Subscribe to RSS
Please copy the URL and add it into your RSS Feed Reader.
https://www.thieme-connect.de/rss/thieme/en/10.1055-s-00000077.xml
Download PDF
Semin Thromb Hemost 2002; 28(1): 79-88
DOI: 10.1055/s-2002-20566
DOI: 10.1055/s-2002-20566
Improved Cancer Mortality with Low-Molecular-Weight Heparin Treatment: A Review of the Evidence
Further Information
Publication History
Publication Date:
05 March 2002 (online)
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
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
MissingFormLabel
- 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