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Should VTE prophylaxis be administered to inpatients and outpatients with cancer?
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Further study will help to identify appropriate patients.
Although it is well recognized that certain forms of cancer are associated with a high risk for thrombosis, and thrombosis is said to be the second leading cause of death in patients with cancer, none of the existing clinical trials have shown an impressive reduction in thrombotic events with anticoagulation. This may be for several reasons: (1) standard forms of anticoagulation (unfractionated heparin, low–molecular-weight heparin, warfarin) may be ineffective or less effective given the pathogenesis of this form of thrombosis; (2) many forms of cancer are not associated with thrombosis, so clinical trials have not been sufficiently large to detect positive responses when all forms of cancer are lumped together in even large studies; and (3) no biomarkers have existed to identify those patients with cancer who are at increased risk of thrombosis.
The development of consensus recommendations, established in 2007 by ASCO for issues involving venous thromboembolic events and cancer, state: “Ambulatory patients with cancer should not receive anticoagulant venous thromboembolism prophylaxis during chemotherapy unless they receive thalidomide (Thalomid, Celgene) or lenalidomide (Revlimid, Celgene).” The comment is made that “research identifying better markers of ambulatory patients with cancer most likely to develop VTE is urgently needed.”
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Our group and others have been exploring tumor-derived tissue factor-bearing microparticles as a potential biomarker for the thrombotic risk associated with cancer. Whether tissue factor is monitored by its antigen or its activity, these microparticles are elevated in certain forms of cancer. The single clinical trial demonstrating a statistical association between tissue factor-bearing microparticles and thrombotic risk by Zwicker et al (in press) indicates a fourfold increased risk. A definitive prospective, randomized trial is necessary to confirm these results. Then the question will emerge as to which anticoagulant is most efficacious.
Bruce Furie, MD, is Professor of Medicine at Harvard Medical School in Boston, and a HemOnc Today Editorial Board member.
More research for specific types of cancer is needed.
Cancer patients are a very heterogeneous group, so it is impossible to make a blanket statement that all cancer patients, whether inpatients or outpatients, should receive primary thromboprophylaxis.
We desperately need to do randomized, controlled trials in both the inpatient and outpatient oncology setting to address this question. For example, there hasn’t been a randomized, controlled trial performed to study the efficacy and safety of thromboprophylaxis in cancer patients admitted to the hospital with medical problems. Despite this lack of data, there is consensus recommendation that these patients should receive prophylaxis because many have multiple risk factors for thrombosis. Although this is good common sense advice, it lacks rigorous evidence. Furthermore, the risk of bleeding has not been studied, and so many oncologists are still reluctant to place patients on prophylaxis for fear of bleeding. Physician compliance with prophylaxis in patients with cancer admitted to the hospital is dismally low as a result.
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We also need to do more randomized, controlled trials in outpatients. Ideally, these trials would be tumor specific and focus on patients with advanced disease who are receiving chemotherapy because the risk of thrombosis is dependent on these factors. Two recent trials have shown that outpatient prophylaxis with low–molecular-weight heparin reduces thrombotic complications in patients receiving chemotherapy without increasing bleeding. One trial was in patients with advanced pancreatic cancer (CONKO study) and the other included patients with several different tumor types (PROTECHT study).
Whether these findings will change clinical practice remains to be seen, as low–molecular-weight heparin must be given by subcutaneous injection and is expensive to use. Advances in this area also include the development of simple risk assessment scores that use clinical biomarkers to help identify patients who would benefit from prophylaxis.
It is important that the oncology community recognize their patients have a high risk for thrombosis and take measures to reduce this common, costly and potentially deadly complication. Oncologists should champion for their patient population and help design studies to address this growing problem.
Agnes Y.Y. Lee, MD, MSc, FRCP(c), is Medical Director of the Thrombosis Program in the Division of Hematology at the University of British Columbia, Vancouver, Canada.