Incidence and management of bevacizumab-related toxicities in colorectal cancer

Bevacizumab, a recombinant, humanised monoclonal antibody against vascular endothelial growth factor, when used in combination with intravenous 5-fluorouracil (5-FU)-based chemotherapy as first-line treatment of metastatic colorectal cancer (CRC) improves survival. In a randomised, placebo-controlled Phase III study, the addition of bevacizumab to irinotecan/5-FU/leucovorin (IFL) resulted in significant improvement in survival compared with IFL alone, which led to its approval for first-line use in CRC. Bevacizumab also demonstrates improved efficacy in combination with 5-FU/LV over chemotherapy alone when data were pooled from two randomised Phase II studies utilising bevacizumab with 5-FU/leucovorin, and also in a third treatment arm of bevacizumab/5-FU/LV of a randomised Phase III study. More recently, in the second-line setting, bevacizumab in combination with FOLFOX improved survival from 10.8 to 12.9 months in the ECOG 3200 trial. Clinical activity with the addition of bevacizumab to oxaliplatin and either 5-FU or capecitabine-based regimens has also been shown in TREE-2, and activity with the combination of bevacizumab and the EGFR inhibitor cetuximab has been documented in BOND-2. In this study, bevacizumab was generally well-tolerated with no unexpected toxicities when combined with cetuximab. A few toxicities were uniformly encountered in all of the above studies, in particular grade 3 medically-manageable hypertension (3 - 16%). In addition, other toxicities were haemorrhage (2 - 9.3%), gastrointestinal perforation (1.5%), arterial thromboembolism (3.8%), wound healing (1 - 2%) and proteinuria (1 - 2%). As bevacizumab is becoming widely used in general oncology practice, it is important to understand the toxicities which can arise and to develop practice guidelines for their management. This review addresses the toxicities noted in trials using bevacizumab for the treatment of CRC and provides recommendations for toxicity management.