- Email: [email protected]
Antithrombotic therapy and survival in cancer patients
Best Practice & Research Clinical Haematology 22 (2009) 147–151
Contents lists available at ScienceDirect
Best Practice & Research Clinical Haematology journal homepage: www.elsevier.com/locate/beha
14
Antithrombotic therapy and survival in cancer patients A.K. Kakkar, MBBS (Hon), BSc, PhD, FRCS, Professor Barts and the London School of Medicine and Dentistry, Thrombosis Research Institute, London, UK
Keywords: thrombosis antithrombotic therapy cancer survival
Venous thromboembolism is a common complication in patients with malignant disease. The development of symptomatic thromboembolism is associated with a poor prognosis for patients with cancer. Retrospective analysis of studies comparing unfractionated heparin with low-molecular-weight heparin (LMWH) for the initial treatment of deep vein thrombosis indicated improved survival for cancer patients receiving LMWH therapy. Prospective studies exposing cancer patients to LMWH therapy, in the absence of established thrombosis, suggest that survival may be prolonged in these patients after LMWH exposure. Ongoing studies, with careful attention to distribution of prognostic variables for cancer outcome, will help to answer the question regarding whether LMWH may indeed be used for this indication. Ó 2009 Elsevier Ltd. All rights reserved.
Venous thromboembolism and cancer It was Armand Trousseau in 1865 [1] who first recognized the association between thrombosis and malignant disease. Thromboembolism may be the first clinical manifestation of underlying malignancy [2–4]. It is also recognized that thrombosis is more commonly seen in patients with established cancer. The coagulation system is activated in patients with cancer [5]. Patients with malignant disease have higher circulating levels of the physiological initiator of blood coagulation – tissue factor – and this is associated with higher levels of activated factor VII, indicating activation of the extrinsic pathway of blood coagulation, compared with non-cancer subjects. These changes are associated with higher circulating levels of thrombin–antithrombin complexes and prothrombin fragments, indicating a systemic hypercoagulable state. The interaction between tumours and blood coagulation is complex. Tumour-derived procoagulant factors, such as tissue factor, are associated with systemic activation of blood coagulation. However, the host response to the tumour, particularly activation of monocytes, may also be associated with
E-mail address: [email protected] 1521-6926/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.beha.2009.01.004
148
A.K. Kakkar / Best Practice & Research Clinical Haematology 22 (2009) 147–151
tissue-factor-dependent activation of blood coagulation. Other elements of the haemostatic system are also activated in patients with malignant disease. These include platelets and the endothelium itself [6]. The activation of blood coagulation is associated with symptomatic thromboembolic disease. In a large series of over 230 000 cases with five different cancer types, rates of symptomatic thromboembolism within 700 days of diagnosis ranged from under 1% for breast cancer to approximately 5% for pancreatic cancer, for those patients with early-stage disease. The rates increased for those with advanced disease, with a near doubling for those with breast cancer and rates nearly three times as high for patients with pancreatic cancer who presented with metastatic disease [7]. The presence of cancer is associated with a higher reported frequency for pulmonary embolism. In a large series of patients undergoing either surgical or medical intervention for their gastrointestinal disease, those with cancer undergoing surgery had pulmonary embolism rates of 2.34% compared with 0.36% for noncancer patients undergoing surgery. Similarly, for patients undergoing non-surgical management, the rates of pulmonary embolism were 0.73% for those with cancer compared with 0.1% for those without cancer [8]. In a large study of some 23 000 patients undergoing major surgical intervention and randomized to receive either low-dose unfractionated heparin or low-molecular-weight heparin (LMWH), a retrospective subgroup analysis determined the outcome for patients by indication for operation either cancer or no cancer. In the group of patients receiving peri-operative prophylaxis without cancer, the autopsy-proven fatal pulmonary embolism rate was 0.09%, whereas for those undergoing operation with cancer and receiving heparin-based prophylaxis, the frequency of pulmonary embolism was 0.33% [9]. All these data indicate that thromboembolic disease, which may be fatal, is seen more commonly in patients with cancer. A number of studies have tried to determine the impact of symptomatic venous thromboembolism on clinical outcome for patients with malignant disease. In a large study utilizing data from the Medicare system in the USA, analysis was made of the probability of death within 6 months of initial hospitalization for two groups of cancer patients; those initially admitted with a diagnosis of cancer alone, and those admitted with a combined diagnosis of cancer and some form of thromboembolic disease. Approximately 20% of patients with a diagnosis of cancer alone died in the initial 6-month period, compared with nearly 90% of patients with a combined diagnosis [10]. It is difficult to explain these data. It may be that patients with malignant disease who develop a thrombosis are at higher risk for the subsequent development of fatal recurrent thromboembolism, often missed because autopsies are seldomly performed. Alternatively, the development of systemic thromboembolism may be a surrogate marker for a biologically aggressive tumour which would have killed the patient anyway, with thrombosis only being a marker for that specific aggressive phenotype. Finally, it could be that the activation of blood coagulation seen with intravascular thrombosis, and generation of the associated coagulation proteases which are able to interact with specific tumour-cell-expressed protease receptors, might in some way alter the biology of the cancer and make it more aggressive leading to death of the patient. In a second study [11] where over 66 000 hospital admissions were analysed, the reported frequency of inpatient mortality was higher in patients with venous thromboembolism than in patients without thrombosis. For the overall study population, a mortality rate of 7.9% was seen in patients without thrombosis, and this increased to nearly 15% in patients with thrombosis. This impact on adverse clinical outcome associated with the development of venous thromboembolism was seen for patients with non-metastatic and metastatic disease. Interestingly, a diagnosis of cancer is seen more frequently after presentation with idiopathic thromboembolic disease. Against a population without thrombosis, the standardized incidence ratio for cancer is more than three for populations of patients presenting with either deep vein thrombosis or pulmonary embolism, within 6 months of that presentation. A higher reported frequency for subsequent cancer diagnosis is maintained for more than 10 years after presentation with a spontaneous thromboembolic episode [3]. Antithrombotic therapy and survival in cancer The VA Co-operative Trial evaluated the potential benefit of vitamin K antagonist therapy with warfarin with regard to survival in cancer. In those studies, patients were randomized to standard
A.K. Kakkar / Best Practice & Research Clinical Haematology 22 (2009) 147–151
149
treatment alone or standard treatment combined with warfarin. No survival benefit was associated with warfarin therapy for a variety of different tumour types included in the initial study (lung, colon, head and neck, and prostate). However, for the 50 patients with small cell lung cancer, warfarin therapy did show a benefit in terms of disease-free and overall survival [12]. In a subsequent study involving a larger number of small cell lung cancer patients, an effect on response to chemotherapy and a trend towards improved overall survival was associated with randomization to receive warfarin [13]. A similar study, randomizing 277 patients with small cell lung cancer to no antithrombotic therapy or subcutaneous unfractionated heparin at full treatment doses for 5 weeks, established a significant increase in complete response to chemotherapy from 23% in the control group to 37% in the heparin group, and improved median survival from 261 days to 317 days for those receiving heparin [14]. More recently, studies evaluating intravenous unfractionated heparin compared with subcutaneous LMWH for initial treatment of deep vein thrombosis have indicated improved survival at 3 months after presentation with thrombosis for cancer patients randomized to receive LMWH therapy for up to 10 days [15,16]. Considerable caution is required in interpreting such meta-analyses since the primary objective of the original studies was not to determine long-term cancer outcome, and little is known about the distribution of prognostic variables between the cancer patients receiving unfractionated heparin and those receiving LMWH for treatment of their thrombosis. The first prospective randomized clinical trial to report outcomes with regard to the potential benefits of chronic exposure of cancer patients to LMWH therapy, in the absence of established thrombosis, was the Fragmin Advanced Malignancy Outcome Study [17]. In this study, 385 patients with a variety of advanced solid tumours were randomized to receive up to 1 year of the LMWH dalteparin at a dose of 5000 units once daily or normal saline placebo injections. Three hundred and eighty-five patients were randomized, with the assumption that LMWH therapy would be associated with a 15% improvement in survival at 1 year after randomization; that is a mortality rate of 50% in the placebo group reduced to 35% in the group of patients receiving LMWH. At 1 year after randomization, the difference in survival was 5%, with a survival rate of 41% in the placebo group and 46% in the LMWH group; this was not statistically significant. In a post-hoc subgroup analysis of patients surviving beyond 17 months, randomization to receive LMWH was associated with a median survival of 43 months compared with only 24 months in patients randomized to receive placebo (P ¼ 0.03). In a small trial of patients with small cell lung carcinoma, 84 patients were randomized to receive standard chemotherapy alone or in combination with dalteparin at a dose of 5000 units once daily for up to 18 weeks [18]. There was an improvement in overall survival for the entire population associated with LMWH therapy, with the greatest benefit seen in patients with a better prognosis, where median survival was improved from 8 to 13 months. In a further study, 302 patients with advanced solid tumour malignancy were randomized to 6 weeks of the LMWH nadroparin or placebo. Median survival was improved from 6.6 months in the placebo group to 8 months in the group of patients receiving LMWH therapy (P ¼ 0.021) [19]. A small trial of 141 patients with breast, lung or prostate cancer, all with advanced disease and randomized to receive no antithrombotic therapy or dalteparin therapy at a dose of 5000 units once daily, failed to show any difference in survival [20]. Recently, a meta-analysis evaluated the totality of data with regard to exposure to LMWH in patients with malignant disease but without underlying thrombosis at the time of inclusion in clinical trials. The odds ratio for 1-year mortality was 0.7 [95% confidence interval (CI) 0.49–1.00; P ¼ 0.05] for patients with limited and advanced disease, and 0.75 (95%CI 0.57–0.99; P ¼ 0.04) for those with advanced disease. The odds ratio for 2-year mortality was 0.57 (95%CI 0.34–0.96; P ¼ 0.03) for patients with limited and advanced disease, and 0.59 (95%CI 0.42–0.84; P ¼ 0.004) for patients with advanced disease [21]. A further study has evaluated the potential impact on survival of long-term exposure to LMWH in patients receiving treatment for established venous thromboembolism. The CLOT in Cancer Study randomized 676 patients with a cancer-associated thrombosis to a standard therapy group with 5–7 days of full treatment doses of dalteparin followed by 6 months of warfarin to achieve a target international normalized ratio of 2.5, or 6 months of dalteparin therapy at full treatment doses for 1 month and 80% of the full treatment dose for the subsequent 5 months. At the end of this 6-month treatment period, there was no difference in survival between the two groups. At 1-year follow-up after initial initiation of
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A.K. Kakkar / Best Practice & Research Clinical Haematology 22 (2009) 147–151
treatment for venous thromboembolism, there was no difference in survival for patients who presented with metastatic cancer at the time of randomization. However, for those with non-metastatic disease, numbering 150 in this study, there was a difference in survival at 1 year, with a survival rate of 64% for patients receiving vitamin K antagonist therapy and 80% for those receiving LMWH [22]. Mechanistic explanation for prolongation of survival in cancer patients A number of potential explanations have been proposed for the interesting survival observations seen in patients with malignant disease receiving LMWH therapy. Amongst these is the prevention of fatal thromboembolic events associated with active LMWH therapy. However, the benefits of exposure to LMWH appeared to continue beyond active exposure, indicating that some of the benefit must be independent of preventing fatal thromboembolic events. Coagulation proteases have been shown to play an important role in tumour biology. LMWH, through potentiation of antithrombin, neutralized activated factor X and activated factor II thrombin, thus preventing their interaction with tumourexpressed protease receptors. The impact of coagulation proteases has been seen in enhancing tumour growth invasion metastasis and angiogenesis [23]. A further explanation for these potential benefits is associated with the direct cellular effects of heparin like molecules which have been shown to inhibit angiogenesis [24] and to enhance apoptosis in experimental tumour models [25]. A further explanation is neutralization of tumour heparinase activity through exposure to heparin-like molecules. Heparinase plays an important role in remodelling of the extracellular matrix, and its overexpression is associated with a more aggressive phenotype. Conclusions There is no doubt that there is a complex relationship between the coagulation system and tumours. This is associated with a higher reported frequency for the development of symptomatic thromboembolic disease, which can be fatal, in cancer patients. Equally, presentation with spontaneous thromboembolism is associated with a higher subsequent rate for the diagnosis of new malignant disease. The coagulation proteases have been shown to play a potential role in determining the phenotype of tumours in the experimental setting. Inhibition of the coagulation system therefore may play a role in altering the behaviour of tumours. Prospective clinical trials indicate that exposure to LMWH is associated with prolonged survival, although studies which provide definitive evidence of this benefit have yet to be completed. Conflict of interest statement None declared. References [1] Trousseau A. Plegmasia Alba Dolens. London: The New Syndeham Society; 1872. pp 282–332. [2] Prandoni P. Venous thromboembolism and cancer: a two-way clinical association. Front Biosci 1997;2:e12–20. [3] Sorensen HT, Mellemkjaer L, Steffensen FH, et al. The risk of a diagnosis of cancer after primary deep venous thrombosis or pulmonary embolism. N Engl J Med 1998;338:1169–73. [4] Baron JA, Gridley G, Weiderpass E, et al. Venous thromboembolism and cancer. Lancet 1998;351:1077–80. [5] Kakkar AK, DeRuvo N, Chinswangwatanakul V, et al. Extrinsic-pathway activation in cancer with high factor VIIa and tissue factor. Lancet 1995;346:1004–5. [6] Varki A. Trousseau’s syndrome: multiple definitions and multiple mechanisms. Blood 2007;110:1723–9. [7] Chew HK, Wun T, Harvey D, et al. Incidence of VTE and its effect on survival among patients with common cancers. Arch Intern Med 2006;166:458–64. [8] Huber O, Bounameaux H, Borst F, et al. Postoperative pulmonary embolism after hospital discharge. An underestimated risk. Arch Surg 1992;127:310–3. [9] Kakkar AK, Haas S, Wolf H, et al. Evaluation of perioperative fatal pulmonary embolism and death in cancer surgical patients: the MC-4 cancer substudy. Thromb Haemost 2005;94:867–71. [10] 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 1999;78:285–91. [11] Khorana AA, Francis CW, Culakova E, et al. Thromboembolism in hospitalized neutropenic cancer patients. J Clin Oncol 2006;24:484–90.
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[12] Zacharski LR, Henderson WG, Rickles FR, et al. 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. [13] Chahinian AP, Propert KJ, Ware JH, et al. A randomised 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. [14] Lebeau B, Chastang C, Brechot JM, et al. Subcutaneous heparin treatment increases survival in small cell lung cancer. ‘‘Petites Cellules’’ Group. Cancer 1994;74:38–45. [15] Green D, Hull RD, Brant R, et al. Lower mortality in cancer patients treated with low-molecular-weight versus standard heparin. Lancet 1992;339:1476. [16] 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;100:269–77. [17] 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;22:1944–8. [18] Altinbas M, Coskun HS, Er O, et al. A randomized clinical trial of combination chemotherapy with and without lowmolecular-weight heparin in small cell lung cancer. J Thromb Haemost 2004;2:1266–71. [19] Klerk CP, Otten JM, Buller HR, on behalf of the MALT Study Group. Malignancy and low molecular weight heparin therapy: the MALT trial. Pathophysiol Haemost Thromb 2003;33:75. [20] 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;81:758–67. [21] 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;5:729–37. [22] Lee AY, Rickles FR, Julian JA, et al. Randomized comparison of low molecular weight heparin and coumarin derivatives on the survival of outpatients with cancer and venous thromboembolism. J Clin Oncol 2005;23:1–7. [23] Yu JL, May L, Lhotak V, et al. Oncogenic events regulate tissue factor expression in colorectal cancer cells: implications for tumor progression and angiogenesis. Blood 2005;105:1734–41. [24] Folkman J, Langer R, Linhardt RJ, et al. Angiogenesis inhibition and tumor regression caused by heparin or a heparin fragment in the presence of cortisone. Science 1983;221:719–25. [25] Nasir FA, HKP, Scully MF, et al. The low molecular weight heparin dalteparin sodium inhibits angiogenesis and induces apoptosis in an experimental tumour model. Blood 2003:102 (Abstract 2993).
Contents lists available at ScienceDirect
Best Practice & Research Clinical Haematology journal homepage: www.elsevier.com/locate/beha
14
Antithrombotic therapy and survival in cancer patients A.K. Kakkar, MBBS (Hon), BSc, PhD, FRCS, Professor Barts and the London School of Medicine and Dentistry, Thrombosis Research Institute, London, UK
Keywords: thrombosis antithrombotic therapy cancer survival
Venous thromboembolism is a common complication in patients with malignant disease. The development of symptomatic thromboembolism is associated with a poor prognosis for patients with cancer. Retrospective analysis of studies comparing unfractionated heparin with low-molecular-weight heparin (LMWH) for the initial treatment of deep vein thrombosis indicated improved survival for cancer patients receiving LMWH therapy. Prospective studies exposing cancer patients to LMWH therapy, in the absence of established thrombosis, suggest that survival may be prolonged in these patients after LMWH exposure. Ongoing studies, with careful attention to distribution of prognostic variables for cancer outcome, will help to answer the question regarding whether LMWH may indeed be used for this indication. Ó 2009 Elsevier Ltd. All rights reserved.
Venous thromboembolism and cancer It was Armand Trousseau in 1865 [1] who first recognized the association between thrombosis and malignant disease. Thromboembolism may be the first clinical manifestation of underlying malignancy [2–4]. It is also recognized that thrombosis is more commonly seen in patients with established cancer. The coagulation system is activated in patients with cancer [5]. Patients with malignant disease have higher circulating levels of the physiological initiator of blood coagulation – tissue factor – and this is associated with higher levels of activated factor VII, indicating activation of the extrinsic pathway of blood coagulation, compared with non-cancer subjects. These changes are associated with higher circulating levels of thrombin–antithrombin complexes and prothrombin fragments, indicating a systemic hypercoagulable state. The interaction between tumours and blood coagulation is complex. Tumour-derived procoagulant factors, such as tissue factor, are associated with systemic activation of blood coagulation. However, the host response to the tumour, particularly activation of monocytes, may also be associated with
E-mail address: [email protected] 1521-6926/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.beha.2009.01.004
148
A.K. Kakkar / Best Practice & Research Clinical Haematology 22 (2009) 147–151
tissue-factor-dependent activation of blood coagulation. Other elements of the haemostatic system are also activated in patients with malignant disease. These include platelets and the endothelium itself [6]. The activation of blood coagulation is associated with symptomatic thromboembolic disease. In a large series of over 230 000 cases with five different cancer types, rates of symptomatic thromboembolism within 700 days of diagnosis ranged from under 1% for breast cancer to approximately 5% for pancreatic cancer, for those patients with early-stage disease. The rates increased for those with advanced disease, with a near doubling for those with breast cancer and rates nearly three times as high for patients with pancreatic cancer who presented with metastatic disease [7]. The presence of cancer is associated with a higher reported frequency for pulmonary embolism. In a large series of patients undergoing either surgical or medical intervention for their gastrointestinal disease, those with cancer undergoing surgery had pulmonary embolism rates of 2.34% compared with 0.36% for noncancer patients undergoing surgery. Similarly, for patients undergoing non-surgical management, the rates of pulmonary embolism were 0.73% for those with cancer compared with 0.1% for those without cancer [8]. In a large study of some 23 000 patients undergoing major surgical intervention and randomized to receive either low-dose unfractionated heparin or low-molecular-weight heparin (LMWH), a retrospective subgroup analysis determined the outcome for patients by indication for operation either cancer or no cancer. In the group of patients receiving peri-operative prophylaxis without cancer, the autopsy-proven fatal pulmonary embolism rate was 0.09%, whereas for those undergoing operation with cancer and receiving heparin-based prophylaxis, the frequency of pulmonary embolism was 0.33% [9]. All these data indicate that thromboembolic disease, which may be fatal, is seen more commonly in patients with cancer. A number of studies have tried to determine the impact of symptomatic venous thromboembolism on clinical outcome for patients with malignant disease. In a large study utilizing data from the Medicare system in the USA, analysis was made of the probability of death within 6 months of initial hospitalization for two groups of cancer patients; those initially admitted with a diagnosis of cancer alone, and those admitted with a combined diagnosis of cancer and some form of thromboembolic disease. Approximately 20% of patients with a diagnosis of cancer alone died in the initial 6-month period, compared with nearly 90% of patients with a combined diagnosis [10]. It is difficult to explain these data. It may be that patients with malignant disease who develop a thrombosis are at higher risk for the subsequent development of fatal recurrent thromboembolism, often missed because autopsies are seldomly performed. Alternatively, the development of systemic thromboembolism may be a surrogate marker for a biologically aggressive tumour which would have killed the patient anyway, with thrombosis only being a marker for that specific aggressive phenotype. Finally, it could be that the activation of blood coagulation seen with intravascular thrombosis, and generation of the associated coagulation proteases which are able to interact with specific tumour-cell-expressed protease receptors, might in some way alter the biology of the cancer and make it more aggressive leading to death of the patient. In a second study [11] where over 66 000 hospital admissions were analysed, the reported frequency of inpatient mortality was higher in patients with venous thromboembolism than in patients without thrombosis. For the overall study population, a mortality rate of 7.9% was seen in patients without thrombosis, and this increased to nearly 15% in patients with thrombosis. This impact on adverse clinical outcome associated with the development of venous thromboembolism was seen for patients with non-metastatic and metastatic disease. Interestingly, a diagnosis of cancer is seen more frequently after presentation with idiopathic thromboembolic disease. Against a population without thrombosis, the standardized incidence ratio for cancer is more than three for populations of patients presenting with either deep vein thrombosis or pulmonary embolism, within 6 months of that presentation. A higher reported frequency for subsequent cancer diagnosis is maintained for more than 10 years after presentation with a spontaneous thromboembolic episode [3]. Antithrombotic therapy and survival in cancer The VA Co-operative Trial evaluated the potential benefit of vitamin K antagonist therapy with warfarin with regard to survival in cancer. In those studies, patients were randomized to standard
A.K. Kakkar / Best Practice & Research Clinical Haematology 22 (2009) 147–151
149
treatment alone or standard treatment combined with warfarin. No survival benefit was associated with warfarin therapy for a variety of different tumour types included in the initial study (lung, colon, head and neck, and prostate). However, for the 50 patients with small cell lung cancer, warfarin therapy did show a benefit in terms of disease-free and overall survival [12]. In a subsequent study involving a larger number of small cell lung cancer patients, an effect on response to chemotherapy and a trend towards improved overall survival was associated with randomization to receive warfarin [13]. A similar study, randomizing 277 patients with small cell lung cancer to no antithrombotic therapy or subcutaneous unfractionated heparin at full treatment doses for 5 weeks, established a significant increase in complete response to chemotherapy from 23% in the control group to 37% in the heparin group, and improved median survival from 261 days to 317 days for those receiving heparin [14]. More recently, studies evaluating intravenous unfractionated heparin compared with subcutaneous LMWH for initial treatment of deep vein thrombosis have indicated improved survival at 3 months after presentation with thrombosis for cancer patients randomized to receive LMWH therapy for up to 10 days [15,16]. Considerable caution is required in interpreting such meta-analyses since the primary objective of the original studies was not to determine long-term cancer outcome, and little is known about the distribution of prognostic variables between the cancer patients receiving unfractionated heparin and those receiving LMWH for treatment of their thrombosis. The first prospective randomized clinical trial to report outcomes with regard to the potential benefits of chronic exposure of cancer patients to LMWH therapy, in the absence of established thrombosis, was the Fragmin Advanced Malignancy Outcome Study [17]. In this study, 385 patients with a variety of advanced solid tumours were randomized to receive up to 1 year of the LMWH dalteparin at a dose of 5000 units once daily or normal saline placebo injections. Three hundred and eighty-five patients were randomized, with the assumption that LMWH therapy would be associated with a 15% improvement in survival at 1 year after randomization; that is a mortality rate of 50% in the placebo group reduced to 35% in the group of patients receiving LMWH. At 1 year after randomization, the difference in survival was 5%, with a survival rate of 41% in the placebo group and 46% in the LMWH group; this was not statistically significant. In a post-hoc subgroup analysis of patients surviving beyond 17 months, randomization to receive LMWH was associated with a median survival of 43 months compared with only 24 months in patients randomized to receive placebo (P ¼ 0.03). In a small trial of patients with small cell lung carcinoma, 84 patients were randomized to receive standard chemotherapy alone or in combination with dalteparin at a dose of 5000 units once daily for up to 18 weeks [18]. There was an improvement in overall survival for the entire population associated with LMWH therapy, with the greatest benefit seen in patients with a better prognosis, where median survival was improved from 8 to 13 months. In a further study, 302 patients with advanced solid tumour malignancy were randomized to 6 weeks of the LMWH nadroparin or placebo. Median survival was improved from 6.6 months in the placebo group to 8 months in the group of patients receiving LMWH therapy (P ¼ 0.021) [19]. A small trial of 141 patients with breast, lung or prostate cancer, all with advanced disease and randomized to receive no antithrombotic therapy or dalteparin therapy at a dose of 5000 units once daily, failed to show any difference in survival [20]. Recently, a meta-analysis evaluated the totality of data with regard to exposure to LMWH in patients with malignant disease but without underlying thrombosis at the time of inclusion in clinical trials. The odds ratio for 1-year mortality was 0.7 [95% confidence interval (CI) 0.49–1.00; P ¼ 0.05] for patients with limited and advanced disease, and 0.75 (95%CI 0.57–0.99; P ¼ 0.04) for those with advanced disease. The odds ratio for 2-year mortality was 0.57 (95%CI 0.34–0.96; P ¼ 0.03) for patients with limited and advanced disease, and 0.59 (95%CI 0.42–0.84; P ¼ 0.004) for patients with advanced disease [21]. A further study has evaluated the potential impact on survival of long-term exposure to LMWH in patients receiving treatment for established venous thromboembolism. The CLOT in Cancer Study randomized 676 patients with a cancer-associated thrombosis to a standard therapy group with 5–7 days of full treatment doses of dalteparin followed by 6 months of warfarin to achieve a target international normalized ratio of 2.5, or 6 months of dalteparin therapy at full treatment doses for 1 month and 80% of the full treatment dose for the subsequent 5 months. At the end of this 6-month treatment period, there was no difference in survival between the two groups. At 1-year follow-up after initial initiation of
150
A.K. Kakkar / Best Practice & Research Clinical Haematology 22 (2009) 147–151
treatment for venous thromboembolism, there was no difference in survival for patients who presented with metastatic cancer at the time of randomization. However, for those with non-metastatic disease, numbering 150 in this study, there was a difference in survival at 1 year, with a survival rate of 64% for patients receiving vitamin K antagonist therapy and 80% for those receiving LMWH [22]. Mechanistic explanation for prolongation of survival in cancer patients A number of potential explanations have been proposed for the interesting survival observations seen in patients with malignant disease receiving LMWH therapy. Amongst these is the prevention of fatal thromboembolic events associated with active LMWH therapy. However, the benefits of exposure to LMWH appeared to continue beyond active exposure, indicating that some of the benefit must be independent of preventing fatal thromboembolic events. Coagulation proteases have been shown to play an important role in tumour biology. LMWH, through potentiation of antithrombin, neutralized activated factor X and activated factor II thrombin, thus preventing their interaction with tumourexpressed protease receptors. The impact of coagulation proteases has been seen in enhancing tumour growth invasion metastasis and angiogenesis [23]. A further explanation for these potential benefits is associated with the direct cellular effects of heparin like molecules which have been shown to inhibit angiogenesis [24] and to enhance apoptosis in experimental tumour models [25]. A further explanation is neutralization of tumour heparinase activity through exposure to heparin-like molecules. Heparinase plays an important role in remodelling of the extracellular matrix, and its overexpression is associated with a more aggressive phenotype. Conclusions There is no doubt that there is a complex relationship between the coagulation system and tumours. This is associated with a higher reported frequency for the development of symptomatic thromboembolic disease, which can be fatal, in cancer patients. Equally, presentation with spontaneous thromboembolism is associated with a higher subsequent rate for the diagnosis of new malignant disease. The coagulation proteases have been shown to play a potential role in determining the phenotype of tumours in the experimental setting. Inhibition of the coagulation system therefore may play a role in altering the behaviour of tumours. Prospective clinical trials indicate that exposure to LMWH is associated with prolonged survival, although studies which provide definitive evidence of this benefit have yet to be completed. Conflict of interest statement None declared. References [1] Trousseau A. Plegmasia Alba Dolens. London: The New Syndeham Society; 1872. pp 282–332. [2] Prandoni P. Venous thromboembolism and cancer: a two-way clinical association. Front Biosci 1997;2:e12–20. [3] Sorensen HT, Mellemkjaer L, Steffensen FH, et al. The risk of a diagnosis of cancer after primary deep venous thrombosis or pulmonary embolism. N Engl J Med 1998;338:1169–73. [4] Baron JA, Gridley G, Weiderpass E, et al. Venous thromboembolism and cancer. Lancet 1998;351:1077–80. [5] Kakkar AK, DeRuvo N, Chinswangwatanakul V, et al. Extrinsic-pathway activation in cancer with high factor VIIa and tissue factor. Lancet 1995;346:1004–5. [6] Varki A. Trousseau’s syndrome: multiple definitions and multiple mechanisms. Blood 2007;110:1723–9. [7] Chew HK, Wun T, Harvey D, et al. Incidence of VTE and its effect on survival among patients with common cancers. Arch Intern Med 2006;166:458–64. [8] Huber O, Bounameaux H, Borst F, et al. Postoperative pulmonary embolism after hospital discharge. An underestimated risk. Arch Surg 1992;127:310–3. [9] Kakkar AK, Haas S, Wolf H, et al. Evaluation of perioperative fatal pulmonary embolism and death in cancer surgical patients: the MC-4 cancer substudy. Thromb Haemost 2005;94:867–71. [10] 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 1999;78:285–91. [11] Khorana AA, Francis CW, Culakova E, et al. Thromboembolism in hospitalized neutropenic cancer patients. J Clin Oncol 2006;24:484–90.
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