Multiple Agents At Time Of Hyperthermic Intraperitoneal Chemotherapy

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Tumor cell biology warrants the use of concurrent agents to minimize the phenomena of drug resistance. Solid tumors are derived from a multitude of clonal variants with different mutations and patterns of resistance. After several cycles of chemotherapy, clinical response may occur, but at the expense of selecting for clonal lines with intrinsic drug resistance. Several first-line treatments for solid tumors of the abdomen include multiple drug regimens, in the hopes of decreasing the production of intrinsic drug resistance and obtaining a complete clinical response.

Multiple drug regimens at the time of HIPEC are of interest. Factors that should be considered include potential drug-drug incompatibility when mixed in the HIPEC perfusate, increased toxicity of multiple agents during HIPEC, and the increase in operative time and HIPEC time if two or more agents are used to treat carcinomatosis. Currently, there are no studies published that explore simultaneous use of two agents during HIPEC for ovarian carcinoma. If future studies show docetaxel and platinum agents to be compatible with simultaneous infusion in the peritoneum, then phase II trials with HIPEC for ovarian cancer patients should be explored.

Simultaneous use of two agents for the treatment of colorectal carcinoma using HIPEC is relatively uncommon. Elias reported on a pharmacokinetics trial using standard-dose oxaliplatin and escalating doses of irinotecan with HIPEC at 43°C (22). Irinotecan levels in tissue were noted to be 16-23 times higher than in nonbathed tissues, while having no effect on the oxaliplatin concentration in these tissues. Interestingly, they reported a 58% rate of grade 3-4 hematologic toxicity, which is higher than seen with oxaliplatin alone in HIPEC (22). Long-term survival information for the 39 patients studied in this project are unavailable, but may warrant a phase III trial of oxaliplatin vs oxaliplatin plus irinotecan with HIPEC.

Several HIPEC studies involving colorectal patients utilize perioperative infusions with 5-fluorouracil (5-FU) and leucovorin. These drugs are components of the systemic therapy for colorectal cancer, but 5-FU has shown no increased cytotoxicity with hyperthermia (23). These same principles can potentially be used during HIPEC treatments for ovarian cancers, with IV paclitaxel given during the perioperative period to see if greater long-term response rates occur.

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