Toronto, Canada. Epidemiology Large, population-based, case-control studies have demonstrated that cancer is

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1 CE update [coagulation and hematology] Recent Advances in the Epidemiology, Pathophysiology, and Management of Thrombosis in Cancer Patients Lisa K Hicks, MD, FRCP(C), Rita Selby, MBBS, FRCP(C) 1 Division of Medical Oncology and Hematology 2 Departments of Medicine and Clinical Pathology, University of Toronto, Toronto, Canada DOI: /E0RHURW88U472LQU After reading this article, the reader should understand how cancer biology and treatments promote venous thromboembolism (VTE) in cancer patients. The reader should have an approach to prevention and treatment of VTE in cancer patients, and should recognize that in the future, anticoagulation may be used as a form of adjuvant cancer therapy. Hematology exam questions and corresponding answer form are located after the Your Lab Focus section on p Many cancer patients are at increased risk of venous thromboembolism (VTE). Cancer biology, the host response to cancer, and cancer treatments all contribute to this increased risk of clotting. In the treatment of some patients with cancer and associated VTE, the administration of long-term low molecular heparin is superior to oral anticoagulants with respect to preventing recurrent VTE and minimizing bleeding. Anticoagulants may inhibit cancer progression and are being investigated as a form of adjuvant cancer therapy. The association between thrombosis and malignancy has been recognized for more than a century. However, it is only within the past few decades that the complicated biology responsible for this relationship has begun to be unraveled. As our understanding of the pathophysiology of cancer and thrombosis has advanced, so too has our appreciation of the clinical implications of these paired disease processes. In this review, we summarize recent advances in the epidemiology, pathophysiology, and management of thrombosis in patients with malignancy. Epidemiology Large, population-based, case-control studies have demonstrated that cancer is an important independent risk factor for VTE. 1,2 Heit and colleagues reported a 6.5-fold increase in the risk of VTE in patients with malignant neoplasms over a 15-year study period (1976 to 1990). 1 In another study of more than 9 million Medicare recipients with and without concurrent cancer, patients with cancer and VTE had an increased incidence of both recurrent VTE and mortality, compared to patients with VTE alone. 2 Just as cancer is an important risk factor for developing VTE, the occurrence of idiopathic VTE may precede the detection of an underlying cancer. Registry data have shown that the incidence of cancer is increased in patients presenting with idiopathic VTE. 3,4 In 1998, a Swedish study of more than 60,000 patients reported that in the year following admission for VTE the standardized incidence ratio (SIR) for cancer was A similar Danish study reported a SIR of 3.0 for cancer in the 6 months following VTE. 4 The most frequently reported cancers associated with thrombosis in these studies have been those involving the ovaries, pancreas, brain, and liver [T1]. 2-4 Pathophysiology of Thrombosis and Cancer Virchow s triad of stasis, endothelial injury, and hypercoagulability has long been used to illustrate the major risk factors predisposing patients to VTE. This model is particularly illustrative for cancer Tumor Sites with High Risk of Thrombosis 2-4 Cancers with Highest Risk of VTE Ovarian carcinoma Pancreatic carcinoma Brain cancer Liver cancer T1 and thrombosis [F1]. Prothrombotic factors may also be classified as intrinsic or extrinsic to the patient. Intrinsic factors are related to cancer biology and/or the host response to malignancy. Extrinsic factors involve treatments and procedures which patients undergo because they have cancer. Intrinsic Factors Hemostasis is maintained through a complex network of procoagulants and anticoagulants (for a recent overview of hemostasis, readers are referred to Ogedegbe). 5 In cancer, this delicate balance is disrupted. Key procoagulant factors are upregulated, while coagulation inhibitors are decreased. This imbalance usually favors a prothrombotic state that may result in both pathologic thrombosis and cancer spread. Non-specific markers of coagulation activation such as Factor VIIa, prothrombin fragment 1+2 (F1+2), thrombinantithrombin (TAT) complex, soluble fibrin, fibrinopeptide A, D-dimer, and plasmin anti-plasmin complexes (PAP) are often markedly elevated in patients

2 with malignancy [T2]. 6,7 In some studies, the elevation of various markers has been correlated with tumor burden or found to predict a poor prognosis. 8,9 However, the clinical relevance of this increase, especially in the prediction of thrombosis in the individual patient with cancer, is not known. Some key mechanisms believed to result in this hypercoagulable state are discussed below. Tissue Factor Tissue factor (TF) is a transmembrane protein expressed by endothelial cells and monocytes. It is upregulated by inflammation and tissue injury. Tissue factor is 1 of the primary triggers of the coagulation cascade. It activates and forms a complex with factor VIIa. The TF-VIIa complex then activates factors IX and X, ultimately resulting in thrombin production. Thrombin is responsible for fibrin formation and platelet activation [F2]. Tissue factor is expressed by a multitude of tumor cells. 10 Malignancy can also induce TF overexpression by nonmalignant endothelial cells and monocytes. 11 In addition to predisposing to a prothrombotic state, there is growing evidence that TF and thrombin contribute to angiogenesis and thus to cancer spread. 10,12 Fibrin generated by the action of thrombin on fibrinogen may help to form a supportive scaffold for endothelial cell growth. Platelets activated by thrombin release vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF). In addition, TF and thrombin contribute to angiogenesis through clotting-independent intracellular signal transduction via the cytoplasmic tail of TF and the plasminogen activator receptor (PAR) family of membrane-bound receptors. For a more detailed discussion of the role of TF and thrombin in tumor growth, the reader is referred to 2 recent reviews. 10,12 Cancer Procoagulant Another important factor implicated in cancer-hypercoagulability is cancer procoagulant. Cancer procoagulant is a cysteine proteinase that directly activates factor X [F2]. To Endothelial Injury tumor invasion surgery chemotherapy radiation central venous catheter Venous Stasis date, cancer procoagulant has been identified exclusively in malignant and fetal tissues. 13 Elevated levels of cancer procoagulant have been reported in both in vitro and in vivo studies of malignancy Some reports have correlated cancer procoagulant activity with tumor burden and have demonstrated decreased cancer procoagulant activity following cancer treatment. 15,17,18 Decreased Inhibitor Levels Physiologic anticoagulants such as antithrombin, protein C, protein S, and tissue factor pathway inhibitor (TFPI) are important checks on the coagulation cascade. Several studies have reported low levels of each of these inhibitors in cancer patients Activated protein C resistance has also been associated with malignancy The mechanism of these alterations has not been determined; possibilities include a direct tumor effect, downregulation secondary to changes in the cytokine milieu, increased consumption, and/or decreased hepatic production. Altered Fibrinolysis Tumor cells can express urokinasetype plasminogen activator (upa) and/or tissue-type plasminogen activator (tpa). 25 This is believed to be the mechanism for the bleeding diathesis associated with acute promyelocytic leukemia. 26 decreased patient mobility extrinsic compression by tumor/node venous invasion by tumor Hypercoagulability increased TF, CP, and PAI-1 expression by tumor and normal tissues decreased PC, PS, AT, TFPI APC resistance increased activation of platelets [F1] Virchow s triad: A model for understanding thrombosis and cancer. Note: TF=tissue factor; CP=cancer procoagulant; PAI-1=plasminogen activator inhibitor; PC=protein C; PS=protein S; AT=antithrombin; TFPI=tissue factor pathway inhibitor; APC=activated protein C. Markers of Hemostatic Alterations in Cancer 6,7,19-25 Elevation in coagulation activation and thrombin generation Factor VIIa Prothrombin fragment (F1+2) Thrombin-antithrombin complex (TAT) Soluble fibrin Fibrinopeptide A D-dimer Alterations in fibrinolysis Plasmin anti-plasmin complexes (PAP) PAI-1 Decreased inhibitors TFPI Antithrombin Protein C Protein S Activated protein C resistance T2 Plasminogen activator inhibitor (PAI) levels can also be increased thereby shifting the balance towards thrombosis. 25 Similar to TF, there is emerging evidence that PA and PAI contribute to cancer migration, growth, and metastases. 25,27 Cytokines Cytokines are low molecular weight polypeptides that mediate inflammation. They are part of the normal host response to infection, tissue injury, and malignancy. Tumor necrosis factor (TNF), IL-1, and IL-6 are potent inflammatory mediators that are frequently elevated in patients with cancer and may activate coagulation 493

3 by several different mechanisms. Specific cytokines (TNF, IL-1, and IL-6) can induce TF expression by endothelial cells and monocytes. 28,29 As outlined above, TF is a potent trigger of coagulation. Tumor necrosis factor and IL-1 can also inhibit the natural anticoagulant protein C by decreasing levels of thrombomodulin, an important cofactor in the activation of protein C. 30 Finally, TNF and IL-1 can increase levels of PAI-1, thereby inhibiting fibrinolysis. 28 All of these actions may contribute to hypercoagulability in cancer patients. TF + VII VIIa CP X Xa II IIa Platelet Thrombin Activation I Ia Fibrinogen Fibrin [F2] Role of tissue factor and cancer procoagulant in thrombosis. Note: TF=tissue factor; CP= cancer procoagulant. 494 Extrinsic Factors It has long been recognized that extrinsic factors, such as advanced patient age, patient immobility, and tumor compression of the venous system, increase the risk of thrombosis in cancer patients. Recently, there has also been increasing attention paid to the significant influence of cancer treatments in predisposing patients to venous thromboembolism. Surgery Surgery is a primary treatment modality for patients with cancer. However, it is also a major risk factor for thrombosis in all patients. 31 Depending on the type of surgery, age of the patient, and presence of comorbidities, the incidence of post-operative proximal deep vein thrombosis ranges between 0.4% and 20%. 31 In cancer patients, the risk of thrombosis following surgery is doubled. 32 The mechanism by which surgery triggers thrombosis has not been completely elucidated. It likely involves a complex interaction between endothelial damage, inflammation, and immobility. Antineoplastic Agents Antineoplastic therapy increases the risk of thrombosis in cancer patients above and beyond the baseline risk associated with their malignancy. The strongest evidence of this association comes from clinical studies in patients with breast cancer. The baseline risk of VTE in women with early stage breast cancer is less than 1%. 33,34 When such women are administered adjuvant chemotherapy however, the risk of VTE increases significantly Estimates of VTE risk in this setting range between 7% and 11%, depending on the chemotherapy regimen used and the menopausal status of the patient. 33,35 It has also been noted that the increased risk of VTE is largely confined to the period of time when patients are actively receiving chemotherapy. 35 There is a growing amount of literature implicating a number of other antineoplastic agents in thrombotic complications. Tamoxifen, a hormonal agent, has been observed to increase the risk of thrombosis in patients with and without breast cancer. 36,37 Thalidomide has also been reported to increase the risk of thrombosis, particularly when combined with an anthracyline in the treatment of multiple myeloma. 38,39 Finally, L-asparginase, an enzyme that interferes with normal protein synthesis and is used in the treatment of acute lymphoblastic leukemia, has been implicated in thrombotic complications. 40 The prothrombotic mechanisms of many of these drugs have not been determined. L-asparginase, however, is believed to induce thrombosis through decreased antithrombin production. 41 Radiation Therapy Ionizing radiation kills cancer cells through energy transfer causing DNA damage, vascular injury, and secondary tissue hypoxia. Given its mechanism of action, one might expect that radiation would increase the risk of VTE in cancer patients. There is, however, a paucity of published literature in this area. A single cohort study has reported that preoperative radiotherapy for patients with rectal carcinoma significantly increases the incidence of VTE compared to patients who do not receive radiotherapy for the same diagnosis. 42 Further investigations are required to determine if this association is unique to rectal carcinoma or more broadly applicable. Central Lines Central venous catheters (CVCs) are frequently used in cancer patients for the administration of chemotherapy and blood products and to facilitate blood collection. The CVCs involve a mechanical disruption of the vascular endothelium and can act as a nidus for thrombosis. Estimates of the incidence of symptomatic upper-limb thrombosis in cancer patients with CVCs, range from 0.3% to 28%. 43 Asymptomatic thrombosis has been reported in 17% to 66% of cancer patients with CVCs Estimates of risk are inconsistent in this area due to variability in study design, different diagnostic techniques, and different diagnostic criteria. Nonetheless, there is little argument that CVCs represent an additional risk factor for thrombosis in cancer patients. Treatment Primary Prophylaxis Prophylactic anticoagulation of cancer patients has principally been considered in 3 scenarios: in post-operative patients, in patients with central venous catheters, and in patients

4 receiving chemotherapy. The benefit of prophylactic post-operative anticoagulation for cancer patients with either unfractionated low dose heparin (UFH) or low molecular weight heparin (LMWH) has been clearly demonstrated and should be considered the standard of care. 31 Prophylactic anticoagulation of patients who have CVCs is more controversial. There is a growing body of literature suggesting that cancer patients with CVCs may benefit from prophylactic anticoagulation. 43 However, most of the studies are small and/or limited to particular tumor sites. Moreover, 3 recent and as yet unpublished randomized controlled trials did not demonstrate the benefits seen in earlier studies Thus, it is premature to recommend universal prophylactic anticoagulation in cancer patients with CVCs. There is some evidence that patients with advanced breast cancer who are receiving chemotherapy may benefit from primary prophylactic anticoagulation. 49 However, a recent randomized controlled trial did not detect a decrease in symptomatic VTE in patients with advanced cancer who received either a prophylactic dose of LMWH or placebo. 50 In addition, there remain concerns regarding hemorrhagic complications in patients who may have low platelets and/or an increased risk of bleeding from their tumor. Until there is further evidence regarding the risk-benefit profile of primary prophylaxis in this setting, the practice cannot be recommended. Secondary Prophylaxis Standard treatment for acute VTE includes initial treatment with either heparin or LMWH followed by longterm treatment with an oral anticoagulant. This strategy is effective in most patients with VTE; however, cancer patients do not have satisfactory outcomes. A prospective study of more than 800 patients reported that 20% of cancer patients suffered a recurrent VTE during the first year of follow-up when treated with this strategy (an incidence 3-fold greater than that experienced by noncancer patients). 51 Major bleeding was also more common in cancer patients, with a 12-month cumulative incidence rate of 12% in this study. These findings, combined with the practical difficulties of using vitamin K antagonists in cancer patients (due to irregular oral intake, malnutrition, vomiting, drug interactions, and frequent interruption of anticoagulants for procedures) has increased interest in alternative strategies. Two large randomized controlled trials comparing long-term administration of LMWH with initial LMWH followed by oral anticoagulants for VTE in cancer patients have recently been published. Meyer and colleagues reported a significant improvement in the composite end-point of recurrent VTE and major bleeding at 3 months with the use of the LMWH enoxaparin. 52 The major benefit in their trial was accrued through decreased bleeding. Lee and colleagues reported a significant decrease at 6 months in the incidence of recurrent VTE with the LMWH dalteparin. 53 However, the incidence of major bleeding was found to be similar in both groups. On the basis of these studies, cancer patients with VTE are increasingly being managed with long-term LMWH rather than oral anticoagulants. Anticoagulation and Cancer Survival In addition to their anticoagulant effect, heparins may inhibit tumor progression through modification of enzyme systems, cellular growth, and tumor angiogenesis. 54 Data from metaanalyses of clinical trials comparing LMWH with UFH for VTE have demonstrated a survival benefit with LMWH in a subgroup of cancer patients. This survival advantage was attributable not to a reduction in fatal VTE but possibly to improved cancer control. 54 This finding has led to clinical studies assessing the impact of LMWH on the survival of cancer patients who do not have thrombosis. Two recently presented studies compared LMWH to placebo in patients with advanced, solid tumors. 50,55 Both reported that LMWH resulted in improved survival in a subgroup of good-prognosis cancer patients. Bleeding risk was found to be acceptable. 50,55 In patients with early cancer and VTE, a recent subgroup analysis of the Lee trial 53 reports improved survival with LMWH, independent of age, tumor type, cancer treatment, performance status, or initial qualifying episode of VTE. 56 The results of further clinical studies in this exciting new area of research will further elucidate if anticoagulants may play a role as anticancer therapy in the future. Summary The past decade has seen a rapid acceleration in our understanding of, and approach to, thrombosis in patients with malignancy. We now appreciate the hemostatic changes favoring thrombosis in cancer patients may also promote cancer growth. We recognize that cancer treatments such as surgery and chemotherapy contribute significantly to patients risk of VTE. As well, we are learning how to tailor thrombosis treatments to suit the unique needs of patients with cancer. There are, however, numerous basic science and clinical questions that remain; one of the most pressing unanswered questions is whether we can influence cancer progression and prognosis using anticoagulant therapy. Acknowledgements: The authors wish to thank Dr. Matthew Cheung for reviewing the manuscript, Dr. William Geerts for his helpful suggestions, and Dr. Jeff Singh for creating the figure. 1. Heit JA, Silverstein MD, Mohr DN, et al. 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