Docetaxel/radiation combinations: rationale and preclinical findings

Concurrent chemoradiotherapy, administration of chemotherapeutic agents during the course of radiation therapy, has increasingly been used for treatment of advanced locoregional cancer. Improvements in radiation therapy are achieved through independent cytotoxic action of drugs and their ability to sensitize tumor cells to radiation. Laboratory investigations showed that docetaxel is potent in both of these actions. The drug increased the radiosensitivity of in vitro cultured cells and the in vivo tumor radioresponse. In contrast to exerting a strong enhancement of tumor radioresponse, the ability of docetaxel to modify normal tissue radiation damage was much lower. Thus, docetaxel can significantly increase therapeutic gain when combined with radiation therapy. The initial rationale for using docetaxel and other taxanes as radiation enhancers was the ability of these agents to arrest cells in the radiosensitive G2/M phases of the cell cycle. Additional mechanisms were subsequently detected, including the ability of docetaxel to eliminate radioresistant S-phase cells, cause tumor reoxygenation, stimulate antitumor immune resistance mechanisms, and possibly inhibit tumor angiogenesis. Because combined chemoradiotherapy treatments are limited by normal tissue toxicity, additional treatment strategies are needed to improve the antitumor efficacy and to minimize normal tissue toxicity. In this regard, many research avenues are being explored, particularly the possibility of combining chemoradiotherapy with molecular targeting. This overview addresses the rationale for major findings on the interaction of docetaxel and radiation in preclinical models and discusses how these findings may impact practical use of chemoradiotherapy.