Epidemiology, risk and outcomes of venous thromboembolism in cancer

A. Falanga; L. Russo

doi:10.5482/ha-1170

Hämostaseologie, Table of Contents

Hamostaseologie 2012; 32(02): 115-125
DOI: 10.5482/ha-1170

Review

Schattauer GmbH

Epidemiology, risk and outcomes of venous thromboembolism in cancer

Epidemiologie, Risiken und Verlauf venöser Thromboembolien bei Krebs

A. Falanga

¹Division of Immunohematology and Transfusion Medicine, Dept. Oncology-Hematology, Ospedali Riuniti, Bergamo, Italy

,

L. Russo

¹Division of Immunohematology and Transfusion Medicine, Dept. Oncology-Hematology, Ospedali Riuniti, Bergamo, Italy

› Author Affiliations

Abstract

Summary

Cancer is associated with a fourfold increased risk of venous thromboembolism (VTE). The risk of VTE varies according to the type of malignancy (i. e. pancreatic cancer, brain cancer, lymphoma) and its disease stage and individual factors (i. e. sex, race, age, previous VTE history, immobilization, obesity). Preventing cancer-associated VTE is important because it represents a significant cause of morbidity and mortality. In order to identify cancer patient at particularly high risk, who need thromboprophylaxis, risk prediction models have become available and are under validation. These models include clinical risk factors, but also begin to incorporate biological markers. The major American and European scientific societies have issued their recommendations to guide the management of VTE in patients with cancer.

In this review the principal aspects of epidemiology, risk factors and outcome of cancer-associated VTE are summarized.

Zusammenfassung

Krebserkrankungen sind mit einem vierfach erhöhten Risiko für venöse Thromboembolien (VTE) assoziiert. Das VTE-Risiko variiert nach Art des malignen Tumors (d. h. Pankreas-karzinom, Hirntumoren, Lymphome), Krankheitsstadium und individuellen Faktoren (d. h. Geschlecht, ethnische Abstammung, Lebensalter, VTE in der Anamnese, Immobilisierung, Adipositas). Die Prävention paraneoplastischer VTE ist wichtig, da sie eine bedeutende Morbiditäts- und Mortalitätsursache darstellt. Zur Identifizierung von Krebspatienten mit besonders hohem Risiko, die eine Thromboseprophylaxe benötigen, gibt es Modelle für die Risikovorhersage, die zurzeit validiert werden. Diese Modelle umfassen klinische Risikofaktoren, schließen aber auch erste biologische Marker ein. Die wichtigsten amerikanischen und europäischen Fachgesellschaften haben ihre Empfehlungen zum Management von VTE bei Krebspatienten vorgelegt.

In dieser Übersicht werden die wichtigsten Aspekte zu Epidemiologie, Risikofaktoren und Verlauf krebsbedingter VTE präsentiert.

Keywords

Venous thrombosis - hypercoagulability - cancer - thromboprophylaxis

Schlüsselwörter

Venöse Thrombose - Hyperkoagulabilität - Krebs - Thromboseprophylaxe

Full Text

References

References
1 Khorana AA, Francis CW, Culakova E. et al. Frequency, risk factors, and trends for venous thromboembolism among hospitalized cancer patients. Cancer 2007; 110: 2339-2346.
2 Lee AY, Levine MN. Venous thromboembolism and cancer: risks and outcomes. Circulation 2003; 107: I17-I21.
3 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.
4 Alikhan R, Cohen AT, Combe S. et al. Risk factors for venous thromboembolism in hospitalized patients with acute medical illness: analysis of the MEDENOX Study. Arch Intern Med 2004; 164: 963-968.
5 Spencer FA, Lessard D, Emery C. et al. Venous thromboembolism in the outpatient setting. Arch Intern Med 2007; 167: 1471-1475.
6 Imberti D, Agnelli G, Ageno W. et al. Clinical characteristics and management of cancer-associated acute venous thromboembolism: findings from the MASTER Registry. Haematologica 2008; 93: 273-278.
7 Seddighzadeh A, Shetty R, Goldhaber SZ. Venous thromboembolism in patients with active cancer. Thromb Haemost 2007; 98: 656-661.
8 Geerts WH, Bergqvist D, Pineo GF. et al. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. (8^th ed). Chest 2008; 133: 381S-453S.
9 International Consensus Statement. Prevention and treatment of venous thromboembolism. Int Angiol 2006; 25: 101-161.
10 Streiff MB. The National Comprehensive Cancer Center Network (NCCN) guidelines on the management of venous thromboembolism in cancer patients. Thromb Res 2010; 125 (Suppl. 02) S128-S133.
11 Mandala M, Falanga A, Piccioli A. et al. Venous thromboembolism and cancer: guidelines of the Italian Association of Medical Oncology (AIOM). Crit Rev Oncol Hematol 2006; 59: 194-204.
12 Farge D, Bosquet L, Kassab-Chahmi D. et al. 2008 French national guidelines for the treatment of venous thromboembolism in patients with cancer: report from the working group. Crit Rev Oncol Hematol 2010; 73: 31-46.
13 Mandala M, Falanga A, Roila F. Venous thromboembolism in cancer patients: ESMO Clinical Practice Guidelines for the management. Ann Oncol 2010; 21 (Suppl. 05) v274-v276.
14 Lyman GH, Kuderer NM. Prevention and treatment of venous thromboembolism among patients with cancer: the American Society of Clinical Oncology Guidelines. Thromb Res 2010; 125 (Suppl. 02) S120-S127.
15 Blom JW, Doggen CJ, Osanto S, Rosendaal FR. Malignancies, prothrombotic mutations, and the risk of venous thrombosis. JAMA 2005; 293: 715-722.
16 Khorana AA, Francis CW, Culakova E. et al. Thromboembolism in hospitalized neutropenic cancer patients. J Clin Oncol 2006; 24: 484-490.
17 Levitan N, Dowlati A, Remick SC. et al. Rates of initial and recurrent thromboembolic disease among patients with malignancy versus those without malignancy. Risk analysis using Medicare claims data. Medicine (Baltimore) 1999; 78: 285-291.
18 Sallah S, Wan JY, Nguyen NP. Venous thrombosis in patients with solid tumors: determination of frequency and characteristics. Thromb Haemost 2002; 87: 575-579.
19 Stein PD, Beemath A, Meyers FA. et al. Incidence of venous thromboembolism in patients hospitalized with cancer. Am J Med 2006; 119: 60-68.
20 Hutten BA, Prins MH, Gent M. et al. Incidence of recurrent thromboembolic and bleeding complications among patients with venous thromboembolism in relation to both malignancy and achieved international normalized ratio: a retrospective analysis. J Clin Oncol 2000; 18: 3078-3083.
21 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.
22 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.
23 Sorensen HT, Mellemkjaer L, Olsen JH, Baron JA. Prognosis of cancers associated with venous thromboembolism. N Engl J Med 2000; 343: 1846-1850.
24 Semrad TJ, O’Donnell R, Wun T. et al. Epidemiology of venous thromboembolism in 9489 patients with malignant glioma. J Neurosurg 2007; 106: 601-608.
25 Wun T, White RH. Epidemiology of cancer-related venous thromboembolism. Best Pract Res Clin Haematol 2009; 22: 9-23.
26 Blom JW, Vanderschoot JP, Oostindier MJ. et al. Incidence of venous thrombosis in a large cohort of 66,329 cancer patients: results of a record linkage study. J Thromb Haemost 2006; 04: 529-535.
27 Falanga A. The incidence and risk of venous thromboembolism associated with cancer and nonsurgical cancer treatment. Cancer Invest 2009; 27: 105-115.
28 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.
29 Agnelli G, Bolis G, Capussotti L. et al. A clinical outcome-based prospective study on venous thromboembolism after cancer surgery: the @RISTOS project. Ann Surg 2006; 243: 89-95.
30 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; 05: 632-634.
31 Deitcher SR, Gomes MP. The risk of venous thromboembolic disease associated with adjuvant hormone therapy for breast carcinoma: a systematic review. Cancer 2004; 101: 439-449.
32 Baum M, Budzar AU, Cuzick J. et al. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet 2002; 359: 2131-2139.
33 Levine MN. Adjuvant therapy and thrombosis: how to avoid the problem?. Breast 2007; 16 (Suppl. 02) S169-S174.
34 Hurwitz H, Fehrenbacher L, Novotny W. et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004; 350: 2335-2342.
35 Herbst RS, Sandler AB. Non-small cell lung cancer and antiangiogenic therapy: what can be expected of bevacizumab?. Oncologist 2004; 09 (Suppl. 01) 19-26.
36 Rugo HS. Bevacizumab in the treatment of breast cancer: rationale and current data. Oncologist 2004; 09 (Suppl. 01) 43-49.
37 Nalluri SR, Chu D, Keresztes R. et al. Risk of venous thromboembolism with the angiogenesis inhibitor bevacizumab in cancer patients: a meta-analysis. JAMA 2008; 300: 2277-2285.
38 Hussein MA. Thromboembolism risk reduction in multiple myeloma patients treated with immunomodulatory drug combinations. Thromb Haemost 2006; 95: 924-930.
39 Zangari M, Anaissie E, Barlogie B. et al. Increased risk of deep-vein thrombosis in patients with multiple myeloma receiving thalidomide and chemotherapy. Blood 2001; 98: 1614-1615.
40 Wun T, Law L, Harvey D. et al. Increased incidence of symptomatic venous thrombosis in patients with cervical carcinoma treated with concurrent chemotherapy, radiation, and erythropoietin. Cancer 2003; 98: 1514-1520.
41 Khorana AA, Francis CW, Culakova E, Lyman GH. Risk factors for chemotherapy-associated venous thromboembolism in a prospective observational study. Cancer 2005; 104: 2822-2829.
42 Khorana AA, Francis CW, Blumberg N. et al. Blood transfusions, thrombosis, and mortality in hospitalized patients with cancer. Arch Intern Med 2008; 168: 2377-2381.
43 Kuter DJ. Thrombotic complications of central venous catheters in cancer patients. Oncologist 2004; 09: 207-216.
44 Vescia S, Baumgartner AK, Jacobs VR. et al. Management of venous port systems in oncology: a review of current evidence. Ann Oncol 2008; 19: 9-15.
45 Couban S, Goodyear M, Burnell M. et al. Randomized placebo-controlled study of low-dose warfarin for the prevention of central venous catheter-associated thrombosis in patients with cancer. J Clin Oncol 2005; 23: 4063-4069.
46 Karthaus M, Kretzschmar A, Kroning H. et al. Dalteparin for prevention of catheter-related complications in cancer patients with central venous catheters: final results of a double-blind, placebo-controlled phase III trial. Ann Oncol 2006; 17: 289-296.
47 Verso M, Agnelli G, Bertoglio S. et al. Enoxaparin for the prevention of venous thromboembolism associated with central vein catheter: a double-blind, placebo-controlled, randomized study in cancer patients. J Clin Oncol 2005; 23: 4057-4062.
48 Munoz FJ, Mismetti P, Poggio R. et al. Clinical outcome of patients with upper-extremity deep vein thrombosis: results from the RIETE Registry. Chest 2008; 133: 143-148.
49 Levine MN, Gent M, Hirsh J. et al. The thrombogenic effect of anticancer drug therapy in women with stage II breast cancer. N Engl J Med 1988; 318: 404-407.
50 Luzzatto G, Schafer AI. The prethrombotic state in cancer. Semin Oncol 1990; 17: 147-159.
51 Nand S, Fisher SG, Salgia R, Fisher RI. Hemostatic abnormalities in untreated cancer: incidence and correlation with thrombotic and hemorrhagic complications. J Clin Oncol 1987; 05: 1998-2003.
52 Edwards RL, Rickles FR, Moritz TE. et al. Abnormalities of blood coagulation tests in patients with cancer. Am J Clin Pathol 1987; 88: 596-602.
53 Klepfish A, Schattner A G. L. Platlets and cancer. In: Lugassy G, Fanlanga A, Kakkar A. et al. (eds). Thrombosis and cancer. 2004: 31-46.
54 Donati MB. Cancer and thrombosis: from Phlegmasia alba dolens to transgenic mice. Thromb Haemost 1995; 74: 278-281.
55 Rickles FR, Falanga A. Molecular basis for the relationship between thrombosis and cancer. Thromb Res 2001; 102: V215-V224.
56 Weitz IC, Israel VK, Waisman JR. et al. Chemotherapy-induced activation of hemostasis: effect of a low molecular weight heparin (dalteparin sodium) on plasma markers of hemostatic activation. Thromb Haemost 2002; 88: 213-220.
57 Falanga A, Vignoli A, Marchetti M. Coagulation in hematological malignancies. Cancer Invest 2009; 27: 17-27.
58 Falanga A, Ofosu FA, Cortelazzo S. et al. Preliminary study to identify cancer patients at high risk of venous thrombosis following major surgery. Br J Haematol 1993; 85: 745-750.
59 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.
60 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.
61 Toth B, Liebhardt S, Steinig K. et al. Platelet-derived microparticles and coagulation activation in breast cancer patients. Thromb Haemost 2008; 100: 663-669.
62 Trappenburg MC, van Schilfgaarde M, Marchetti M. et al. Elevated procoagulant microparticles expressing endothelial and platelet markers in essential thrombocythemia. Haematologica 2009; 94: 911-918.
63 Zwicker JI, Liebman HA, Neuberg D. et al. Tumorderived tissue factor-bearing microparticles are associated with venous thromboembolic events in malignancy. Clin Cancer Res 2009; 15: 6830-6840.
64 Khorana AA, Kuderer NM, Culakova E. et al. Development and validation of a predictive model for chemotherapy-associated thrombosis. Blood 2008; 111: 4902-4907.
65 Khorana AA, Herman K, Rubens D, Francis CW. A predictive risk score for cancer-associated thrombosis: Role of screening in a prospective study. Blood Cells 2010; 116: 3173.
66 Ay C, Dunkler D, Marosi C. et al. Prediction of venous thromboembolism in cancer patients. Blood 2010; 116: 5377-5382.
67 Falanga A, Panova-Noeva M, Russo L. Procoagulant mechanisms in tumour cells. Best Pract Res Clin Haematol 2009; 22: 49-60.
68 Furie B, Furie BC. Mechanisms of thrombus formation. N Engl J Med 2008; 359: 938-949.
69 Gay LJ, Felding-Habermann B. Contribution of platelets to tumour metastasis. Nat Rev Cancer 2011; 11: 123-134.
70 Ho-Tin-Noe B, Goerge T, Wagner DD. Platelets: guardians of tumor vasculature. Cancer Res 2009; 69: 5623-5626.
71 Magnus N, Garnier D, Rak J. Oncogenic epidermal growth factor receptor up-regulates multiple elements of the tissue factor signaling pathway in human glioma cells. Blood 2010; 116: 815-818.
72 ENOXACAN Study Group. Efficacy and safety of enoxaparin versus unfractionated heparin for prevention of deep vein thrombosis in elective cancer surgery: a double-blind randomized multicentre trial with venographic assessment. Br J Surg 1997; 84: 1099-1103.
73 Bergqvist D, Agnelli G, Cohen AT. et al. Duration of prophylaxis against venous thromboembolism with enoxaparin after surgery for cancer. N Engl J Med 2002; 346: 975-980.
74 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.
75 Rasmussen MS, Jorgensen LN, Wille-Jorgensen P. et al. Prolonged prophylaxis with dalteparin to prevent late thromboembolic complications in patients undergoing major abdominal surgery: a multicenter randomized open-label study. J Thromb Haemost 2006; 04: 2384-2390.
76 Samama MM, Cohen AT, Darmon JY. et al. A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. Prophylaxis in Medical Patients with Enoxaparin Study Group. N Engl J Med 1999; 341: 793-800.
77 Alikhan R, Cohen AT, Combe S. et al. Prevention of venous thromboembolism in medical patients with enoxaparin: a subgroup analysis of the MEDENOX study. Blood Coagul Fibrinolysis 2003; 14: 341-346.
78 Riess H, Pelzer U, Deutschinoff G. et al. A prospective, randomized trial of chemotherapy with or without the low molecular weight heparin (LMWH) enoxaparin in patients (pts) with advanced pancreatic cancer (APC): Results of the CONKO 004 trial. J Clin Oncol 2009; 27: LBA4506.
79 Riess H, Pelzer U, Hilbig A. et al. Rationale and design of PROSPECT-CONKO 004: a prospective, randomized trial of simultaneous pancreatic cancer treatment with enoxaparin and chemotherapy). BMC Cancer 2008; 08: 361.
80 Maraveyas A, Waters J, Roy R. et al. Gemcitabine with or without prophylactic weight-adjusted dalteparin in patients with advanced or metastatic pancreatic cancer (APC): a multicentre, randomised phase IIB trial (the UK FRAGEM study). Eur J Cancer 2009; 07 (Suppl): 362.
81 Haas SK, Kakkar AK, Kemkes-Matthes B. et al. Prevention of venous thromboembolism with lowmolecular-weight heparin in patients with metastatic breast or lung cancer – Results of the TOPIC Studies. J Thromb Haemost 2005; 03: OR059.
82 Perry JR, Julian JA, Laperriere NJ. et al. PRODIGE: a randomized placebo-controlled trial of dalteparin low-molecular-weight heparin thromboprophylaxis in patients with newly diagnosed malignant glioma. J Thromb Haemost 2010; 08: 1959-1965.
83 Agnelli G, Gussoni G, Bianchini C. et al. Nadroparin for the prevention of thromboembolic events in ambulatory patients with metastatic or locally advanced solid cancer receiving chemotherapy: a randomised, placebo-controlled, double-blind study. Lancet Oncol 2009; 10: 943-949.
84 Lyman GH, Khorana AA, Falanga A. et al. American Society of Clinical Oncology guideline: recommendations for venous thromboembolism prophylaxis and treatment in patients with cancer. J Clin Oncol 2007; 25: 5490-5505.
85 Kearon C, Kahn SR, Agnelli G. et al. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. (8^th ed). Chest 2008; 133: 454S-545S.
86 Schulman S, Kearon C, Kakkar AK. et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009; 361: 2342-2352.
87 Buller H. EINSTEIN. European Society of Cardiology. Sep 2010 meeting2010.
88 Van Dongen CJ, van den Belt AG, Prins MH, Lensing AW. Fixed dose subcutaneous low molecular weight heparins versus adjusted dose unfractionated heparin for venous thromboembolism. Cochrane database of systematic reviews (Online) 2004; CD001100.
89 Akl EA, Rohilla S, Barba M. et al. Anticoagulation for the initial treatment of venous thromboembolism in patients with cancer. Cochrane database of systematic reviews (Online) 2008; CD006649.
90 Buller HR, Davidson BL, Decousus H. et al. Subcutaneous fondaparinux versus intravenous unfractionated heparin in the initial treatment of pulmonary embolism. N Engl J Med 2003; 349: 1695-1702.
91 Buller HR, Davidson BL, Decousus H. et al. Fondaparinux or enoxaparin for the initial treatment of symptomatic deep venous thrombosis: a randomized trial. Ann Intern Med 2004; 140: 867-873.
92 Van Doormaal FF, Raskob GE, Davidson BL. et al. Treatment of venous thromboembolism in patients with cancer: subgroup analysis of the Matisse clinical trials. Thromb Haemost 2009; 101: 762-769.
93 Akl EA, Barba M, Rohilla S. et al. Anticoagulation for the long term treatment of venous thromboembolism in patients with cancer. Cochrane database of systematic reviews (Online) 2008; CD006650.
94 Meyer G, Marjanovic Z, Valcke J. et al. Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer: a randomized controlled study. Arch Intern Med 2002; 162: 1729-1735.
95 Lee AY, Levine MN, Baker RI. et al. Low-molecularweight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 2003; 349: 146-153.
96 Deitcher SR, Kessler CM, Merli G. et al. Secondary prevention of venous thromboembolic events in patients with active cancer: enoxaparin alone versus initial enoxaparin followed by warfarin for a 180-day period. Clin Appl Thromb Hemost 2006; 12: 389-396.
97 Hull RD, Pineo GF, Brant RF. et al. Long-term lowmolecular-weight heparin versus usual care in proximal-vein thrombosis patients with cancer. Am J Med 2006; 119: 1062-1072.
98 Liebman H, Levine MN, Deitchman D. et al. Apixaban in patients with metastatic cancer: a randomized phase II feasibility study. J Thromb Haemost 2009; 07: 792.
99 Louzada ML, Lazo-Langner A, Dao V. et al. Development of a clinical prediction rule for risk stratification of recurrent venous thromboembolism in patients with cancer-associated venous thromboembolism. Blood 2010; 116: 475a.
100 Carrier M, Le Gal G, Cho R. et al. Dose escalation of low molecular weight heparin to manage recurrent venous thromboembolic events despite systemic anticoagulation in cancer patients. J Thromb Haemost 2009; 07: 760-765.