For example, despite proven benefit in metastatic colon cancer (12), irinotecan has not shown benefit

in the adjuvant setting. While signals of activity were seen in one trial, overall there were no statistically significant differences in DFS or OS with the addition of irinotecan to 5-FU/leucovorin in the adjuvant setting (13-15). This finding gave an early indication that the mechanism of chemotherapy action might be different in the setting of macrometastatic versus micrometastatic disease, a theme that Inhibitors,research,lifescience,medical has pervaded the testing of biologic agents in adjuvant colon cancer as well. Biologic agents in colon cancer Anti-VEGF therapy Vascular endothelial growth factor (VEGF) regulates angiogenesis both in health and disease, and contributes to angiogenesis in malignancy (16). For this reason, bevacizumab Inhibitors,research,lifescience,medical (Avastin®), a humanized monoclonal antibody to circulating vascular endothelial growth factor A (VEGF-A) was developed. Preclinical studies have shown multiple mechanisms of action for bevacizumab including inhibition of angiogenesis (17) by pruning of existing vessels and normalization of aberrant

vessels which is thought to improve delivery of concurrently administered chemotherapy (18). Notably, however, bevacizumab is thought to be cytostatic rather than cytotoxic, which may explain its success only in combination with cytotoxic Inhibitors,research,lifescience,medical chemotherapy, rather than as monotherapy (17). Of note, however, the majority of pre-clinical work with bevacizumab has been in models of metastatic disease and the importance of these mechanisms of action are less clear in the adjuvant setting. Clinically, in 2004, bevacizumab received Food and Drug Administration (FDA) approval Inhibitors,research,lifescience,medical for use as first line therapy in metastatic colorectal cancer based on studies Protein Tyrosine Kinase inhibitor showing improved response rate (RR), progression free survival (PFS), and OS when bevacizumab was added to 5-FU

containing regimens (19). Soon thereafter, approval for use in the 2nd line metastatic setting was granted, again based on studies indicating improved OS in combination with 5-FU containing regimens (20). Inhibitors,research,lifescience,medical In 2013, bevacizumab received an additional indication for continuation therapy at progression of metastatic disease based on data showing improved OS with ongoing bevacizumab use after progression also when the chemotherapy backbone was changed (21). In 2012, two additional anti-VEGF agents received FDA approval for use in metastatic colorectal cancer. Ziv-aflibercept (Zaltrap®) is a recombinant fusion protein with VEGF binding regions that function as decoy receptors binding intra- and extra-vascular VEGF-A such that they cannot bind to their usual receptors. The VELOUR trial showed improved OS with FOLIFRI plus ziv-aflibercept versus FOLFIFI plus placebo in metastatic colorectal cancer that progressed following an oxaliplatin-containing regimen (22). Regorafenib (Stivarga®) is an oral tyrosine kinase inhibitor that inhibits VEGF receptors 1 and 3.