Current perspective: bevacizumab in colorectal cancer--a time for reappraisal?

Bevacizumab was the first anti-angiogenic drug to be licensed in malignant disease, based on the results of a randomised trial in advanced colorectal cancer, in which the addition of bevacizumab to chemotherapy with irinotecan plus fluorouracil/leucovorin (IFL) significantly improved tumour response, progression-free survival (PFS) and overall survival (median 15.6-20.3 months, p<0.001). A subsequent randomised trial of bevacizumab combined with fluoropyrimidine and oxaliplatin (FOLFOX or CAPOX) confirmed an improvement in PFS, but without a survival benefit, probably due to the limited duration of bevacizumab treatment. However, in the second-line setting a randomised trial of bevacizumab combined with FOLFOX showed a significant improvement in survival, similar to that observed with IFL in the first-line. A benefit from the use of bevacizumab plus chemotherapy beyond progression remains unproven but data from non-randomised trials are encouraging. In contrast, bevacizumab monotherapy has limited efficacy in advanced disease and currently there are no data to support maintenance monotherapy. Bevacizumab is recognised to cause hypertension, arterial and venous thrombosis, intestinal perforation and impairment of wound healing but can be safely used in patients undergoing surgery, particularly when the timing of surgery is controlled. At the 2009 ASCO annual meeting, the first adjuvant study to report its primary end-point, NSABP protocol C-08, failed to demonstrate an improvement in 3-year disease-free survival from the addition of bevacizumab to modified FOLFOX6 for resected stage II/III disease. Health economics have unfortunately limited the universal use of bevacizumab, but it is hoped that the future identification of predictive biomarkers may enhance the benefits and thereby improve cost-effectiveness.