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Adverse Impact of Venous Thromboembolism on Patients with Cancer Ted Wun, MD, FACP1,2,3,4
1 Division of Hematology and Oncology, Department of Internal
Medicine, UC Davis School of Medicine, Sacramento, California 2 Department of Pathology and Laboratory Medicine, UC Davis School of Medicine, Sacramento, California 3 Section of Hematology and Oncology, VA Northern California Health Care System, Mather, California 4 Clinical and Translational Science Center, UC Davis School of Medicine, Sacramento, California
Address for correspondence Ted Wun, MD, FACP, Division of Hematology and Oncology, UC Davis School of Medicine, VANCHCS, 4610 X Street, Sacramento, CA 95817 (e-mail: [email protected]).
Semin Thromb Hemost 2014;40:313–318.
Abstract Keywords
► venous thromboembolism ► cancer ► chemotherapy ► anticoagulation ► survival ► bleeding
Venous thromboembolism (VTE) is a common complication of malignancy. This is related to the underlying cancer and thrombogenic effects of various therapies. Compared with VTE in patients without malignancies, cancer-associated thrombosis is associated with increased mortality, recurrence, and bleeding while on anticoagulants. These worse outcomes are due to a complex interplay between the underlying cancer, host response, antitumor therapies, and interactions between anticoagulants and cancer drugs. Primary prevention of VTE may decrease morbidity and possibly even improve cancer-related survival, but studies to date have not clearly identified a patient population that might be of most benefit nor consistently shown a survival benefit to anticoagulation.
A strong association exists between venous thromboembolism (VTE) and cancer. Trousseau is often credited with observing the association in 1865, when he noted the association of malignancies, especially of the gastrointestinal tract and thrombosis. Up to 20% of incident VTE occurs in patients with cancer; conversely, thrombosis complicates the course of 1 to 20% of cancer patients, depending on the particular type, stage, therapies, and comorbidities.1 The pathogenesis of cancer-associated thrombosis is multifactorial. Virchow triad of venous stasis, hypercoagulability, and vascular injury is often present. Cancer-specific factors include the primary tumor site: pancreatic and gastric cancers carry a high-risk of cancer-associated thrombosis. Other higher risk malignancies include lung cancer, lymphoma, ovarian cancer, bladder cancer, testicular cancer, and leukemia.2 Histological subtype also plays a role, with mucin-secreting adenocarcinoma more commonly associated with VTE than squamous cell histology. Incident VTE is more common in the first year after diagnosis and higher in those with metastatic disease.
Treatment also plays a role in pathogenesis. Major surgery, central venous catheters, various systemic therapies including L-asparaginase, thalidomide, lenalidomide, high-dose dexamethasone, hormonal therapy, and antiangiogenic agents (e.g., bevacizumab), and erythropoietic agents have all been associated with increased incidence of VTE. Finally, patient related factors such as age, comorbidities, sex, immobilization, genetic thrombophilia, and history of thromboembolism contribute to the increased incidence of VTE.3,4 Incident VTE in cancer patients may contribute to adverse outcomes in several ways. First is the morbidity and mortality associated with the VTE itself. Second, both VTE recurrence and bleeding complication from anticoagulation is more common in patients with cancer. Third, anticoagulation may complicate therapy for the cancer because of drug interactions or increasing the risk of adverse events. Finally, cancer-associated VTE is associated with decreased survival for most cancers. This has raised the intriguing notion that primary or secondary prevention of VTE might actually improve cancer survival, a hypothesis
published online March 5, 2014
Copyright © 2014 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
Issue Theme Cancer and Thrombosis: An Update; Guest Editor, Hau C. Kwaan, MD, FRCP.
DOI http://dx.doi.org/ 10.1055/s-0034-1370769. ISSN 0094-6176.
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Mili Arora, MD1
Adverse Impact of VTE on Patients with Cancer
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that has been tested in clinical trials with mixed results. Each of these issues will be discussed.
Morbidity and Mortality from Venous Thromboembolism There is no data demonstrating that major acute complications of deep venous thrombosis (DVT), such as phlegmasia alba dolens and phlegmasia cerulea dolens due to massive venous thrombosis is more common in patients with cancer than those without. Similarly, there is no data that acute complications of hepatic or splanchnic circulation thrombosis is more severe in patients with malignancies. Mortality after pulmonary embolism (PE) in patients with cancer is higher than those without malignancies, but there is no data on whether massive or submassive PE is more common in the cancer population.5,6 The increased risk of death is likely related to progressive cancer and the higher prevalence of comorbidities in patients with malignancies.
Recurrence and Bleeding Complications in Patients with Cancer-Associated Thrombosis Using the Medicare claims data, Levitan et al noted an increased risk of recurrent DVT and pulmonary embolus compared with VTE patients without cancer.7 Prandoni et al evaluated patients with recently diagnosed VTE and hypothesized that recurrent venous thrombosis and bleeding complications would occur more frequently among patients with a diagnosis of cancer during anticoagulant treatment than those without cancer.8 Of the 842 patients with VTE who were evaluated, 181 had a concurrent cancer diagnosis. The 12-month Kaplan-Meier incidence of recurrence was 20.7% (95% confidence interval [CI], 15.6–25.8%) for patients with cancer compared with 6.8% (95% CI, 3.9–9.7%) in patients without cancer (hazard ratio [HR] ¼ 3.2; 95% CI, 1.9–5.4). The 12-month cumulative incidence of major bleeding was 12.4% (95% CI, 6.5–18.2%) in patients with cancer and 4.9% (95% CI, 2.5–7.4%) in patients without cancer, for a HR of 2.2 (95% CI, 1.2–4.1). Bleeding events and recurrence of VTE were thought to be related to cancer stage and appeared to occur more frequently in the 1st month of anticoagulation. However, bleeding events were not related to supra- or subtherapeutic anticoagulation. The risk of recurrent VTE was approximately fourfold higher during the entire anticoagulation period and the risk of bleeding did change over time. One-third of the bleeding events occurred while on initial heparin, while the rest occurred during the oral anticoagulant period that followed. The CLOT (Comparison of Low-molecular-weight heparin versus Oral anticoagulant Therapy) trial was a prospective randomized study comparing dalteparin followed by warfarin to dalteparin alone for secondary prevention of recurrence for cancer patients with incident VTE. Similar to results of the Prandoni et al analysis, the rate of recurrence at 6 months on warfarin was 17% although the risk of major bleeding was only 4%. The overall rate of bleeding at 6 months for the warfarin arm was 19%. Seminars in Thrombosis & Hemostasis
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Another study published by Trujillo-Santos and Monreal evaluated over 3,800 patients from the RIETE (Registro Informatizado de la Enfermedad Trombo Embolica or Computerized Registry of Patients with Venous Thromboembolism) registry.9 This is a multi-institutional, international, prospective registry of consecutive patients with an acute diagnosis of VTE. Consecutive patients with a concurrent diagnosis of VTE and malignancy were analyzed and variables predictive of a higher risk for recurrent VTE or major bleeding complications during the first 3 months of anticoagulation were identified. In this report, 2.4% of patients had recurrent VTE, 44% of which were fatal. Bleeding events occurred in 4.1%, out of which 29% events proved fatal. In this study, many patients were recruited in 2001, before the release of the CLOT study, therefore many patients remained on vitamin K antagonists (VKAs) for their anticoagulation treatment. The authors speculated that increased rates of recurrent VTE and bleeding complications compared with those without cancer likely occur due to concomitant medications, comorbidities that increase risk of VTE, and bleeding independent of the malignancy. There are many potential reasons why both recurrence and bleeding should occur with higher frequency than in patients without malignancy. Cancer patients are typically older and have more medical comorbidities. They undergo operations and have periods of relative immobility. Tumors may invade blood vessels, leading to vascular damage, which would both increase thrombotic risk. The tumor itself can also embolize leading to further clot burden. Based on biomarkers of coagulation activation, there is an overwhelming evidence for a marked hypercoagulable state in cancer that is more profound than in other patients with VTE and varies by the particular malignancy.10–12 Many systemic therapies are also thrombogenic. High-dose corticosteroids, immunomodulators used in myeloma (thalidomide, lenalidomide), erythropoietic agents, and antiangiogenic agents have all been associated with an increased risk of venous and arterial thrombosis.13–16 Bleeding is more common due to many of the same factors that predispose to recurrence. Invasive procedures, systemic therapy that results in thrombocytopenia, renal and hepatic insufficiency due to the effects on tumor obstruction or toxicity of drugs, and antiangiogenic therapies that impede normal blood vessel integrity are the major contributing factors.17–19 Overall, the preponderance of evidence shows increased risk of both recurrent thrombosis and bleeding in patients with cancer-associated thrombosis versus those who have VTE without concurrent malignancy. The reported rates and hazards vary depending on the study. Another important issue not often addressed is the use of competing risk models to determine rates and hazards for recurrent nondeath events more accurately when there is a high mortality in a population.20
Potential Drug Interactions A detailed discussion of potential drug interactions with systemic antineoplastic agents and anticoagulants is beyond
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the scope of this review. It is well appreciated that warfarin has interactions with many drugs, and systemic cancer drugs are no exception. One of the most recent was the potentiation by the oral chemotherapy drug capecitabine on warfarin effect.21–23 There are less documented interactions with heparins and the newer oral anticoagulant drugs. However, and discussed in the next section, there are provocative data that anticoagulation may have a positive effect on survival.
Effect of Cancer-Associated Venous Thromboembolism on Survival Survival of patients with cancer that develop VTE is decreased. There are several potential reasons for this, alone or in combination. As already discussed, the case-fatality rate in cancer patients with DVT/PE may be higher than in noncancer patients.5,6 Patients with cancer and VTE may also have inherently more aggressive tumors. Finally, the milieu of VTE may accelerate the progression of cancer. Multiple studies have shown survival is worse in cohorts with cancer-associated thrombosis. Levitan et al showed that among those patients with DVT/PE and malignant disease, the probability of death within 183 days of initial hospitalization was 0.94 versus 0.29 among those with DVT/PE and no malignancy (p ¼ 0.001).7 Sørensen et al published data in 2000 from the Danish National Registry of Patients, the Danish Cancer Registry, and the Danish Mortality Files examining survival for patients who had a concurrent diagnosis of a malignancy and VTE compared with those patients’ survival outcomes who had a diagnosis of cancer without a VTE (comparator group) using a retrospective case-control design.24 Of the 668 patients who had a diagnosis of cancer concurrent with a VTE, 44% had distant metastases at the time of diagnosis as compared with 35.1% in the non-VTE comparator group (prevalence ratio, 1.26; 95% CI, 1.13–1.40). The 1year probability of survival in the non-VTE group was 36% as compared with 12% in the cancer and VTE group (p < 0.001). Limitations of this study included lack of multivariable analysis, and the comparator group was not matched for stage at cancer diagnosis. One large study by Anderson et al looked at over 400,000 US veterans with DVT. Individuals with (vs. without) a concomitant DVT and cancer diagnosis had a higher risk of dying (HR ¼ 1.38; 95% CI, 1.28–1.49).25 The most prominent excess mortality (HR ¼ 1.29–2.55) was observed among patients diagnosed with DVT at the time of diagnosis of lung, gastric, prostate, bladder, or kidney cancer. Increased risk of dying was also found among cancer patients diagnosed with DVT 1 year (HR ¼ 1.14; 95% CI, 1.07–1.22), 1 to 5 years (HR ¼ 1.14; 95% CI, 1.10–1.19), and > 5 years (HR ¼ 1.27; 95% CI, 1.23–1.31) before cancer. Limitations of this analysis included lack of information on cancer stage, comorbidities, treatment (for both VTE and cancer), and the overwhelmingly male population, all covariates that might affect survival. In a single institution retrospective study, 1,874 patients between 2005 and 2012, with a diagnosis of cancer, were studied for VTE.26 Overall 270 (14.4%) of the patients had a thrombotic event either within 3 months or after cancer
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diagnosis, and these were considered cancer related. Unlike other studies, the events included arterial (28 patients) and combined arterial and venous events. The worst survival was noted in the cohort of patients whose VTE was diagnosed within 3 months before or shortly after their malignancy. This study also found no difference in survival when comparing all potential sites of thrombosis and the median survival following the diagnosis of a VTE event was 16.7 months as compared with 13.5 months in previous studies looking at patients from 1977 to 1992. Survival rates were 96.8, 93.4, 90.0, and 43.4% at 6 months, 1, 2, and 5 years, respectively. These rates were better than those seen in other series from older cohorts and the authors postulated that the improved survival outcomes seen in this study were likely due to improvements in cancer therapy outcomes. Of the 47 patients who died within 3 months of the VTE, 43 were attributed to cancer progression and only 1 to PE. Although, access to source documentation is the strength of this study, the lack of multivariable proportional hazard modeling, for time to event outcomes that should include covariates such as stage and comorbidities, and the relatively low numbers of certain tumor types limit conclusions. In 2011, Trujillo-Santos et al examined 30 day outcomes for 2,472 women with cancer-associated VTE from RIETE data.27 The most common sites of malignancy were breast, colon, gynecologic, and hematologic. Major outcomes that were identified included fatal PE and fatal bleeding events. Initial therapy for VTE included low-molecular-weight heparin (LMWH) in the majority of patients (91%). A total of 34% patients were transitioned to VKAs). During the 30-day study period, 329 (13%) patients died. Of those who died, 71 deaths were attributed to PE and 22 to bleeding, with a few deaths due to infection. Cancer progression was thought to be the cause of the majority of deaths. The 30-day mortality is slightly lower than the 16.1% found in an analysis of 14,000 patients with acute VTE and cancer in California (Wun et al, oral abstract presentation, American Society of Hematology Annual Meeting, 2013, New Orleans, LA). Chew et al examined the incidence of, risk factors for, and effect on mortality of cancer-associated thrombosis using a large population-based dataset from California.28 Adjusting for age, race, and stage, diagnosis of VTE was a significant predictor of decreased survival during the 1st year for all 12 cancer types (HR, 1.6–4.2; p < 0.01). More detailed analyses of individual tumors types by this same group have corroborated the adverse effect of survival.29–33 These analyses were able to include analysis of important covariates for survival such as age, stage, comorbidities, and ethnicity. However, detailed treatment information (for both VTE and cancer) was not available. In addition to the possible higher case-fatality rate in patients with cancer, there are several lines of evidence which suggest that more aggressive cancers are associated with an increased risk of VTE, and that VTE may promote both local and metastatic spread. The incidence of cancer-associated thrombosis varies widely with the primary site, presenting stage, and histology.28,34 Clinically more aggressive tumors, such as primary brain tumors and pancreas cancer, are Seminars in Thrombosis & Hemostasis
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Adverse Impact of VTE on Patients with Cancer
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associated with highest risk of VTE.14 Biomarkers indicative of thrombotic risk, such as increased tissue factor bearing microparticles (TFMP), are generally more prevalent in more aggressive tumors as well.11,15,35 There is also provocative more recent data on the interaction of tissue factor and protease activated receptors (PARs) expressed by tumor cells and vascular cells leading to angiogenesis, cell adhesion, and migration. With more advanced or clinically aggressive disease, there is an increase in procoagulant factors generated by tumor cells, including tissue factor and PARs. This has also been correlated with oncogene expression profiles that are associated with poor prognosis.36–40 In this construct, increased tissue and circulating levels of activated coagulation factors, such as seen in acute thrombosis, also promotes tumor invasion, angiogenesis, and metastases. The reader is referred to an excellent review on the topic by Ruf.37
Role of Anticoagulants in Cancer Therapy Given the adverse outcomes associated with VTE in patients with cancer, at least two important questions arise: (1) is it worthwhile to give primary pharmacological prophylaxis to patients with cancer to prevent VTE? (2) Can anticoagulant therapy improve cancer cause-specific survival? The answers to these questions are still uncertain. It is fairly noncontroversial that hospitalized cancer patients should receive pharmacological VTE prophylaxis so this will not be discussed. There have been two large randomized studies of primary VTE prophylaxis for ambulatory patients receiving antineoplastic therapy recently published, following on an original small study in advanced breast cancer patients by Levine et al.41 In the PROTECHT (PROphylaxis of ThromboEmbolism during CHemoTherapy) study, 1,150 patients were randomized 2:1 to receive nadroparin or placebo. Most patients had advanced disease. The outcomes were any symptomatic thrombotic event, arterial or venous. Overall 15 (2.0%) of 769 patients were treated with nadroparin, and 15 (3.9%) of 381 patients treated with placebo had a thromboembolic event (single-sided p ¼ 0.02). The benefit was proportionately greatest in those with lung and nonpancreas gastrointestinal tumors, but the low numbers in any one subgroup precluded formal subset analysis. Importantly, there was no difference in survival between the nadroparin and placebo arms. Although, there was a statistically significant reduction in thrombosis, the low absolute incidence of 3.9% in the placebo arm calls into question whether a daily parenteral drug associated with increased risk of bleeding is worth the 1.9% absolute reduction in events. In the SAVE-ONCO study, patients with metastatic or locally advanced solid tumors who were beginning to receive a course of chemotherapy were randomly assigned 1:1 to receive subcutaneous semuloparin or placebo.42 The primary efficacy outcome was the composite of any symptomatic DVT, any nonfatal PE, and death related to VTE. VTE occurred in 20 of 1,608 patients (1.2%) receiving semuloparin, as compared with 55 of 1,604 (3.4%) receiving placebo (HR, 0.36; 95% CI, 0.21–0.60; p < 0.001). There was no heterogeneity of effect Seminars in Thrombosis & Hemostasis
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based on stage or site of cancer origin. The incidence of clinically relevant bleeding was 2.8 and 2.0% in the semuloparin and placebo groups, respectively (HR, 1.40; 95% CI, 0.89–2.21). There was no effect on survival for these patients with locally advanced and metastatic cancer. Once again the relative risk reduction was significant, but the absolute difference was small given the risk of clinically relevant bleeding. A strategy to improve the therapeutic index and absolute risk reduction is to target higher risk patients for thromboprophylaxis. If a population of cancer patients could be identified at high enough absolute risk of VTE, if one could achieve the same degree of relative risk reduction as in PROTECT and SAVE-ONCO, primary thromboprophylaxis might have a better benefit:risk ratio. In the Microtec study, Zwicker et al identified higher risk patients using levels of circulating TFMP.43 In this randomized phase 2 trial the cumulative incidence of VTE at 2 months in the higher TFMP group randomized to enoxaparin (n ¼ 23) was 5.6% while the higher TFMP group observation arm (n ¼ 11) was 27.3% (Gray test, p ¼ 0.06). The cumulative incidence of VTE in the low TFMP was 7.2% (n ¼ 32). This study suggests that one can effectively target a higher risk population for primary VTE risk reduction. The Prophylaxis in High-Risk Ambulatory Cancer Patients Study (PHACS; ClinicalTrials.gov NCT00876915) is currently ongoing and uses a validated risk stratification score to identify patients for primary VTE prophylaxis.44 Retrospective subset analysis of anticoagulant trials in patients with cancer had suggested improved survival, especially for those treated with LMWH.45–47 The strongest evidence for beneficial effect is seen with small cell lung cancer, and it is somewhat surprising there are no confirmatory studies.48,49 Two trials, FAMOUS (Fragmin Advanced Malignancy Outcome Study) and MALT (Malignancy and Lowmolecular weight heparin Trial) examined the effect of LMWHs on survival.50,51 Overall there was no survival advantage to LMWH versus placebo. Another study using nadroparin, the same LMWH as used in MALT, was more recently published.52 A total of 244 patients were allocated to nadroparin, and 259 were allocated to the control group. A median survival of 13.1 months was observed in the nadroparin recipients compared with 11.9 months in the no treatment arm (HR, 0.94; 95% CI, 0.75–1.18, adjusted for cancer type). No difference in time to progression was observed. The number of major bleedings was comparable at 4.1% in the nadroparin set and 3.5% in the control set. Almost all patients in these negative trials had advanced disease and poor prognosis. Interestingly, subset analysis of these studies revealed survival advantages to LMWH for patients with less advanced disease and better prognosis. These findings were corroborated by another post hoc analysis of the CLOT trial, a randomized prospective study of dalteparin versus warfarin for patients with cancer-associated VTE.53 Among patients without metastatic disease, the probability of death at 12 months was 20% in the dalteparin group, as compared with 36% in the oral anticoagulant group (HR, 0.50; 95% CI, 0.27–0.95; p ¼ 0.03). In patients with metastatic cancer, no difference in mortality between the treatment
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Adverse Impact of VTE on Patients with Cancer
Summary A variety of factors contribute to increased incident VTE in cancer. Recurrence of VTE, bleeding, and mortality rates are higher among patients with a concurrent diagnosis of VTE and cancer than those without malignancy. There are multiple reasons for this including patient-related factors (comorbidities), tumor-related factors (more aggressive malignancies are associated with increased thrombogenic potential), and treatment-related factors (thrombogenic agents such as lenalidomide). In addition, the treatment for VTE is often more complicated in cancer patients due to interactions between the anticoagulants and cancer treatment leading to increased adverse events. Research to determine which populations of cancer patients might benefit from primary prophylaxis with anticoagulants is still preliminary. However, predictive scores and biomarkers may identify patients in whom prophylaxis will result in most overall clinical impact. The results of these studies are much anticipated.
8 Prandoni P, Lensing AW, Piccioli A, et al. Recurrent venous throm-
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Acknowledgments The authors wish to thank Theresa Muniz for editorial assistance. T.W. is supported by a grant from the National Centers for Advancing Translational Science (grant number NIH TR000002).
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with elevated tissue factor-bearing microparticles: a randomizedcontrolled phase II trial (the Microtec study). Br J Haematol 2013; 160(4):530–537 Khorana AA, Kuderer NM, Culakova E, Lyman GH, Francis CW. Development and validation of a predictive model for chemotherapy-associated thrombosis. Blood 2008;111(10): 4902–4907 Kuderer NM, Khorana AA, Lyman GH, Francis CW. A meta-analysis and systematic review of the efficacy and safety of anticoagulants as cancer treatment: impact on survival and bleeding complications. Cancer 2007;110(5):1149–1161 Smorenburg SM, Hettiarachchi RJ, Vink R, Büller HR. The effects of unfractionated heparin on survival in patients with malignancy—a systematic review. Thromb Haemost 1999;82(6): 1600–1604 Hettiarachchi RJ, Smorenburg SM, Ginsberg J, Levine M, Prins MH, Büller HR. Do heparins do more than just treat thrombosis? The influence of heparins on cancer spread. Thromb Haemost 1999; 82(2):947–952 Lebeau B, Chastang C, Brechot JM, et al. Subcutaneous heparin treatment increases survival in small cell lung cancer. “Petites Cellules” Group. Cancer 1994;74(1):38–45 Altinbas M, Coskun HS, Er O, et al. A randomized clinical trial of combination chemotherapy with and without low-molecularweight heparin in small cell lung cancer. J Thromb Haemost 2004;2(8):1266–1271 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(10):1944–1948 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(10):2130–2135 van Doormaal FF, Di Nisio M, Otten HM, Richel DJ, Prins M, Buller HR. Randomized trial of the effect of the low molecular weight heparin nadroparin on survival in patients with cancer. J Clin Oncol 2011;29(15):2071–2076 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(10):2123–2129
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Adverse Impact of Venous Thromboembolism on Patients with Cancer Ted Wun, MD, FACP1,2,3,4
1 Division of Hematology and Oncology, Department of Internal
Medicine, UC Davis School of Medicine, Sacramento, California 2 Department of Pathology and Laboratory Medicine, UC Davis School of Medicine, Sacramento, California 3 Section of Hematology and Oncology, VA Northern California Health Care System, Mather, California 4 Clinical and Translational Science Center, UC Davis School of Medicine, Sacramento, California
Address for correspondence Ted Wun, MD, FACP, Division of Hematology and Oncology, UC Davis School of Medicine, VANCHCS, 4610 X Street, Sacramento, CA 95817 (e-mail: [email protected]).
Semin Thromb Hemost 2014;40:313–318.
Abstract Keywords
► venous thromboembolism ► cancer ► chemotherapy ► anticoagulation ► survival ► bleeding
Venous thromboembolism (VTE) is a common complication of malignancy. This is related to the underlying cancer and thrombogenic effects of various therapies. Compared with VTE in patients without malignancies, cancer-associated thrombosis is associated with increased mortality, recurrence, and bleeding while on anticoagulants. These worse outcomes are due to a complex interplay between the underlying cancer, host response, antitumor therapies, and interactions between anticoagulants and cancer drugs. Primary prevention of VTE may decrease morbidity and possibly even improve cancer-related survival, but studies to date have not clearly identified a patient population that might be of most benefit nor consistently shown a survival benefit to anticoagulation.
A strong association exists between venous thromboembolism (VTE) and cancer. Trousseau is often credited with observing the association in 1865, when he noted the association of malignancies, especially of the gastrointestinal tract and thrombosis. Up to 20% of incident VTE occurs in patients with cancer; conversely, thrombosis complicates the course of 1 to 20% of cancer patients, depending on the particular type, stage, therapies, and comorbidities.1 The pathogenesis of cancer-associated thrombosis is multifactorial. Virchow triad of venous stasis, hypercoagulability, and vascular injury is often present. Cancer-specific factors include the primary tumor site: pancreatic and gastric cancers carry a high-risk of cancer-associated thrombosis. Other higher risk malignancies include lung cancer, lymphoma, ovarian cancer, bladder cancer, testicular cancer, and leukemia.2 Histological subtype also plays a role, with mucin-secreting adenocarcinoma more commonly associated with VTE than squamous cell histology. Incident VTE is more common in the first year after diagnosis and higher in those with metastatic disease.
Treatment also plays a role in pathogenesis. Major surgery, central venous catheters, various systemic therapies including L-asparaginase, thalidomide, lenalidomide, high-dose dexamethasone, hormonal therapy, and antiangiogenic agents (e.g., bevacizumab), and erythropoietic agents have all been associated with increased incidence of VTE. Finally, patient related factors such as age, comorbidities, sex, immobilization, genetic thrombophilia, and history of thromboembolism contribute to the increased incidence of VTE.3,4 Incident VTE in cancer patients may contribute to adverse outcomes in several ways. First is the morbidity and mortality associated with the VTE itself. Second, both VTE recurrence and bleeding complication from anticoagulation is more common in patients with cancer. Third, anticoagulation may complicate therapy for the cancer because of drug interactions or increasing the risk of adverse events. Finally, cancer-associated VTE is associated with decreased survival for most cancers. This has raised the intriguing notion that primary or secondary prevention of VTE might actually improve cancer survival, a hypothesis
published online March 5, 2014
Copyright © 2014 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
Issue Theme Cancer and Thrombosis: An Update; Guest Editor, Hau C. Kwaan, MD, FRCP.
DOI http://dx.doi.org/ 10.1055/s-0034-1370769. ISSN 0094-6176.
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Mili Arora, MD1
Adverse Impact of VTE on Patients with Cancer
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that has been tested in clinical trials with mixed results. Each of these issues will be discussed.
Morbidity and Mortality from Venous Thromboembolism There is no data demonstrating that major acute complications of deep venous thrombosis (DVT), such as phlegmasia alba dolens and phlegmasia cerulea dolens due to massive venous thrombosis is more common in patients with cancer than those without. Similarly, there is no data that acute complications of hepatic or splanchnic circulation thrombosis is more severe in patients with malignancies. Mortality after pulmonary embolism (PE) in patients with cancer is higher than those without malignancies, but there is no data on whether massive or submassive PE is more common in the cancer population.5,6 The increased risk of death is likely related to progressive cancer and the higher prevalence of comorbidities in patients with malignancies.
Recurrence and Bleeding Complications in Patients with Cancer-Associated Thrombosis Using the Medicare claims data, Levitan et al noted an increased risk of recurrent DVT and pulmonary embolus compared with VTE patients without cancer.7 Prandoni et al evaluated patients with recently diagnosed VTE and hypothesized that recurrent venous thrombosis and bleeding complications would occur more frequently among patients with a diagnosis of cancer during anticoagulant treatment than those without cancer.8 Of the 842 patients with VTE who were evaluated, 181 had a concurrent cancer diagnosis. The 12-month Kaplan-Meier incidence of recurrence was 20.7% (95% confidence interval [CI], 15.6–25.8%) for patients with cancer compared with 6.8% (95% CI, 3.9–9.7%) in patients without cancer (hazard ratio [HR] ¼ 3.2; 95% CI, 1.9–5.4). The 12-month cumulative incidence of major bleeding was 12.4% (95% CI, 6.5–18.2%) in patients with cancer and 4.9% (95% CI, 2.5–7.4%) in patients without cancer, for a HR of 2.2 (95% CI, 1.2–4.1). Bleeding events and recurrence of VTE were thought to be related to cancer stage and appeared to occur more frequently in the 1st month of anticoagulation. However, bleeding events were not related to supra- or subtherapeutic anticoagulation. The risk of recurrent VTE was approximately fourfold higher during the entire anticoagulation period and the risk of bleeding did change over time. One-third of the bleeding events occurred while on initial heparin, while the rest occurred during the oral anticoagulant period that followed. The CLOT (Comparison of Low-molecular-weight heparin versus Oral anticoagulant Therapy) trial was a prospective randomized study comparing dalteparin followed by warfarin to dalteparin alone for secondary prevention of recurrence for cancer patients with incident VTE. Similar to results of the Prandoni et al analysis, the rate of recurrence at 6 months on warfarin was 17% although the risk of major bleeding was only 4%. The overall rate of bleeding at 6 months for the warfarin arm was 19%. Seminars in Thrombosis & Hemostasis
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Another study published by Trujillo-Santos and Monreal evaluated over 3,800 patients from the RIETE (Registro Informatizado de la Enfermedad Trombo Embolica or Computerized Registry of Patients with Venous Thromboembolism) registry.9 This is a multi-institutional, international, prospective registry of consecutive patients with an acute diagnosis of VTE. Consecutive patients with a concurrent diagnosis of VTE and malignancy were analyzed and variables predictive of a higher risk for recurrent VTE or major bleeding complications during the first 3 months of anticoagulation were identified. In this report, 2.4% of patients had recurrent VTE, 44% of which were fatal. Bleeding events occurred in 4.1%, out of which 29% events proved fatal. In this study, many patients were recruited in 2001, before the release of the CLOT study, therefore many patients remained on vitamin K antagonists (VKAs) for their anticoagulation treatment. The authors speculated that increased rates of recurrent VTE and bleeding complications compared with those without cancer likely occur due to concomitant medications, comorbidities that increase risk of VTE, and bleeding independent of the malignancy. There are many potential reasons why both recurrence and bleeding should occur with higher frequency than in patients without malignancy. Cancer patients are typically older and have more medical comorbidities. They undergo operations and have periods of relative immobility. Tumors may invade blood vessels, leading to vascular damage, which would both increase thrombotic risk. The tumor itself can also embolize leading to further clot burden. Based on biomarkers of coagulation activation, there is an overwhelming evidence for a marked hypercoagulable state in cancer that is more profound than in other patients with VTE and varies by the particular malignancy.10–12 Many systemic therapies are also thrombogenic. High-dose corticosteroids, immunomodulators used in myeloma (thalidomide, lenalidomide), erythropoietic agents, and antiangiogenic agents have all been associated with an increased risk of venous and arterial thrombosis.13–16 Bleeding is more common due to many of the same factors that predispose to recurrence. Invasive procedures, systemic therapy that results in thrombocytopenia, renal and hepatic insufficiency due to the effects on tumor obstruction or toxicity of drugs, and antiangiogenic therapies that impede normal blood vessel integrity are the major contributing factors.17–19 Overall, the preponderance of evidence shows increased risk of both recurrent thrombosis and bleeding in patients with cancer-associated thrombosis versus those who have VTE without concurrent malignancy. The reported rates and hazards vary depending on the study. Another important issue not often addressed is the use of competing risk models to determine rates and hazards for recurrent nondeath events more accurately when there is a high mortality in a population.20
Potential Drug Interactions A detailed discussion of potential drug interactions with systemic antineoplastic agents and anticoagulants is beyond
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the scope of this review. It is well appreciated that warfarin has interactions with many drugs, and systemic cancer drugs are no exception. One of the most recent was the potentiation by the oral chemotherapy drug capecitabine on warfarin effect.21–23 There are less documented interactions with heparins and the newer oral anticoagulant drugs. However, and discussed in the next section, there are provocative data that anticoagulation may have a positive effect on survival.
Effect of Cancer-Associated Venous Thromboembolism on Survival Survival of patients with cancer that develop VTE is decreased. There are several potential reasons for this, alone or in combination. As already discussed, the case-fatality rate in cancer patients with DVT/PE may be higher than in noncancer patients.5,6 Patients with cancer and VTE may also have inherently more aggressive tumors. Finally, the milieu of VTE may accelerate the progression of cancer. Multiple studies have shown survival is worse in cohorts with cancer-associated thrombosis. Levitan et al showed that among those patients with DVT/PE and malignant disease, the probability of death within 183 days of initial hospitalization was 0.94 versus 0.29 among those with DVT/PE and no malignancy (p ¼ 0.001).7 Sørensen et al published data in 2000 from the Danish National Registry of Patients, the Danish Cancer Registry, and the Danish Mortality Files examining survival for patients who had a concurrent diagnosis of a malignancy and VTE compared with those patients’ survival outcomes who had a diagnosis of cancer without a VTE (comparator group) using a retrospective case-control design.24 Of the 668 patients who had a diagnosis of cancer concurrent with a VTE, 44% had distant metastases at the time of diagnosis as compared with 35.1% in the non-VTE comparator group (prevalence ratio, 1.26; 95% CI, 1.13–1.40). The 1year probability of survival in the non-VTE group was 36% as compared with 12% in the cancer and VTE group (p < 0.001). Limitations of this study included lack of multivariable analysis, and the comparator group was not matched for stage at cancer diagnosis. One large study by Anderson et al looked at over 400,000 US veterans with DVT. Individuals with (vs. without) a concomitant DVT and cancer diagnosis had a higher risk of dying (HR ¼ 1.38; 95% CI, 1.28–1.49).25 The most prominent excess mortality (HR ¼ 1.29–2.55) was observed among patients diagnosed with DVT at the time of diagnosis of lung, gastric, prostate, bladder, or kidney cancer. Increased risk of dying was also found among cancer patients diagnosed with DVT 1 year (HR ¼ 1.14; 95% CI, 1.07–1.22), 1 to 5 years (HR ¼ 1.14; 95% CI, 1.10–1.19), and > 5 years (HR ¼ 1.27; 95% CI, 1.23–1.31) before cancer. Limitations of this analysis included lack of information on cancer stage, comorbidities, treatment (for both VTE and cancer), and the overwhelmingly male population, all covariates that might affect survival. In a single institution retrospective study, 1,874 patients between 2005 and 2012, with a diagnosis of cancer, were studied for VTE.26 Overall 270 (14.4%) of the patients had a thrombotic event either within 3 months or after cancer
Arora, Wun
diagnosis, and these were considered cancer related. Unlike other studies, the events included arterial (28 patients) and combined arterial and venous events. The worst survival was noted in the cohort of patients whose VTE was diagnosed within 3 months before or shortly after their malignancy. This study also found no difference in survival when comparing all potential sites of thrombosis and the median survival following the diagnosis of a VTE event was 16.7 months as compared with 13.5 months in previous studies looking at patients from 1977 to 1992. Survival rates were 96.8, 93.4, 90.0, and 43.4% at 6 months, 1, 2, and 5 years, respectively. These rates were better than those seen in other series from older cohorts and the authors postulated that the improved survival outcomes seen in this study were likely due to improvements in cancer therapy outcomes. Of the 47 patients who died within 3 months of the VTE, 43 were attributed to cancer progression and only 1 to PE. Although, access to source documentation is the strength of this study, the lack of multivariable proportional hazard modeling, for time to event outcomes that should include covariates such as stage and comorbidities, and the relatively low numbers of certain tumor types limit conclusions. In 2011, Trujillo-Santos et al examined 30 day outcomes for 2,472 women with cancer-associated VTE from RIETE data.27 The most common sites of malignancy were breast, colon, gynecologic, and hematologic. Major outcomes that were identified included fatal PE and fatal bleeding events. Initial therapy for VTE included low-molecular-weight heparin (LMWH) in the majority of patients (91%). A total of 34% patients were transitioned to VKAs). During the 30-day study period, 329 (13%) patients died. Of those who died, 71 deaths were attributed to PE and 22 to bleeding, with a few deaths due to infection. Cancer progression was thought to be the cause of the majority of deaths. The 30-day mortality is slightly lower than the 16.1% found in an analysis of 14,000 patients with acute VTE and cancer in California (Wun et al, oral abstract presentation, American Society of Hematology Annual Meeting, 2013, New Orleans, LA). Chew et al examined the incidence of, risk factors for, and effect on mortality of cancer-associated thrombosis using a large population-based dataset from California.28 Adjusting for age, race, and stage, diagnosis of VTE was a significant predictor of decreased survival during the 1st year for all 12 cancer types (HR, 1.6–4.2; p < 0.01). More detailed analyses of individual tumors types by this same group have corroborated the adverse effect of survival.29–33 These analyses were able to include analysis of important covariates for survival such as age, stage, comorbidities, and ethnicity. However, detailed treatment information (for both VTE and cancer) was not available. In addition to the possible higher case-fatality rate in patients with cancer, there are several lines of evidence which suggest that more aggressive cancers are associated with an increased risk of VTE, and that VTE may promote both local and metastatic spread. The incidence of cancer-associated thrombosis varies widely with the primary site, presenting stage, and histology.28,34 Clinically more aggressive tumors, such as primary brain tumors and pancreas cancer, are Seminars in Thrombosis & Hemostasis
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Adverse Impact of VTE on Patients with Cancer
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associated with highest risk of VTE.14 Biomarkers indicative of thrombotic risk, such as increased tissue factor bearing microparticles (TFMP), are generally more prevalent in more aggressive tumors as well.11,15,35 There is also provocative more recent data on the interaction of tissue factor and protease activated receptors (PARs) expressed by tumor cells and vascular cells leading to angiogenesis, cell adhesion, and migration. With more advanced or clinically aggressive disease, there is an increase in procoagulant factors generated by tumor cells, including tissue factor and PARs. This has also been correlated with oncogene expression profiles that are associated with poor prognosis.36–40 In this construct, increased tissue and circulating levels of activated coagulation factors, such as seen in acute thrombosis, also promotes tumor invasion, angiogenesis, and metastases. The reader is referred to an excellent review on the topic by Ruf.37
Role of Anticoagulants in Cancer Therapy Given the adverse outcomes associated with VTE in patients with cancer, at least two important questions arise: (1) is it worthwhile to give primary pharmacological prophylaxis to patients with cancer to prevent VTE? (2) Can anticoagulant therapy improve cancer cause-specific survival? The answers to these questions are still uncertain. It is fairly noncontroversial that hospitalized cancer patients should receive pharmacological VTE prophylaxis so this will not be discussed. There have been two large randomized studies of primary VTE prophylaxis for ambulatory patients receiving antineoplastic therapy recently published, following on an original small study in advanced breast cancer patients by Levine et al.41 In the PROTECHT (PROphylaxis of ThromboEmbolism during CHemoTherapy) study, 1,150 patients were randomized 2:1 to receive nadroparin or placebo. Most patients had advanced disease. The outcomes were any symptomatic thrombotic event, arterial or venous. Overall 15 (2.0%) of 769 patients were treated with nadroparin, and 15 (3.9%) of 381 patients treated with placebo had a thromboembolic event (single-sided p ¼ 0.02). The benefit was proportionately greatest in those with lung and nonpancreas gastrointestinal tumors, but the low numbers in any one subgroup precluded formal subset analysis. Importantly, there was no difference in survival between the nadroparin and placebo arms. Although, there was a statistically significant reduction in thrombosis, the low absolute incidence of 3.9% in the placebo arm calls into question whether a daily parenteral drug associated with increased risk of bleeding is worth the 1.9% absolute reduction in events. In the SAVE-ONCO study, patients with metastatic or locally advanced solid tumors who were beginning to receive a course of chemotherapy were randomly assigned 1:1 to receive subcutaneous semuloparin or placebo.42 The primary efficacy outcome was the composite of any symptomatic DVT, any nonfatal PE, and death related to VTE. VTE occurred in 20 of 1,608 patients (1.2%) receiving semuloparin, as compared with 55 of 1,604 (3.4%) receiving placebo (HR, 0.36; 95% CI, 0.21–0.60; p < 0.001). There was no heterogeneity of effect Seminars in Thrombosis & Hemostasis
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based on stage or site of cancer origin. The incidence of clinically relevant bleeding was 2.8 and 2.0% in the semuloparin and placebo groups, respectively (HR, 1.40; 95% CI, 0.89–2.21). There was no effect on survival for these patients with locally advanced and metastatic cancer. Once again the relative risk reduction was significant, but the absolute difference was small given the risk of clinically relevant bleeding. A strategy to improve the therapeutic index and absolute risk reduction is to target higher risk patients for thromboprophylaxis. If a population of cancer patients could be identified at high enough absolute risk of VTE, if one could achieve the same degree of relative risk reduction as in PROTECT and SAVE-ONCO, primary thromboprophylaxis might have a better benefit:risk ratio. In the Microtec study, Zwicker et al identified higher risk patients using levels of circulating TFMP.43 In this randomized phase 2 trial the cumulative incidence of VTE at 2 months in the higher TFMP group randomized to enoxaparin (n ¼ 23) was 5.6% while the higher TFMP group observation arm (n ¼ 11) was 27.3% (Gray test, p ¼ 0.06). The cumulative incidence of VTE in the low TFMP was 7.2% (n ¼ 32). This study suggests that one can effectively target a higher risk population for primary VTE risk reduction. The Prophylaxis in High-Risk Ambulatory Cancer Patients Study (PHACS; ClinicalTrials.gov NCT00876915) is currently ongoing and uses a validated risk stratification score to identify patients for primary VTE prophylaxis.44 Retrospective subset analysis of anticoagulant trials in patients with cancer had suggested improved survival, especially for those treated with LMWH.45–47 The strongest evidence for beneficial effect is seen with small cell lung cancer, and it is somewhat surprising there are no confirmatory studies.48,49 Two trials, FAMOUS (Fragmin Advanced Malignancy Outcome Study) and MALT (Malignancy and Lowmolecular weight heparin Trial) examined the effect of LMWHs on survival.50,51 Overall there was no survival advantage to LMWH versus placebo. Another study using nadroparin, the same LMWH as used in MALT, was more recently published.52 A total of 244 patients were allocated to nadroparin, and 259 were allocated to the control group. A median survival of 13.1 months was observed in the nadroparin recipients compared with 11.9 months in the no treatment arm (HR, 0.94; 95% CI, 0.75–1.18, adjusted for cancer type). No difference in time to progression was observed. The number of major bleedings was comparable at 4.1% in the nadroparin set and 3.5% in the control set. Almost all patients in these negative trials had advanced disease and poor prognosis. Interestingly, subset analysis of these studies revealed survival advantages to LMWH for patients with less advanced disease and better prognosis. These findings were corroborated by another post hoc analysis of the CLOT trial, a randomized prospective study of dalteparin versus warfarin for patients with cancer-associated VTE.53 Among patients without metastatic disease, the probability of death at 12 months was 20% in the dalteparin group, as compared with 36% in the oral anticoagulant group (HR, 0.50; 95% CI, 0.27–0.95; p ¼ 0.03). In patients with metastatic cancer, no difference in mortality between the treatment
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Adverse Impact of VTE on Patients with Cancer
Summary A variety of factors contribute to increased incident VTE in cancer. Recurrence of VTE, bleeding, and mortality rates are higher among patients with a concurrent diagnosis of VTE and cancer than those without malignancy. There are multiple reasons for this including patient-related factors (comorbidities), tumor-related factors (more aggressive malignancies are associated with increased thrombogenic potential), and treatment-related factors (thrombogenic agents such as lenalidomide). In addition, the treatment for VTE is often more complicated in cancer patients due to interactions between the anticoagulants and cancer treatment leading to increased adverse events. Research to determine which populations of cancer patients might benefit from primary prophylaxis with anticoagulants is still preliminary. However, predictive scores and biomarkers may identify patients in whom prophylaxis will result in most overall clinical impact. The results of these studies are much anticipated.
8 Prandoni P, Lensing AW, Piccioli A, et al. Recurrent venous throm-
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Acknowledgments The authors wish to thank Theresa Muniz for editorial assistance. T.W. is supported by a grant from the National Centers for Advancing Translational Science (grant number NIH TR000002).
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groups was observed (72 and 69%, respectively; HR, 1.1; 95% CI, 0.87–1.4; p ¼ 0.46). Thus, the overall evidence does not support the use of LMWH to improve survival in patients with advanced cancers, but it remains possible that LMWH may have a positive effect on survival in those with less advanced cancer.
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