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A Phase I Trial of Oxaliplatin for Intraperitoneal Hyperthermic Chemoperfusion for the Treatment of Peritoneal Surface Dissemination from Colorectal and Appendiceal Cancers

¹ Surgical Oncology Service, Department of General Surgery, Medical Center Blvd, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
² Biostatistics Section, Department of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, USA
³ Department of Physics, Wake Forest University, Winston-Salem, NC, USA
⁴ Research Triangle Institute, Research Triangle Park, NC, USA
⁵ Department of Chemistry, Wake Forest University, Winston-Salem, NC, USA

Correspondence: Address correspondence and reprint requests to: John H. Stewart IV, MD; E-mail: jhstewar{at}wfubmc.edu

Background: Cytoreductive surgery with intraperitoneal hyperthermic chemoperfusion (IPHC) has evolved into a promising approach for peritoneal surface malignancy. A large body of literature suggests that oxaliplatin has excellent cytotoxicity against colorectal cancer. Therefore, we undertook a phase I evaluation of IPHC with oxaliplatin for peritoneal dissemination from colorectal and appendiceal cancers to establish the dose-limiting toxicity (DLT) and the maximum tolerated dose (MTD).

Methods: Cohorts of three patients underwent cytoreductive surgery followed by a 2-h IPHC with escalating doses of oxaliplatin at a target outflow temperature of 40°C. The initial peritoneal oxaliplatin dose was 200 mg/M² with increases planned in 50 mg/M² increments. Plasma and perfusate samples were collected during the IPHC and evaluated using emission spectrometry techniques. Normal tissue and tumor samples were collected before and after the IPHC for analysis. DLT was defined as a grade 3 toxicity lasting 5 days.

Results: Fifteen patients were enrolled at two dose levels. Peritoneal fluid areas under the curve (AUCs) were above those of plasma. Additionally, intratumoral oxaliplatin was similar to that of surrounding normal tissue. Dose-limiting toxicities at 250 mg/M² were observed in two of three patients enrolled in this study.

Conclusion: We found that IPHC with 200 mg/M² of oxaliplatin is well tolerated and is the MTD for a 2-h chemoperfusion. Higher doses are not feasible with this perfusion protocol given the significant toxicities associated with 250 mg/M² oxaliplatin. Based on the data from this phase I study, we propose to conduct further studies with oxaliplatin delivered at 200 mg/M².

Key Words: Oxaliplatin • Surgery • Intraperitoneal hyperthermic chemoperfusion • Carcinomatosis • Phase I trial