The potential of step-up heating protocols to improve the efficacy of oxaliplatin-based HIPEC: in silico study on a rat model

Hyperthermic intraperitoneal chemotherapy (HIPEC) following cytoreductive surgery (CRS) represents a primary curative option for peritoneal metastasis of colorectal cancer (PMCRC). A typical protocol involves administering oxaliplatin through a 30-minute HIPEC session at 42 °C, but this short duration is criticized, as it may be associated with sub-optimal effectiveness. Nevertheless, prolonged duration yields a potential risk of toxicity. This study proposes and numerically investigates step-up heating to permit extension of the duration of oxaliplatin-based HIPEC. Different step-up heating protocols, comprising sequential low- to high-temperature phases ranging from 39 to 43 °C, were simulated on a rat abdominal model mimicking open HIPEC. The risk of thermal and chemotherapeutic toxicity was evaluated. The pharmacokinetic profile of step-up heating, in terms of effective oxaliplatin accumulation and penetration in the tumor, was compared to that of short-duration HIPEC at 42 °C, which served as the control case. The extended duration of HIPEC through step-up heating can enhance the availability of oxaliplatin and alleviate the challenge of low penetration in tumors situated in areas with higher oxaliplatin heterogeneity and slower coverage, particularly advantageous for less vascularized tumors (up to 40% increase in penetration depth). The administered dose must be adjusted according to the maximum tolerated dose, given the increased oxaliplatin concentration in organs and the systemic compartment. Thermal dose analysis showed that temperatures beyond 42 °C should be avoided in both phases of step-up heating. The step-up heating approach can provide an opportunity to safely extend the duration of oxaliplatin-based HIPEC, thereby improving its clinical efficacy.