End Points in Advanced Colon Cancer Clinical Trials: A Review and Proposal

Colorectal cancer accounts for the death of more than 55,000 individuals in the United States each year. 1 The vast majority of these patients receive systemic chemotherapy with one or more of several agents presently approved for treatment in this setting. Given the relatively recent and rapid identification of new active therapeuticsforpatientswithadvancedcolorectalcancer,thealgorithm for patient management is undergoing a similarly rapid evolution. The traditional paradigm, dating from the initial use of fluorouracil in the 1960s, dictated that patients receive continuous systemic therapy until disease progression or unacceptable toxicity.Thistreatmentmodelhasgenerallybeenappliedtotherapeutic clinical trials and forms the foundation on which the currently accepted intermediate end points designed to assess the efficacy of new agents (eg, progression-free survival [PFS]) are based. The high level of activity of newer regimens and a particular element of treatment with the agent oxaliplatin are challenging these standard paradigms. Although highly effective when used in combination with fluorouracil, oxaliplatin is associated with a cumulative sensory neuropathy that occurs at clinically significant levels after approximately 5 months (approximately 850 mg/m 2 total dose) of therapy. 2 This adverse event generally precludes long-term continuous therapy with this agent. In other tumor types (eg, lung, ovary), the use of platinum therapy has resulted in preplanned, fixed therapeutic windows of 4 to 6 months. Similar approaches are beginning to be explored in colorectal cancer, driven primarily by the desire to obviate or at least mitigate neurotoxicity. In addition, as three-, four-, and five-drug regimens become more common and a majority of patients respond to treatment (or at least establish stable disease), in many cases, toxicityexceedstolerablelimitsbeforetheeffectivenessofaregimenis fully exploited. A recent study reported in abstract form may serve as an example of this phenomenon. 3 In this investigation, bevacizumab did not seem to improve the PFS of oxaliplatin-based regimens to the extent expected based on prior trials. 4 A possible