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Originally published as JCO Early Release 10.1200/JCO.2005.10.975 on February 7 2005 © 2005 American Society of Clinical Oncology.
Antithrombotic Therapy in CancerInstitute of Cancer, Barts and the London School of Medicine, Queen Mary University of London, London, United Kingdom There is increasing interest in the potential role of antithrombotic agents in the management of cancer patients. Low molecular weight heparins (LMWHs) have generated particular excitement because they have been validated in both the prevention and the treatment of thromboembolic disease in patients with malignancy. Retrospective analyses of clinical trials in which LMWH had been used to treat established thrombosis in cancer patients have suggested a survival advantage for the treated groups.1-3 The studies that formed the basis of these meta-analyses were not primarily designed to assess cancer outcomes, and little was known about the distribution of prognostic variables between groups of patients treated with different antithrombotic therapies in these trials. Thus, clear conclusions about the potential benefits of LMWH and long-term survival could not be established. Earlier this year, the first prospective, randomized, double-blind study designed to assess the potential value of long-term LMWH therapy to improve survival in cancer patients was reported.4 The study failed to achieve the predefined difference in mortality between groups of patients randomly assigned to placebo or LMWH, but did suggest a striking survival advantage for heparin treatment in a subgroup of patients with good-prognosis tumors. More recently, a second clinical trial in patients with small-cell lung carcinoma—again with random assignment to standard care with combination chemotherapy alone compared with LMWH plus standard care—showed advantages in terms of progression-free and overall survival for patients who received LMWH for 18 weeks.5 In this issue of the Journal of Clinical Oncology, two additional studies report on the potential benefits of longer term LMWH therapy for cancer patients. The first, by Lee et al,6 is the long-term follow-up patients in the Comparison of Low Molecular Weight Heparin Versus Oral Anticoagulant Therapy for Long Term Anticoagulation in Cancer Patients With Venous Thromboembolism (CLOT) trial. This study randomly assigned 676 patients to oral anticoagulant therapy or LMWH therapy for 6 months for treatment of acute, symptomatic, proximal vein thrombosis. The primary end point of the study was to determine rates of recurrent thromboembolic disease, but included a secondary end point of survival at 1 year. This trial showed that there is a survival benefit with LMWH therapy in the subgroup of patients without evident metastatic disease at the time of random assignment to treatment. A second study, by Klerk et al,7 showed the value of up to 6 weeks of LMWH therapy compared with placebo in patients with advanced malignant disease. A variety of tumor types were included in this study and for both the overall trial population and for a subgroup of patients with better prognosis at the time of random assignment, LMWH therapy was associated with a significant survival advantage. How might these interesting observations be explained? It could be that the administration of antithrombotic therapy to patients in these trials reduced the frequency of fatal pulmonary embolism. However, in the study by Klerk et al,7 the benefits of LMWH therapy were seen for months and years after the period of active administration (indeed, there was no obvious survival advantage in the acute treatment period), suggesting the mechanism is not purely an antithrombotic effect. This feature was also seen in other studies in which LMWH therapy was given to patients without underlying thromboembolic disease. It is more likely that the mechanism of this long-term benefit can be explained through effects on tumor cell biology. In this regard, there has been extensive evaluation of the potential role that the coagulation proteases play in tumor-stromal interactions at a molecular level. Tissue factor (TF) is frequently overexpressed as a result of progression from benign to malignant phenotype, and that overexpression is associated with aggressive behavior and poor outcome in pancreatic cancer, among other tumors.8
TF, the physiological initiator of blood coagulation, is also known to have a strong structural homology with the class II cytokine receptor family. Identification of filamin A, as an intracellular protein recruited to the cytoplasmic tail of TF on formation of the complex with factor VIIa, initially implicated it in cellular motility.9 Experimental manipulation of TF is associated with enhanced tumor growth, invasion, and metastasis. The mechanism for this enhanced tumor cell invasiveness appears to be secondary to an upregulation of expression of plasminogen activators and, to a lesser extent, their inhibitors.10-12 However, Belting et al13 have recently identified a more fundamental role for TF in tumor angiogenesis. Activation of the TF-VIIa protease complex, independent of triggering coagulation, can promote tumor and developmental angiogenesis through protease-activated receptor 2 (PAR-2) signaling.13 The TF cytoplasmic domain negatively regulates PAR-2 signaling, and mice from which the TF cytoplasmic domain has been deleted (TF
In addition to these interesting possibilities are the long-standing observations that suggest that heparins have direct effects that may influence cell behavior, in particular tumor cell behavior. Heparins have been particularly implicated in influencing the function of integrins, thus potentially interfering with tumor cell invasion and metastasis. Unfractionated heparin binds to the platelet integrin The positive impact of antithrombotic therapies in cancer patients demonstrated in the two reports in this issue is a welcome advance that should stimulate additional clinical trials to develop optimized regimes. Much work needs to be done to identify the mechanisms involved, but there are already indications that the interface between the coagulation system and the cancer cell will be a rewarding area for cell biology and cancer therapeutics. Author's Disclosures of Potential Conflicts of Interest The author indicated no potential conflicts of interest. REFERENCES 1. Green D, Hull RD, Brant R, et al: Lower mortality in cancer patients treated with low-molecular-weight versus standard heparin. Lancet 339:1476, 1992[Medline] 2. 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 100:269-277, 1996[CrossRef][Medline]
3. 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 130:800-809, 1999
4. 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 22:1944-1948, 2004 5. 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 2:1266-1271, 2004[CrossRef][Medline] 6. Lee AYY, Rickles FR, Julian JA, et al: A randomized comparison of low molecular weight heparin and coumarin derivatives on the survival of patients with cancer and venous thromboembolism. J Clin Oncol 23:2123-2129, 2005 7. Klerk CPW, Smorenburg SM, Otten HM, et al: The effect of low molecular weight heparin on survival in patients with advanced malignancy. J Clin Oncol 23:2130-2135, 2005 8. Kakkar AK, Lemoine NR, Scully MF, et al: Tissue factor expression correlates with histological grade in human pancreatic cancer. Br J Surg 82:1101-1104, 1995[Medline]
9. Ott I, Fischer EG, Miyagi Y, et al: A role for tissue factor in cell adhesion and migration mediated by interaction with actin-binding protein 280. J Cell Biol 140:1241-1253, 1998
10. Taniguchi T, Kakkar AK, Tuddenham EG, et al: Enhanced expression of urokinase receptor induced through the tissue factor-factor VIIa pathway in human pancreatic cancer. Cancer Res 58:4461-4467, 1998 11. Kakkar AK, Chinswangwatanakul V, Tebbutt S, et al: A characterization of the coagulant and fibrinolytic profile of human pancreatic carcinoma cells. Haemostasis 28:1-6, 1998[Medline] 12. Wojtukiewicz MZ, Rucinska M, Zacharski LR, et al: Localization of blood coagulation factors in situ in pancreatic carcinoma. Thromb Haemost 86:1416-1420, 2001[Medline] 13. Belting M, Dorrell MI, Sandgren S, et al: Regulation of angiogenesis by tissue factor cytoplasmic domain signaling. Nat Med 10:502-509, 2004[CrossRef][Medline] 14. Mousa SA, Mohamed S: Inhibition of endothelial cell tube formation by the low molecular weight heparin, tinzaparin, is mediated by tissue factor pathway inhibitor. Thromb Haemost 92:627-633, 2004[Medline] 15. Mousa SA, Mohamed S: Anti-angiogenic mechanisms and efficacy of the low molecular weight heparin, tinzaparin: Anti-cancer efficacy. Oncol Rep 12:683-688, 2004[Medline] 16. Da Silva MS, Horton JA, Wijelath JM, et al: Heparin modulates integrin-mediated cellular adhesion: Specificity of interactions with alpha and beta integrin subunits. Cell Commun Adhes 10:59-67, 2003[Medline] 17. Yoshitomi Y, Nakanishi H, Kusano Y, et al: Inhibition of experimental lung metastases of Lewis lung carcinoma cells by chemically modified heparin with reduced anticoagulant activity. Cancer Lett 207:165-174, 2004[CrossRef][Medline]
18. Muramatsu H, Zou P, Suzuki H, et al:
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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CT mice) show enhanced PAR-2–dependent angiogenesis, in synergy with platelet-derived growth factor BB. Mousa and Mohamed
IIbß3 and enhances ligand binding, and heparin differentially modulates integrin-mediated adhesion of cancer cells to vitronectin (LMWH and chondroitin sulfate induce significantly less enhancement of adhesion, and the effects are also influenced by the identity of the integrin ß-chain).
