BERKELEY, CA (UroToday.com) - Cancer patients are approximately four times more likely to experience a thromboembolism compared to those without cancer. The study by Patel et al. investigated the risk of arterial (ATE) and venous thromboembolism (VTE) in metastatic, castration-resistant prostate cancer patients treated with docetaxel and prednisone with or without bevacizumab on a large randomized phase III trial, Cancer and Leukemia Group B (CALGB) 90401.
Bevacizumab is an antitumor agent whose mechanism of action is inhibition of vascular endothelial growth factor (VEGF), resulting in interference with tumor vessel growth. This unique mechanism of action may also contribute to thromboembolic complications. Given that the direct influence of bevacizumab on VTE risk is somewhat controversial, investigators examined the association of bevacizumab treatment on VTE risk in a homogenous population of cancer patients considered “low risk” for VTE compared to other tumor types.[4 Secondly, investigators examined the influence of patient-specific parameters on both ATE and VTE risk.
According to the methodology described, the advantage of this study was the utility of a time to event analysis, which was carried out under a competing risk model, in a large homogenous population. Previous similar analyses have either used summary event rates or traditional Kaplan-Meier methods, which do not take into account competing or intervening events, such as disease progression, death, or other treatment-terminating adverse events, and may have falsely overestimated the true cumulative incidence. A limitation of this study is the lack of clinical utility of bevacizumab in the treatment of prostate cancer patients, given the findings from CALGB 90401. Regardless, 50% of patients were treated with standard docetaxel chemotherapy allowing interpretation of patient-specific risk factors that influence ATE/VTE in this population. Additionally, bevacizumab is widely used in other tumor types, underscoring the need to understand the adverse event profile of this agent.
As expected, study results demonstrated that treatment with bevacizumab significantly increased the risk of ATE, but interestingly there was no association with VTE risk; in fact, there was a trend towards reduced VTE risk in bevacizumab treated patients. Given the findings from CALGB 90401, including superior response rates, progression-free survival (PFS), and prostate specific antigen (PSA) response (but not overall survival), investigators have speculated that this apparent reduction in risk may be secondary to better tumor control with bevacizumab and thus a lower risk for tumor-related complications, such as VTE; however, this cannot be confirmed. Investigators also identified lack of significant associations between prior thrombosis and VTE risk, and baseline antiplatelet/anticoagulant use and ATE/VTE risk, while increasing age was significantly associated with both ATE/VTE risk. Lastly, a unique objective of this study was the validation of a VTE risk score, developed by Khorana et al., in a homogenous cohort of patients with a “low-risk” tumor type. These results are important to highlight as many clinicians will either not take into account patient-specific risk factors, or assume for certain risk factors to be true.
Although current guidelines do not recommend the use of routine thromboprophylaxis in the outpatient setting, these results are critical given that American Society of Clinical Oncology (ASCO) practice guidelines support the use of VTE risk score, in addition to other clinical factors, to identify cancer patients at high risk of developing VTE. The balance of benefit and harm with thromboprophylaxis for high-risk patients identified by the VTE risk score is currently under study (NCT00876915, NCT02048865). Now that ATE risk of bevacizumab is well established and multiple large analyses have demonstrated lack of significant association with VTE risk, focus should be shifted to identifying methods of ameliorating these severe vascular complications in practice. Therefore, it is critical that clinicians actively engage patients in the discussion about signs, symptoms, and risk factors of VTE and ATE, in addition to methods in reducing this risk (e.g., smoking cessation in smokers, statin use in hypercholesterolemic patients, aggressive blood pressure control, thromboprophylaxis in high-risk patients identified by the VTE risk score, exercise, etc.).
- Heit JA, Silverstein MD, Mohr DN et al. Risk factors for deep vein thrombosis and pulmonary embolism: a population-based case-control study. Arch Intern Med 2000; 160: 809-815.
- Patel JN, Jiang C, Hertz DL et al. Bevacizumab and the risk of arterial and venous thromboembolism in patients with metastatic, castration-resistant prostate cancer treated on Cancer and Leukemia Group B (CALGB) 90401 (Alliance). Cancer 2014.
- Kelly WK, Halabi S, Carducci M et al. Randomized, double-blind, placebo-controlled phase III trial comparing docetaxel and prednisone with or without bevacizumab in men with metastatic castration-resistant prostate cancer: CALGB 90401. J Clin Oncol 2012; 30: 1534-1540.
- Van Hemelrijck M, Adolfsson J, Garmo H et al. Risk of thromboembolic diseases in men with prostate cancer: results from the population-based PCBaSe Sweden. Lancet Oncol 2010; 11: 450-458.
- Khorana AA, Kuderer NM, Culakova E et al. Development and validation of a predictive model for chemotherapy-associated thrombosis. Blood 2008; 111: 4902-4907.
- Lyman GH, Khorana AA, Kuderer NM et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 2013; 31: 2189-2204.
Jai N. Patel, PharmD as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
Chief, Pharmacology Research, Phase I Trials
Levine Cancer Institute | Carolinas HealthCare System
Adjunct Assistant Professor, UNC Eshelman School of Pharmacy
Bevacizumab and the risk of arterial and venous thromboembolism in patients with metastatic, castration-resistant prostate cancer treated on Cancer and Leukemia Group B (CALGB) 90401 (Alliance) - Abstract