Bevicizumab and thrombosis: Some answers but questions remain

In this issue of Cancer, a report by Patel and colleagues examines the risk of arterial and venous thromboembolism in patients with metastatic, castration-resistant prostate cancer. Using the results from Cancer and Leukemia Group B (CALGB) trial 90401, which evaluated the addition of bevacizumab to standard docetaxel chemotherapy, the authors demonstrate that bevacizumab treatment is associated with an increased risk of arterial—but not venous—thromboembolism in patients with metastatic, castrate-resistant prostate cancer. Bevacizumab is an antitumor agent whose mechanism of action is not direct cytotoxicity but interference with tumor vessel growth through the inhibition of vascular endothelial growth factor (VEGF). This unique mechanism of action may also be responsible for the complications discussed in the report by Patel et al: thrombosis. The association between bevacizumab and thrombosis is important, both because cancer patients are at high risk of developing thrombosis and because the patients who have the tumors that often are treated with bevacizumab (brain, colon, and lung tumors) suffer from high rates of thrombosis at baseline. It is believed that the etiology of thrombosis in patients with cancer is multifactorial. Tumors themselves are thrombogenic, perhaps because of increased expression of prothrombotic proteins, such as tissue factor. Cancer treatments add to this risk. The same surgery performed in patients who have cancer increases the risk of thrombosis 3-fold compared with patients who do not have cancer. Cytotoxic chemotherapy also increases the risk of thrombosis. The development of noncytotoxic cancer therapies has revealed that certain agents are associated with a substantial risk of thrombosis. For example, thalidomide in association with chemotherapy produces venous thrombosis in up to 25% of patients treated, and the VEGF tyrosine kinase inhibitor ponatinib (Iclusig; ARIAD Pharmaceuticals, Cambridge, Mass) leads to arterial thrombosis in greater than 20% of patients who receive it (prescribing information for ponatinib is available at: http:// www.iclusig.com/pi/; accessed October 19, 2014). Past studies have demonstrated an increased rate of arterial thrombosis with the receipt of bevacizumab. Single studies and meta-analyses have indicated an increase in the relative risk ranging from 1.5-fold to 2-fold among patients who receive bevacizumab compared with controls. The risk of venous thrombosis has been less clear, with some studies demonstrating an increased risk but a large meta-analysis demonstrating no increase in risk. Given the use of bevacizumab for common tumors, such as lung cancer, even a small increase in vascular complications would put many patients at risk. Thus, the vascular risks associated with this agent are an important subject. The CALGB 90401 study helps provide important information about bevacizumab and the risk of thrombosis for patients with prostate cancer who are receiving chemotherapy. In that study, 1008 patients with prostate cancer received prednisone and docetaxel with or without bevacizumab. The median age of the patients was 69 years. Patients who had previous arterial or venous events were included, with the exception of those who had arterial thrombotic events in the previous 12 months. The overall study indicated that the addition of bevacizumab improved progression-free survival but not overall survival and increased the risk of treatment-related death. The relatively homogenous population of the study allowed for a detailed analysis of the vascular risks associated with bevacizumab. The study confirmed the elevated risk of arterial thrombosis from the receipt of bevacizumab, with a 2.70-fold increase (range, 1.14-fold to 6.43-fold increase) in risk observed. Prior arterial thrombosis and increasing age were