High antitumor efficacy of a combination between sunitinib, cetuximab and irradiation on an orthotopic head and neck cancer model.

4040 Combination of anti-epidermal growth factor receptor (EGFR) therapy with radiotherapy (RT) has demonstrated clinical benefit in head and neck cancer. Recent pre-clinical and clinical studies have suggested promising efficacy of RT combined with anti-angiogenic agents. The aim of the present study was to test the association of a monoclonal antibody directed against EGFR (cetuximab) with a multi-target tyrosine kinase inhibitor directed against VEGFRs (sunitinib) and RT. Investigations were performed on a VEGF-secreting human head and neck cancer cell line (CAL33) with a high EGFR content, injected as orthotopic xenografts into the mouth floor of nude mice. The anti-tumor efficacy of cetuximab (1 mg/kg 5 days a week, i.p. ), sunitinib (20 mg/kg 5 days/week, p.o.) and RT (6 Gy, 3 days/week) administered alone or in combination was assessed at day 10 after starting treatment (animal sacrifice for ethical reasons, 10 animals per treatment group). Tumor volume, proportion of well-differentiated cells, tumor cell proliferation (Ki67), VEGFR2 labeling in tumor cells, number of vessels in the center and at the periphery of the tumor were examined. Bilateral node chain dissection was performed and the number of inflammatory nodes, either invaded or not, was measured. Differences between treatments were tested according to the non-parametric Mann-Whitney test. The interactions between combined treatments were assessed by computing the combination ratio (CR) defined as FTvA x FTvB / FTv (A+B), where FTvx is the fractional tumor volume for the agent x.
 As compared to control, concomitant administration of cetuximab and sunitinib produced a marked and significant supra-additive decrease in tumor volume (CR = 1.78, p