BERKELEY, CA (UroToday.com) - Anticoagulation while on docetaxel chemotherapy is an independent predictor of survival in men with metastatic castration-resistant prostate cancer (mCRPC). There have been a number of studies that evaluated the association between the use of anticoagulants and clinical outcomes in cancer patients. However, the majority of these trials included heterogeneous patient populations with various tumor types. No study has evaluated the impact of anticoagulation therapy in patients with prostate cancer. Hence, we conducted a single-institution retrospective analysis to evaluate the impact of therapeutic anticoagulation on survival in patients with mCRPC.
Our retrospective analysis of 247 patients with mCRPC treated with docetaxel chemotherapy between 1998 and 2001 at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center showed that patients who concomitantly received therapeutic anticoagulation showed a 39% relative reduction in risk of death compared with men who did not receive anticoagulation. After adjusting for multiple confounding factors, anticoagulation use was associated with a significant 51% decreased mortality. All the patients who received the anticoagulant had a documented venous thromboembolism (VTE) such as deep vein thrombosis (DVT) and/or pulmonary embolism (PE) and the control group had comparable baseline prognostic characteristics but had no VTE. Median survival was 20.9 months in the anticoagulation group vs 17.1 months in the control group.
This finding is particularly interesting since VTE in cancer patients has been validated as an independent risk factor for mortality and adds to the growing body of evidence that anticoagulant agents possess antitumor properties in addition to their antithrombotic effects. Several antitumor mechanisms of anticoagulants have been proposed including fibrin structure modification, inhibition of the endothelial/tissue factor pathway, and direct inhibition of ligand biding to the VEGF receptor.[1, 2] Furthermore, heparin has also shown to enhance tumor responses to chemotherapy when combined with various chemotherapy regimens.[3, 4, 5]
Our next questions were: what type of anticoagulants should be used and what is the optimal duration of anticoagulation?
In this study, the survival benefit was more robust with heparin than with warfarin use. This observation is consistent with previous reports in other solid tumor types where heparin consistently showed a superior survival benefit over warfarin.[6, 7, 8]
While no specific recommendations exist for optimal duration of anticoagulation therapy in cancer patients with established VTE, the majority of these patients receive anticoagulation therapy for at least 6 months or longer. Previous prospective trials assessing the survival benefit of anticoagulants used various durations of anticoagulation (from 4 weeks to lifelong).[9, 10]
Many questions still remain to be answered; what is the impact of the anticoagulants on the clinical outcomes in cancer patients without established VTE? Should we use anticoagulant in all patients with mCRPC? With the introduction of next-generation oral anticoagulants (such as direct factor X inhibitors or thrombin inhibitors), do they also have antitumor or chemotherapy-enhancing properties?
Our study has several limitations besides the inherent limitations of this retrospective analysis and a relatively small sample size. This study did not assess the radiographic or PSA response or progression-free survival, thus it is not clear if the observed survival benefit is due to actual anticancer effects of the anticoagulant or from other mechanism such as inhibition of microthrombi. We will need prospective studies to validate our findings as well as to answer these remaining questions.
References:
- Norrby, K., Heparin and angiogenesis: a low-molecular-weight fraction inhibits and a high-molecular-weight fraction stimulates angiogenesis systemically. Haemostasis, 1993. 23 Suppl 1: p. 141-9.
- Collen, A., et al., Unfractionated and low molecular weight heparin affect fibrin structure and angiogenesis in vitro. Cancer Res, 2000. 60(21): p. 6196-200.
- Lebeau, B., et al., Subcutaneous heparin treatment increases survival in small cell lung cancer. "Petites Cellules" Group. Cancer, 1994. 74(1): p. 38-45.
- Altinbas, M., et al., A randomized clinical trial of combination chemotherapy with and without low-molecular-weight heparin in small cell lung cancer. J Thromb Haemost, 2004. 2(8): p. 1266-71.
- Robert, F., et al., Phase II study of docetaxel plus enoxaparin in chemotherapy-naive patients with metastatic non-small cell lung cancer: preliminary results. Lung Cancer, 2003. 42(2): p. 237-45.
- Akl, E.A., et al., Oral anticoagulation may prolong survival of a subgroup of patients with cancer: a cochrane systematic review. J Exp Clin Cancer Res, 2007. 26(2): p. 175-84.
- Kuderer, N.M., et al., A meta-analysis and systematic review of the efficacy and safety of anticoagulants as cancer treatment: impact on survival and bleeding complications. Cancer, 2007. 110(5): p. 1149-61.
- Lee, A.Y., et al., Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med, 2003. 349(2): p. 146-53.
- Akl, E.A., et al., Oral anticoagulation in patients with cancer who have no therapeutic or prophylactic indication for anticoagulation. Cochrane Database Syst Rev, 2011(6): p. CD006466.
- Akl, E.A., et al., Parenteral anticoagulation in patients with cancer who have no therapeutic or prophylactic indication for anticoagulation. Cochrane Database Syst Rev, 2011(4): p. CD006652.
Written by:
Jong Chul Park, MD 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.
Genitourinary Oncology Fellow
The Sidney Kimmel Comprehensive Cancer Center
Johns Hopkins Medical Institutions
Baltimore, MD USA