Improving the Efficacy of Chemoradiation with Targeted Agents

Chemoradiation is the standard therapy for the majority of inoperable, locally advanced cancers. Although there is a need to improve chemoradiation efficacy, normal-tissue toxicity limits our ability to give additional chemotherapy or higher doses of radiation. Thus, there is excitement about the addition of molecularly targeted agents, which tend to be less toxic than chemotherapy, to chemoradiation regimens. Unfortunately, initial empiric attempts have not been successful. This review will focus on the evidence that supports rational combinations of targeted agents with chemoradiation, with an emphasis on agents that target the DNA damage response and radiation-induced membrane signaling. Significance: Too often, clinical trials are designed without comprehensive preclinical investigation. To design more rational trials of targeted agents with chemoradiation, it is necessary to understand the complex biology underlying the interactions between the targeted agent and chemoradiation. Thorough preclinical studies to evaluate key issues such as mechanisms of interaction, scheduling, selection of the appropriate patients through the use of biomarkers, and normal-tissue toxicity will lead to improved clinical trial designs and patient outcomes. Cancer Discov; 4(3); 280–91.