Revisiting the Cancer and Leukemia Group B/Southwest Oncology Group 80405 Trial: A Phase III Trial of Chemotherapy and Biologic Agents for Patients with Untreated Advanced Colorectal Adenocarcinoma

The management of patients with metastatic colorectal cancer (CRC) has changed dramatically over the past 5 years. The availability of new cytotoxic and biologic treatment agents, namely irinotecan, oxaliplatin, capecitabine, bevacizumab, cetuximab, and panitumumab, has altered the therapeutic strategies used as successive phases of treatment. The exposure of patients to multiple lines of chemotherapy has dramatically improved the median survival for patients with advanced CRC.1 Although the optimal timing and sequencing of these agents are unknown, the potential impact of biologic agents used in combination with chemotherapy might be more dramatic than when used alone. Further increasing the complexity, there are no predictive tests that enable the individualization of “optimal” firstline therapy before treatment. This could be increasingly important because of emerging evidence that certain patients with advanced CRC (eg, those with isolated hepatic or lung metastases) might be cured when a surgical approach is used in conjunction with the “optimal” chemotherapy.2 Current data suggest that combining oxaliplatin or irinotecan with infusional 5-fluorouracil (5-FU) and leucovorin (FOLFOX or FOLFIRI, respectively) confers relatively similar survival outcomes in the first-line setting,3,4 and the decision of which regimen to use in this setting is a function of comorbidities, anticipated toxicities, and the possibility of previous exposure to oxaliplatin in the adjuvant setting.5 Although it is also clear that biologic agents have efficacy in this disease setting, their role is less certain. There is compelling evidence that bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor, improves the efficacy of bolus irinotecan/5-FU/leucovorin (IFL)6 in previously untreated patients and FOLFOX in patients with disease refractory to IFL.7 However, bevacizumab, as a single agent or as thirdor further-line treatment appears to be, at best, minimally active. Bevacizumab is currently approved for use with 5-FU–containing chemotherapy in the firstand second-line management of patients with advanced CRC. Cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor (EGFR), was first studied in secondor subsequent-line treatment in patients with tumors overexpressing EGFR by immunohistochemistry and has demonstrated single-agent efficacy and additive activity in combination with irinotecan.8 The role of cetuximab as first-line treatment remains unclear, but evidence suggests that using it solely in patients with EGFR-positive tumors by Submitted: May 11, 2007; Accepted: May 17, 2007 1Cancer and Leukemia Group B 2University of California, San Francisco 3Southwest Oncology Group 4Oregon Health Sciences University, Portland 5Duke University, Durham, NC 6University of Southern California, Los Angeles Alan P. Venook,1,2 Charles D. Blanke,3,4 Donna Niedzwiecki,1,5 Heinz-Josef Lenz,3,6 John R. Taylor,1 Donna R. Hollis,1,5 Susan Sutherland,1,5 Richard M. Goldberg1,2