NCCN: Continuing Education
Accreditation Statement
This activity has been designated to meet the educational needs of physicians and nurses involved in the management of patients with cancer. There is no fee for this article. No commercial support was received for this article. The National Comprehensive Cancer Network (NCCN) is accredited by the ACCME to provide continuing medical education for physicians.
NCCN designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
NCCN is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center‘s Commission on Accreditation.
This activity is accredited for 1.0 contact hour. Accreditation as a provider refers to recognition of educational activities only; accredited status does not imply endorsement by NCCN or ANCC of any commercial products discussed/displayed in conjunction with the educational activity. Kristina M. Gregory, RN, MSN, OCN, is our nurse planner for this educational activity.
All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: 1) review the learning objectives and author disclosures; 2) study the education content; 3) take the posttest with a 66% minimum passing score and complete the evaluation at http://education.nccn.org/node/31857; and 4) view/print certificate.
Release date: November 14, 2013; Expiration date: November 14, 2014
Learning Objectives
Upon completion of this activity, participants will be able to:
Describe the rationale for a risk-adapted approach to the prophylaxis of VTE in patients with cancer
Summarize the guidelines on VTE management in cancer as it pertains to outpatient settings
Identify 3 recommendations for clinician interactions with patients with cancer in an outpatient setting
Venous thromboembolism (VTE), which commonly presents as deep vein thrombosis or pulmonary embolism (PE), is a highly prevalent complication of cancer and anticancer therapy. VTE is associated with significant consequences for patients with cancer, including a need for chronic anticoagulation, high risk of recurrent VTE, risk of bleeding and, above all, a strong association with mortality.1,2 It follows, therefore, that VTE is also associated with a significant consumption of health care resources. In a recent US study, patients with cancer with VTE had approximately 3 times as many all-cause hospitalizations (mean, 1.38 vs 0.55 per patient) and incurred higher total health care costs than patients with cancer without VTE ($74,959 vs $41,691 per patient; P<.0001).3
Emerging data also suggest that VTE is much more prevalent than previously estimated. In a study of more than 17,000 commercially insured patients in the United States, VTE events occurred in 12.6% of the cancer cohort (n=2170) over 12 months after the initiation of chemotherapy versus 1.4% of controls (n=237; P<.0001); incidence ranged by cancer type from 8.2% (bladder) to as high as 19.2% (pancreas).4 In a retrospective analysis of patients treated with cisplatin-based chemotherapy at Memorial Sloan-Kettering Cancer Center in 2008, 18.1% experienced thromboembolism.5 The authors described this as an unacceptably high burden.
In the past, public health efforts to reduce VTE have focused primarily on inpatients. This was a reasonable approach given the known high rates of VTE in the postsurgical and hospitalized medical settings. However, in oncology, most care is now delivered in the outpatient setting. In a retrospective, observational, cohort study of more than 17,000 patients, 78.3% of all VTE events occurred in the outpatient setting versus 21.7% in the inpatient setting (P<.0001).6 Thus, even perfect compliance with inpatient prophylaxis would not prevent nearly 80% of VTE in patients with cancer. Recognizing this, multiple randomized clinical trials (RCTs) have focused on preventing VTE in outpatients with cancer. This article focuses on the results of these studies, and describes updates from recent major guidelines panels to inform clinical decision-making regarding outpatient thromboprophylaxis in malignancy.
Thromboprophylaxis Studies in Outpatients With Cancer
The safety and efficacy of outpatient thromboprophylaxis has been evaluated in multiple RCTs (Table 1) and also summarized in 3 systematic reviews.7-9 The 2 largest, Prophylaxis of Thromboembolism during Chemotherapy (PROTECHT) trial and SAVE-ONCO included patients with a mix of solid tumors,10,11 as did the Microtec study, which also included biomarker-based risk stratification.12 Two other RCTs, FRAGEM and CONKO-004, included only patients with pancreas cancer13-15 and the PRODIGE trial included only patients with malignant glioma.16 Two additional studies evaluated thromboprophylaxis specifically in multiple myeloma.17,18
Mixed Solid Tumors
The PROTECHT study evaluated the efficacy of daily nadroparin, a low-molecular-weight heparin (LMWH) available in Europe, in high-risk sites of cancer, including those with locally advanced or metastatic lung, gastrointestinal, pancreatic, breast, ovarian, and head/neck cancers actively undergoing chemotherapy.11 Overall, 15 (2.0%) of 769 patients treated with nadroparin and 15 (3.9%) of 381 patients treated with placebo had thromboembolism (single-sided P=.02). Five (0.7%) of 769 patients in the nadroparin group and no patients in the placebo group had a major bleeding event (2-sided P=.18). The study thus proved the concept that outpatient LMWH is safe and feasible but its results did not translate into practice because of the low event rate.
SAVE-ONCO was a prospective, double-blind, multicenter study of 3200 patients with locally advanced or metastatic high-risk solid tumors (defined for this study as lung, pancreas, stomach, colorectal, bladder, or ovary) randomized to daily subcutaneous semuloparin (a novel ultra-LMWH) or placebo.10 Patients receiving prophylactic semuloparin had a 64% relative risk reduction of VTE (hazard ratio [HR], 0.36; 95% CI, 0.21, 0.60; P<.0001), but the absolute rates and absolute risk reduction were not as substantial (1.2% vs 3.4% in the placebo arm). Clinically relevant bleeding occurred in 2.8% and 2.0% in the semuloparin and placebo groups, respectively (HR, 1.40; 95% CI, 0.89-2.21). Similar to PROTECHT, the results of this study, although statistically significant, were not deemed to be clinically significant because of the low event rate, and the FDA rejected semuloparin’s application for the proposed indication of outpatient prophylaxis in malignancy.
Recent Clinical Studies of Thromboprophylaxis in Outpatients With Cancer
A more innovative approach to outpatient prophylaxis was adopted by investigators of the Microtec study.12 Elevated levels of circulating tissue factor-bearing microparticles (TF-MP) have been associated with VTE in cancer. This study evaluated TF-MP levels in advanced pancreas, colorectal, non-small cell lung, ovarian, or gastric cancers. Those with lower levels of TF-MP did not receive thromboprophylaxis but were followed for VTE, and those with higher levels of TF-MP were randomized to enoxaparin or observation. The cumulative incidence of VTE at 2 months in the higher TF-MP group randomized to enoxaparin (n=23) was 5.6%, whereas the higher TF-MP group randomized to observation (n=11) was 27.3% (Gray test P=.06). The cumulative incidence of VTE in the low TF-MP arm was 7.2% (n=32). No major bleeding episodes were observed in the enoxaparin arm. Unfortunately, the study did not accrue to its predetermined sample size and the final results were not statistically significant; additionally, the TF-MP assay is investigational and not clinically available. Both of these factors are barriers to adoption into clinical practice.
Pancreas Cancer
Two RCTs focused on pancreas cancer, generally considered a very-high-risk site for VTE. FRAGEM was a phase IIb RCT comparing thromboprophylaxis with therapeutic doses of dalteparin up to 12 weeks versus observation in 123 patients with advanced pancreas cancer receiving gemcitabine-based chemotherapy.13 All VTE during the treatment period was reduced from 23.0% to 3.4% (P=.002), with a risk ratio (RR) of 0.145 (95% CI, 0.035-0.612) and an 85% risk reduction. 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).15 Full publication of this study is awaited. No significant increase was seen in major bleeding in either trial. Together, however, these studies suggest that, at least in pancreas cancer, LMWH therapy may require higher than typical prophylactic dosing to achieve a substantial benefit in VTE reduction.
Multiple Myeloma
Two large studies have focused on thromboprophylaxis in multiple myeloma. The first studied thromboprophylaxis in 667 patients with myeloma.18 In this substudy of 2 RCTs, patients treated with 1 of 3 specific thalidomide-containing regimens were randomized to LMWH (enoxaparin, 40 mg/d), aspirin (100 mg/d), or warfarin (1.25 mg/d). VTE occurred in 5.0% in the LMWH group, 6.4% in the aspirin 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 aspirin are likely to be similarly effective prophylactic regimens, except in elderly patients, in whom warfarin showed less efficacy than LMWH. The study was not adequately powered to detect superiority of any particular agent. In another study of patients with newly diagnosed myeloma treated with lenalidomide-based therapy, 342 low-risk patients in a substudy were randomized to low-dose aspirin (100 mg/d) or enoxaparin, 40 mg/d.17 VTE occurred in 2.3% of the aspirin group and 1.2% of the LMWH group (absolute difference, 1.07%; P=.452). Given its relative efficacy, the authors suggested that aspirin could be an effective alternative to LMWH as prophylaxis in this (relatively) low-risk setting.
Malignant Glioma
The PRODIGE trial focused on prophylaxis with dalteparin 5000 anti-Xa units or placebo in patients with malignant glioma, which is strongly associated with VTE.16 The target sample size was 512 patients, but only 186 were randomized and the study was stopped early because of expiration of medication. Ninety-nine patients were randomized to LMWH and 87 to placebo. The trend favored reduction in VTE with dalteparin (HR, 0.51; 95% CI, 0.19-1.4; P=.29), but 5 (5.1%) major bleeds occurred on LMWH compared with only 1 (1.2%) on placebo (HR, 4.2; 95% CI, 0.48-36; P=.22). Notably, all major bleeds were intracranial and occurred while on study medication. Given this high complication rate, additional trials of prophylaxis in this specific setting are not being considered, and certainly prophylaxis is not recommended in the clinic.
Systematic Review
A recent Cochrane review considered 9 RCTs with a total of 3538 patients.7 The authors found that LMWH significantly reduced the incidence of symptomatic VTE (RR, 0.62; 95% CI, 0.41-0.93), with no evidence of heterogeneity (I2=0%). The number needed to treat (NNT) to prevent a symptomatic VTE was 60. However, LMWH was associated with a 60% nonsignificant increase in major bleeding (RR, 1.57; 95% CI, 0.69-3.60; I2=10%). A 45% reduction in overall VTE was seen (RR, 0.55; 95% CI, 0.34-0.88; I2=0%), whereas the differences in symptomatic PE, asymptomatic VTE, minor bleeding, and 1-year mortality between the LMWH and control groups were not statistically significant.
The Case for Targeted Prophylaxis
The overall picture that emerges from the trials discussed earlier is that outpatient thromboprophylaxis is safe, feasible, and, to a certain extent, effective. Evidence suggests a benefit to patients in terms of reduction of VTE; however, this is accompanied by a potential risk of increased bleeding. Identifying patients at higher risk for VTE, therefore, would optimize the risk/benefit ratio in favor of prophylaxis. Patient selection is therefore key, both in interpreting the results of clinical trials and in applying these results into clinical practice.
Patient selection approaches in the RCTs discussed earlier can be categorized as “generalist” versus “niche.” The lesson learned from generalist studies, such as PROTECHT and SAVE-ONCO, has been that when prophylaxis is applied to a broad, heterogeneous population, event rates are low and the clinical impact of thromboprophylaxis is also low. In contrast, the niche studies have focused on single high-risk sites, such as the pancreas or myeloma, and have shown substantial clinical benefit. However, the public health application of these studies is limited: if thromboprophylaxis were limited to just these 2 cancers, the burden of cancer-associated VTE would be unlikely to be significantly lessened.
Does a middle way exist between these contrasting approaches? In 2008, the author and his research group developed a predictive risk score that identifies patients at high- or low-risk for VTE at the time of initiation of a new chemotherapy regimen. The risk score includes combination of easily available clinical and laboratory variables, including site of cancer, components of the CBC count, and body mass index (Table 2).19 This model was externally validated in the prospective Vienna Cancer and Thrombosis Study of 819 patients with cancer.20 The score was also found to be the only predictor of VTE in an analysis of 1412 patients enrolled in phase I studies.21 Multiple retrospective and prospective studies have further validated this risk score.22 The score meets criteria for a level 1 clinical decision rule,23 and has been endorsed by multiple guidelines, including those from ASCO24 and NCCN.25
The score thus has prognostic benefit, but does it also have predictive benefit? Two recent analyses of PROTECHT and SAVE-ONCO have substantially added to the existing knowledge in this regard (Figure 1). Verso et al26 reported a post hoc subgroup analysis of the PROTECHT study population based on risk category. For the overall study population, NNT to prevent 1 thromboembolic event was 50. In subgroup analysis, approximately 12% of the population was defined as high risk (score ≥3). In this subgroup, rates of VTE were 11.1% in the placebo arm and 4.5% in the nadroparin arm, and thus the NNT to prevent 1 event was 15, a significant reduction compared with that for the overall study population. In contrast, the benefit of prophylaxis in low-risk patients was minimal (NNT=77). Similar results were obtained when the risk score was applied to SAVE-ONCO in a prespecified per-protocol analysis. George et al27 reported that the risk reduction was greater in high-risk patients: 5.4% for placebo versus 1.4% for semuloparin, for a score of 3 or greater (HR, 0.27) compared with 1.3% versus 1%, respectively, for a score of 0 (HR, 0.71); NNT=25 for high-risk patients vs 333 for low-risk patients). No significant differences were seen in bleeding rates between high- and low-risk populations in either study. This approach is also being studied in an ongoing clinical trial of dalteparin prophylaxis in patients with a score of 3 or greater.
Predictive Model for Venous Thromboembolism
Using risk stratification to improve risk/benefit ratio of outpatient prophylaxis. Venous thromboembolism rates in the anticoagulant and placebo arms of SAVE-ONCO and PROTECHT studies in the full population and high-risk subgroups (risk score ≥3).
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 11, 11; 10.6004/jnccn.2013.0164
Together, these subgroup analyses confirm not only that the risk score can successfully identify high-risk patients but also that these patients derive a clinically significant absolute risk reduction in VTE, whereas low-risk patients derive minimal benefit and therefore could be excluded from thromboprophylaxis. Targeted prophylaxis, based on appropriate risk assessment, seems to be the way forward.
Recommendations From Major Guidelines Panels
Three major cancer-specific panels, ASCO, NCCN, and ESMO, have recently updated their guidelines on cancer-associated thrombosis, with sections devoted to outpatient prophylaxis (Table 3).24,25,28 In general, broad agreement exists between these various guidelines. The panels agree that although specific cancer subgroups are at high risk for outpatient VTE, event rates in the general outpatient population do not warrant routine prophylaxis. The panels also agree about at least 1 specific subgroup of patients for whom prophylaxis is recommended: those with myeloma receiving immunomodulary drugs (IMiD)-based regimens. The ASCO panel recommends aspirin for those with low-risk myeloma and LMWH for those with high-risk myeloma.24 The NCCN VTE Panel recommends aspirin for low-risk patients and either warfarin or LMWH for high-risk patients (to view the most recent version of these guidelines, visit NCCN.org).25 Finally, the panels also agree that additional cancer outpatients may benefit from thromboprophylaxis. The ASCO guidelines state that clinicians may consider LMWH prophylaxis on a case-by-case basis in highly selected outpatients with solid tumors undergoing chemotherapy.24 They add the caveat that consideration of this therapy should be accompanied by a discussion with the patient about the uncertainty concerning benefits and harms, and about dose and duration of prophylaxis in this setting. The NCCN Clinical Practice Guidelines in Oncology for Venous Thromboembolic Disease25 also suggest a conversation about the risks and benefits of prophylaxis in patients with a risk score of 3 or greater (available at NCCN.org). Finally, the ESMO guidelines recommend consideration of prophylaxis in high-risk ambulatory patients with cancer, and that the risk score may be used to identify high-risk patients.28 The ESMO guidelines do not recommend prophylaxis in patients receiving adjuvant chemotherapy or hormonal therapy alone.
Updated Cancer Panel Guideline Recommendations for Outpatient Thromboprophylaxis
The Clinical Setting: What’s An Oncologist To Do?
As is evident from the earlier discussion, clinicians must reconcile 2 separate strands of evidence. First, considerable data exist regarding the high prevalence and serious consequences of VTE in outpatients with cancer, and about a validated risk assessment tool that can help clinicians identify patients particularly at risk. Second, clear evidence shows that outpatient prophylaxis is safe, feasible, and effective. Limited data exist marrying these 2 strands: only subgroup analyses of the 2 largest outpatient prophylaxis studies.26,27 In this author’s opinion, clinicians interacting with outpatients with cancer should:
Educate patients about the risk of developing VTE, and warning signs and symptoms thereof. Most patients with cancer are unaware of the increased risk of VTE associated with malignancy.29,30 Educated patients are more likely to report symptoms that could lead to early intervention, and are more likely to accept prevention efforts.31 The 2013 ASCO guidelines include a new recommendation that oncologists educate patients regarding VTE, particularly in settings that increase risk, such as major surgery, hospitalization, and while receiving systemic antineoplastic therapy.24
Conduct risk assessment periodically and be cognizant of VTE, particularly in high-risk patients. The 2013 ASCO guidelines recommend risk assessment, using the risk score, at the time of chemotherapy initiation and periodically thereafter.24
Recommend outpatient thromboprophylaxis to select patients. These may include patients at high risk based on the risk score, those with pancreas cancer initiating chemotherapy, and those with myeloma initiating IMiD-based combination regimens, in the absence of contraindications to prophylaxis. Patients who are low risk based on the score can safely be excluded from consideration of thromboprophylaxis. The preferred prophylactic agent is LMWH, except for in the myeloma population, in whom aspirin, warfarin, or LMWH could be considered.
Future Directions
In the past decade, clinicians and investigators alike have become increasingly aware of the risk and consequences of VTE in ambulatory patients with cancer. Considerable effort has gone into clinical studies, and the results have helped optimize ways to reduce the burden of VTE in cancer. From a patient-centered perspective, however, much work remains. Risk assessment could be improved, particularly for intermediate-risk patients, so that the concept of “precision medicine” can be applied in the supportive care arena, as elsewhere in oncology. Modifying the risk score with the addition of biomarkers is currently being explored. Although LMWHs are effective, they are cumbersome to use and copayments can be high. The use of oral agents as prophylactics, including novel oral anticoagulants, statins, and antiplatelet agents, in this setting warrants further exploration. The goal should be to safely reduce the burden of cancer-associated VTE and its consequences while maintaining patient quality of life.
Dr. Khorana has disclosed that he is on the steering committee for LEO Pharma Inc. and is a consultant for sanofi-aventis. He also receives research support from the Sondra and Stephen Hardis Endowed Chair in Oncology. This work was previously supported by grants from the National Cancer Institute (K23 CA120587); the National Heart, Lung and Blood Institute (R01HL095109); and the V Foundation.
EDITOR
Kerrin M. Green, MA, Assistant Managing Editor, JNCCN—Journal of the National Comprehensive Cancer Network
Ms. Green has disclosed that she has no relevant financial relationships.
CE AUTHORS
Deborah J. Moonan, RN, BSN, Manager, CE Supporter Outreach
Ms. Moonan has disclosed the following relationship with commercial interests: AstraZeneca: Stockholder/Former Employee.
Ann Gianola, MA, Manager, Medical Education Accreditation and Grant Development
Ms. Gianola has disclosed the following relationship with commercial interests: Actelion: Grant/Research Support.
Kristina M. Gregory, RN, MSN, OCN, Vice President, Clinical Information Operations
Ms. Gregory has disclosed that she has no relevant financial relationships.
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