Development of new agents for the treatment of advanced colorectal cancer.

During the past decade, there have been several significant advances in the treatment of metastatic colorectal cancer. These include the introduction of the cytotoxic agents capecitabine, irinotecan, and oxaliplatin. Given their diverse mechanisms of action and toxicity profiles, combinations of fluoropyrimidines, irinotecan, and oxaliplatin have proven feasible and have improved patient outcomes compared with 5-fluorouracil alone. Recently, improved understanding of the biology of colorectal cancer has led to the identification of new molecular targets and the development of pharmacologic agents that hold promise for greater tumor selectivity than traditional cytotoxic agents. Two approaches with early indications of clinical activity against colorectal cancer are inhibition of epidermal growth factor receptor signaling and inhibition of the vascular endothelial growth factor pathway. Furthermore, biochemical and genetic profiling of individual tumors, as well as patient genotyping, may ultimately guide clinicians in making rational treatment decisions based on predicted antitumor efficacy or toxicity of selected agents. This article reviews these recent advances in the systemic treatment of colorectal cancer, including discussion of promising agents in clinical development.