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Cytoreductive Surgery and Intraoperative Hyperthermic Intraperitoneal Chemotherapy with Paclitaxel: A Clinical and Pharmacokinetic Study

¹ Department of Surgical Oncology, University Hospital, Crete University Medical School, P.O. Box 1352, 71 110, Herakleion, Greece
² Department of Pharmacy and Pharmacology, Slotervaart Hospital/The Netherlands Cancer Institute, Louwesweg 6, 1066 CE, Amsterdam, The Netherlands
³ Department of Medical Oncology, University Hospital, Crete University Medical School, P.O. Box 1352, 71 110, Herakleion, Greece

Correspondence: Address correspondence and reprint requests to: Eelco deBree, MD; E-mail: debree{at}med.uoc.gr

Background: Intraperitoneal chemotherapy has been recommended as a treatment option for ovarian cancer with peritoneal dissemination. Although its treatment duration is significantly shorter, intraoperative hyperthermic intraperitoneal perfusion chemotherapy (HIPEC) has several advantages over simple intraperitoneal instillation chemotherapy. While platinum compounds have usually been used, only a few have administered paclitaxel during HIPEC. Its large molecular weight suggests a much more favorable pharmacokinetic profile than that of platinum compounds. The pharmacokinetics of paclitaxel during and after HIPEC have not been studied before.

Methods: Thirteen women, mainly with ovarian cancer, underwent cytoreductive surgery and HIPEC with 175 mg/m² paclitaxel for 2 h. Morbidity was noted. Peritoneal fluid samples and blood samples were harvested during and until 5 days after HIPEC for pharmacokinetic study in ten patients.

Results: No treatment-related mortality was noted. Overall morbidity was 38% (two wound infections, one deep venous thrombosis, two grade 1 thrombopenia, one grade 2 neutropenia, and one grade 3 pancytopenia). Mean maximal intraperitoneal paclitaxel concentration was 101 mg/L, which was an average of 1178 times higher than the peak plasma levels. The peritoneal fluid versus plasma AUC ratio was 1462 for the 2-h HIPEC duration and 366 for the total 5-day study period. Cytotoxic drug concentrations were detected in peritoneal fluid for a mean period of 2.7 days, despite drainage of the drug solution after 2 h of treatment.

Conclusions: HIPEC with paclitaxel following cytoreductive surgery is feasible, relatively safe, and associated with a highly favorable pharmacokinetic profile, despite its short treatment duration. Larger studies with a more homogenous patient cohort and adequate follow-up should be performed to demonstrate its efficacy.