Subscribe to RSS
DOI: 10.1160/TH15-02-0124
Anticoagulant therapy of cancer patients: Will patient selection increase overall survival?
Publication History
Received:
10 February 2015
Accepted after minor revision:
11 March 2015
Publication Date:
01 December 2017 (online)
Summary
Already since the early 1800s, it has been recognised that malignancies may provoke thromboembolic complications, and indeed cancer patients are at increased risk of developing venous thrombosis. Interestingly, case control studies of deep-vein thrombosis suggested that low-molecular-weight heparin (LMWH) improved survival of cancer patients. This led to the hypothesis that cancer cells might ‘take advantage’ of a hypercoagulable state to more efficiently metastasise. Initial randomised placebo control trials showed that LMWH improve overall survival of cancer patients, especially in those patients with a relatively good prognosis. The failure of recent phase III trials, however, tempers enthusiasm for anticoagulant treatment in cancer patients despite an overwhelming body of literature showing beneficial effects of anticoagulants in preclinical models. Instead of discarding LMWH as potential (co)treatment modality in cancer patients, these disappointing recent trials should guide future preclinical research on anticoagulants in cancer biology. Most and for all, the underlying mechanisms by which coagulation drives tumour progression need to be elucidated. This could ultimately allow selection of cancer patients most likely to benefit from anticoagulant treatment and/or from targeted therapy downstream of coagulation factor signalling.
-
References
- 1 Bouillaud S. De l’obliteration des veines et de son influence sur la formation des hydropisies partielles: considerations sur l’hydropisie passive et generale. Arch Gen Med 1823; 01: 188-204.
- 2 Buller HR, van Doormaal FF, van Sluis GL, Kamphuisen PW. Cancer and thrombosis: from molecular mechanisms to clinical presentations. J Thromb Haemost 2007; 05 (Suppl. 01) 246-254.
- 3 Trousseau A. Phlegmasia alba dolens. Clinique medicale de l’Hotel-Dieu de Paris. 1865: 654-712.
- 4 Varki A. Trousseau’s syndrome: multiple definitions and multiple mechanisms. Blood 2007; 110: 1723-1729.
- 5 Chew HK, Wun T, Harvey D. et al. Incidence of venous thromboembolism and its effect on survival among patients with common cancers. Arch Intern Med 2006; 166: 458-464.
- 6 Blom JW, Doggen CJM, Osanto S, Rosendaal FR. Malignancies, prothrombotic mutations, and the risk of venous thrombosis. J Am Med Assoc 2005; 293: 715-722.
- 7 Sallah S, Wan JY, Nguyen NP. Venous thrombosis in patients with solid tumours: determination of frequency and characteristics. Thromb Haemost 2002; 87: 575-579.
- 8 Thodiyil PA, Kakkar AK. Variation in relative risk of venous thromboembolism in different cancers. Thromb Haemost 2002; 87: 1076-1077.
- 9 Timp JF, Braekkan SK, Versteeg HH, Cannegieter SC. Epidemiology of cancer-associated venous thrombosis. Blood 2013; 122: 1712-1723.
- 10 Sorensen HT, Mellemkjaer L, Olsen JH, Baron JA. Prognosis of cancers associated with venous thromboembolism. N Engl J Med 2000; 343: 1846-1850.
- 11 Levitan N, Dowlati A, Remick SC. et al. Rates of initial and recurrent thromboembolic disease among patients with malignancy versus those without malignancy. Risk analysis using Medicare claims data. Medicine (Baltimore) 1999; 78: 285-291.
- 12 Nierodzik ML, Plotkin A, Kajumo F, Karpatkin S. Thrombin stimulates tumour-platelet adhesion in vitro and metastasis in vivo. J Clin Invest 1991; 87: 229-236.
- 13 Nierodzik ML, Kajumo F, Karpatkin S. Effect of thrombin treatment of tumour cells on adhesion of tumour cells to platelets in vitro and tumour metastasis in vivo. Cancer Res 1992; 52: 3267-3272.
- 14 Bruggemann LW, Versteeg HH, Niers TM. et al. Experimental melanoma meta-stasis in lungs of mice with congenital coagulation disorders. J Cell Mol Med 2008; 12: 2622-2627.
- 15 Van Sluis GL, Niers TM, Esmon CT. et al. Endogenous activated protein C limits cancer cell extravasation through sphingosine-1-phosphate receptor 1-mediated vascular endothelial barrier enhancement. Blood 2009; 114: 1968-1973.
- 16 Horowitz NA, Blevins EA, Miller WM. et al. Thrombomodulin is a determinant of metastasis through a mechanism linked to the thrombin binding domain but not the lectin-like domain. Blood 2011; 118: 2889-2895.
- 17 Degen JL, Palumbo JS. Hemostatic factors, innate immunity and malignancy. Thromb Res 2012; 129 (Suppl. 01) S1-5.
- 18 Amirkhosravi A, Mousa SA, Amaya M, Francis JL. Antimetastatic effect of tinzaparin, a low-molecular-weight heparin. J Thromb Haemost 2003; 01: 1972-1976.
- 19 Hejna M, Raderer M, Zielinski CC. Inhibition of metastases by anticoagulants. J Natl Cancer Inst 1999; 91: 22-36.
- 20 Maat B, Hilgard P. Anticoagulants and experimental metastases-evaluation of antimetastatic effects in different model systems. J Cancer Res Clin Oncol 1981; 101: 275-283.
- 21 Im JH, Fu W, Wang H. et al. Coagulation facilitates tumour cell spreading in the pulmonary vasculature during early metastatic colony formation. Cancer Res 2004; 64: 8613-8619.
- 22 Gil-Bernabé AM, Lucotti S, Muschel RJ. Coagulation and metastasis: what does the experimental literature tell us?. Br J Haematol 2013; 162: 433-441.
- 23 Hu L, Lee M, Campbell W. et al. Role of endogenous thrombin in tumour implantation, seeding, and spontaneous metastasis. Blood 2004; 104: 2746-2751.
- 24 DeFeo K, Hayes C, Chernick M. et al. Use of dabigatran etexilate to reduce breast cancer progression. Cancer Biol Ther 2010; 10: 1001-1008.
- 25 Schulze EB, Hedley BD, Goodale D. et al. The thrombin inhibitor Argatroban reduces breast cancer malignancy and metastasis via steopontin-dependent and osteopontin-independent mechanisms. Breast Cancer Res Treat 2008; 112: 243-254.
- 26 Asanuma K, Wakabayashi H, Okamoto T. et al. The thrombin inhibitor, argatroban, inhibits breast cancer metastasis to bone. Breast Cancer 2013; 20: 241-246.
- 27 Smorenburg SM, Vink R, Otten HM. et al. The effects of vitamin K–antagonists on survival of patients with malignancy: a systematic analysis. Thromb Hae-most 2001; 86: 1586-1587.
- 28 Pengo V, Noventa F, Denas G. et al. Long-term use of vitamin K antagonists and incidence of cancer: a population-based study. Blood 2011; 117: 1707-1709.
- 29 Prandoni P, Lensing AW, Büller HR. et al. Comparison of subcutaneous low-molecular-weight heparin with intravenous standard heparin in proximal deep-vein thrombosis. Lancet 1992; 339: 441-445.
- 30 Hettiarachchi RJ, Smorenburg SM, Ginsberg J. et al. Do heparins do more than just treat thrombosis? The influence of heparins on cancer spread. Thromb Hae-most 1999; 82: 947-952.
- 31 Siragusa S, Cosmi B, Piovella F. et al. Low-molecular-weight heparins and unfractionated heparin in the treatment of patients with acute venous thromboembolism: results of a meta-analysis. Am J Med 1996; 100: 269-277.
- 32 Gould MK, Dembitzer AD, Doyle RL. et al. Low-molecular-weight heparins compared with unfractionated heparin for treatment of acute deep venous thrombosis. A meta-analysis of randomized, controlled trials. Ann Intern Med 1999; 130: 800-809.
- 33 Kakkar AK, Levine MN, 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: 1944-1948.
- 34 Altinbas M, Coskun HS, 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; 02: 1266-1271.
- 35 Klerk CP, Smorenburg SM, Otten HM. et al. The effect of low molecular weight heparin on survival in patients with advanced malignancy. J Clin Oncol 2005; 23: 2130-2135.
- 36 Lecumberri R, López Vivanco G, Font A. et al. Adjuvant therapy with bemiparin in patients with limited-stage small cell lung cancer: results from the ABEL study. Thromb Res 2013; 132: 666-670.
- 37 Sideras K, Schaefer PL, Okuno SH. et al. Low-molecular-weight heparin in patients with advanced cancer: a phase 3 clinical trial. Mayo Clin Proc 2006; 81: 758-767.
- 38 Agnelli G, Gussoni G, Bianchini C. et al. Nadroparin for the prevention of thromboembolic events in ambulatory patients with metastatic or locally advanced solid cancer receiving chemotherapy: a randomised, placebo-controlled, double-blind study. Lancet Oncol 2009; 10: 943-949.
- 39 Perry JR, Julian JA, Laperriere NJ. et al. PRODIGE: a randomized placebo-controlled trial of dalteparin low-molecular-weight heparin thromboprophylaxis in patients with newly diagnosed malignant glioma. J Thromb Haemost 2010; 08: 1959-1965.
- 40 van Doormaal FF, Di Nisio M, Otten HM. et al. Randomized trial of the effect of the low molecular weight heparin nadroparin on survival in patients with cancer. J Clin Oncol 2011; 29: 2071-2076.
- 41 Agnelli G, George DJ, Kakkar AK. et al. Semuloparin for thromboprophylaxis in patients receiving chemotherapy for cancer. N Engl J Med 2012; 366: 601-609.
- 42 Haas SK, Freund M, Heigener D. et al. Low-molecular-weight heparin versus placebo for the prevention of venous thromboembolism in metastatic breast cancer or stage III/IV lung cancer. Clin Appl Thromb Hemost 2012; 18: 159-165.
- 43 Maraveyas A, Waters J, Roy R. et al. Gemcitabine versus gemcitabine plus dalteparin thromboprophylaxis in pancreatic cancer. Eur J Cancer 2012; 48: 1283-1292.
- 44 Sanford D, Naidu A, Alizadeh N. et al. The effect of low molecular weight heparin on survival in cancer patients: an updated systematic review and meta-analysis of randomized trials. J Thromb Haemost 2014; 12: 1076-1085.
- 45 Akl EA, Kahale LA, Ballout RA. et al. Parenteral anticoagulation in ambulatory patients with cancer. Cochrane Database Syst Rev 2014; 12: CD006652.
- 46 Lee AY, Rickles FR, Julian JA. et al. Randomized comparison of low molecular weight heparin and coumarin derivatives on the survival of patients with cancer and venous thromboembolism. J Clin Oncol 2005; 23: 2123-2129.
- 47 Lazo-Langner A, Goss GD, Spaans JN. et al. The effect of low-molecular-weight heparin on cancer survival. A systematic review and meta-analysis of randomized trials. J Thromb Haemost 2007; 05: 729-737.
- 48 Niers TM, Brüggemann LW, Klerk CP. et al. Differential effects of anticoagulants on tumour development of mouse cancer cell lines B16, K1735 and CT26 in lung. Clin Exp Metastasis 2009; 26: 171-178.
- 49 Smorenburg SM, Vink R, te Lintelo M. et al. In vivo treatment of rats with unfractionated heparin (UFH) or low molecular weight heparin (LMWH) does not affect experimentally induced colon carcinoma metastasis. Clin Exp Meta-stasis 1999; 17: 451-456.
- 50 Klerk CP, Niers TM, Brüggemann LW. et al. Prophylactic plasma levels of the low molecular weight heparin nadroparin does not affect colon cancer tumour development in mouse liver. Thromb Res 2010; 125: 235-238.
- 51 Klerk CP, Smorenburg SM, Spek CA, Van Noorden CJ. Colon cancer metastasis in mouse liver is not affected by hypercoagulability due to Factor V Leiden mutation. J Cell Mol Med 2007; 11: 561-568.
- 52 Spek CA, Arruda VR. The protein C pathway in cancer metastasis. Thromb Res 2012; 129 (Suppl. 01) S80-84.
- 53 Bezuhly M, Cullen R, Esmon CT. et al. Role of activated protein C and its receptor in inhibition of tumour metastasis. Blood 2009; 113: 3371-3374.
- 54 Niers TM, Brüggemann LW, Van Sluis GL. et al. Long-term thrombin inhibition promotes cancer cell extravasation in a mouse model of experimental metastasis. J Thromb Haemost 2009; 07: 1595-1597.
- 55 La Thangue NB, Kerr DJ. Predictive biomarkers: A paradigm shift towards personalized cancer medicine. Nat Rev Clin Oncol 2011; 08: 587-596.
- 56 Fukuoka M, Yano S, Giaccone G. et al. Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non–small-cell lung cancer (The IDEAL 1 Trial). J Clin Oncol 2003; 21: 2237-2246.
- 57 Kris MG, Natale RB, Herbst RS. et al. Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non–small cell lung cancer: a randomized trial. J Am Med Assoc 2003; 290: 2149-2158.
- 58 Arora P, Ricks TK, Trejo J. Protease-activated receptor signalling, endocytic sorting and dysregulation in cancer. J Cell Sci 2007; 120: 921-928.
- 59 Nierodzik ML, Karpatkin S. Thrombin induces tumour growth, metastasis, and angiogenesis: Evidence for a thrombin-regulated dormant tumour phenotype. Cancer Cell 2006; 10: 355-362.
- 60 Dorfleutner A, Hintermann E, Tarui T. et al. Cross-talk of integrin alpha3beta1 and tissue factor in cell migration. Mol Biol Cell 2004; 15: 4416-4425.
- 61 Ghio P, Cappia S, Selvaggi G. et al. Prognostic role of protease-activated receptors 1 and 4 in resected stage IB non-small-cell lung cancer. Clin Lung Cancer 2006; 07: 395-400.
- 62 Eroglu A, Karabiyik A, Akar N. The association of protease activated receptor 1 gene –506 I/D polymorphism with disease-free survival in breast cancer patients. Ann Surg Oncol 2012; 19: 1365-1369.
- 63 Massi D, Naldini A, Ardinghi C. et al. Expression of protease-activated receptors 1 and 2 in melanocytic nevi and malignant melanoma. Hum Pathol 2005; 36: 676-685.
- 64 Cisowski J, O’Callaghan K, Kuliopulos A. et al. Targeting protease-activated receptor-1 with cell-penetrating pepducins in lung cancer. Am J Pathol 2011; 179: 513-523.
- 65 Queiroz KC, Shi K, Duitman J. et al. Protease-activated receptor-1 drives pancreatic cancer progression and chemoresistance. Int J Cancer 2014; 135: 2294-2304.
- 66 Rydén L, Grabau D, Schaffner F. et al. Evidence for tissue factor phosphorylation and its correlation with protease-activated receptor expression and the prognosis of primary breast cancer. Int J Cancer 2010; 126: 2330-2340.
- 67 Chang JH, Park JM, Kim SW. et al. Expression of protease activated receptor-2 in human colorectal cancer and its association with tumour progression. Dis Colon Rectum 2010; 53: 1202-1208.
- 68 Versteeg HH, Schaffner F, Kerver M. et al. Protease-activated receptor (PAR) 2, but not PAR1, signalling promotes the development of mammary adenocarcinoma in polyoma middle T mice. Cancer Res 2008; 68: 7219-7227.
- 69 Schaffner F, Versteeg HH, Schillert A. et al. Cooperation of tissue factor cytoplasmic domain and PAR2 signalling in breast cancer development. Blood 2010; 116: 6106-6113.
- 70 Shi X, Gangadharan B, Brass LF. et al. Protease-activated receptors (PAR1 and PAR2) contribute to tumour cell motility and metastasis. Mol Cancer Res 2004; 02: 395-402.
- 71 Ohshiro K, Bui-Nguyen TM, Divijendra Natha RS. et al. Thrombin stimulation of inflammatory breast cancer cells leads to aggressiveness via the EGFRPAR1-Pak1 pathway. Int J Biol Markers 2012; 27: e305-313.
- 72 Arora P, Cuevas BD, Russo A. et al. Persistent transactivation of EGFR and ErbB2/HER2 by protease-activated receptor-1 promotes breast carcinoma cell invasion. Oncogene 2008; 27: 4434-4445.
- 73 Darmoul D, Gratio V, Devaud H. et al. Activation of proteinase-activated receptor 1 promotes human colon cancer cell proliferation through epidermal growth factor receptor transactivation. Mol Cancer Res 2004; 02: 514-522.
- 74 Bergmann S, Junker K, Henklein P. et al. PAR-type thrombin receptors in renal carcinoma cells: PAR1-mediated EGFR activation promotes cell migration. Oncol Rep 2006; 15: 889-893.
- 75 Caruso R, Pallone F, Fina D. et al. Protease-activated receptor-2 activation in gastric cancer cells promotes epidermal growth factor receptor trans-activation and proliferation. Am J Pathol 2006; 169: 268-278.
- 76 Åberg M, Eriksson O, Mokhtari D. et al. Tissue factor/factor VIIa induces cell survival and gene transcription by transactivation of the insulin-like growth factor 1 receptor. Thromb Haemost 2014; 111: 748-760.
- 77 Lièvre A, Bachet JB, Le Corre D. et al. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res 2006; 66: 3992-3995.
- 78 Karapetis CS, Khambata-Ford S, Jonker DJ. et al. K–ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 2008; 359: 1757-1765.
- 79 Palumbo JS, Talmage KE, Massari JV. et al. Tumour cell-associated tissue factor and circulating hemostatic factors cooperate to increase metastatic potential through natural killer cell-dependent and-independent mechanisms. Blood 2007; 110: 133-141.
- 80 Palumbo JS, Talmage KE, Massari JV. et al. Platelets and fibrin(ogen) increase metastatic potential by impeding natural killer cell-mediated elimination of tumour cells. Blood 2005; 105: 178-185.
- 81 Nieswandt B, Hafner M, Echtenacher B. et al. Lysis of tumour cells by natural killer cells in mice is impeded by platelets. Cancer Res 1999; 59: 1295-1300.
- 82 Labelle M, Begum S, Hynes RO. Direct signalling between platelets and cancer cells induces an epithelial-mesenchymal-like transition and promotes metastasis. Cancer Cell 2011; 20: 576-590.
- 83 Grady WM, Myeroff LL, Swinler SE. et al. Mutational inactivation of transforming growth factor beta receptor type II in microsatellite stable colon cancers. Cancer Res 1999; 59: 320-324.
- 84 Gil-Bernabé AM, Ferjancic S, Tlalka M. et al. Recruitment of monocytes/macrophages by tissue factor-mediated coagulation is essential for metastatic cell survival and premetastatic niche establishment in mice. Blood 2012; 119: 3164-3175.