Venous thromboembolism in cancer patients – Risk scores and recent randomised controlled trials

Johannes Thaler; Cihan Ay; Ingrid Pabinger

doi:10.1160/TH12-04-0241

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2012; 108(06): 1042-1048
DOI: 10.1160/TH12-04-0241

Theme Issue Article

Schattauer GmbH

Venous thromboembolism in cancer patients – Risk scores and recent randomised controlled trials

Johannes Thaler

¹Clinical Division of Haematology and Haemostaseology, Department of Medicine I, Medical University of Vienna, Austria

²Comprehensive Cancer Center Vienna, Medical University of Vienna –Vienna General Hospital, Vienna, Austria

,

Cihan Ay

¹Clinical Division of Haematology and Haemostaseology, Department of Medicine I, Medical University of Vienna, Austria

²Comprehensive Cancer Center Vienna, Medical University of Vienna –Vienna General Hospital, Vienna, Austria

,

Ingrid Pabinger

¹Clinical Division of Haematology and Haemostaseology, Department of Medicine I, Medical University of Vienna, Austria

²Comprehensive Cancer Center Vienna, Medical University of Vienna –Vienna General Hospital, Vienna, Austria

› Author Affiliations

Abstract

Summary

Cancer patients are at increased risk of developing venous thromboembolism (VTE). Guidelines recommend routine thromboprophylaxis in hospitalised acutely ill cancer patients and in myeloma patients receiving combination treatments including thalidomide or lenalidomide. Currently, thromboprophylaxis is not recommended in cancer out-patients. It is the aim of this review to give an overview of studies that applied scores for the risk assessment of cancer-related VTE. We will also discuss randomised controlled trials (RCTs) that investigated primary thromboprophylaxis in cancer patients. Recently, Khorana et al. published a practical and reproducible risk assessment score that includes clinical and laboratory parameters for the stratification of cancer patients according to their propensity to develop VTE. Patients assigned to the high-risk group are likely to benefit most from primary thromboprophylaxis. This score was validated in prospective and retrospective observational studies. In the Vienna Cancer and Thrombosis Study (CATS) the score was expanded by adding two biomarkers, and the prediction of VTE was considerably improved. In recent RCTs including cancer patients with different malignancies it was shown that thromboprophylaxis is safe and effective. However, VTE incidence rates were low. To date, no data is available from interventional studies applying thromboprophylaxis in cancer patients categorised into high-risk groups on the basis of risk assessment with scores. From the available literature we conclude that risk assessment for VTE is feasible in cancer patients;however, interventional studies to investigate the safety and efficacy of thromboprophylaxis in a high risk cancer population have yet to be performed.

Keywords

Cancer - venous thrombosis - risk assessment - randomised controlled trials

Full Text

References

References
1 Khorana AA. Malignancy, thrombosis and Trousseau: the case for an eponym. J Thromb Haemost 2003; 1: 2463-2465.
2 Silverstein MD, Heit JA, Mohr DN. et al. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch Intern Med 1998; 158: 585-593.
3 Lee AY, Levine MN. Venous thromboembolism and cancer: risks and outcomes. Circulation 2003; 107 23 (Suppl. 01) 17-21.
4 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.
5 Cronin CG, Lohan DG, Keane M. et al. Prevalence and significance of asymptomatic venous thromboembolic disease found on oncologic staging CT. AJR Am J Roentgenol 2007; 189: 162-170.
6 Gladish GW, Choe DH, Marom EM. et al. Incidental pulmonary emboli in oncology patients: prevalence, CT evaluation, and natural history. Radiology 2006; 240: 246-255.
7 Rollins KE, Peters CJ, Safranek PM. et al. Venous thromboembolism in oesophago-gastric carcinoma: incidence of symptomatic and asymptomatic events following chemotherapy and surgery. Eur J Surg Oncol 2011; 37: 1072-1077.
8 Khorana AA, Francis CW, Culakova E. et al. Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy. J Thromb Haemost 2007; 5: 632-634.
9 Sorensen HT, Mellemkjaer L, Olsen JH. et al. Prognosis of cancers associated with venous thromboembolism. N Engl J Med 2000; 343: 1846-1850.
10 Chew HK, Wun T, Harvey D. et al. Incidence of venous thromboembolism and its effect on survival among patients with common cancers. Arch Intern Med 2006; 166: 458-464.
11 Prandoni P, Lensing AW, Piccioli A. et al. Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood 2002; 100: 3484-3488.
12 Kakkar VV, Howe CT, Nicolaides AN. et al. Deep vein thrombosis of the leg. Is there a „high risk“group?. Am J Surg 1970; 120: 527-530.
13 Lyman GH. Venous thromboembolism in the patient with cancer: focus on burden of disease and benefits of thromboprophylaxis. Cancer 2011; 117: 1334-1349.
14 Khorana AA, Streiff MB, Farge D. et al. Venous thromboembolism prophylaxis and treatment in cancer: a consensus statement of major guidelines panels and call to action. J Clin Oncol 2009; 27: 4919-4926.
15 Khorana AA. Cancer and thrombosis: implications of published guidelines for clinical practice. Ann Oncol 2009; 20: 1619-1630.
16 Palumbo A, Rajkumar SV, Dimopoulos MA. et al. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia 2008; 22: 414-423.
17 Kahn SR, Lim W, Dunn AS. et al. Prevention of VTE in nonsurgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (Suppl. 02) 195S-226.
18 Khorana AA. Cancer and coagulation. Am J Hematol 2012. epub ahead of print.
19 Kucher N, Koo S, Quiroz R. et al. Electronic alerts to prevent venous thromboembolism among hospitalized patients. N Engl J Med 2005; 352: 969-977.
20 Barbar S, Noventa F, Rossetto V. et al. A risk assessment model for the identification of hospitalized medical patients at risk for venous thromboembolism: the Padua Prediction Score. J Thromb Haemost 2010; 8: 2450-2457.
21 Lip GY, Frison L, Halperin JL. et al. Comparative validation of a novel risk score for predicting bleeding risk in anticoagulated patients with atrial fibrillation: the HAS-BLED (Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol Concomitantly) score. J Am Coll Cardiol 2011; 57: 173-180.
22 Khorana AA, Kuderer NM, Culakova E. et al. Development and validation of a predictive model for chemotherapy-associated thrombosis. Blood 2008; 111: 4902-4907.
23 Doggen CJ. Thromboprophylaxis in cancer outpatients. Blood 2008; 111: 4833.
24 Ay C, Dunkler D, Marosi C. et al. Prediction of venous thromboembolism in cancer patients. Blood 2010; 116: 5377-5382.
25 Ay C, Simanek R, Vormittag R. et al. High plasma levels of soluble P-selectin are predictive of venous thromboembolism in cancer patients: results from the Vienna Cancer and Thrombosis Study (CATS). Blood 2008; 112: 2703-2708.
26 Vormittag R, Simanek R, Ay C. et al. High factor VIII levels independently predict venous thromboembolism in cancer patients: the cancer and thrombosis study. Arterioscler Thromb Vasc Biol 2009; 29: 2176-2181.
27 Ay C, Vormittag R, Dunkler D. et al. D-dimer and prothrombin fragment 1 + 2 predict venous thromboembolism in patients with cancer: results from the Vienna Cancer and Thrombosis Study. J Clin Oncol 2009; 27: 4124-4129.
28 Ay C, Dunkler D, Simanek R. et al. Prediction of venous thromboembolism in patients with cancer by measuring thrombin generation: results from the Vienna Cancer and Thrombosis Study. J Clin Oncol 2010; 29: 2099-2103.
29 Simanek R, Vormittag R, Ay C. et al. High platelet count associated with venous thromboembolism in cancer patients: results from the Vienna Cancer and Thrombosis Study (CATS). J Thromb Haemost 2010; 8: 114-120.
30 Moore RA, Adel N, Riedel E. et al. High incidence of thromboembolic events in patients treated with cisplatin-based chemotherapy: a large retrospective analysis. J Clin Oncol 2011; 29: 3466-3473.
31 Mandala M, Clerici M, Corradino I. et al Incidence, risk factors and clinical implications of venous thromboembolism in cancer patients treated within the context of phase I studies: the ’SENDO experience’. Ann Oncol 2012; 23: 1416-1421.
32 George D, Agnelli G, Fisher W. et al. Venous Thromboembolism (VTE) Prevention with Semuloparin in Cancer Patients Initiating Chemotherapy: Benefit-Risk Assessment by VTE Risk in SAVE-ONCO. Blood (ASH Annual Meeting Abstracts) 2011; 118 Abstract 206.
33 Barni S, Labianca R, Agnelli G. et al. Chemotherapy-associated thromboembolic risk in cancer outpatients and effect of nadroparin thromboprophylaxis: results of a retrospective analysis of the PROTECHT study. J Transl Med 2011; 9: 179.
34 Rajkumar SV, Blood E, Vesole D. et al. Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: a clinical trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol 2006; 24: 431-436.
35 Cavo M, Zamagni E, Tosi P. et al. First-line therapy with thalidomide and dexamethasone in preparation for autologous stem cell transplantation for multiple myeloma. Haematologica 2004; 89: 826-831.
36 Rajkumar SV, Hayman S, Gertz MA. et al. Combination therapy with thalidomide plus dexamethasone for newly diagnosed myeloma. J Clin Oncol 2002; 20: 4319-4323.
37 Zonder JA, Barlogie B, Durie BG. et al. Thrombotic complications in patients with newly diagnosed multiple myeloma treated with lenalidomide and dexamethasone: benefit of aspirin prophylaxis. Blood 2006; 108 403; author reply 404.
38 Agnelli G, George DJ, Kakkar AK. et al. Semuloparin for thromboprophylaxis in patients receiving chemotherapy for cancer. N Engl J Med 2012; 366: 601-609.
39 Khorana AA, Fine RL. Pancreatic cancer and thromboembolic disease. Lancet Oncol 2004; 5: 655-663.
40 Maraveyas A, Waters J, Roy R. et al. Gemcitabine versus gemcitabine plus dalteparin thromboprophylaxis in pancreatic cancer. Eur J Cancer 2012; 48: 1283-1292.
41 Riess UP, Deutschinoff G, Opitz B. et al. A prospective, randomized trial of chemotherapy with and without the low molecular weight heparin (LMWH) enoxaparin in patients (pts) with advanced pancreatic cancer (APC): Results of the CONKO 004 trial. ASCO Annual Meeting Proceedings, Poster-Meeting 2009. J Clin Oncol 2009; 27: 18S.