Relative risk similarly increased for low and high dose of bevacizumab

Vascular complications, including venous thromboembolism (VTE) are one of the leading causes of morbidity and mortality in patients with cancer. A variety of antineoplastic agents with angiogenesis inhibiting activity (thalidomide, lenalidomide, bevacizumab, sunitinib, sorafenib) have received for clinical use while others have entered clinical trials.

Given the well-known interplay between the blood clotting system, angiogenesis, and tumor growth, researchers observed a variety of vascular complications, including venous or arterial thromboembolism and hemorrhage, as relevant toxicities with the use of angiogenesis inhibitors. Concerns were especially alarming with bevacizumab, a recombinant humanized monoclonal antibody to vascular endothelial growth factor that is widely used in cancer treatment. Currently, the role of bevacizumab in venous thromboembolism is controversial.

Bloomberg and HealthDay News both reported on a meta-analysis recently published in the Journal of American Medical Association (JAMA).

To assess the overall risk of venous thromboembolism associated with the use of bevacizumab, Dr Nalluri and his team of researchers from the Division of Medical Oncology, Department of Medicine, Stony Brook University, Stony Brook, New York, NY 11794, systematic reviewed and analyzed a number of randomized controlled trials.Eligible studies included prospective randomized controlled trials in which standard antineoplastic therapy was used with and without bevacizumab for which data on venous thromboembolism were available.

Summary incidence rates, relative risks (RRs), and 95% confidence intervals (CIs) were calculated using random-effects or fixed-effects models based on the heterogeneity of the included studies.

The researchers found 15 randomized controlled trials and identified a total of 7956 patients with a variety of advanced solid tumors. Among those patients receiving bevacizumab, the summary incidences of all-grade and high-grade venous thromboembolism were 11.9% (95% CI, 6.8%-19.9%) and 6.3% (95% CI, 4.8%-8.3%), respectively.

Patients treated with bevacizumab had a significantly increased risk of venous thromboembolism with a relative risk of 1.33 (95% CI, 1.13-1.56; P < .001) compared with controls. The risk was significantly increased for both all-grade and high-grade venous thromboembolism. In addition, the relative risk was similarly increased for bevacizumab at 2.5 mg/kg per week (low dose; RR, 1.31 [95% CI, 1.08-1.60]; P = .007) and 5 mg/kg per week (high dose; RR, 1.31 [95% CI, 1.02-1.68]; P = .04).

The authors of the meta-analysis concluded that the use of bevacizumab in cancer patients was associated with an increased risk of developing venous thromboembolism.

In an unrelated study published in American Journal of Hematology, Dr Francesca Elice and her team of researchers from Department of Cell Therapy and Hematology, San Bortolo Hospital, Vicenza, Italy, concluded that careful documentation of hemostatic complications during treatment with each of the new antiangiogenic drugs, including bevacizumab, is warranted and that further studies are urgently required to better define the causal association of these new agents with hemostatic complications and to establish the best prophylactic strategy.

PubMed abstracts:

• 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 Nov 19;300(19):2277-85.
• Elice F, Jacoub J, Rickles FR Hemostatic complications of angiogenesis inhibitors in cancer patients. Am J Hematol 2008 Nov;83(11):862-70.