Is dual antibody therapy with chemotherapy for metastatic colorectal cancer ready for prime time?

Great advances have been made in the past 10 years in the management of metastatic colorectal cancer (MCC). Median overall survival has improved from approximately 6 months with best supportive care, to 10–12 months with 5FU monotherapy, to more than 20 months with current regimens. Much of this progress stems from the addition of new cytotoxic and biologic agents to the medical oncologist’s armamentarium. Currently, the most active agents against MCC include cytotoxics (fluoropyrimidines, oxaliplatin, and irinotecan) and biologics (EGFR inhibitors such as cetuximab and panitumumab, and VEGF inhibitors such as bevacizumab). Numerous studies demonstrate that combining cytotoxic chemotherapy agents improves clinical outcomes. Overall survival, for instance, with 5FU/LV is estimated at 12 months, whereas doublet combinations with 5FU/LV plus oxaliplatin have resulted in survival rates of 16 months [1,2]. Other trials demonstrate an even greater improvement in overall survival with the addition of bevacizumab to irinotecanor oxaliplatin-based doublets [3]. Based on these observations, bevacizumab plus chemotherapy represents a standard of care for the first-line treatment of MCC. By contrast, there is no direct evidence demonstrating whether cetuximab in combination with irinotecan improves overall survival in comparison with best supportive care or oxaliplatin/5FU/LV, although the evidence on tumor response rate suggests that cetuximab plus irinotecan has some clinical activity. Given the improvements seen with the use of multiple cytotoxic treatments, in addition to the benefit seen with adding bevacizumab, it was logical to ask whether adding yet another targeted agent (an anti-EGFR, such as cetuximab or p anitumumab) might improve outcomes even more. CApecitabine, IRinotecan, Oxaliplatin-2 (CAIRO-2) and Panitumumab Advanced Colorectal Cancer Evaluation (PACCE) are two recently published randomized Phase III trials aimed at addressing the role of dual antibody therapy as first-line treatment for MCC. CAIRO-2 was a multiinstitutional Phase III trial of 732 patients conducted in the Netherlands, where patients with previously untreated MCC were randomized to receive capecitabine, oxaliplatin and bevacizumab with or without cetuximab every 3 weeks [4]. Tumor response was evaluated every 9 weeks and the primary end point of the study was progression-free survival. After a median follow-up of 23 months, the arm that received cetuximab had a worse median progressionfree survival (9.4 months vs 10.7 months, p = 0.01), but similar median overall survival (19.4 months vs 20.3 months, p = 0.16). A total of 528 patients (71%) had KRAS gene mutation status tested and 206 Research Highlights