C225 antiepidermal growth factor receptor antibody enhances the efficacy of docetaxel chemoradiotherapy

Purpose: C225 anti-EGFR (epidermal growth factor receptor) antibody has been shown to enhance tumor response to radiation and a number of chemotherapeutic agents. Because of increased use of concurrent chemoradiotherapy in cancer treatment, it is important to determine whether C225 enhances also the antitumor efficacy of radiation when combined with chemotherapy. This study assessed the effect of C225 on tumor response when combined with docetaxel plus single or fractionated radiation. Methods and Materials: MDA468 human adenocarcinoma and A431 human epidermoid carcinoma cells growing as xenografts in the right hind leg of nude mice were used. Mice bearing 8-mm tumors were treated with C225 antibody at a dose of 1 mg given i.p. once, twice, or three times 3 days apart, 10 or 30 mg/kg docetaxel given i.v., and/or local tumor irradiation of 8 or 10 Gy single dose or fractionated irradiation consisting of 2 Gy daily for 5 days. When all three agents were combined, C225 was given 6 h before or 18 h after docetaxel, and radiation was given 24 h after docetaxel. The treatment end point was tumor growth delay. Results: C225 enhanced the antitumor efficacy of docetaxel, local tumor irradiation, and docetaxel combined with radiation. The response of both MDA468 and A431 carcinomas was enhanced. The enhancement factors ranged from 1.19 to 8.52, the degree of the enhancement depending on experimental conditions such as administration of multiple vs. single dose C225 or single or fractionated irradiation. C225 given twice or 3 times was more effective than when administered as a single dose. The effect of C225 was more pronounced when combined with single than fractionated irradiation with or without docetaxel. The triple-agent therapy was more effective than a single agent or double combination therapies, expressed by both increased tumor growth delay and the rate of tumor cure. Conclusions: Our results show that C225 anti-EGFR antibody is a potent enhancer of tumor response to docetaxel or radiation as single agents, and to docetaxel when combined with radiation. Thus, these findings provide strong preclinical evidence in support of combination of anti-EGFR blockade with chemoradiotherapy. (C) 2004 Elsevier Inc.