Chemoradiotherapy: Emerging treatment improvement strategies

Background. The use of chemotherapeutic drugs in combination with radiotherapy has become a common strategy for the treatment of advanced cancer. Solid evidence exists showing that chemotherapy administered during the course of radiotherapy (concurrent chemoradiotherapy) increases both local tumor control and patient survival in a number of cancer sites, including head and neck cancer. These therapy improvements, however, have been achieved at the expense of considerable toxicity, which underscores the need for further improvements. Methods. The current status of chemoradiotherapy clinical trials for head and neck cancer and research on the emerging treatment improvements were reviewed. A review of potential treatment improvement strategies focused on preclinical investigations on newer chemotherapeutic agents, notably taxanes and nucleoside analogues, as well as on molecular targets such as epidermal growth factor receptor (EGFR) or cyclooxygenase-2 (COX-2) enzyme. Results. Concurrent, but not induction (drugs given before radiotherapy), chemoradiotherapy improves locoregional tumor control and survival benefit in head and neck carcinoma relative to radiotherapy alone. In comparison, both concurrent and induction chemoradiotherapy showed therapeutic advantage over radiotherapy alone in the treatment of lung cancer. These therapeutic improvements were achieved with standard chemotherapeutic drugs, most commonly cisplatin-based chemotherapy. Biologically, chemotherapy interacts with radiation through a number of mechanisms, including inhibition of cellular repair, cell cycle effects, and inhibition of tumor cell regeneration. Potential avenues emerged to further improve chemoradiotherapy. One of these involves the newer chemotherapeutic agents, taxanes and nucleoside analogues, which in preclinical studies exhibited strong tumor radiosensitization and therapeutic gain. The clinical benefit of these agents is currently under testing. Another approach for improvement of chemoradiotherapy consists of inhibiting molecules selectively or preferentially expressed on tumor cells, such as EGFR and COX-2, both shown to render cellular resistance to drugs or radiation. Agents that selectively inhibit these molecules are becoming available at a rapid rate, and many of them have been shown in preclinical testing to be highly effective in improving tumor radioresponse or chemoresponse without affecting normal tissues. Conclusions. Concurrent chemoradiotherapy, using standard chemotherapeutic agents, has emerged as an effective treatment for advanced cancer, but unfortunately at the expense of considerable increase in normal tissue toxicity. There are a number of potential emerging treatment strategies to further improve chemoradiotherapy. One consists of using newer chemotherapeutic drugs, which in preclinical studies are potent enhancers of tumor radioresponse. Another approach consists of targeting EGFR or COX-2 with selective inhibitors of these molecules.