Antitumor activity of cetuximab associated with the taxotere–cisplatin–fluorouracil (TPF) combination on an orthotopic head and neck cancer model

Abstract

Cetuximab (Cet), an anti-epidermal growth factor receptor (EGFR) monoclonal antibody, is a standard of care in advanced head and neck (HN) cancer when combined with irradiation or cisplatin. The TPF association combining docetaxel (T), cisplatin (P) and fluorouracil (F) has become a chemotherapy of reference in the management of HN tumors. The aim of the study was to evaluate the anti-tumor activity of the association of Cet with TPF. In addition, the potential benefit from adding bevacizumab (Bev), an anti-VEGF monoclonal antibody, was examined. Investigations were performed on CAL33 human head and neck cancer cell line (high content of EGFR) injected as an orthotopic xenograft into the mouth floor of nude mice. The anti-tumor efficacy of Cet (2.5 mg/kg), Bev (20 mg/kg) and of TPF (at the MTD: T 20 mg/kg, P 6 mg/kg, F 17 mg/kg), administered alone or in combination on day 3 and day 10 after tumor cell injection, was assessed on day 12 (animal sacrifice for ethical reasons, 10 animals per treatment group). Tumor volume, tumor histology, tumor cell proliferation (Ki67, immunochemistry) and apoptosis (Bcl2, immunochemistry) were examined. As compared to controls, TPF-Cet and TPF-Cet-Bev had a significant impact on tumor volume and histological response. The highest efficacy was observed with the TPF-Cet combination. The effects of the TPF-Cet-Bev association were not significantly different from those observed with TPF-Cet. Data were corroborated by a diminution in Ki67 labeling and Bcl2 expression. The association of Cet with TPF can be considered a beneficial clinical option in advanced HN cancer patients.