Semin Thromb Hemost 2007; 33(7): 695-698
DOI: 10.1055/s-2007-991537
© Thieme Medical Publishers

The Role of Oral Anticoagulants in Tumor Biology

Ilene C. Weitz1 , Howard A. Liebman1
  • 1Division of Hematology, Department of Medicine, University of Southern California-Keck School of Medicine, Los Angeles, California
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Publikationsdatum:
14. November 2007 (online)

ABSTRACT

Pathology studies of human cancers suggested to early investigators that the hemostatic system may play an important role in cancer metastasis. Subsequent studies in animal models have demonstrated a reduction of tumor metastasis and improved animal survival with systemic anticoagulation. In many of these experiments, vitamin K antagonists (VKAs) were utilized. Although warfarin was effective in reducing metastasis in a majority of these animal models, effects on the growth of the primary tumor and on animal survival have been less consistent. Clinical studies on the effect of warfarin in human malignancy are limited and less than conclusive. Several small, uncontrolled and controlled clinical studies have been reported but do not definitively suggest a benefit in most malignancies. However, none of the studies of VKAs in humans are adequately designed or sufficiently powered to definitively exclude an impact of oral anticoagulants on cancer survival. Because of the difficulties in managing VKA oral anticoagulation in cancer patients and recent studies suggesting a positive effect on cancer survival with low-molecular-weight heparins, it unlikely that further studies on the use of VKAs in cancer patients will be undertaken.

REFERENCES

  • 1 Billroth T. Lectures on Surgical Pathology and Therapeutics (trans. from the 8th ed.) London; New Sydenham Society 1878
  • 2 Agostino D, Cliffton E E, Girolami A. Effect of prolonged coumadin treatment on the production of pulmonary metastases in the rat.  Cancer. 1966;  19 284-288
  • 3 Ryan J J, Ketcham A S, Wexler H. Warfarin treatment of mice bearing autochthonous tumors: effect on spontaneous metastases.  Science. 1968;  162 1493-1494
  • 4 Lione A, Bosmann H B. The inhibitory effect of heparin and warfarin treatments on the intravascular survival of B16 melanoma cells in syngeneic C57 mice.  Cell Biol Int Rep. 1978;  2 81-86
  • 5 Brown J M. A study of the mechanism by which anticoagulation with warfarin inhibit blood-borne metastases.  Cancer Res. 1973;  33 1217-1224
  • 6 Thornes R D, Edlow D W, Wood Jr S. Inhibition of locomotion of cancer cells in vivo by anticoagulant therapy. I. Effects of sodium warfarin on V2 cancer cells, granulocytes, lymphocytes and macrophages in rabbits.  Johns Hopkins Med J. 1968;  123 305-316
  • 7 Higashi H, Heidelberger C. Lack of effect of warfarin (NSC-59813) alone or in combination with 5-fluorouracil (NSC-19893) on primary and metastatic L1210 leukemia and adenocarcinoma 755.  Cancer Chemother Rep. 1971;  55 29-33
  • 8 Chang J C, Hall T C. In vitro effect of sodium warfarin on DNA and RNA synthesis of mouse L1210 leukemic cells and walker tumor cells.  Oncology. 1973;  28 232-237
  • 9 Thornes R D. Oral anticoagulant therapy of human cancer.  J Med. 1974;  5 83-91
  • 10 Michaels L. The incidence and course of cancer in patients receiving anticoagulant therapy. Retrospective and prospective studies.  J Med. 1974;  5 98-106
  • 11 Hoover H C, Ketcham A S, Millar R C, Gralnick H R. Osteosarcoma: improved survival with anticoagulation and amputation.  Cancer. 1978;  41 2475-2480
  • 12 Zacharski L R, Henderson W G, Rickles F R et al.. Rationale and experimental design for the VA Cooperative Study of anticoagulation (warfarin) in the treatment of cancer.  Cancer. 1979;  44 732-741
  • 13 Zacharski L R, Henderson W G, Rickles F R et al.. Effect of warfarin anticoagulation on survival in carcinoma of the lung, colon, head and neck and prostate.  Cancer. 1984;  53 2046-2052
  • 14 Maurer L H, Herndon J E, Hollis D R et al.. Randomized trial of chemotherapy and radiation therapy with or without warfarin for limited-stage small-cell lung cancer: a Cancer and Leukemia Group B study.  J Clin Oncol. 1997;  15 3378-3387
  • 15 Chahinian A P, Propert K J, Ware J H et al.. A randomized tiral of anticoagulation with warfarin and of alternating chemotherapy in extensive small-cell lung cancer by the Cancer and Leukemia Group B.  J Clin Oncol. 1989;  7 993-1002
  • 16 Levine M, Hirsh J, Gent M et al.. Double-blind randomized trial of very-low-dose warfarin for prevention of thromboembolism in stage IV breast cancer.  Lancet. 1994;  343 886-889
  • 17 Daly L. The first international urokinase/warfarin trial in colorectal cancer.  Clin Exp Metastasis. 1991;  9 3-11
  • 18 Michaels L. Cancer incidence and mortality in patients having anticoagulant therapy.  Lancet. 1964;  2 832-835
  • 19 Schulman S, Lindmarker P. Incidence of cancer after prophylaxis with warfarin against recurrent venous thromboembolism.  N Engl J Med. 2000;  342 1953-1958
  • 20 Taliani M R, Agnelli G, Prandoni P et al.. Incidence of cancer after a first episode of idiopathic venous thromboembolism treated with 3 months or 1 year of oral anticoagulation.  J Thromb Haemost. 2003;  1 1730-1733
  • 21 Schulman S, Lindmarker P. Vitamin K antagonists and cancer: rebuttal.  J Thromb Haemost. 2004;  2 377-378
  • 22 Taliani M R, Agnelli G, Prandoni P. Vitamin K antagonists and cancer: reply to rebuttal.  J Thromb Haemost. 2004;  2(2) 378-379
  • 23 Kakkar A K, Levine M N, Kadziola Z et al.. Low molecular weight heparin, therapy with dalteparin, and survival in advanced cancer: the fragmin advanced malignancy outcome study (FAMOUS).  J Clin Oncol. 2004;  22(10) 1944-1948
  • 24 Klerk C PW, Smorenburg S M, Otten J MMB et al.. The effect of low molecular weight heparin on survival in patients with advanced malignancy.  J Clin Oncol. 2005;  23 2130-2135
  • 25 Lee A YY, Julian J A, Levine M N et al.. Long-term treatment with dalteparin low-molecular weight heparin (LMWH) may improve survival in patients with non-metastatic malignancy and venous thromboembolism.  J Clin Oncol. 2005;  23 2123-2129
  • 26 Altinbas M, Colkun H S, Er O et al.. A randomized clinical trial of combination chemotherapy with and without low-molecular-weight heparin in small cell lung cancer.  J Thromb Haemost. 2004;  2 1266-1271

Howard A LiebmanM.D. 

Norris Cancer Hospital, Room 3466

1441 Eastlake Ave., Los Angeles, CA 90033

eMail: liebman@usc.edu