Rationale and clinical basis for combining gefitinib (IRESSA, ZD1839) with radiation therapy for solid tumors.

PURPOSE: The role of dysregulated epidermal growth factor receptor-tyrosine kinase (EGFR-TK) activity in promoting tumor resistance to radiation therapy is discussed, and evidence supporting the rationale for the use of gefitinib (IRESSA, ZD1839) to enhance tumor radiosensitivity is reviewed. METHODS AND MATERIALS: A review of the literature regarding the role of EGFR-TK signaling in tumor response to radiation therapy was conducted, and results were summarized from preclinical and clinical studies of gefitinib in the treatment of solid tumors alone and in combination with radiation therapy.
RESULTS: Preclinical results indicate that EGFR-TK activity in tumors can block the cytotoxic effects of radiation therapy and enhance tumor repopulation, resulting in failure of local tumor control. In xenograft tumor models, gefitinib in combination with ionizing radiation resulted in additive to synergistic growth inhibition. In randomized clinical trials, gefitinib has demonstrated efficacy with favorable tolerability as monotherapy for patients with advanced non-small-cell lung cancer or head-and-neck carcinomas who had previously received standard therapies.
CONCLUSIONS: These results indicate that there is potential for improved responses by combining gefitinib with radiation therapy in non-small-cell lung cancer, head-and-neck cancers, and other solid tumors.