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Release date: July 5, 2011; Expiration date: July 5, 2012
Learning Objectives
Upon completion of this activity, participants will be able to:
Describe clinical risk factors for VTE in cancer, based on a review
Describe biomarkers predictive of VTE and a recently validated risk model for VTE
Describe the role of thromboprophylaxis in patients at high risk for VTE
Patients with cancer, particularly those undergoing active treatment, frequently experience thromboembolic events. These can include deep vein thrombosis (DVT), pulmonary embolism (PE), which together are categorized as venous thromboembolism (VTE), and arterial events, including stroke and myocardial infarction. The frequency of both VTE and arterial events has increased substantially in the past decade,1 as have trends for venous thromboembolism among hospitalized cancer patients. However, despite the well-known prevalence of VTE in the cancer population, the risk varies widely among subgroups of patients and in individual patients over time.2,3 Anticoagulants, including low-molecular-weight heparins (LMWHs) and warfarin, have been shown to be safe and effective in preventing VTE in high-risk settings. Understanding the risk for VTE in individual cancer patients or in specific settings therefore becomes especially important to applying targeted thromboprophylaxis.
Knowledge gained within the past decade has improved understanding of risk assessment and prophylaxis of cancer-associated VTE. This article focuses on clinical risk factors, biomarkers, and risk assessment tools that can help clinicians identify cancer patients at risk for VTE, and trials of prophylaxis in various settings, with a particular emphasis on recent developments. VTE is the primary focus of this article; when available, data relevant to arterial events are also discussed.
Risk Assessment
Clinical Risk Factors
Clinical risk factors for VTE include patient-related, cancer-related, and treatment-related risk factors (Table 1). Patient-related risk factors include older age, African-American race, and presence of comorbidities1 and trends for VTE among hospitalized cancer patients. Comorbid conditions are strongly associated with VTE, particularly infection, pulmonary disease, renal disease, and obesity.4 Cancer patients with a prior history of VTE have a 6- to 7-fold increased risk of developing VTE compared with those with no history of VTE.5 The primary site of cancer is an especially important risk factor, and is often the basis of selection of cancer patients for trials of prophylaxis. The highest rates of VTE have been observed in patients with brain, pancreas, stomach, kidney, ovary, and lung cancers.2 However, recent data suggest that patients with hematologic malignancies are also at high risk (in one study the odds ratio [OR] was 28; 95% CI, 4.0-199.7).3 The rate of VTE peaks during the initial period after diagnosis. In the population-based study discussed earlier, risk of VTE was highest in the first 3 months after initial cancer diagnosis (OR, 53.5; 95% CI, 8.6-334.3), although some degree of elevated risk persisted for several years.3
Selected Clinical Risk Factors for Cancer-Associated Thrombosis
Active treatment further enhances the risk of VTE. The use of systemic chemotherapy is associated with a 2- to 6-fold increased risk of VTE compared with the general population.6,7 The use of a central venous catheter to deliver treatment adds to this risk, although recent studies have shown an overall low risk with contemporary catheters.8 Cancer patients undergoing surgery have a 2-fold increased risk of postoperative VTE compared with noncancer patients, and this elevation in risk can persist for up to 7 weeks after the procedure.9 Hospitalization substantially increases the risk of VTE development in cancer patients (OR, 2.34; 95% CI, 1.63-3.36).10 Antiangiogenic agents, particularly thalidomide and lenalidomide, have been associated with high rates of VTE when given in combination with dexamethasone or chemotherapy.
Bevacizumab-containing regimens have been associated with increased risk for an arterial thromboembolic event (hazard ratio [HR], 2.0; 95% CI, 1.05-3.75), but the data on VTE risk are conflicting.11,12 In the most recent meta-analysis, VTE occurred in 11.9% of patients treated with bevacizumab (relative risk [RR], 1.33; 95% CI, 1.13-1.56; P < .001).12 However, patients with bevacizumab stay on treatment longer because of its efficacy; in a subsequent reanalysis, the investigators found no significant association with VTE when time on therapy was included as a variable (RR, 1.10; 95% CI, 0.89-1.36). Sunitinib and sorafenib, agents targeting the angiogenesis pathway, have also been associated with an elevated risk for arterial events (RR, 3.03; 95% CI, 1.25-7.37), suggesting that this may be a class effect for antiangiogenic agents.13
Biomarkers
Multiple recent studies, conducted primarily in cancer outpatients, have identified several novel biomarkers predictive of VTE (Table 2). Some of these biomarkers are easily available, whereas others are available only through specialized laboratories and should be considered investigational.
Selected Biomarkers Predictive of Cancer-Associated Thrombosis
Baseline (prechemotherapy) elevated platelet and leukocyte counts, and low hemoglobin levels, have all been shown to be risk factors for chemotherapy-associated VTE.14,15 For instance, in a prospective analysis of 4405 ambulatory cancer patients initiating chemotherapy, VTE occurred in 25 of 561 patients (4.5%) with baseline leukocytosis compared with 68 of 3830 (1.8%) without leukocytosis (P < .0001).16 Interestingly, elevation of both absolute neutrophil count (ANC; > 7.7 × 109 cells/L) and absolute monocyte count (AMC; > 1.2 × 109 cells/L) was associated (P < .0001 for each) with increased risk of VTE, whereas baseline lymphocytosis (> 4.8 × 109 cells/L) was not.
Several recent studies have examined the role of D-dimer levels before chemotherapy or major surgery in predicting VTE. In colorectal cancer, patients with elevated D-dimer (defined as > 0.3 mg/L) had a 20% (95% CI, 12%-31%) 1-year incidence of DVT versus 5% (95% CI, 2%-12%) for other patients (adjusted HR, 6.53; 95% CI, 1.58-27.0).17 Elevated D-dimer in addition to prothrombin split products (as defined by a cutoff set at the 75th percentile of the total study population) were associated with an increased risk of VTE (HR, 1.8; 95% CI, 1.0-3.2; P = .048, and HR, 2.0; 95% CI, 1.2-3.6; P = .015, respectively) in the Vienna CATS registry.18
The best-known investigational biomarker is tissue factor (TF), the physiologic initiator of hemostasis, which is also widely expressed across a variety of human malignancies.19 Unfortunately, no consensus currently exists on a standard assay to evaluate TF; published methods include immunohistochemical grading of TF expression on tumor cells,20 measurement of TF antigen using enzyme-linked immunosorbent assay (ELISA),21 TF microparticle procoagulant activity,22 or impedance-based flow cytometry.23 Reports suggest a significant association between elevated TF and subsequent VTE; for instance, a retrospective analysis revealed a 1-year cumulative incidence of VTE of 34.8% in patients with TF-bearing microparticles versus 0% in those without detectable TF-bearing microparticles (P = .002).23 However, most of these data have been derived from patients with certain cancers, particularly pancreas,20 ovary,24 and brain,25 and whether these findings can be extrapolated to other sites of cancer remains to be seen. In this context, it is disconcerting to note that in a recent large study with a heterogeneous mix of cancer patients, elevated procoagulant microparticles (albeit not TF-specific) were not found to be predictive of VTE.26
Risk Assessment Tools
Cancer-associated VTE is a multifactorial illness. A recently developed risk score can identify cancer patients at high-risk for VTE by using a combination of easily available clinical and laboratory variables (Table 3).14 The risk score for VTE was derived from a development cohort of 2701 patients and then validated in an independent cohort of 1365 patients from a prospective registry. The stage-adjusted multivariate model identified 5 predictive variables. Observed rates of VTE in the development and validation cohorts were 0.8% and 0.3% in the low-risk category, 1.8% and 2% in the intermediate-risk category, and 7.1% and 6.7% in the high-risk category, respectively.
Predictive Model for ChemotherapyAssociated Venous Thromboembolic Disease
This model has now been externally validated by the Vienna CATS study in 819 cancer patients.27 The 6-month cumulative probabilities of developing VTE in this study population were 1.5% (score of 0), 3.8% (score of 1), 9.4% (score of 2), and 17.7% (score > 3). Multiple other retrospective and prospective studies have further validated this risk score, although rates vary between studies because of varying patient selection and follow-up periods (Table 4). In addition, the Vienna group has described expansion of this original risk score with the inclusion of 2 additional biomarkers: D-dimer and soluble P-selectin. In the expanded risk model, the cumulative VTE probability after 6 months in patients with the highest score (> 5; n = 30) was 35.0% and 10.3% in those with an intermediate score (score 3; n = 130), as opposed to only 1.0% in patients with a score of 0 (n = 200). This expanded risk score, while promising, requires further validation in other studies. Additional limitations of the expanded score include the lack of wide availability of the P-selectin assay and the small number of patients at the higher risk levels.
Rates of Venous Thromboembolic Disease According to Risk Score
Patients with myeloma are at very high risk for VTE, particularly when treated with specific regimens. A risk assessment algorithm has recently been proposed by the International Myeloma Working Group.28 The group recommended that patients with 0 to 1 risk factor receive daily aspirin for prophylaxis, whereas those with 2 or more risk factors receive LMWH or warfarin. All patients receiving thalidomide or lenalidomide in addition to high-dose dexamethasone or doxorubicin are recommended to receive LMWH. It is important to note that this algorithm is based on expert consensus and has not been validated.
Prophylaxis of VTE in Cancer
Multiple randomized controlled trials (RCTs) and meta-analyses have demonstrated the safety and efficacy of anticoagulants in reducing the incidence of VTE in several high-risk settings. In the cancer population, VTE can occur in three specific settings and it is important to consider the evidence for prophylaxis separately in these settings.
Hospitalized Medical Cancer Patients
Three large RCTs in acutely ill medical patients have shown reduced rates of VTE with the use of prophylactic LMWH or fondaparinux (Figure 1).29-31 Unfortunately, no cancer-specific RCTs have been conducted and in the medical studies, cancer patients (including those with previous history of cancer) represented only a small minority (5%-15%) of the study population. Despite this lack of cancer-specific evidence, current guidelines recommend thromboprophylaxis based on the known high risk of VTE in the hospitalized cancer population and extrapolation from the data in medical patients.32,33 In a recent multinational survey, only 58% of surgical patients and 39% of medical patients at risk for VTE received appropriate prophylaxis during hospitalization.34 Adherence rates were higher in the United States, where nearly 60% of at-risk medical patients received prophylaxis.
In this context, it is important to note an innovative study of computerized order-entry alerts was conducted that randomized providers to receive or not receive an alert regarding a patient's risk for VTE and need for prophylaxis.35 The computer alert reduced the risk of VTE by an impressive 41% (4.9% VTE in the alert group vs. 8.2% in controls; HR, 0.59; 95% CI, 0.43-0.81; P = .001). Nearly 80% of patients in this study had cancer. A similar finding was reported when an order entry alert was introduced into a large tertiary care medical center.36 These reports therefore provide further support for the efficacy of thromboprophylaxis in hospitalized cancer patients.
Surgery and Extended Postsurgical Period
Multiple randomized controlled trials have shown the benefit of anticoagulant prophylaxis in patients undergoing cancer surgery, who are at very high risk for VTE.37-40 Based on this large body of literature, the ASCO Clinical Practice Guidelines32 and the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for VTE33 (in this issue; to view the most recent version of these guidelines, visit the NCCN Web site at www.NCCN.org) recommend thromboprophylaxis in the surgical oncology setting. However, patients undergoing cancer surgery also remain at elevated risk for VTE for an extended period after hospital discharge.9 Recent reports have therefore focused on extending the period of prophylaxis after surgery. Three RCTs have shown that extending prophylaxis up to 4 weeks is effective and safe in reducing postoperative VTE.41-43 Both ASCO and NCCN Guidelines recommend that all high-risk cancer patients undergoing major abdominopelvic surgery be considered for extended VTE prophylaxis.32,33 In the NCCN Guidelines, high-risk features in this setting include surgery for gastrointestinal malignancies, prior history of VTE, anesthesia time greater than 2 hours, bed rest greater than 4 days, advanced stage cancer, and age older than 60 years.33
Results of trials of thromboprophylaxis in high-risk hospitalized patients, including patients with cancer. Rates of VTE in 3 large randomized controlled trials of thromoprophylaxis in hospitalized patients with acute medical illnesses are shown here.
From Francis CW. Clinical practice. Prophylaxis for thromboembolism in hospitalized medical patients. N Engl J Med 2007;356:14381444, with permission.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 9, 7; 10.6004/jnccn.2011.0064
Results of trials of thromboprophylaxis in high-risk hospitalized patients, including patients with cancer. Rates of VTE in 3 large randomized controlled trials of thromoprophylaxis in hospitalized patients with acute medical illnesses are shown here.
From Francis CW. Clinical practice. Prophylaxis for thromboembolism in hospitalized medical patients. N Engl J Med 2007;356:14381444, with permission.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 9, 7; 10.6004/jnccn.2011.0064
Results of trials of thromboprophylaxis in high-risk hospitalized patients, including patients with cancer. Rates of VTE in 3 large randomized controlled trials of thromoprophylaxis in hospitalized patients with acute medical illnesses are shown here.
From Francis CW. Clinical practice. Prophylaxis for thromboembolism in hospitalized medical patients. N Engl J Med 2007;356:14381444, with permission.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 9, 7; 10.6004/jnccn.2011.0064
Outpatient Chemotherapy
Most VTE now occurs in the outpatient setting; correspondingly, major recent RCTs have focused on outpatient thromboprophylaxis for patients with solid tumors undergoing systemic therapy (Figure 2). The Prophylaxis of Thromboembolism during Chemotherapy Trial (PROTECHT) study evaluated the efficacy of daily nadroparin, a LMWH, in high-risk cancer sites, including those with locally advanced or metastatic lung, gastrointestinal, pancreatic, breast, ovarian, and head/neck cancers actively undergoing chemotherapy.44 Event rates were low: 2% of the treatment group and 3.9% of the placebo group developed a thromboembolic event (single-sided, 95% CI, 0.303%; P = .02), with a nonsignificant increase in major bleeding. Notably, in the contemporary era, patients with breast and head/neck cancers have not been typically considered high-risk for VTE and their inclusion in this study may have reduced the event rate.
Two other RCTs focused on pancreatic cancer, which is generally considered a very high-risk site for VTE. In the CONKO-004 study, VTE occurred in 5.0% (8 of 160) of patients randomized to enoxaparin (1 mg/kg/d for 3 months, then 40 mg/d) versus 14.5% (22 of 152) in the observation arm (P < .01).45 In the FRAGEM study, patients were randomized to full therapeutic doses of dalteparin versus observation.46 Overall incidence of VTE in patients undergoing chemotherapy alone was 31% versus 12% in the dalteparin arm (RR, 0.38; 95% CI, 0.17-0.84; P = .019). These studies show that in high-risk patients, extremely high event rates of VTE occur and can safely be reduced. These studies also suggest that prophylactic doses of LMWHs may not be sufficient to reduce VTE in this population: the CONKO study initially used a higher dose of enoxaparin and the FRAGEM study used the full therapeutic dose of dalteparin. These findings therefore have significant implications for the design of future prophylaxis studies in patients with cancer. However, these data have only been published in abstract form.
Thromboprophylaxis in the outpatient setting. Rates of venous thromboembolic disease (%) in 3 recent randomized controlled trials of low-moelcular-weight heparin (LMWH) prophylaxis in patients with solid tumors are shown. These included PROTECHT (P = .02; various locally advanced or metastatic solid tumors), and preliminary results from CONKO-004 (P < .01) and FRAGEM (P = .019; both advanced pancreatic cancers only).
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 9, 7; 10.6004/jnccn.2011.0064
Thromboprophylaxis in the outpatient setting. Rates of venous thromboembolic disease (%) in 3 recent randomized controlled trials of low-moelcular-weight heparin (LMWH) prophylaxis in patients with solid tumors are shown. These included PROTECHT (P = .02; various locally advanced or metastatic solid tumors), and preliminary results from CONKO-004 (P < .01) and FRAGEM (P = .019; both advanced pancreatic cancers only).
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 9, 7; 10.6004/jnccn.2011.0064
Thromboprophylaxis in the outpatient setting. Rates of venous thromboembolic disease (%) in 3 recent randomized controlled trials of low-moelcular-weight heparin (LMWH) prophylaxis in patients with solid tumors are shown. These included PROTECHT (P = .02; various locally advanced or metastatic solid tumors), and preliminary results from CONKO-004 (P < .01) and FRAGEM (P = .019; both advanced pancreatic cancers only).
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 9, 7; 10.6004/jnccn.2011.0064
In addition to patients with solid tumors, a recent prospective study addressed the efficacy of thromboprophylaxis with either LMWH or lowdose aspirin (ASA) or low-fixed dose warfarin in 667 patients with newly diagnosed myeloma.47 In this common substudy of 2 randomized controlled trials, patients treated with 1 of 3 specific thalidomide-containing regimens were randomly assigned to receive LMWH (enoxaparin, 40 mg/d), ASA (100 mg/d), or warfarin (1.25 mg/d). The incidence of VTE was 5% in the LMWH group, 6.4% in the ASA group, and 8.2% in the warfarin group (P = not significant). Only 3 major bleeding episodes were recorded. The authors concluded that LMWH, warfarin, and ASA are likely to be similarly effective prophylactic regimens, except in elderly patients in whom warfarin showed less efficacy than LMWH. However, current ASCO guidelines (which precede this study publication) recommend against the use of ASA in this setting.32 Together, these data show that outpatient thromboprophylaxis is feasible, safe, and effective. However, the low event rate seen in PROTECHT again emphasizes the importance of patient selection and argues against a broad application of prophylaxis for patients with cancer. Currently, no consensus exists regarding which cancer outpatients should receive prophylaxis.
Current guidelines have also not taken into account more recent studies, and outpatient prophylaxis is currently only recommended by ASCO and NCCN for high-risk patients with myeloma receiving thalidomide- or lenalidomide-based combination regimens.32,33 The NCCN Guidelines do suggest, however, that prophylaxis be “considered” in other outpatients at risk.33 The results of ongoing studies will hopefully allow clinicians to better select patients for targeted thromboprophylaxis.
Future Directions
Current research efforts are focused on outpatient prophylaxis of ambulatory patients with cancer, who account for most VTE events. SAVE-ONCO, which is the largest RCT being conducted, is investigating the efficacy of a novel agent semuloparin (AVE5026) in preventing VTE in patients with locally advanced or metastatic solid tumors of the lung, gastrointestinal tract, bladder, or ovary who are undergoing chemotherapy (ClinicalTrials.gov identifier: NCT00694382). The study completed enrollment of 3200 patients in mid-2010 with results anticipated in mid-2011. The University of Rochester and Duke University are conducting a prospective study sponsored by the National Institutes of Health based on the previously discussed risk score in which cancer outpatients at high risk for VTE (risk score > 3) are treated with dalteparin for 12 weeks (ClinicalTrials.gov identifier: NCT00876915). Finally, the MicroTEC study is investigating enoxaparin in patients with pancreatic, lung, and colorectal cancer with elevated plasma TF microparticles (ClinicalTrials.gov identifier: NCT00908960).
An exciting opportunity is the development of novel anticoagulants, which are rapidly becoming available worldwide. A major advantage of these agents is their oral formulation, which will likely increase acceptability for long-term use. However, little is known about drug-drug interactions with commonly used anticancer agents. Bleeding is always a concern in the cancer population, and no documentation exists regarding reversibility of anticoagulant effect with currently available treatments in case of bleeding. Cancer-specific safety and efficacy studies are therefore essential before these agents can be adopted for use in cancer patients.
The coming decade, therefore, is likely to see further advances in the field of cancer-associated thrombosis. The hope is that the knowledge gained will allow clinicians to identify individual patients at risk for VTE; target these patients with safe, effective, and patient-friendly thromboprophylaxis; and, above all, reduce the burden and mortality associated with VTE for patients with cancer.
EDITOR
Kerrin M. Green, MA, Assistant Managing Editor, Journal of the National Comprehensive Cancer Network
Disclosure: Kerrin M. Green, MA, has disclosed no relevant financial relationships.
AUTHORS AND CREDENTIALS
Alok A. Khorana, MD, Department of Medicine; Associate Professor, James P. Wilmot Cancer Center University of Rochester School of Medicine and Dentistry, Rochester, New York
Disclosure: Alok A, Khorana, MD, has disclosed the following relevant financial relationships:
Participated in funded/unfunded research for: Ortho Biotech Products, L.P.
Served on the steering committee for: Leo Pharma, Inc.; sanofi-aventis
Served as an advisory board member, speakers bureau member, expert witness, or consultant for: Boehringer Ingelheim Pharmaceuticals, Inc.; Daiichi Sankyo, Inc.; Eisai, Inc.; Ortho Biotech Products, L.P.; Roche, sanofi-aventis
Supported by grants from the National Cancer Institute (K23 CA120587), the National Heart, Lung and Blood Institute (R01HL095109), and the V Foundation.
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