Bevacizumab associated with increased risk of venous thromboembolism

Treatment with bevacizumab is associated with a significantly increased risk of venous thromboembolism, according to a meta-analysis published in the Journal of the American Medical Association. The risk of both all-grade and high-grade venous thromboembolism was increased in patients with a variety of metastatic solid tumors and with both low- and high-dose regimens of bevacizumab.

Investigators conducted an independent review of PubMed citations from January 1966 through January 2008, as well as a search of abstracts and virtual meeting presentations from the American Society of Clinical Oncology (ASCO) conferences from January 2000 through January 2008. The investigators also performed an independent search of studies using the citation database Web of Science. Only randomized, controlled phase 2 or 3 trials that directly compared patients treated with bevacizumab with patients not treated with bevacizumab were included in the final analysis. Additional criteria for inclusion were studies that randomized patients to treatment with bevacizumab or control (placebo or best supportive care) plus concurrent treatment with chemotherapy or a biologic agent and studies that reported event or incidence of venous thromboembolism.

The investigators found 209 potentially relevant studies; from these, a total of 15 trials were included in the analysis. Across these trials, a total of 7,956 patients were included for analysis (bevacizumab-treated patients, n=4,292; control patients, n=3,664). Six of the trials were in patients with colorectal cancer, 4 were in patients with non-small cell lung cancer (NSCLC), 2 were in patients with breast cancer, 1 was in patients with pancreatic cancer, 1 was in patients with malignant mesothelioma, and 1 was in patients with renal cell carcinoma.

Across the 15 trials, the summary relative risk of venous thromboembolism among bevacizumab-treated patients was 1.33 (95% CI, 1.13–1.56; P<.001). The summary relative risk of all-grade venous thromboembolism was 1.29 (95% CI, 1.03–1.63; P=.03). The summary relative risk of high-grade venous thromboembolism was 1.38 (95% CI, 1.12–1.70; P=.002). The relative risk was significantly increased with both high-dose (5 mg/kg/wk) and low-dose (2.5 mg/kg/wk) bevacizumab treatment (high-dose relative risk, 1.31; 95% CI, 1.02–1.68; P=.04; low-dose relative risk, 1.31; 95% CI, 1.08–1.60; P=.007).

The authors suggested that the addition of a boxed warning regarding the increased risk of venous thromboembolism associated with bevacizumab treatment may be appropriate "to raise awareness among patients as well as physicians."

SOURCE

Nalluri SR, Chu D, Keresztes R, Zhu X, Wu S. Risk of venous thromboembolism with the angiogenesis inhibitor bevacizumab in cancer patients: A meta-analysis. JAMA. 2008;300:2277–2285.