We have utilized epidemiological data to address three questions in patients with cancer and venous thromboembolism (VTE): (1) What is the risk for occult cancer in patients with idiopathic versus secondary VTE? (2) What is the risk for thrombosis in patients with cancer (vs. noncancer patients)? (3) What is the risk of recurrent VTE in cancer patients with an initial episode of VTE compared to noncancer patients? The risk for a new cancer diagnosis within 6–12 months of the diagnosis of idiopathic VTE (including pulmonary embolism) is well supported by retrospective analyses of large numbers of unselected patients, population-based retrospective cohort analyses from large registries and prospective studies. The odds ratios for these studies are in the range of 4- to 7-fold increased risk. In surgical patients with known cancer the odds ratio for an episode of postoperative VTE is approximately 2, when compared to a control group of noncancer patients subjected to the same procedures. A similar odds ratio of approximately 2 exists for the relative risk for recurrence of VTE in the first 3 months after an initial episode in cancer patients treated with heparin and warfarin (Coumadin®) compared to noncancer patients. Therefore, patients with idiopathic VTE are at increased risk for occult cancer and cancer patients are at increased risk for VTE. Appropriate studies are underway to determine the best strategies for anticoagulant management of these patients.

Keywords:
Cancer, Hypercoagulability, Thrombosis, Trousseau’s syndrome
1.
Trousseau A: Phlegmasia alba dolens; in Clinique médicale de l’Hôtel-Dieu de Paris. Paris, Baillière, 1865, vol 3, pp 654–712.
2.
Billroth T: Lectures on Surgical Pathology and Therapeutics: A Handbook for Students and Practitioners, ed 8 (translated). London, The New Sydenham Society, 1877–1878.
3.
Rickles FR, Levine M, Dvorak HB: Abnormalities of hemostasis in malignancy; in Colman RW, Hirsh J, Marder VJ, Clowes A, George JN (eds): Hemostasis and Thrombosis. Philadelphia, Lippincott, Williams & Wilkins, 2000, chap 69, pp 1132–1152.
4.
Rickles FR, Falanga A: Molecular basis for the relationship between cancer and thrombosis. Thromb Res, in press.
5.
Falanga A: Mechanisms of hypercoagulation in malignancy and during chemotherapy. Haemostasis 1998;28(suppl 3):50–60.
6.
Prandoni P: Antithrombotic strategies in patients with cancer. Thromb Haemost 1997;78:141–144.
7.
Levine MN, Rickles FR: Treatment of venous thromboembolism in cancer patients. Haemostasis 1998;28:66–70.
8.
Achkar A, Laaban JP, Horellou MH, Rabbat A, Conrad J, Nataf J, Samama MM, Rochmaure J: Prospective screening for occult cancer in patients with venous thromboembolism (abstract). Thromb Haemost 1997;78(suppl):383.
9.
Monreal M, Fernandez-Llamazares J, Perandreu J, Urrutia A, Sahuquillo JC, Contel E: Occult cancer in patients with venous thromboembolism: Which patients, which cancers? Thromb Haemost 1997;78:1316–1318.
10.
Rance A, Emmerich J, Guedj C, Fiessinger J-N: Occult cancer in patients with bilateral deep-vein thrombosis. Lancet 1997;350:1448–1449.
11.
Hettiarachchi RJK, Prins MH, Buller HR, Prandoni P: Undiagnosed malignancy in patients with deep-vein thrombosis: Incidence, risk indicators, and diagnosis. Cancer 1998;83:180–185.
12.
Rajan R, Levine M, Gent M, Hirsh J, Geerts W, Skingley P, Julian J: The occurrence of subsequent malignancy in patients presenting with deep vein thrombosis. Results from a historical cohort study. Thromb Haemost 1998;79:19–22.
13.
Nordstrom M, Lindbald B, Anderson H, Berggvist D, Kjellstrom T: Deep vein thrombosis and occult malignancy: An epidemiological study. Br Med J 1994;308:891–894.
14.
Cornuz J, Pearson SD, Creagor MA, Cook EF, Goldman L: Importance of findings on the initial evaluation for cancer in patients with symptomatic idiopathic deep vein thrombosis. Ann Intern Med 1996;25:785–793.
15.
Sorensen HT, Mellemkjaer L, Steffensen FH, Olsen JH, Nielsen GL: The risk of a diagnosis of cancer after primary deep venous thrombosis or pulmonary embolism. N Engl J Med 1998;338:1169–1173.
16.
Baron JA, Gridley G, Weiderpass E, Nyren O, Linet M: Venous thromboembolism and cancer. Lancet 1998;35:1077–1080.
17.
Prins MH, Lensing AWA, Hirsh J: Idiopathic deep vein thrombosis. Is a search for malignant disease justified? Arch Intern Med 1994;154:1310–1312.
18.
Schulman S, Lindmarker P: Incidence of cancer after prophylaxis with warfarin against recurrent venous thromboembolism. N Engl J Med 2000;342:1953–1958.
19.
Rickles FR, Levine MN: Venous thromboembolism in malignancy and malignancy in venous thromboembolism. Haemostasis 1998;28(suppl 3):43–49.
20.
Prandoni P, Lensing AWA, Buller HR, Cogo A, Prins MH, Cattelan AM, Cuppini S, Noventa F, ten Cate JW: Deep-vein thrombosis and the incidence of subsequent symptomatic cancer. N Engl J Med 1992;327:1128–1133.
21.
Monreal M, Lafoz E, Casals A, Inargaja L, Montserrat E, Callejas JM, Martorell A: Occult cancer in patients with deep venous thrombosis: A systematic approach. Cancer 1991;67:541–545.
22.
Monreal M, Casals A, Boix J, Olazabal A, Montserrat E, Mundo MR: Occult cancer in patients with acute pulmonary embolism. A prospective study. Chest 1993;103:816–819.
23.
Bastounis EA, Karyiannakis AJ, Makri GG, Alexious D, Papalambrous EL: The incidence of occult cancer in patients with deep vein thrombosis: A prospective study. J Intern Med 1996;239:153–156.
24.
Barosi G, Marchetti M, Dazzi L, Quaglini S: Testing for occult cancer in patients with idiopathic deep vein thrombosis – A decision analysis. Thromb Haemost 1997;78:1319–1326.
25.
Schulman S, Rhedin A-S, Lindmarker P, Carlsson AM, Larfars G, Nicol P, Loogna E, Svensson E, Ljunberg B, Walter H, Viering S, Nordlander S, Leijd B, Jonsson K, Hjorth M, Linder O, Boberg J, Duration of Anticoagulation Trial Study Group: A comparison of six weeks and six months of oral anticoagulant therapy after a first episode of venous thromboembolism. N Engl J Med 1995;332:1661–1665.
26.
Sproul EE: Carcinoma and venous thrombosis: The frequency of association of carcinoma in the body or tail of the pancreas with multiple venous thrombosis. Am J Med Sci 1938;34:566–570.
27.
Thompson CM, Rodgers RL: Analysis of the autopsy records of 157 cases of carcinoma of the pancreas with particular reference to the incidence of thromboembolism. Am J Med Sci 1952;223:469–476.
28.
Peuscher FW: Thrombosis and bleeding in cancer patients. Neth J Med 1981;24:23–35.
29.
Levine MN: Prevention of thrombotic disorders in cancer patients undergoing chemotherapy. Thromb Haemost 1997;78:133–136.
30.
Levine MN, Gent M, Hirsh J, Arnold A, Goodyear MD, Hryniuk W, DePauw S: The thrombogenic effect of anticancer drug therapy in women with stage II breast cancer. N Engl J Med 1988;318:404–407.
31.
Weiss RB, Tormey DC, Holland JF, Weinberg VE: Venous thrombosis during multimodal treatment of primary breast cancer. Cancer Treat Rep 1981;65:677–679.
32.
Goodnough LT, Saito H, Manni A, Jones PK, Pearson OH: Increased incidence of thromboembolism in stage IV breast cancer patients treated with a five-day chemotherapy regimen. A study of 159 patients. Cancer 1984;54:1264–1268.
33.
Saphner T, Tormey DC, Gray R: Venous and arterial thrombosis in patients who received adjuvant chemotherapy for breast cancer. J Clin Oncol 1991;9:286–294.
34.
Pritchard KI, Paterson AHG, Paul NA, Zee B, Fine S, Pater J, for the National Cancer Institute of Canada Clinical Trials Group: Increased thromboembolic complications with concurrent tamoxifen and chemotherapy in a randomized trial of adjuvant therapy for women with breast cancer. J Clin Oncol 1996;14:2731–2737.
35.
Wall JG, Weiss RB, Norton L: Arterial thrombosis associated with adjuvant chemotherapy for breast cancer: A Cancer and Leukemia Group B study. Am J Med 1989;87:501–504.
36.
Von Tempelhoff GF, Dietrich M, Hommel G, Heilmann L: Blood coagulation during adjuvant epirubicin/cyclophosphamide chemotherapy in patients with primary operable breast cancer. J Clin Oncol 1996;14:2560–2568.
37.
Clahsen PC, van de Velde CJH, Julien JP, Floiras JL, Mignolet FY: Thromboembolic complications after perioperative chemotherapy in women with early breast cancer: A European Organization for Research and Treatment of Breast Cancer Cooperative Group Study. J Clin Oncol 1994;12:1266–1271.
38.
Fisher B, Redmond C, Legault-Poisson S, Dimitrov NV, Brown AM, Wickerham DL, Wolmark N, Margolese RG, Bowman D, Glass AG: Postoperative chemotherapy and tamoxifen compared with tamoxifen alone in the treatment of positive node breast cancer patients aged 50 years and older with tumors responsive to tamoxifen: Results from the National Surgical Adjuvant Breast and Bowel Project B16. J Clin Oncol 1990;8:1005–1018.
39.
Rivkin SE, Green S, Metch B, Cruz AB, Abeloff MD, Jewell WR, Costanzi JJ, Farrar WB, Minton JP, Osborne CK: Adjuvant CMFVP versus tamoxifen versus concurrent CMFVP and tamoxifen for postmenopausal node positive and estrogen receptor positive breast cancer patients: A Southwest Oncology Group Study. J Clin Oncol 1994;12:2078–2085.
40.
Fisher B, Constantino J, Redmond C, Poisson R, Bowman D, Couture J, Dimitrov NV, Wolmark N, Wickerham DL, Fisher ER: A randomized clinical trial evaluating tamoxifen in the treatment of patients with node negative breast cancer who have estrogen-receptor positive tumors. N Engl J Med 1989;320:479–484.
41.
Fisher B, Dignam J, Wolmark N, DeCillis A, Emir B, Wicherham DL, Bryant J, Dimitrov NV, Abramson N, Atkins JN, Shibata H, Deschenes L, Margolese RG: Tamoxifen and chemotherapy for lymph node negative, estrogen receptor positive breast cancer. J Natl Cancer Inst 1997;89:1673–1682.
42.
Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM, Vogel V, Robidoux A, Dimitrov N, Atkins J, Daly M, Wieand S, Tan-Chiu E, Ford L, Wolmark N: Tamoxifen for prevention of breast cancer: Report of the National Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 1998;90:1371–1388.
43.
Gail MH, Costantino JP, Bryant J, Croyle R, Freedman L, Helzlsouer K, Vogel V: Weighing the risks and benefits of tamoxifen treatment for preventing breast cancer. J Natl Cancer Inst 1999;91:1829–1846.
44.
Von Tempelhoff GF, Dietrich M, Niemann F, Schneider D, Hommel G, Heilmann L: Blood coagulation and thrombosis in patients with ovarian malignancy. Thromb Haemost 1997;77:456–461.
45.
Weijl NI, Rutten MFJ, Zwinderman AH, Aeilko H, Keizer HJ, Nooy MA, Rosendaal FR, Cleton FJ, Osanto S: Thromboembolic events during chemotherapy for germ cell cancer: A cohort study and review of the literature. J Clin Oncol 2000;18:2169–2178.
46.
Sawaya R, Zuccarello M, Elkalliny M, Nishiyama H: Postoperative venous thromboembolism and brain tumors. I. Clinical profile. J Neurooncol 1992;14:119–125.
47.
Dhami MS, Bona RD, Calogero JA, Hellman RM: Venous thromboembolism and high- grade gliomas. Thromb Haemost 1993;70:393–396.
48.
Quevedo JF, Buckner JC, Schmidt JL, Dinapoli RP, O’Fallon JR: Thromboembolism in patients with high-grade glioma. Mayo Clin Proc 1994;69:329–332.
49.
Cantwell BMJ, Carmichael J, Ghani SE, Harris AL: Thromboses and thromboemboli in patients with lymphoma during cytotoxic chemotherapy. Br Med J 1998;297:179–180.
50.
Clarke CS, Otridge BW, Carney DN: Thromboembolism. A complication of weekly chemotherapy in the treatment of non-Hodgkin’s lymphoma. Cancer 1990;66:2027–2030.
51.
Ottinger H, Belka C, Kozole G, Engelhard M, Meusers P, Paar D, Metz KA, Leder L-D, Cyrus C, Gnoth S, Gerhartz H, Huhn D, Siegert W, Thiel E, Aydemir U, Tintrup W, Lennert K, Brittinger G: Deep venous thrombosis and pulmonary artery embolism in high-grade non-Hodgkin’s lymphoma: Incidence, causes and prognostic relevance. Eur J Haematol 1995;54:186–194.
52.
Barbui T, Finazzi G, Grassi A, Marchioli R: Thrombosis in cancer patients treated with hematopoietic growth factors – A meta-analysis. Thromb Haemost 1996;75:368–371.
53.
Bern MM, Lokich JJ, Wallach SR, Bothe A Jr, Benotti PN, Arkin CF, Greco FA, Huberman M, Moore C: Very low doses of warfarin can prevent thrombosis in central vein catheters: A randomized prospective trial. Ann Intern Med 1990;112:423–428.
54.
Monreal M, Alastrue A, Rull M, Mira X, Muxart J, Rosell R, Abad A: Upper extremity deep vein thrombosis in cancer patients with venous access devices – Prophylaxis with a low molecular weight heparin (fragmin). Thromb Haemost 1996;75:251–253.
55.
Kakkar VV, Howe CT, Nicolaides AN, Renney JTG, Clarke MB: Deep vein thrombosis of the leg. Is there a high-risk group? Am J Surg 1970;120:527–531.
56.
Clagett GP, Reisch JS: Prevention of venous thromboembolism in general surgical patients. Ann Surg 1988;208:227–240.
57.
Levine MN: Cancer patients; in Goldhaber S (ed): Prevention of Venous Thromboembolism. New York, Dekker, pp 463–483.
58.
Prandoni P: Antithrombotic strategies in patients with cancer. Thromb Haemost 1997;78:141–144.
59.
Geerts WH, Heit JA, Clagett GP, Pinto GF, Colwell CW, Anderson FA, Wheeler HB: Prevention of venous thromboembolism. Chest 2001;119(suppl):132–175.
60.
Rickles FR, Edwards RL: Activation of blood coagulation in cancer: Trousseau’s syndrome revisited. Blood 1983;62:14–31.
61.
Sack GH, Levin J, Bell WR: Trousseau’s syndrome and other manifestations of chronic disseminated coagulopathy in patients with neoplasms. Medicine 1977;56:1–37.
62.
Lieberman JS, Borrero J, Urdoncta E, Wright IS: Thrombophlebitis and cancer. J Am Med Assoc 1961;177:542–545.
63.
Levine M, Gent M, Hirsh J, Leclerc J, Anderson D, Weitz J, Cusson J, Cruickshank M, Powers P, Brien W, Haley S, Willan A: A comparison of low molecular weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep vein thrombosis. N Engl J Med 1996;334:677–681.
64.
Prandoni P, Lensing AWA, Cogo A, Cuppini S, Villalta S, Carta M, Cattelan AM, Polistena P, Bernardi E, Prins MH: The long-term clinical course of acute deep venous thrombosis. Ann Intern Med 1996;125:1–7.
65.
Hutten BA, Prins MH, Gent M, Ginsberg J, Tijssen J, Buller HR: 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.
66.
Palareti G, Legnani C, Lee A, Manotti C, Hirsh J, D’Angelo D, Pengo V, Moia M, Coccheri S: A comparison of the safety and efficacy of oral anticoagulation for the treatment of venous thromboembolic disease in patients with or without malignancy. Thromb Haemost 2000;84:805–810.
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2001
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