Widely used cancer drug bevacizumab associated with significantly increased risk of gastrointestinal perforation

Cancer patients treated with the widely used drug bevacizumab in combination with chemotherapy are at significantly greater risk of potentially life-threatening gastrointestinal (GI) perforations (a hole in the wall of the stomach, small intestine or large bowel)—particularly patients with advanced colorectal cancer and renal cell cancer, according to an article published in The Lancet Oncology.

Bevacizumab belongs to a class of drugs called angiogenesis inhibitors, that slow down the growth of tumours by cutting off their blood supply. Bevacizumab has been shown to be beneficial in the treatment of many types of cancer including colorectal cancer, renal cell cancer, non-small cell lung cancer, and breast cancer. Despite concerns about the use of bevacizumab and GI perforation, including a black-box warning issued by the US Food and Drug Administration to discontinue bevacizumab in patients with GI perforation, the link is not well established and so far no trials have proved a significant association.

To resolve this uncertainty, Shenhong Wu and colleagues from Stony Brook University Cancer Center, New York, did a meta-analysis of 17 randomised trials involving 12 294 patients with a variety of solid tumours to assess the role of bevacizumab in GI perforation. The authors also examined whether the dose of bevacizumab or having a specific type of cancer was related to a higher risk of developing GI perforation.

Findings showed that the incidence of GI perforation was 0.9%, with a two-fold increased risk of GI perforation in patients receiving bevacizumab compared with controls, and a mortality of 21.7% in patients who developed GI perforation. Interestingly, the likelihood of developing GI perforation was found to be dose-dependent. Versus controls, lower doses of bevacizumab (2.5 mg/kg per week) increased risk of GI perforation by 61%; while at a higher dose (5 mg/kg per week), the risk of a GI perforation increased by 167%.

The incidence of GI perforation with bevacizumab also varied among different tumours―with the highest incidence observed among patients with advanced colorectal cancer and renal cell cancer, and the lowest in patients with pancreatic cancer.

The authors conclude that: “As bevacizumab is extensively used in routine cancer treatment...it will be increasingly important to recognise symptoms indicating perforation and intervene promptly to reduce morbidity and fatality...our study might help to identify a subset of patients receiving bevacizumab at high risk of bevacizumab-associated perforation.”