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Thromb Haemost 1999; 82(06): 1600-1604
DOI: 10.1055/s-0037-1614885
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Schattauer GmbH

The Effects of Unfractionated Heparin on Survival in Patients with Malignancy – A Systematic Review

Susanne M. Smorenburg
1   From the Departments of Vascular Medicine, University of Amsterdam, Amsterdam, The Netherlands
,
Rohan J. K. Hettiarachchi
2   Clinical Epidemiology and Biostatistics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
,
Roel Vink
1   From the Departments of Vascular Medicine, University of Amsterdam, Amsterdam, The Netherlands
,
Harry R. Büller
1   From the Departments of Vascular Medicine, University of Amsterdam, Amsterdam, The Netherlands
› Author Affiliations
Further Information

Publication History

Received 21 May 1999

Accepted after resubmission 21 July 1999

Publication Date:
10 December 2017 (online)

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Summary

Clinical and experimental studies have suggested that unfractionated heparin (UFH) effects malignancy progression. We reviewed all published clinical reports concerning the effects of UFH, as compared to no treatment on survival of cancer patients. Studies were classified on methodological strength and subdivided as to whether therapeutic or prophylactic dosages of UFH were used. Mortality rates after 3 years were extracted or calculated. One randomized study that evaluated the use of UFH in therapeutic dosages in patients with small cell lung carcinoma reported on an improved survival (odds ratio (OR) 0.64; 95% confidence interval (CI): 0.25 to 1.62). A detrimental effect was observed in 2 randomized studies which investigated the effects of intraportal UFH treatment in a prophylactic dose after surgery for gastrointestinal cancer (OR 1.66; 95% CI: 1.02 to 2.71). In contrast, level 2 studies in which either therapeutic or prophylactic dosages of UFH on mortality of patients with gastrointestinal cancer were evaluated, showed OR of 0.58 (95% CI; 0.11-3.13) and 0.65 (95% CI 0.51 to 0.84), respectively. We conclude that there is no convincing evidence of either positively or negatively effects of UFH on survival of patients with malignancy.

Harry R. Büller is an Established Investigator of the Dutch Heart Foundation

Key Words

Unfractionated heparin - cancer - survival - meta analysis
 

  • References

  • 1 Lensing AW, Prins MH, Davidson BL, Hirsh J. Treatment of deep venous thrombosis with low-molecular-weight heparins. A meta-analysis. Arch Intern Med 1995; 155: 601-7.
    CrossrefPubMedGoogle Scholar
  • 2 Green D, Hull RD, Brant R, Pineo GF. Lower mortality in cancer patients treated with low-molecular-weight versus standard heparin. Lancet 1992; 339: 1476.
    PubMedGoogle Scholar
  • 3 Hettiarachchi RJK, Smorenburg SM, Redekop WK, Ginsberg J, Levine M, Prins MH, Büller HR. Do heparins do more than just treat thrombosis? The Influence of heparins on cancer spread. Thromb Haemost 1999; 82: 947-52.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 4 Vlodavsky I, Mohsen M, Lider O, Svahn CM, Ekre HP, Vigoda M, Ishai-Michaeli R, Peretz T. Inhibition of tumor metastasis by heparanase inhibiting species of heparin. Invasion Metastasis 1994; 14: 290-302.
    PubMedGoogle Scholar
  • 5 Hagmar B, Boeryd B. Disseminating effect of heparin on experimental tumour metastases. Pathol Eur 1969; 4: 274-82.
    PubMedGoogle Scholar
  • 6 Hagmar B, Boeryd B. Distribution of intravenously induced metastases in heparin- and coumarin-treated mice. Pathol Eur 1969; 4: 103-11.
    PubMedGoogle Scholar
  • 7 Norrby K. Heparin and angiogenesis: a low-molecular-weight fraction inhibits and a high-molecular-weight fraction stimulates angiogenesis systemically. Haemostasis 1993; 23 (Suppl. 01) 141-9.
    PubMedGoogle Scholar
  • 8 Lapierre F, Holme K, Lam L, Tressler RJ, Storm N, Wee J, Stack RJ, Castellot J, Tyrell DJ. Chemical modifications of heparin that diminish its anticoagulant but preserve its heparanase-inhibitory, angiostatic, anti-tumor and anti-metastatic properties. Glycobiology 1996; 6: 355-66.
    CrossrefPubMedGoogle Scholar
  • 9 Sciumbata T, Caretto P, Pirovano P, Pozzi P, Cremonesi P, Galimberti G, Leoni F, Marcucci F. Treatment with modified heparins inhibits experimental metastasis formation and leads, in some animals, to long-term survival. Invasion Metastasis 1996; 16: 132-43.
    PubMedGoogle Scholar
  • 10 Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Canc Inst 1959; 22: 719-48.
    PubMedGoogle Scholar
  • 11 Lebeau B, Chastang C, Brechot JM, Capron F, Dautzenberg B, Delaisements C, Mornet M, Brun J, Hurdebourcq JP, Lemarie E. Subcutaneous heparin treatment increases survival in small cell lung cancer. Cancer 1994; 74: 38-45.
    CrossrefPubMedGoogle Scholar
  • 12 Nitti D, Wils J, Sahmoud T, Curran D, Couvreur ML, Lise M, Rauschecker H, Guimaraes dos Santos J, Stremmel W, Roelofsen F. Final results of a phase III clinical trial on adjuvant intraportal infusion with heparin and 5-fluorouracil (5-FU) in resectable colon cancer. Eur J Cancer 1997; 33: 1209-15.
    CrossrefPubMedGoogle Scholar
  • 13 Fielding LP, Hittinger R, Grace RH, Fry JS. Randomised controlled trial of adjuvant chemotherapy by portal-vein perfusion after curative resection for colorectal adenocarcinoma. Lancet 1992; 340: 502-6.
    CrossrefPubMedGoogle Scholar
  • 14 Papaioannou AN, Polychronis AP, Kozonis JA, Nomicos J, Tsamouri M, Plataniotis Papageorgiou JK. Chemotherapy with or without anticoagulation as initial management of patients with operable colorectal cancer: a prospective study with at least 5 years follow-up. Recent Results Cancer Res 1986; 103: 135-41.
    PubMedGoogle Scholar
  • 15 Kohanna FH, Sweeney J, Hussey S, Zacharski LR, Salzman EW. Effect of perioperative low-dose heparin administration on the course of colon cancer. Surgery 1983; 93: 433-8.
    PubMedGoogle Scholar
  • 16 Kingston RD, Fielding JW, Palmer MK. Peri-operative heparin: a possible adjuvant to surgery in colo-rectal cancer?. Int J Colorectal Dis 1993; 8: 111-5.
    CrossrefPubMedGoogle Scholar
  • 17 Kakkar AK, Hedges AR, Williamson RCN, Kakkar VV. Perioperative heparin therapy inhibits late death from metastatic cancer. Int J Oncol 1995; 6: 885-8.
    PubMedGoogle Scholar
  • 18 Törngren S, Rieger A. The influence of heparin and curable resection on the survival of colorectal cancer. Acta Chir Scand 1983; 149: 427-9.
    PubMedGoogle Scholar
  • 19 Elias EG, Brugarolas A. The role of heparin in the chemotherapy of solid tumors: preliminary clinical trial in carcinoma of the lung. Cancer Chemother Rep 1972; 56: 783-5.
    PubMedGoogle Scholar
  • 20 Jamieson GG, Angove RC. Heparinized chemotherapy in the treatment of disseminated lung cancer. Aust N Z J Med 1979; 9: 381-4.
    CrossrefPubMedGoogle Scholar
  • 21 Metzger U, Mermillod B, Aeberhard P, Gloor F, Bissat A, Egeli R, Laffer U, Martinoli S, Muelller W, Schroeder R, Weber W. Intraportal chemotherapy in colorectal carcinoma as an adjuvant modality. World J Surg 1987; 11: 452-8.
    CrossrefPubMedGoogle Scholar
  • 22 Rohwedder JJ, Sagastume E. Heparin and polychemotherapy for treatment of lung cancer. Cancer Treat Rep 1977; 61: 1399-401.
    PubMedGoogle Scholar
  • 23 Stanford CF. Anticoagulants in the treatment of small cell carcinoma of the bronchus. Thorax 1979; 34: 113-6.
    CrossrefPubMedGoogle Scholar
  • 24 Taylor I, Machin D, Mullee M, Trotter G, Cooke T, West C. A randomized controlled trial of adjuvant portal vein cytotoxic perfusion in colorectal cancer. Br J Surg 1985; 72: 359-63.
    CrossrefPubMedGoogle Scholar
  • 25 Taylor I, Rowling J, West C. Adjuvant cytotoxic liver perfusion for colorectal cancer. Br J Surg 1979; 66: 833-7.
    CrossrefPubMedGoogle Scholar
  • 26 Wereldsma JC, Bruggink ED, Meijer WS, Roukema JA, van Putten WL. Adjuvant portal liver infusion in colorectal cancer with 5-fluorouracil/heparin versus urokinase versus control. Cancer 1990; 65: 425-32.
    CrossrefPubMedGoogle Scholar
  • 27 Elias EG, Sepulveda F, Mink IB. Increasing the efficiency of cancer chemotherapy with heparin: “clinical study”. J Surg Oncol 1973; 5: 189-93.
    CrossrefPubMedGoogle Scholar
  • 28 Moher D, Pham B, Jones A, Cook A, Jadad AR, Moher M, Tugwell P, Klassen TP. Does quality of reports of randomised trials affect estimates of intervention efficacy reported in meta-analyses?. Lancet 1998; 352: 609-13.
    CrossrefPubMedGoogle Scholar
  • 29 Kunz R, Oxman A. The unpredictability paradox: review of empirical comparisons of randomised and non-randomised clinical trials. Br Med J 1998; 317: 1185-90.
    CrossrefPubMedGoogle Scholar
  • 30 Zacharski LR, Wojtukiewicz MZ, Costantini V, Ornstein DL, Memoli VA. Pathways of coagulation/fibrinolysis activation in malignancy. Semin Thromb Hemost 1992; 18: 104-16.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 31 Zacharski LR, Memoli VA, Rousseau SM. Thrombin-specific sites of fibrinogen in small cell carcinoma of the lung. Cancer 1988; 62: 299-302.
    CrossrefPubMedGoogle Scholar
  • 32 Seitz R, Heidtmann HH, Wolf M, Immel A, Egbring R. Prognostic impact of an activation of coagulation in lung cancer. Annals of Oncology 1997; 8: 781-4.
    CrossrefPubMedGoogle Scholar
  • 33 Calvo FA, Hidalgo OF, Gonzalez F, Rebollo J, Martin Algarra S, Ortiz de urbina D, Brugarolas A. Urokinase combination chemotherapy in small cell lung cancer. A phase II study. Cancer 1992; 70: 2624-30.
    PubMedGoogle Scholar
  • 34 Chahinian AP, Propert KJ, Ware JH, Zimmer B, Perry MC, Hirsh V, Skarin A, Kopel S, Holland JF, Comis RL. A randomized trial 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.
    CrossrefPubMedGoogle Scholar
  • 35 Zacharski LR, Henderson WG, Rickles FR, Forman WB, Cornell jr CJ, Forcier RJ, Edwards RL, Headley E, Kim SH, O’Donnell JF. Effect of warfarin anticoagulation on survival in carcinoma of the lung, colon, head and neck, and prostate. Final report of VA Cooperative Study: 75. Cancer 1984; 53: 2046-52.
    CrossrefPubMedGoogle Scholar
  • 36 Jayson GC, Gallagher JT. Heparin oligosaccharides: Inhibitors of the biological activity of bFGF on Caco-2 cells. Br J Cancer 1997; 75: 9-16.
    CrossrefPubMedGoogle Scholar
  • 37 Soker S, Goldstaub D, Svahn CM, Vlodavsky I, Levi BZ, Neufeld G. Variations in the size and sulfation of heparin modulate the effect of heparin on the binding of VEGF165 to its receptors. Biochem Biophys Res Commun 1994; 203: 1339-47.
    CrossrefPubMedGoogle Scholar
  • 38 Norrby K, Ostergaard P. Basic-fibroblast-growth-factor-mediated de novo angiogenesis is more effectively suppressed by low-molecular-weight than by high-molecular-weight heparin. Int J Microcirc Clin Exp 1996; 16: 8-15.
    CrossrefPubMedGoogle Scholar
  • 39 Brunner G, Reimbold K, Meissauer A, Schirrmacher V, Erkell LJ. Sulfated glycosaminoglycans enhance tumor cell invasion in vitro by stimulating plasminogen activation. Exp Cell Res 1998; 239: 301-10.
    CrossrefPubMedGoogle Scholar
  • 40 Yamazaki H, Oi H, Matsushita M, Inoue T, Tang JT, Nose T, Koizumi M, Tanaka E, Teshima T, Ozeki S, Nakamura H, Inoue T. Heparin induces rapid and remarkable elevation of hepatocyte growth factor/scatter factor during trans arterial embolization of renal cell carcinoma. Anticancer Res 1997; 17: 1435-7.
    PubMedGoogle Scholar