An update on treatment advances for the first-line therapy of metastatic colorectal cancer

The treatment of metastatic colorectal cancer (mCRC) has evolved significantly over the past 10 years. For nearly 40 years, the fluoropyrimidine 5-fluorouracil (5-FU) was the only agent to be used for advanced metastatic disease. However, since the mid-1990s, the chemotherapy treatment options for patients with mCRC have been greatly facilitated with the introduction of several new cytotoxic and biologic agents. In particular, combination regimens that incorporate infusional schedules of 5-FU in combination with oxaliplatin (FOLFOX) and/or irinotecan (FOLFIRI) have significantly improved clinical efficacy as related to overall response rates, time to tumor progression, and median overall survival. Capecitabine, an oral fluoropyrimidine, has now been shown in several phase III studies to be as effective as infusional 5-FU when combined with oxaliplatin. During this same time frame, intense efforts have focused on integrating novel biologic agents with cytotoxic chemotherapy regimens. These biologic agents target critical signaling pathways such as the vascular endothelial growth factor (VEGF) and the epidermal growth factor receptor (EGFR). Bevacizumab is a monoclonal antibody targeting VEGF-A, and when combined with fluoropyrimidine-based chemotherapy, which includes oxaliplatin or irinotecan, significantly improves clinical efficacy in the management of patients with mCRC. Cetuximab and panitumumab are monoclonal antibodies targeting EGFR, and each of these agents is approved to treat mCRC patients who have progressed on previous chemotherapy treatments. Recent studies have shown that cetuximab, when combined with cytotoxic chemotherapy, significantly enhances the management of patients with mCRC in the first-, second-, and disease-refractory settings. With these advances in treatment options, much attention is now focused on identifying the critical molecular biomarkers that can predict response and/or toxicity to facilitate the evolution of empiric chemotherapy to individually tailored treatments for patients with mCRC.