Gastrointestinal perforation due to bevacizumab in colorectal cancer

Bevacizumab is the first U.S. Food and Drug Association-approved vascular endothelial growth factor-targeted agent that greatly increases progression-free and overall survival in combination with standard chemotherapy regimens in patients with metastatic colorectal cancer. Although bevacizumab is generally well tolerated, some serious adverse events have occurred in some patients in clinical trials, including arterial thromboembolism and gastrointestinal (GI) perforation. GI perforation was first observed in the pivotal phase 3 trial, in which six events occurred in bevacizumab group (1.5%), compared with no events in the control group. Since then, similar rates of GI perforation have been observed in other large trials. Typical presentation was abdominal pain associated with constipation and vomiting. Such events occurred throughout treatment and were not correlated with duration of exposure. No difference in rate of GI perforations was found in patients who did and did not have a baseline history of peptic ulcer disease, diverticulosis, and history of chronic use of nonsteroidal anti-inflammatory drugs. However, the incidence of GI perforation seemed to be higher in patients with primary tumor intact, recent history of sigmoidoscopy or colonoscopy, or previous adjuvant radiotherapy, but it is necessary to confirm these preliminary findings by multivariate analyses. The mechanism responsible for causing GI perforation is not known and may be multifactorial. Bevacizumab should be permanently discontinued in patients who develop GI perforation. This article reviews the incidence, presentation, pathogenesis, risk factors, and management of GI perforation in patients with colorectal cancer who are treated with bevacizumab.