Dr. Cornelis J. A. Punt, at Radboud University Nijmegen Medical Center, and co-researchers based their prospective, phase III trial on the theory that “inhibition of a single signal-transduction pathway is unlikely to provide optimal results, and therefore a combination of agents appears to be a valid strategy.”
Bevacizumab, a monoclonal antibody against vascular endothelial growth factor, combined with fluoropyrimidine-based chemotherapy is standard first-line treatment for metastatic colorectal cancer.
The CAIRO2 trial compared capecitabine, oxaliplatin, and bevacizumab (CB regimen) with the same regimen plus weekly treatment with the anti-epidermal growth factor receptor antibody cetuximab (CBC regimen). There were 368 patients in each treatment arm.
The median progression-free survival was significantly shorter in the CBC group (9.4 months vs 10.7 months, p = 0.01). The authors report that the hazard ratio for disease progression or death in the CBC group was 1.22.
Although quality of life and global health status did not differ between groups at baseline, both measures improved significantly more during treatment with the CB regimen than with CBC (p = 0.007 and p = 0.03, respectively).
These results “might be due to a negative interaction between cetuximab and bevacizumab,” Dr. Punt’s team speculates. Whatever the reason, they conclude, “our results… argue against the combined use of anti-VEGF and anti-EGFR monoclonal antibodies with chemotherapy in cases of metastatic colorectal cancer.”
In a related editorial, Dr. Robert J. Mayer, from Dana-Farber Cancer Institute in Boston, comments that “combining multiple forms of targeted therapies may not be analogous to combining different types of cytotoxic chemotherapy, presumably because of subtle interactions in intracellular signaling.”
In other words, he concludes, “More is not always better.”
N Engl J Med 2009;360:563-572,623-625.