Meta-analysis: Drug associated with increased risk for gastrointestinal perforation

Bevacizumab was associated with a twofold increased risk for gastrointestinal perforation in patients with cancer who were also being treated with chemotherapy, according to a meta-analysis.

Additionally, the likelihood of developing perforation was dose-dependent: Higher doses of bevacizumab were associated with a 167% increased risk.

“As bevacizumab is used extensively in routine cancer treatment and in clinical trials, it will be increasingly important to recognize symptoms indicating perforation and intervene promptly to reduce morbidity and fatality,” the authors wrote in the published report.

The researchers used PubMed and Web of Science articles published between January 1966 and July 2008 as well as abstracts presented at ASCO conferences between January 2000 and July 2008 to identify randomized controlled trials that compared bevacizumab (Avastin, Genentech) with controls in combination with standard antineoplastic therapy. The analysis was based on data from 12,294 patients with solid tumors from 17 randomized controlled trials.

Data from the meta-analysis showed a significantly increased risk for gastrointestinal perforation with the use of bevacizumab compared with controls (RR 2.14, 95% CI, 1.19-3.85). The incidence of gastrointestinal perforation with bevacizumab was highest in patients with advanced colorectal cancer and renal cell cancer, and the lowest was in patients with pancreatic cancer.

According to the researchers, the mortality rate was 21.7% (95% CI, 11.5-37.0) for patients with gastrointestinal perforation associated with bevacizumab compared with 15.7% (95% CI, 4.6-41.9) for controls.

There was a dose-dependent relationship between bevacizumab and the risk for gastrointestinal perforation: The RR with low-dose treatment (2.5 mg/kg/week) was 1.61 (95% CI, 0.76-3.38) compared with 2.67 (95% CI, 1.14-6.26) for high-dose treatment (5 mg/kg/week).

Researchers commented that there could be “multiple distinct mechanisms” that could be involved in the pathogenesis of the perforations. The drug may promote tumor regression and necrosis by stabilization of tumor vasculature and a “decrease in the permeability of interstitial pressure resulting in more effective delivery of chemotherapy.

“A tumor invasion of gastrointestinal serosa with subsequent necrosis would predispose patients to develop bowel perforation,” the researchers wrote.

“Future studies are recommended to investigate risk reduction and the possible use of bevacizumab in selected patients who have recovered from a complication,” they wrote.

Hapani S. Lancet Oncol. 2009;doi:10.1016/S1470-2045(09)70112-3.