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Targeted agents in GI radiotherapy: Clinical efficacy and side effects. Approximately 50% of all patients with cancer receive radiotherapy (RT) at some point during their treatment. Despite the advent of modern imaging and advances in planning and delivering highly-conformal and precise RT, further dose escalation to improve clinical outcome is often limited by the potential side-effects to adjacent tissues. Addition of chemotherapy to radiotherapy (CRT) has led to significant clinical improvements in many gastrointestinal malignancies but at the expense of increased toxicity as most chemotherapy drugs lack specificity. Targeted agents modulate specific biological pathways and can potentially enhance RT efficacy. However, so far, the majority of clinical studies incorporating targeted agents into RT and CRT have produced disappointing results in gastrointestinal malignancies. Also, we lack validated biomarkers and methods for monitoring and predicting the efficacy of these agents when combined with RT/CRT. In the present article, we will review the most important targeted therapies, and examine the efficacy and toxicity of these agents when combined with RT/CRT in gastrointestinal malignancies. The shortcomings as well as future challenges and perspectives for the successful use of these compounds with RT/CRT in future trials will also be outlined.