In this review article we discuss the evolution of second-line treatment options for patients with metastatic colorectal cancer (mCRC). The benefits of second-line chemotherapy have been established for some time, but in the last decade a number of trials have evaluated combinations of irinotecan- and oxaliplatin-based chemotherapy with molecular-targeted agents; e.g., vascular endothelial growth factor (VEGF)-targeting agents (bevacizumab, aflibercept), epidermal growth factor receptor antibodies (cetuximab, panitumumab), and tyrosine kinase inhibitors (vatalanib). Recent developments include the availability of the new VEGF-targeted agent aflibercept and the new concept of continuing bevacizumab after failure of first-line bevacizumab, which is likely to become a new treatment option in the second-line setting. Choosing the most appropriate second-line treatment regimen for mCRC patients remains a complex issue. All of the currently available molecular-targeted agents seem to be active even after patients have received a bevacizumab-based first-line regimen. Overall, the selection of second-line treatment for mCRC depends on several variables and should be determined taking into account the patient's performance and disease status.
