 30 minutes. These results were corroborated for both solvents at relevant drug concentrations by classical end-point assays for cytotoxicity in two cancer cell lines. Further results suggest that penetration depth, drug dosage, exposure time and drug solvents may constitute critical factors for HIPEC effectiveness. Accordingly, we witnessed substantial cell shrinkage with both PDS and D5W, potentially contributing to reduced drug effects. Based on these results, intensified pharmacological research seems essential to establish effective HIPEC protocols before clinical application.