Turning Point for Colorectal Cancer Clinical Trials

Abstract

The recent introduction of therapeutic antibodies for the treatment of patients with colorectal cancer has garnered welldeserved attention and excitement. 1-4 However, it is notable that traditional cytotoxics remain the backbone of systemic therapy for this disease. The benefits of both bevacizumab and cetuximab are augmented by concurrent administration of chemotherapy. 2,3 In fact, both of these targeted therapeutics may be appropriately viewed as chemotherapy sensitizers. Therefore, efforts to refine understanding and optimize the clinical use of available cytotoxics remain important. In this issue, Goldberg et al 5 report outcomes for a subset of patients enrolled onto North Central Cancer Treatment Group trial9741,aNorthAmericanintergroupstudyofinitialtherapyfor patientswithmetastaticcolorectalcancer.Thelatestdatafromthis rich clinical resource continue to answer relevant clinical questions, while highlighting those that remain. In addition, the design andconductofthistrialillustratehowtheworldofclinicalresearch in colorectal cancer has evolved over the past decade. North Central Cancer Treatment Group trial 9741 was the first phase III cooperative group study to move beyond the question of how best to deliver fluorouracil (FU). 6 It was designed at a time when irinotecan and oxaliplatin were new to our armamentarium. Whereas irinotecan was commercially available at the initiation of this trial, oxaliplatin was not. The study began as a six-arm trial. Bolus FU/leucovorin (LV) was the control arm, with two irinotecan plus FU/LV schedules, two oxaliplatin plus FU/LV schedules, and a nonfluoropyrimidine irinotecan plus oxaliplatin arm. 7 After the study was initiated, emerging data showed improved survival for irinotecan/FU/LV compared with FU/LV, and a new standard treatment for patients with metastatic colorectal cancer was established. Consequently, the FU/LV control arm was deleted. In addition, the arms containing a daily times five bolus schedule of FU/LV with either oxaliplatin or irinotecan, which were regimens that had not undergone extensive previous clinical testing, proved too toxic and were also discontinued. The initial inclusionofthesearmsrepresentedanewlevelofconfidencebythe GI intergroup in the ability to successfully monitor toxicity in real time and react rapidly with appropriate protocol modification if needed. Thus, 9741 was reduced to the following three arms: weekly irinotecan/FU/LV (IFL), biweekly oxaliplatin/bolus plus infusional FU/LV (FOLFOX4), and 3-weekly irinotecan plus oxaliplatin. Approximately 1 year after the three-arm design was