Improved Cancer Mortality with Low-Molecular-Weight Heparin Treatment: A Review of the Evidence

Richard H. Cosgrove; Leo R. Zacharski; Eric Racine; Judith C. Andersen

doi:10.1055/s-2002-20566

Seminars in Thrombosis and Hemostasis, Inhaltsverzeichnis

Semin Thromb Hemost 2002; 28(1): 79-88
DOI: 10.1055/s-2002-20566

Improved Cancer Mortality with Low-Molecular-Weight Heparin Treatment: A Review of the Evidence

Richard H. Cosgrove¹ , Leo R. Zacharski² , Eric Racine³ , Judith C. Andersen⁴

¹Department of Pharmacy, Harper University Hospital, Detroit Medical Center, Detroit, Michigan
²Department of Veteran's Affairs Medical Center, White River Junction, Vermont, and Department of Medicine, Dartmouth Medical School, Lebanon, New Hampshire
³Clinical Pharmacy Services, Harper University Hospital, Detroit Medical Center and Wayne State University School of Pharmacy, Detroit, Michigan
⁴Department of Medicine, Wayne State University, Harper University Hospital, Detroit, Michigan

Abstract

ABSTRACT

Work with low-molecular-weight heparins (LMWHs) continues to provide suggestions for survival advantages among patients with cancer diagnoses. Momentum is building in support of this theory through reports, the vast majority of which are derived from secondary analyses of clinical trials on the treatment of thromboembolism. The data retrieved from such studies that compare unfractionated heparin (UFH) with LMWH indicate that LMWH is equally beneficial if not more beneficial to cancer patients in terms of survival. In retrospective analysis, this improved life expectancy is not considered a result of reduced complications from thromboembolism. Thus, theories of antitumor effects of LMWH have developed, supported by evidence that most of the survival benefits are during long-term comparisons. Reports describing the effects of heparin in the setting of cancer have existed for over a half-century, although specific mechanisms for the marginal results seen thus far have yet to surface. Proposals for the most likely targets of the effective heparins include enzyme interaction, cellular growth modifications, and antiangiogenesis.

KEYWORD

Low-molecular-weight heparin - cancer - mortality

Volltext

Referenzen

REFERENCES

1 Prandoni P, Lensing A WA, Büller H R. Comparison of subcutaneous low-molecular-weight heparin with intravenous standard heparin in proximal deep-vein thrombosis. Lancet . 1992; 339 441-445
2 The Columbus Investigators. Low-molecular weight heparin in the treatment of patients with venous thromboembolism. N Engl J Med . 1997; 337 663-669
3 Levine M, Gent M, Hirsh J. 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; 334 677-687
4 Hull R D, Raskob G E, Pineo G F. Subcutaneous low-molecular-weight heparin compared with continuous intravenous heparin in the treatment of proximal-vein thrombosis. N Engl J Med . 1992; 326 975-982
5 Simonneau G, Charbonnier B, Decousus H. Subcutaneous low molecular weight heparin compared with continuous intravenous unfractionated heparin in the treatment of proximal deep vein thrombosis. Arch Intern Med . 1993; 153 1541-1546
6 The Tasman Study Group, Koopman M MW, Prandoni P, Piovella F. Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low-molecular-weight heparin administered at home. N Engl J Med . 1996; 334 682-687
7 Hull R D, Raskob G E, Brant R F. Low-molecular-weight heparin vs heparin in the treatment of patients with pulmonary embolism. Arch Intern Med . 2000; 160 229-236
8 Leizorovicz A, Simonneau G, Decousus H, Boissel J P. Comparison of efficacy and safety of low-molecular-weight heparin and unfractionated heparin in the initial treatment of deep venous thrombosis: a meta-analysis. BMJ . 1994; 309 299-309
9 Lensing A WA, Prins M H, Davidson B L, Hirsh J. Treatment of deep venous thrombosis with low-molecular-weight heparins. A meta-analysis. Arch Intern Med . 1995; 155 601-607
10 Hirsh J, Siragusa S, Cosmi B, Ginsberg J S. Low-molecular-weight heparins (LMWH) in the treatment of patients with acute venous thromboembolism. Thromb Haemost . 1995; 74 360-363
11 Siragusa S, Cosmi B, Piovella F, Hirsh J, Ginsberg J. Low-molecular-weight heparin and unfractionated heparin in the treatment of patients with acute venous thromboembolism: results of a meta-analysis. Am J Med . 1996; 100 269-277
12 Gould M K, Dembitzer A D, Doyle R L, Hastie T J, Garber A M. Low-molecular-weight heparins compared with unfractionated heparin for the treatment of acute deep venous thrombosis, a meta-analysis of randomized controlled trials. Ann Intern Med . 1999; 130 800-809
13 Ornstein D L, Zacharski L R. The use of heparin for treating human malignancy. Haemostasis . 1999; 29(Suppl 1) 48-60
14 Dolovich L R, Ginsberg J S, Douketis J D, Holbrook A M, Cheah G. A meta-analysis comparing low-molecular-weight heparins with unfractionated heparin in the treatment of venous thromboembolism, examining some unanswered questions regarding location of treatment, product type, and dosing frequency. Arch Intern Med . 2000; 160 181-188
15 Valentine K A, Hull R D, Pineo G F. Low-molecular-weight heparin and mortality. Semin Thromb Hemost . 1997; 23 173-178
16 von Tempelhoff G-F, Harenberg J, Niemann F. Effect of low molecular weight heparin (Certoparin) versus unfractionated heparin on cancer survival following breast and pelvic cancer surgery: a prospective randomized double-blind trial. Int J Oncol . 2000; 16 815-824
17 Hettiarachchi R JK, Smorenburg S M, Ginsberg J. Do heparins do more than just treat thrombosis?. <~>The influence of heparins on cancer spread. Thromb Haemost . 1999; 82 947-952
18 Wille Jørgensen P, Larsen I, Jørgensen L N, Lebeck M. Long term survival after operation for malignancies with and without long term prophylaxis with low-molecular-weight heparin (LMWH). Thromb Haemost . 1995; 73 980-980 Abst
19 Pineo G, Hull R, Raskob G, Brant R, Green D. Decreased mortality in cancer patients treated for proximal deep vein thrombosis with low-molecular-weight heparin as compared with unfractionated heparin. Thromb Haemost . 1997; Suppl 384-384 Abst
20 von Tempelhoff F G, Dietrich M, Neimann F. Blood coagulation and thrombosis in patients with ovarian malignancy. Thromb Haemost . 1997; 77 456-461
21 Goerner A. The influence of anticlotting agents on transplantation and growth of tumor tissue. J Lab Clin Med . 1930; 16 369-372
22 Albert-Weil J, Nehorais J. Apropos de deux cas de néoplasies non-justiciable des thérapeutiques classiques, traitées par des injections intraveineuses d'héparine et des injections intramusculaires d'un extract de sangsue. Rev Pathol Gen Comparee . 1954; 54 1014-1020
23 Lebeau B, Chastang C, Brechot J-M. Subcutaneous heparin treatment increases survival in small cell lung cancer. Cancer . 1994; 74 38-45
24 Kakkar A, Hedges A, Williamson R, Kakkar V. Perioperative heparin treatment inhibits late death from metastatic cancer. Int J Oncol . 1995; 6 885-888
25 Zacharski L R, Ornstein D L. Heparin and cancer. Thromb Haemost . 1998; 80 10-23
26 Ying Q L, Kemme M, Saunders D, Simon S R. Glycosaminoglycans regulate elastase inhibition by oxidized secretory leukoprotease inhibitor. Am J Physiol . 1997; 272 1533-1541
27 Ermolieff J, Boudier C, Laine A, Meyer B, Bierth J G. Heparin protects cathepsin G against inhibition by protein protease inhibitors. J Biol Chem . 1994; 269 29502-29508
28 Hermans J M, Monard D, Jones R, Stone S R. Inhibition of acrosin by serpins. A suicide substrate mechanism. Biochemistry . 1995; 34 3678-3685
29 Hermans J M, Jones R, Stone S R. Rapid inhibition of the sperm protease acrosin by protein C inhibitor. Biochemistry . 1994; 33 5440-5444
30 Adachi T, Marklaund S L. Interactions between human extracellular superoxide dismutase C and sulfated polysaccharides. J Biol Chem . 1989; 264 8537-8541
31 Kopitz J, Mukl C, Ehemann V, Lehmann C, Canty M. Effects of cell surface ganglioside sialidase inhibition on growth control and differentiation of human neuroblastoma cells. Eur J Cell Biol . 1997; 73 1-9
32 Di Cioccio A R, Srivastava B IS. Inhibition of deoxynucleotide-polymerizing enzyme activities of human cells and of simian sarcoma virus by heparin. Cancer Res . 1978; 38 2401-2407
33 Stetler-Stevenson W G, Hewitt R, Corcoran M. Matrix-metalloproteases and tumor invasion: from correlation and causality to the clinic. Semin Cancer Biol . 1996; 7 147-154
34 Zacharski L R, Wojtukiewicz M Z, Constantini V, Ornstein D L, Memoli V A. Pathways of coagulation/fibrinolysis activation in malignancy. Semin Thromb Haemost . 1992; 18 104-116
35 Fenton J. Thrombin and cancer. In: Piffare R, ed. New Anticoagulants for the Cardiovascular Patient Philadelphia: Hanley and Belfus 1997: 517-520
36 Schmitt M, Harbeck N, Thomssen C. Clinical aspects of plasminogen activation system in tumor invasion and metastasis: prognostic relevance and targets for therapy. Thromb Haemost . 1997; 78 285-296
37 van Meyer M, Smilde A, Tans G. The suicide substrate reaction between plasminogen activator inhibitor 1 and thrombin is regulated by the cofactors vitronectin and heparin. Blood . 1997; 90 1874-1882
38 Espana F, Estelles A, Fernandez P J. Evidence for the regulation of urokinase and tissue type plasminogen activators by serpin, protein C inhibitor, in semen and blood plasma. Thromb Haemost . 1993; 70 989-994
39 Tyagi S C, Kumar S, Katwa L. Differential regulation of extracellular matrix metalloproteinase and tissue inhibitor by heparin and cholesterol in fibroblast cells. J Mol Cell Cardiol . 1997; 29 391-404
40 Marsh N A, Minter A J, Hesterman C N. The effect of heparin and other glycosaminoglycans on the levels of tissue plasminogen activator and plasminogen activator inhibitor in cultured human umbilical vein endothelial cells. Blood Coagul Fibrinolysis . 1990; 1 133-138
41 Nelson R M, Cecconi O, Roberts W G. Heparin oligosaccharides bind L- and P-selectin and inhibit acute inflammation. Blood . 1993; 82 3253-3258
42 Abbate R, Gori A M, Modesti P A. Heparin, monocytes, and procoagulant activity. Haemostasis . 1990; 20(Suppl 1) 98-100
43 Au Y PT, Kenagy R D, Clowes M M, Clowes A W. Mechanism of inhibition by heparin of vascular smooth muscle cell proliferation and migration. Haemostasis . 1993; 23(Suppl 1) 177-182
44 Cerletti C, Rajtar G, Marchi E, De Gaetano G. Interaction between glycosaminoglycans, platelets, and leukocytes. Semin Thromb Hemost . 1994; 20 245-253
45 Vlodavsky I, Mohsen M, Lider O. Inhibition of tumor metastasis by heparanase inhibiting species of heparin. Invasion Metastasis . 1995; 14 290-302
46 Parish C R, Coombe D R, Jakobsen K B, Bennett F A, Underwood P A. Evidence that sulphated polysaccharides inhibit tumor metastasis by blocking tumor-cell-derived heparanases. Int J Cancer . 1987; 40 511-518
47 Maeda S, Kimura H, Koga N, Lin K H, Saito T. Cell density-dependent DNA fragmentation and its suppression by heparin in primary culture of adult rat hepatocytes. Biochem Biophys Res Commun . 1993; 195 270-275
48 Wang A, Templeton D M. Inhibition of mitogenesis and c-fos induction in mesangial cells by heparin and heparan sulfates. Kidney Int . 1996; 49 437-438
49 Bianconi L, Martino A D, Orlandi V. Development of inflammatory angiogenesis by local stimulation of Fas in vivo. J Exp Med . 1997; 186 147-152
50 Manaster J, Chezar J, Shurtz-Swirski R. Heparin induces apoptosis in human peripheral blood neutrophils. Br J Haematol . 1996; 94 48-52
51 Granerus M, Engstrom W. Growth factors and apoptosis. Cell Prolif . 1996; 29 309-314
52 Wright S C, Wei Q S, Zhong J. Purification of a 24-kD protease from apoptotic tumor cells that activates DNA fragmentation. J Exp Med . 1994; 180 2113-2123
53 Maia R C, Wagner K, Cabral R H, Rumjanek V M. Heparin rhodamine 123 extrusion by multidrug resistant cells. Cancer Lett . 1996; 106 101-108
54 Folkman J, Langer R, Linhardt R J, Haudenschild C, Taylor S. Angiogenesis inhibition and tumor regression caused by heparin or a heparin fragment in the presence of cortisone. Science . 1983; 221 719-725
55 Jacobson A M, Hahnenberger R. Antiangiogenic effect of heparin and other sulphated glycosamino-glycans in the chick embryo chorioallantoic membrane. Phamacol Toxicol . 1991; 69 122-126
56 Derbyshire E J, Comin G A, Yang Y C. Anti-tumor and anti-angiogenic effects in mice of heparin conjugated to angiostatic steroids. Int J Cancer . 1995; 63 694-701
57 Ziche M, Ruggiero M, Pasquali F, Chiarugi V P. Effects of cortisone with and without heparin on angiogenesis induced by prostaglandin E1 and by S180 cells, and on growth of murine transplantable tumors. Int J Cancer . 1985; 35549-35552
58 }Thorpe P E, Derbyshire E J, Andrade S P. Heparin-steroid conjugates: new angiogenesis inhibitors with antitumor activity in mice. Cancer Res . 1993; 53 3000-3007
59 Quyyumi A A, Diodati J G, Lakatos E, Bonow R O, Epstein S E. Angiogenic effect of low molecular weight heparin in patients with stable coronary artery disease: a pilot study. J Am Coll Cardiol . 1993; 22 635-641
60 Norrby K, Ostergaard P. Basic-fibroblast-growth-factor-mediated de novo angiogenesis is more effectively suppressed by low-molecular-weight heparin than by high-molecular-weight heparin. Int J Microcirc . 1996; 16 8-15
61 Jayson G C, Gallagher J T. Heparin oligosaccharides: inhibitors of the biological activity of bFGF on Caco-2 cells. Br J Cancer . 1997; 75 9-16
62 Sciumbata T, Caretto P, Pirovano P. Treatment with modified heparins inhibits experimental metastasis formation and leads, in some animals, to long term survival. Invasion Metastasis . 1996; 16 132-143
63 Duroux P. A randomised trial of subcutaneous low-molecular-weight heparin (CY 216) compared with intravenous unfractionated heparin in the treatment of deep vein thrombosis. Thromb Haemost . 1991; 65 251-256
64 Sakuragawa N, Hasegawa H, Maki M, Nakagawa M, Nakashima M. Clinical evaluation of low-molecular-weight heparin on disseminated intravascular coagulation (DIC)-a multicenter co-operative double-blind trial in comparison with heparin. Thromb Res . 1993; 72 475-500
65 Bergqvist D, Burmark V S, Flordal P A. Low-molecular-weight heparin started before surgery as prophylaxis against deep vein thrombosis: 2500 versus 5000 XaI units in 2070 patients. Br J Surg . 1995; 82 496-501
66 Monreal M, Alastrue A, Rull M. Upper extremity deep venous thrombosis in cancer patients with venous access devices-prophylaxis with a low molecular weight heparin (Fragmin). Thromb Haemost . 1996; 75 251-3
67 The 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
68 Elias E, Shulka S, Mink I. Heparin and chemotherapy in the management of inoperable lung cancer. Cancer . 1975; 36 129-136
69 Halkin H, Goldberg J, Modan M, Modan B. Reduction of mortality in general medicine patients by low dose heparin prophylaxis. Ann Intern Med . 1982; 96 561-565
70 Torngren S, Reiger A. The influence of heparin and curable resection on the survival of colon cancer. Acta Chir Scand . 1983; 149 427-429
71 Kohanna F H, Sweeney J, Hussey S, Zacharski L R, Salzman E W. Effect of peri-operative low-dose heparin administration on the course of colon cancer. Surgery . 1983; 93 433-438
72 Wereldsma J, Bruggink E, Meijer W, Roukema J, van Patten W. Adjuvant portal liver infusion in colorectal cancer, with 5-fluorouracil/heparin versus urokinase versus control. Cancer . 1990; 65 425-432
73 Fielding L P, Hittinger R, Grace R H, Fry J S. Randomized controlled trial of adjuvant chemotherapy by portal vein infusion after curative resection for colorectal adenocarcinoma. Lancet . 1992; 340 502-506
74 Kingston R, Fielding L D, Palmer M. Peri-operative heparin a possible adjuvant to surgery in colo-rectal cancer?. Int J Colorectal Dis . 1993; 8 111-115
75 Weitz J L. Low molecular weight heparins. N Engl J Med . 1997; 337 688-698
76 Piazolo L, Harenberg J, Malsch R, Huttner F G, Heene D L. Comparison of the pharmacodynamic and pharmacokinetic profiles of two low-molecular-mass heparins in rats. Semin Thromb Hemost . 1997; 23 109-117