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Therapeutic Approaches to Coagulopathy in Cancer Patients

Tara Newcomb, PharmD
Oncology Clinical Pharmacy Resident
University of Texas M. D. Anderson Cancer Center, Houston, Texas

Sheetal Sheth, PharmD, BCOP
Oncology Clinical Pharmacy Specialist
University of Texas M. D. Anderson Cancer Center, Houston, Texas

7/13/2007

US Pharm. 2007;32(7):5-10.

ABSTRACT: In the United States, it is estimated that the frequency of venous thromboembolism (VTE) among cancer patients is approximately 1 in 200. Aggressive prophylaxis and treatment of thrombotic events should be initiated in this patient population, and research shows that heparins are effective in the prevention and treatment of VTE--and possibly survival--in oncology patients.

Oncology patients have a sevenfold overall increased risk of venous thromboembolism (VTE) when compared to patients without malignancy and are two to three times more likely to develop postoperative thrombosis.1 Oncology patients who develop VTE are also at increased risk for recurrent thrombosis compared to nononcology patients (hazard ratio, 1.72).2 Venous thrombosis is the second leading cause of death among oncology patients, after malignancy itself.2 In addition, thrombosis may be a presenting symptom of malignancy. An almost 10-fold increased incidence of cancer is seen in patients who have recurrent idiopathic deep vein thrombosis (DVT) without known risk factors for thrombosis.2

Etiology and Risk Factors
When monocytes and macrophages interact with malignant cells, they release cytokines such as tumor necrosis factor, interleukin-1, and interleukin-6, leading to sloughing of endothelial cells and endothelial damage.3 These changes create a thrombogenic vascular surface that increases the risk of VTE. The interaction between macrophages and tumor cells also leads to activation of platelets, factor XII, and factor X, initiating the clotting cascade and leading to the formation of a thrombus.3

Cancer cells also release substances that can increase thrombogenic risk. These substances, known as cancer procoagulants, include cysteine proteases, tissue factor, and mucin procoagulant.3,4 Tissue factor can also be released by monocytes and macrophages in response to interaction with tumor cells.3 Cysteine proteases act to directly activate factor X, while tissue factor directly activates factor VII.3 Mucin procoagulant, typically seen in adenocarcinomas, works to activate prothrombin and causes nonenzymatic activation of factor X.3,4

Venous stasis and endothelial injury also place oncology patients at risk for VTE. In addition to endothelial injury caused by the release of cytokines, factors such as insertion of central venous catheters (CVCs) and chemotherapy administration can damage the vascular lining.3.4 Venous stasis can be caused by direct vessel compression by the tumor, CVCs, and patient immobility.3,4 Disordered blood flow and venous stasis may also be caused by angiogenesis, which is induced by many tumors.4 Angiogenesis, the formation of new blood vessels, produces vasculature that is abnormal in appearance.4 Flow through these vessels may vary in magnitude as well as direction.4

While all cancer patients are at increased risk for thrombosis, those with certain tumor characteristics may be at particularly high risk (see FIGURE 1). Primary brain tumors, pancreatic cancer, and ovarian cancer are tumor types associated with the highest frequency of VTE.2 In the Medicare Provider Analysis and Review Record database, these malignancies were found to have a statistically significant increased relative risk for VTE when compared with tumor types associated with the lowest risk (i.e., head and neck, bladder, and esophageal cancers).5 Despite a lower frequency of thrombotic events, tumor types with the highest prevalence of VTE include breast, colorectal, and lung cancers, due to the high incidence of these malignancies in the general population.2 Patients with metastatic disease are also at increased risk of VTE when compared with patients without metastasis.1



Agents used in the treatment of malignancy can also be associated with increased risk for VTE. Chemotherapy itself has been shown to increase VTE risk in several studies.6 Specifically, L-asparaginase can increase the risk for thrombosis due to depletion of plasma asparagine, leading to decreased formation of proteins, including the natural anticoagulants protein C and protein S.7 Exogenous estrogenic compounds, such as tamoxifen and diethylstilbestrol, used to treat breast and prostate cancer, respectively, also place patients at higher thrombotic risk.6 The estrogenic effects of oral contraceptives used to prevent pregnancy during chemotherapy can act as an additional risk factor in the oncology population.6 Other agents associated with increased risk of VTE include erythropoietic growth factors and thalidomide and lenalidomide, especially when combined with dexamethasone, for the treatment of multiple myeloma.

Prophylaxis
The high risk of thrombosis in the oncology population makes prophylaxis an important concern in these patients. Factors that must be taken into consideration when determining whether to use prophylaxis in a particular patient include recent or current active bleeding, thrombocytopenia, severe platelet dysfunction, recent major surgery at high risk for bleeding, need for spinal anesthesia or lumbar punctures, recent central nervous system  bleeding or intracranial or spinal lesions at high risk for bleeding, and the patient's risk for falls. 6 All of these factors are considered relative contraindications to anticoagulation and must be weighed in the decision of whether VTE prophylaxis is warranted in an individual patient. The safety of anticoagulation must also be considered in patients with underlying coagulopathy, including clotting factor abnormalities and/or prolonged prothrombin time  or activated partial thromboplastin time.6 Patients who may be at particularly high risk for VTE, requiring consideration of prophylaxis, include those undergoing surgery and those who are hospitalized.

Cancer patients undergoing surgery are twice as likely to develop postoperative DVT and three times as likely to develop fatal pulmonary embolism (PE) as nononcology patients undergoing similar procedures.8 A systematic review of randomized, controlled trials in oncology patients revealed no difference in efficacy, safety, or DVT location between low-dose unfractionated heparin (LDUH) and low-molecular-weight heparin (LMWH) in surgical prophylaxis.9 A statistically significant benefit was seen when higher doses of heparin prophylaxis (defined as LMWH dose more than 3,400 U daily or LDUH 5,000 U three times per day) were used, compared with lower doses.9 The rate of DVT decreased from 12.7% to 5% when mechanical prophylaxis was added to LMWH or LDUH prophylaxis.9

Hospitalized patients with a diagnosis of active malignancy may be at increased risk of thrombosis due to a lack of ambulation while hospitalized. Guidelines for VTE prophylaxis differ in their recommendations.6,10 While guidelines from the National Comprehensive Cancer Network (NCCN) suggest prophylaxis in all inpatients with a diagnosis of active cancer,6 guidelines developed by the American College of Chest Physicians (ACCP) discourage prophylactic anticoagulation in hospitalized patients who are able to ambulate.10 The NCCN  recommends mechanical prophylaxis in all hospitalized cancer patients concomitantly with pharmacological prophylaxis unless anticoagulant therapy is otherwise contraindicated.6 Prophylactic anticoagulation regimens are shown in Table 1.



Patients with indwelling CVCs are also at increased risk for thrombosis. While it was previously thought that all patients with a CVC should receive VTE prophylaxis, randomized, controlled trials have failed to show a benefit of such prophylaxis. A double-blind, multicenter, randomized, controlled trial comparing enoxaparin 40 mg daily to placebo in 385 cancer patients scheduled to undergo CVC insertion showed no statistically significant difference in the rate of DVT between the two groups.11 Similarly, a randomized, multicenter study comparing fixed-dose warfarin at 1 mg daily to placebo in cancer patients after CVC insertion failed to show a benefit in the rates of CVC-associated thrombosis.12 Secondary outcomes of non-CVC–associated thrombosis, CVC life span, premature CVC removal, and CVC lumen occlusions were not significantly different between the two groups. 12 Based on these data, routine prophylaxis of patients with CVCs is not recommended by either the NCCN or ACCP.6,10

Treatment
In patients who develop VTE, treatment and secondary prophylaxis are imperative due to the increased risk for recurrent VTE seen in the oncology population. An ideal treatment regimen would prevent recurrent DVT/PE without compromising patient safety with regard to increased bleeding complications. This is of particular concern in oncology patients who may have preexisting risk factors for bleeding, such as thrombocytopenia or tumor types with a propensity to bleed (e.g., renal cell carcinoma, melanoma). Thus, studies performed specifically with an oncology patient population are most useful in characterizing effective treatment regimens. Four such studies have been published comparing LMWH to warfarin for the treatment and secondary prevention of VTE (see TABLE 1).13-16

Both the ONCENOX and CANTHANOX trials compared enoxaparin to warfarin in cancer patients with VTE.13,14 Due to problems with accrual, both studies were closed early and included only a small number of patients. The CANTHANOX trial was an open-label, multicenter trial including 138 evaluable cancer patients with DVT and/or PE. 13 Patients were randomized to receive enoxaparin 1.5 mg/kg subcutaneously once daily for three months or enoxaparin 1.5 mg/kg subcutaneously once daily followed by oral warfarin, titrated to an international normalized ratio (INR) between 2 and 3 for three months. Twenty percent of the patients in the warfarin group experienced recurrent VTE or major bleeding, compared with 10.5% of patients in the enoxaparin group. This difference was not found to be statistically significant. A significant difference was found between the two groups, however, in regard to the time to event of primary outcome, with enoxaparin being superior (P = .04). Patients randomized to the warfarin group were found to have a therapeutic INR 41% of the treatment time. Six patients in the warfarin group suffered death related to bleeding, while no patients in the enoxaparin group had death attributable to bleeding complications. No significant difference was found, however, in major hemorrhage between the two groups.13

The ONCENOX, a pilot trial, included 102 patients with active malignancy.14 Patients were randomized to receive enoxaparin 1 mg/kg subcutaneously twice daily for five days, followed by either enoxaparin 1.5 mg/kg once daily, enoxaparin 1 mg/kg once daily, or warfarin, titrated to an INR between 2 and 3. Anticoagulation was continued for a total of 180 days. There was no statistically significant difference between the groups in the rates of symptomatic extension of the diagnosed VTE or in recurrent VTE, nor in rates of bleeding.14

The LITE trial was a randomized, multicenter, open-label trial involving 737 patients diagnosed with VTE.15 A cancer subset of 200 patients was identified a priori for separate analysis. These patients were randomized to receive either tinzaparin 175 International Factor Xa Inhibitory Units per kilogram subcutaneously once daily or unfractionated heparin followed by oral warfarin, titrated to an INR between 2 and 3. Study drug was discontinued at 12 weeks unless it was determined by the patient's primary care physician that further oral anticoagulation was indicated. While the rates of recurrent VTE at the end of the study period were not significantly different between the two groups, the tinzaparin group had a significantly decreased rate of recurrent VTE at one year (7% vs. 16%; P = .044). Bleeding complications were similar between the two groups.15

Finally, the CLOT trial was an open-label, multicenter study in 676 patients with active malignancy.16 Treatment randomization involved either dalteparin 200 U/kg subcutaneously once daily for five to seven days and a coumarin derivative for six months or dalteparin alone at a dose of 200 U/kg once daily for one month, followed by 150 U/kg once daily for five months. Follow-up at the end of the six-month study period revealed that 27 of the 336 patients in the dalteparin group had recurrent VTE, compared with 53 of the 336 patients in the oral anticoagulant group (hazard ratio, 0.48; P = .002). The rates of major bleeding and death at six months were not significantly different between the two groups. Patients on oral anticoagulation were found to have INRs in the therapeutic range 46% of the study duratin, with subtherapeutic INRs 30% and supratherapeutic INRs 24%.16

Based on this data, LMWHs have proven efficacy and safety in the prevention of recurrent VTE in the oncology population. Agents with data supporting their superiority over warfarin include dalteparin and tinzaparin.10,15,16 Dosages for LMWH in the treatment of VTE are shown in Table 2.


LMWHs and Survival Benefit
Interest has been generated in the role of LMWHs beyond the treatment and prevention of VTE. While efficacy in the treatment setting has been established, it is thought that LMWH may also play a role in tumor modulatory processes and thus may increase survival in oncology patients. This idea is based on the theoretical role of tissue factor beyond coagulation. Activation of tissue factor leads to the upregulation of vascular endothelial growth factor, and downregulation of thrombospondin-1, an antiangiogenic agent, resulting in an increase in angiogenesis.1 LMWHs increase the release of tissue factor pathway inhibitor, leading to an inhibition in tissue factor expression and, theoretically, a decrease in angiogenic tumor activity.1,17 In vitro experiments and experiments in animal models have shown that heparins can interfere with angiogenesis as well as tumor invasion and adhesion of cancer cells to the vascular endothelium, possibly having a role in the prevention of metastasis--but not actual tumor growth.  In vivo studies in humans have also suggested a survival benefit of LMWH.18-20

A posthoc analysis of the CLOT trial survival data at one year showed no difference in mortality between the LMWH group and the oral anticoagulation group in the subset of patients with metastatic disease.18However, in the group of patients without metastasis, a survival advantage was seen in the dalteparin group at 12-month follow-up (20% probability of death vs. 36% probability of death; P = .03). It is thought that the lack of benefit seen in patients without metastatic disease may be due to the effect of LMWH on modulation of metastasis but lack of effect on tumor growth.18

A second trial, the FAMOUS trial, examined the impact of LMWH on survival in cancer patients without underlying VTE.19 This double-blind, placebo-controlled, multicenter trial included 374 patients with solid malignancies and randomized patients to receive either dalteparin 5,000 U subcutaneously once daily or placebo for one year. Patients entering this study had to have a life expectancy of at least three months from enrollment. No difference in survival was seen in the study population as a whole at one, two, or three years. A subgroup of patients, not defined a priori, was further analyzed for survival benefit. This subgroup included patients with a better prognosis, defined as those patients who were alive 17 months after randomization. Of these patients, a significant survival advantage was seen at both two and three years in the dalteparin group. There was no significant difference between the two groups in regards to bleeding complications.19

The MALT trial was another study conducted in oncology patients without underlying thrombosis.20 This study included 302 patients with metastatic or locally advanced solid tumors. Patients were randomized to receive either nadroparin 9,500 IU subcutaneously once daily or placebo for six weeks. Median survival was increased from 6.6 months in the placebo group to eight months in the nadroparin group (P =  .021). The median survival advantage in the nadroparin group was even more profound in a subset of patients with a life expectancy greater than six months at randomization (15.4 vs. 9.4 months; P = .01). The rate of clinically relevant bleeding was significantly increased in the nadroparin group compared with placebo. Rates of major bleeding, however, were similar between the two groups.20

Conclusion
Oncology patients are at high risk for VTE. Aggressive prophylaxis and treatment of thrombotic events should be initiated in this patient population. LMWHs have proven efficacy and safety in cancer patients and are preferred over warfarin for the prevention and treatment of VTE. Additional clinical trials are needed to further define the role of LMWHs on survival results in oncology patients both with and without underlying thrombosis.

References
1. Burris HA. Low-molecular-weight heparins in the treatment of cancer-associated thrombosis: a new standard of care? Semin Oncol. 2006;33:S3-S16.
2. Pruemer J. Prevalence, causes, and impact of cancer-associated thrombosis. Am J Health Syst Pharm. 2005;62:S4-S6.
3. Bick RL. Cancer-associated thrombosis. N Eng J Med. 2003;349:109-111.
4. Letai A, Kuter DJ. Cancer, coagulation, and anticoagulation. The Oncologist. 1999;4:443-449.
5. Levitan N, Dowlati A, 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;78:285-291.
6. Clinical Practice Guidelines in Oncology: Venous Thromboembolic Disease, version 2.2006. National Comprehensive Cancer Network Web site. Available at: www.nccn.org/professionals/physician_gls/PDF/vte.pdf. Accessed April 8, 2007.
7. Merck & Co., Inc. Elspar package insert. Whitehouse Station, NJ, December 2005.
8. Geerts WH, Pineo GF, et al. Prevention of venous thromboembolism: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126:338-400.
9. Leonardi MJ, McGory ML, Ko CY. A systematic review of deep venous thrombosis prophylaxis in cancer patients: implications for improving quality. Ann Surg Oncol. 2007;14:929-936.
10. Buller HR, Giancarlo A, et al. Antithrombotic therapy for venous thromboembolic disease: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126:401-428.
11. Verso M, Agnelli G, et al. Enoxaparin for the prevention of venous thromboembolism associated with central vein catheter: a double-blind, placebo-controlled, randomized study in cancer patients. J Clin Oncol. 2005;23:4057-4062.
12. Couban S, Goodyear M, et al. Randomized placebo-controlled study of low-dose warfarin for the prevention of central venous catheter-associated thrombosis in patients with cancer. J Clin Oncol. 2005;23:4063-4069.
13. Meyer G, Marjanovic Z, et al. Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer. Arch Intern Med. 2002;162:1729-1735.
14. Deitcher SR, Kessler CM, et al. Secondary prevention of venous thromboembolic events in patients with active cancer: enoxparin alone versus initial enoxparin followed by warfarin for a 180-day period. Clin Appl Thromb Hemost. 2006;12:389-396.
15. Hull RD, Pineo GF, et al. Long-term low-molecular-weight heparin versus usual care in proximal-vein thrombosis patients with cancer. Am J Med. 2006;119: 1062-1072.
16. Lee AY, Levine MN, et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Eng J Med. 2003;349;146-153.
17. Niers TMH, Klerk CPW, et al. Mechanisms of heparin induced anti-cancer activity in experimental cancer models. Crit Rev Oncol Hematol. 2007;61:195-207.
18. Lee AY, Rickles FR, et al. Randomized comparison of low molecular weight heparin and courmarin derivatives on the survival of patients with cancer and venous thromboembolism. J Clin Oncol. 2005;23:2123-2129.
19. Kakkar AK, Levine MN, et al. Low molecular weight heparin, therapy with dalteparin, and survival in advanced cancer: the Fragmin Advanced Malignancy Outcome Study. J Clin Oncol. 2004;22:1944-1948.
20. Klerk CPW, Smorenburg SM, et al. The effect of low molecular weight heparin on survival in patients with advanced malignancy. J Clin Oncol. 2005;23:2130-2135.

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