Hepatic arterial infusion but not systemic application of cetuximab in combination with oxaliplatin significantly reduces growth of CC531 colorectal rat liver metastases

PURPOSE: Systemic chemotherapy still represents the gold standard in the treatment of irresectable colorectal liver metastases. Modern anticancer agents like the monoclonal antibody cetuximab have improved the outcome of patients in clinical studies. As hepatic arterial infusion (HAI) is capable to potentially increase the anticancer effect of cytostatics, we herein studied whether HAI of cetuximab (CE) as a single agent or in combination with oxaliplatin (OX) exerts increased anticancer effects compared to the systemic application (SYS) of the drugs. METHODS: WAG/Rij rats were randomized to eight groups and underwent 10 days after subcapsular hepatic tumor implantation either HAI or SYS of CE, OX, or the combination of both agents (CE + OX). Saline-treated animals served as controls. Tumor volume was measured at days 10 and 13 using three-dimensional ultrasound. On day 13, liver and tumor tissue was sampled for histological and immunohistochemical analysis. RESULTS: In controls, the tumor volume significantly increased from day 10 to 13. Application of OX alone via HAI or SYS did not inhibit tumor growth compared to controls. SYS of CE or CE + OX did also not reduce tumor growth. In contrast, HAI of CE and CE + OX significantly inhibited tumor growth. HAI of CE significantly reduced tumor vascularization as measured by the number of platelet endothelial cell adhesion molecule-1-positive cells and significantly increased the number of apoptotic tumor cells as measured by the cellular caspase-3 expression. CONCLUSION: HAI of CE and CE + OX reduces tumor growth of colorectal rat liver metastases involving the inhibition of angiogenesis and induction of tumor cell apoptosis.