Is venous thromboembolism a problem in patients with cancer in palliative care?
Authors: Per Morten Sandset, Anders E A Dahm
Journal: The Lancet Haematology (2019)

Cancer is an important risk factor for venous thromboembolism, and patients with cancer are therefore good candidates for medical thromboprophylaxis with anticoagulants. Many studies on thromboprophylaxis that include patients with cancer have been done, but these studies excluded patients with advanced cancer and short life expectancy.1Di Nisio M Porreca E Candeloro M De Tursi M Russi I Rutjes AWS Primary prophylaxis for venous thromboembolismin ambulatory cancer patients receiving chemotherapy.Cochrane Database Syst Rev. 2016; 12 (CD008500.)PubMed Google Scholar Estimates of the cumulative incidence of venous thromboembolism in patients with cancer vary from about 1% to 13%.2Timp JF Braekkan SK Versteeg HH Cannegieter SC Epidemiology of cancer-associated venous thrombosis.Blood. 2013; 122: 1712-1723Crossref PubMed Scopus (707) Google Scholar, 3Lyman GH Eckert L Wang Y Wang H Cohen A Venous thromboembolism risk in patients with cancer receiving chemotherapy: a real-world analysis.Oncologist. 2013; 18: 1321-1329Crossref PubMed Scopus (133) Google Scholar Reasons for the variation in these estimates relate to the cancer population investigated, the methods for detecting venous thromboembolism, and the time period for the investigation. Venous thromboembolism is heavily dependent on cancer type, stage, and aggressiveness.4Ahlbrecht J Dickmann B Ay C et al.Tumor grade is associated with venous thromboembolism in patients with cancer: results from the Vienna Cancer and Thrombosis Study.J Clin Oncol. 2012; 30: 3870-3875Crossref PubMed Scopus (95) Google Scholar, 5Blom JW Doggen CJ Osanto S Rosendaal FR Malignancies, prothrombotic mutations, and the risk of venous thrombosis.JAMA. 2005; 293: 715-722Crossref PubMed Scopus (1495) Google Scholar The frequency of venous thromboembolism in patients with cancer is increasing over time,2Timp JF Braekkan SK Versteeg HH Cannegieter SC Epidemiology of cancer-associated venous thrombosis.Blood. 2013; 122: 1712-1723Crossref PubMed Scopus (707) Google Scholar probably related to increasing age of patients, but also because of incidental venous thromboembolism being discovered more frequently by advanced technology, such as CT scans or MRI during staging of the cancer or assessment of treatment response. Thus, the prevalence of venous thromboembolism in patients with cancer could be higher than previously estimated. In a study of edoxaban versus dalteparin for the treatment of cancer-related venous thromboembolism, a third of included venous thromboembolism cases were incidental.6Raskob GE van Es N Verhamme P et al.Edoxaban for the treatment of cancer-associated venous thromboembolism.N Engl J Med. 2018; 378: 615-624Crossref PubMed Scopus (955) Google Scholar To our knowledge, no estimates have previously been reported on the frequency of venous thromboembolism in patients with advanced cancer. In The Lancet Haematology, Clare White and co-workers7White C Noble SIR Watson M et al.Prevalence, symptom burden, and natural history of deep vein thrombosis in people with advanced cancer in specialist palliative care units (HIDDen): a prospective longitudinal observational study.Lancet Haematol. 2019; 6: e79-e88Summary Full Text Full Text PDF PubMed Scopus (40) Google Scholar report the results of an observational study of deep vein thrombosis in 343 patients with advanced cancer admitted to specialist palliative care units (SPCUs) across the UK. Bilateral ultrasonography of the popliteal and femoral veins was done at the bedside by trained study nurses on admission and then weekly for 3 weeks or until discharge. Information about risk factors and clinical signs was also recorded. The investigators report that nearly a third of patients had a proximal deep vein thrombosis on admission (92 [34%, 95% CI 28–40] of 273 patients with evaluable scans had femoral deep vein thrombosis). Most of the deep vein thromboses were asymptomatic, and the risk of deep vein thrombosis was not related to pre-admission thromboprophylaxis. Finally, the presence of deep vein thrombosis was not related to survival. This study shows that patients with advanced cancer have a very high prevalence of deep vein thrombosis. One could easily interpret this result as venous thromboembolism being a hidden major problem in palliative care. However, that conclusion may not be justified, because deep vein thrombosis in many of these patients did not cause symptoms; in a setting where symptom relief and not prolongation of life is the focus, the symptomatic burden is more important than effects on mortality. Patients were enrolled at admission to the SPCU and almost all thromboses were detected at inclusion. Thus, many patients might have undergone active treatment of their cancer quite recently. Does this finding therefore suggest that the prevalence of undetected deep vein thrombosis might also be very high in patients with advanced cancer who are not yet in palliative care? White and colleagues' findings raise important questions about the use of thromboprophylaxis in this cancer population. Guidelines from the American Society of Clinical Oncology state that anticoagulation is of uncertain benefit in "patients receiving end-of-life/hospice care" or with "very limited life expectancy with no palliative or symptom reduction".8Lyman GH Bohlke K Falanga A Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology clinical practice guideline update.J Oncol Pract. 2015; 11: e442-e444Crossref PubMed Scopus (103) Google Scholar The present study provides strong evidence supporting these recommendations. Although the study did not show any relation between deep vein thrombosis and symptoms of venous thromboembolism, venous thromboembolism can cause unusual or vague symptoms that are not readily recognised as venous thromboembolism. For example, symptoms of pulmonary embolism are often interpreted as fatigue in patients with cancer.9O'Connell CL Boswell WD Duddalwar et al.Unsuspected pulmonary emboli in cancer patients: clinical correlates and relevance.J Clin Oncol. 2006; 24: 4928-4932Crossref PubMed Scopus (132) Google Scholar Fatigue is a typical symptom in most advanced cases, and therefore a diagnosis of pulmonary embolism might easily be overlooked. It would be interesting to know if patients with advanced cancer experience less fatigue on thromboprophylaxis; if that is the case, thromboprophylaxis might have a place in palliative care after all. The study by White and colleagues was not designed to assess the effect of thromboprophylaxis, and the investigators concluded that a randomised study is probably not feasible because 72 000 patients would be needed to have the necessary power to find an effect on survival. We would not, however, completely exclude a randomised trial in this population, but the endpoint would need to be related to venous thromboembolism symptoms. Additionally, direct-acting oral anticoagulants might in the future be an alternative to thromboprophylaxis with subcutaneous (low-molecular-weight) heparin, which could greatly simplify and alleviate the burden of parenteral therapy. We find the study of White and co-workers of great value for all physicians involved in palliative care. Clearly, the findings suggest that venous thromboembolism is a manifestation of advanced cancer disease and that thromboprophylaxis is of limited value. These results should be considered when current guidelines are revised. PMS declares no competing interests. AEAD reports personal fees from MSD, Bristol-Myers Squibb, Bayer, and Novartis; and grants and personal fees from Pfizer. Prevalence, symptom burden, and natural history of deep vein thrombosis in people with advanced cancer in specialist palliative care units (HIDDen): a prospective longitudinal observational studyAbout a third of patients with advanced cancer admitted to SPCUs had a femoral deep vein thrombosis. Deep vein thrombosis was not associated with thromboprophylaxis, survival, or symptoms other than leg oedema. These findings are consistent with venous thromboembolism being a manifestation of advanced disease rather than a cause of premature death. Thromboprophylaxis for SPCU inpatients with poor performance status seems to be of little benefit. Full-Text PDF Open Access