Intraperitoneal bevacizumab combined with cytoreductive surgery: a pre-clinical study of tolerance and pharmacokinetics in an animal model

Abstract

Cytoreductive Surgery (CRS) combined with Hyperthermic Intraperitoneal Chemotherapy (HIPEC) is currently the only potentially curative treatment for peritoneal carcinomatosis (PC). Systemic administration of bevacizumab improves survival in patients with metastatic colorectal or ovarian cancer. Intraperitoneal administration of bevacizumab has been shown to be safe and effective in treating malignant ascites. The combination of CRS with intraperitoneal (IP) bevacizumab could maximize local control and survival from PC, but the associated morbidity from this is unknown. The aim of this study was to evaluate the safety of the combination of CRS with IP bevacizumab and to determine the pharmacokinetics of the drug in a rabbit model. Twenty healthy rabbits underwent a standardized procedure of debulking surgery, including peritonectomy and gastrointestinal anastomosis and were randomized to receive IP bevacizumab (25mg/kg) or placebo. Another group of three rabbits underwent an instillation of IP bevacizumab (25mg/kg) without surgery. One rabbit that received IP bevacizumab died with no complication associated with the use of bevacizumab at autopsy. There was no significant difference between IP bevacizumab and placebo in weight loss, length of surgery or morbidity. The plasma concentration of bevacizumab increased to a peak at 24h post IP administration. Bevacizumab was not detected in the plasma of animals without surgery. This study suggests that IP bevacizumab does not increase morbidity and mortality of debulking surgery in an animal model. When surgery is performed, the pharmacokinetics of IP bevacizumab are modified in plasma.