Indeed, induction of tumor hypoxia and an inflammatory state caused by anti-angiogenic agents may promote malignancy (43,47). Other animal models, however, have shown that treatment and subsequent discontinuation of anti-VEGF therapy resulted in tumor re-growth at a slower rate than control-treated animals, speaking against a so-called rebound growth effect (18). Despite the above theoretical concerns, no clinical studies have indicated that exposure to biologic agents select for more aggressive tumors

or promote tumor invasiveness. For example, a study in patients with gliobastoma Inhibitors,research,lifescience,medical multiforme treated with the pan-VEGF Inhibitors,research,lifescience,medical receptor tyrosine kinase inhibitor, cediranib, showed no rebound angiogenesis when the drug with withheld (49). And in multiple large, randomized clinical trials with bevacizumab in multiple disease types

including renal cell carcinoma (50), breast cancer (51), and lung cancer (52), there have been no indication of re-bound tumor effect Inhibitors,research,lifescience,medical after withdrawal of bevacizumab. Conclusions New chemotherapy drug development has traditionally started with testing agents in the refractory, advanced disease setting, followed by the first line metastatic setting with only drugs with success in advanced disease advancing to testing in the adjuvant setting. However the assumption that drugs successful in macrometastatic disease will also be effective in micrometastatic disease (adjuvant setting) is Inhibitors,research,lifescience,medical increasingly being questioned, particularly in the era of biologic agents. In colon cancer, the benefit of cytotoxic agents such as 5-FU, capecitabine, and oxaliplatin did indeed translate to the adjuvant setting for most patient sub-groups. However, irinotecan showed no benefit in the adjuvant setting and bevacizumab Inhibitors,research,lifescience,medical and cetuximab even had trends towards worse outcomes when used adjuvantly. The importance of large-scale clinical trials of drugs in the exact settings in which they will be used cannot be Nutlin-3a manufacturer overstated. An interesting

concern is the idea that agents unsuccessful in the metastatic setting may show efficacy in the adjuvant setting. However, acting on this possibility would involve changing the paradigm of how we currently move new drugs through clinical trials with no current examples also of such a drug at present. Where do we go from here in the adjuvant treatment of colon cancer and other malignancies in the biologic era? Perhaps new classes of biologic agents such as inhibitors of insulin growth factor, MEK, PI3kinase or BRAF may be more successful. Or perhaps anti-VEGF or anti-EGFR therapies have a role, but we have to identify the correct patient population, with predictive markers.