Widely Used Cancer Drug Associated With Significantly Increased Risk of Blood Clots

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An analysis of randomized controlled trials indicates that use of the cancer drug bevacizumab is associated with an increased risk of venous thromboembolism, according to an article in the November 19, 2008, issue of the Journal of the American Medical Association.

Angiogenesis plays a crucial role in growth and metastasis of cancer. Bevacizumab, a new, widely used angiogenesis inhibitor, has shown benefits for the treatment of many types of malignancy including colorectal cancer, non–small-cell lung cancer (NSCLC), renal cell cancer, and breast cancer (Figure). Concerns have arisen, however, regarding the use of bevacizumab and the risk of venous thromboembolism, 1 of the leading causes of illness and death in patients with cancer.

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  Bevacizumab (Genentech/Roche, San Francisco, CA) trade name Avastin is a monoclonal antibody against vascular endothelial growth factor. In the treatment of cancer it inhibits tumor growth by blocking angiogenesis.

To determine the risk of venous thromboembolism associated with bevacizumab use, Shobha R. Nalluri, MD, of Stony Brook University, and colleagues conducted a meta-analysis of 15 randomized controlled trials (RCTs) that included a total of 7956 patients with a variety of advanced solid tumors. The researchers found that among patients receiving bevacizumab, the incidence of all-grade venous thromboembolism was 11.9%, whereas for high-grade venous thromboembolism, the incidence was 6.3%. The risk of developing venous thromboembolism was 33% greater with bevacizumab than with controls. This risk was significantly increased for both all-grade and high-grade venous thromboembolism. Both high (5 mg/kg per week) and low (2.5 mg/kg per week) doses of bevacizumab were associated with a 31% increased risk of venous thromboembolism.

The incidence of all-grade venous thromboembolism with bevacizumab varied among different tumors. The highest incidence was observed among patients with colorectal cancer (19.1%); for patients with NSCLC, the incidence was 14.9%, and for patients with breast cancer, the incidence was 7.3%. The lowest incidence (3.0%) was seen in patients with renal cancer.

“The association of venous thromboembolism with new agents presents a challenge for recognition because many RCTs may not be powered to reveal a significant relationship. Our meta-analysis of 15 RCTs has overcome this limitation of individual trials and demonstrated that bevacizumab may be associated with a significantly increased risk of venous thromboembolism in patients with a variety of metastatic solid tumors,” the authors write. “The increased risk is observed not only for all-grade venous thromboembolism, but also for clinically significant high-grade venous thromboembolism. This finding will help physicians and patients to recognize the risk of venous thromboembolism with the administration of bevacizumab.”

See “Risk of venous thromboembolism with the angiogenesis inhibitor bevacizumab in cancer patients: a meta-analysis,” JAMA 2008;300:2277–2285.