The institution of combined modality therapy for unresected solid tumors has resulted in significant improvements in tumor control and survival benefit compared with radiotherapy (RT) alone. A number of chemotherapy agents that can enhance the effectiveness of RT, such as cisplatin and 5-fluorouracil, are now considered standard treatment for patients with a number of cancer types. There is growing interest in a number of additional agents that have also been found to have radiosensitizing ability. These include paclitaxel, docetaxel, irinotecan, gemcitabine, and vinorelbine, as well as biologic agents. Other agents may be of value because they act to counter dose-limiting toxicities associated with RT. This article provides an update of some important, recently completed and ongoing clinical trials evaluating novel chemoradiation protocols, with examples taken primarily from studies conducted by the Radiation Therapy Oncology Group (RTOG). Theoretical approaches to the development of new agents and combined modality regimens are also discussed.

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