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Review Series
CANCER-ASSOCIATED THROMBOTIC DISEASE
Therapeutic options for the management of venous thromboembolism (VTE) in patients with cancer remain very limited. Although low-molecular-weight heparin monotherapy has been identified as a simple and efficacious regimen compared with an initial parenteral anticoagulant followed by long-term therapy with a vitamin K antagonist, many clinical questions remain unanswered. These include optimal duration of anticoagulant therapy, treatment
of recurrent VTE, and the treatment of patients with concurrent bleeding or those with a high risk of bleeding. Treatment recommendations from consensus clinical guidelines are largely based on retrospective reports or extrapolated data from the noncancer population with VTE, as randomized controlled trials focused on cancer-associated thrombosis are sorely lacking. Furthermore, with improvements in imaging technology and extended
survival duration of patients with cancer, we are encountering more unique challenges, such as the management of incidental VTE. Clinicians should be aware of the limitations of the novel oral anticoagulants and avoid the use of these agents because of the paucity of evidence in the treatment of cancer-associated thrombosis. (Blood. 2013;122(14):23102317)
Introduction
Venous thromboembolism (VTE) is a signicant cause of morbidity and mortality in patients with cancer.1 Although deep vein thrombosis (DVT) and pulmonary embolism (PE) are the most commonly encountered venous thrombotic complications, other vascular territories, such as the splanchnic veins and upper extremity venous system, can also be involved. With the increasing age and cancer prevalence of our population, enhanced detection of incidental thrombosis and greater thrombogenicity of multiagent chemotherapeutic regimens, we have observed a steady increase in the incidence of cancer-associated thrombosis during the past 2 decades.2,3 A leading cause of death in patients with cancer,4 thrombosis is associated with higher mortality risk, irrespective of cancer stage.5,6 Unfortunately, despite the burden of VTE in oncology patients, there has been limited advancement in the management of cancerassociated thrombosis since the introduction of low-molecularweight heparin (LMWH) for long-term therapy. Anticoagulant therapy in malignancy remains burdensome and is viewed as having a negative impact on patient quality of life. It is also associated with a high risk of bleeding and may limit the therapeutic options to treat the underlying cancer.7 In this review, we outline the current evidence and consensus guideline recommendations for the initial and long-term management of the rst and recurrent episodes of VTE in patients with cancer. We also discuss the management of commonly encountered thrombotic complications, recognizing the lack of rigorous evidence in these areas, such as incidentally detected VTE, splanchnic vein thrombosis, catheter-related thrombosis, and VTE treatment in patients with a high risk of bleeding. We close with a critical look at the use of the novel oral anticoagulants (NOACs) in the treatment of cancer-associated thrombosis.
Options for the initial treatment of cancer-associated thrombosis include LMWH, unfractionated heparin (UFH), and fondaparinux. Although studies directly comparing these agents are lacking in oncology patients, data extrapolated from subgroup analysis of trials in unselected patients showed no difference in efcacy between LMWH and UFH in patients with cancer.8 However, a statistically signicant reduction in mortality risk with LMWH at 3 months of follow-up has been noted. The reason for this survival benet is unknown, but research exploring the antineoplastic properties of LMWH is ongoing. In addition to better efcacy, LMWH provides other advantages vs UFH, including lower cost (because hospitalization and laboratory monitoring are not required) and simple dosing (because the total daily dose is based on body weight). LMWH is also associated with a lower risk for heparin-induced thrombocytopenia (HIT).9 Data on the use of fondaparinux for the initial management of DVT and PE in patients with cancer are also derived from post hoc subgroup analysis. In the Matisse trials, the 3-month rate for symptomatic, recurrent VTE was higher for fondaparinux vs enoxaparin in DVT treatment (12.7% vs 5.4%) but was lower for fondaparinux vs UFH in PE treatment (8.9% vs 17.2%).10 Like LMWH, fondaparinux is administered as a once-daily, weight-based subcutaneous injection. Fondaparinux is rarely associated with the development of
Submitted April 3, 2013; accepted June 20, 2013. Prepublished online as Blood First Edition paper, July 10, 2013; DOI 10.1182/blood-2013-04-460162.
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Table 1. Consensus guidelines on treatment of deep vein thrombosis or pulmonary embolism in patients with cancer
ACCP 201221 Initial/acute treatment Not addressed in cancer patients. LMWH Dalteparin 200 U/kg OD Enoxaparin 1 mg/kg BID Tinzaparin 175 U/kg OD Fondaparinux 5 mg (,50 kg), 7.5 mg (50-100 kg), or 10 mg (.100 kg) OD APTT-adjusted UFH infusion Long-term treatment In patients not treated with LMWH, VKA therapy is preferred to dabigatran or rivaroxaban [2C].* Patients receiving extended therapy should continue with the same agent used for the first 3 mo of treatment [2C].* Duration of treatment Extended anticoagulant therapy is preferred to 3 mo of treatment [2B].* Minimum 3 mo. Indefinite anticoagulant if active cancer or persistent risk factors. At least 6 mo duration. Extended anticoagulation with LMWH or VKA may be considered beyond 6 mo for patients with metastatic disease or patients who are receiving chemotherapy. ACCP, American College of Chest Physicians; BID, twice-daily dosing; NCCN, National Comprehensive Cancer Network; OD, once-daily dosing. *ACCP adaptation of the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) Working Group evidence-based recommendations: 2B, weak recommendation, moderate-quality evidence; 2C, weak recommendation, low- or very-low-quality evidence.16 LMWH preferred to VKA [2B].* LMWH is preferred for first 6 mo as monotherapy without warfarin in patients with proximal DVT or PE and metastatic or advanced cancer. Warfarin 2.5-5 mg every day initially with subsequent dosing based on INR value targeted at 2-3. VKAs (target INR, 2-3) are acceptable for long-term therapy if LMWH is not available. LMWH is preferred for long-term therapy. NCCN 201113 ASCO 201314 LMWH is preferred for initial 5-10 d of treatment in patients with a CrCl .30 mL/min.
drug-induced thrombocytopenia and has been used off label for the management of HIT.11 Barriers to its use in oncology patients include a relatively long half-life of 17 to 21 hours, the lack of a reversal agent, and 100% dependence on renal clearance.12 On the basis of currently available evidence, LMWH is the recommended anticoagulant for the initial therapy of VTE in most patients with cancer (Table 1).13-16 However, UFH can be used in those with severe renal impairment (creatinine clearance [CrCl] ,30 mL/min) given its shorter half-life, reversibility with protamine sulfate, and dependence on hepatic clearance. Fondaparinux is a reasonable choice in patients with a history of HIT.
Use of thrombolysis in cancer-associated VTE
As most trials of thrombolytic therapy exclude patients with cancer because of a perceived higher risk of bleeding, evidence for thrombolysis in patients with malignancy is limited to small single-center, retrospective series. These studies compared the degree of clot lysis and short-term complications between patients with vs those without cancer who had presented with extensive DVT or PE.17-19 Although comparable results between cancer and noncancer patient groups were observed, these studies provide a low level of evidence because of insufcient statistical power and patient selection bias. Nonetheless, there is no strong evidence to routinely exclude patients for consideration of thrombolysis on the basis of the presence of malignancy alone. Because the safety, cost-effectiveness, and longterm benet of thrombolysis remain uncertain,20 it is prudent to review each patient carefully and exclude patients with central nervous system lesions or other risk factors for bleeding.
acute VTE in patients without cancer,21 their use is problematic in oncology patients. VKAs are less effective in patients with cancer, with rates of recurrent VTE threefold higher than in patients without cancer despite maintenance of the international normalized ratio (INR) within the therapeutic range.22,23 Several open-label, randomized controlled trials have compared LMWH with VKA therapy for long-term management of cancerassociated PE or proximal DVT (Figure 1).24-27 Three different LMWH preparations, enoxaparin, tinzaparin, and dalteparin, were investigated for 3 to 6 months in similarly designed studies. Overall, the results from these trials provide consistent evidence of improved efcacy of LMWH vs VKA in the prevention of recurrent VTE in patients with cancer-associated VTE. A meta-analysis of 7 studies conrms this nding, reporting a relative risk reduction of 53%.28 In addition to improved efcacy vs VKA therapy, LMWH also offers other advantages including (a) no need for laboratory monitoring of its anticoagulant activity; (b) a shorter half-life that facilitates temporary interruption for procedures or thrombocytopenia; (c) limited drug interactions; and (d) no food interactions or reliance on oral intake or gastrointestinal tract absorption. As a result, LMWH is recommended for both initial and long-term anticoagulation in cancer-associated thrombosis by major consensus guidelines (Table 1).13-15,21 The high cost associated with LMWH therapy and the requirement for daily subcutaneous injections are the major barriers to its use. Yet, qualitative studies have reported that patient acceptance of daily injections is quite favorable.29 In fact, in those who had used warfarin and LMWH therapy, most prefer the convenience and empowerment with LMWH. If LMWH is unavailable, the American Society of Clinical Oncology (ASCO) 2013 VTE Prevention and Treatment Guideline recommends the use of VKA with a target INR of 2 to 3 as an acceptable alternative.14
Anticoagulation in patients with renal impairment
Although vitamin K antagonists (VKAs) have been the mainstay agents for long-term management and secondary prophylaxis of
Renal impairment is not uncommon among patients with malignancy. Because LMWH is partially cleared by renal excretion and metabolism, drug accumulation is expected with long-term use in
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renal impairment has been issued by the US Food and Drug Administration after the results of an interim analysis of a randomized trial comparing tinzaparin with UFH for initial VTE therapy in this vulnerable population.35 Only 33 patients with a history of ongoing malignancy were enrolled in this study; 20 of them were in the tinzaparin group.36
Duration of anticoagulation and anticoagulant options for extended therapy
Figure 1. Comparison of randomized controlled trials of different preparations of LMWH vs VKA for the long-term management of cancer-associated thrombosis. Recurrent VTE (A), major bleeding episodes (B), and mortality (C) during the anticoagulant treatment period are shown for the CLOT24 (6 months of dalteparin or VKA), LITE25 (3 months of tinzaparin or warfarin), and CANTHANOX27 (3 months of enoxaparin or warfarin) trials. NS, not statistically significant.
The decision regarding the continuation of anticoagulation beyond the rst 3 to 6 months is largely based on weighing the risk for recurrent thrombosis against the risk of major bleeding. This evaluative process is best developed in patients with unprovoked VTE, in whom studies have been done to determine whether biomarkers, radiologic imaging, and clinical prediction models can identify patients with a sufciently high risk for recurrent thrombosis to benet from extended anticoagulation, or an acceptably low risk to allow discontinuation of anticoagulation.37-39 A clinical model to predict the risk for recurrent VTE during anticoagulation therapy in cancer-associated thrombosis has been proposed but not yet validated.40 In addition, studies regarding the optimal duration of anticoagulant therapy are lacking in oncology patients. Given that the risk for recurrent thrombosis in patients with active cancer is high even while they are receiving anticoagulation, it is generally recommended that extended anticoagulation be considered in this population.14,21 It has not been established whether risk factors for a rst episode of VTE, such as metastatic or progressive disease and ongoing chemotherapy, will also increase the risk for recurrent VTE, but it has been generally accepted that continuing anticoagulation in patients with these ongoing risk factors is warranted.13-15 Patients given extended anticoagulation require frequent reassessment to review the risk-benet balance of continuing anticoagulant therapy. Factors that need to be taken into account, aside from the risk for recurrent VTE and the risk of bleeding, include the status of the malignancy, type of cancer treatment (if any), quality of life, and patient preference. The choice of anticoagulant for extended anticoagulant therapy (beyond 6 months) also has not been investigated. A randomized trial is currently addressing this question.41 Patient preference and tolerance of previous therapy play signicant roles in this decision. Thus far, long-term toxicity associated with VKA or LMWH has not been a concern, although it remains controversial whether prolonged exposure to LMWH accelerates clinically signicant bone loss.42 As with duration of therapy, the anticoagulant of choice needs to be discussed with each patient and individualized.
Inferior vena cava (IVC) filters
those with signicant renal insufciency (CrCl ,30 mL/min). Of the major LMWH preparations, tinzaparin appears to have the lowest potential to accumulate, whereas enoxaparin shows signicant accumulation in renal insufciency.30 This property reects the chain length of the LMWH, with the longer-chain tinzaparin being partially cleared by the reticuloendothelial system.30,31 Limited data are available on the use of LMWH in patients with signicant renal dysfunction, but they do indicate that the risk of bleeding is higher in patients with renal impairment.32,33 Manufacturer-recommended dose reduction in renal impairment exists for enoxaparin but not for other LMWH preparations.34 Most experts and guidelines recommend dose adjustment based on anti-factor Xa activity in patients with a CrCl ,30 mL/min.13,21 If anti-factor Xa monitoring is not readily available, VKA therapy is likely a safer option for long-term anticoagulation in these patients. A warning against the use of tinzaparin in elderly patients with
Patients with cancer are frequent recipients of IVC lters. Yet, data on the efcacy and safety in this population are limited to retrospective single-center series or anecdotal reports.43,44 Rates of recurrent VTE up to 32% have been reported in patients with cancer treated with IVC lters, and fatal PE after lter insertion has been well documented.45 Evidence on the safety and efcacy of IVC lters in the general population is also sparse. Only 1 randomized trial has been done to evaluate lter placement in patients with proximal DVT who are at high risk for PE. In the PREPIC (Pr evention du Risque dEmbolie Pulmonaire par Interruption Cave) trial, the use of permanent IVC lters in conjunction with anticoagulation resulted in a decreased incidence of PE at the expense of an increase risk for recurrent DVT and without any reduction in overall mortality rate during 8 years of follow-up.46,47 Results for the included 56 patients with cancer
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have not been published. Most importantly, the value of an IVC lter in patients who cannot receive anticoagulation, the major indication for lter insertion, has not been examined in prospective studies. Complications associated with IVC lters raise further concern about the appropriateness of their use. Insertion problems occur in 4% to 11% of patients, and long-term adverse effects such as thrombosis of the IVC or lower extremity veins occur in 4% to 32%.48 A high incidence of mechanical or device failures associated with retrievable lter models led the US Food and Drug Administration to issue a Safety Alert in 2010.49 These problems include lter migration, strut fracture with embolization, and caval perforation.50,51 Given the high rates of complications and the absence of data to support their efcacy, IVC lters should be restricted to patients with acute VTE and contraindications to anticoagulation. Their use in patients with recurrent thrombotic events despite standard anticoagulant therapy goes against biological rationale because lters do not treat the underlying thrombotic condition, and the presence of an intravascular foreign body is likely to promote thrombus formation, which can occur proximally or distally to the lter. In addition, the use of IVC lters may provide a sense of false security regarding the risk for recurrent PE, causing delays or discontinuation of anticoagulant therapy. If retrievable lters are placed, efforts should be made to remove the device and reinitiate anticoagulation as soon as the high-risk period for bleeding has passed.
Figure 2. Management algorithm of recurrent VTE in patients with cancer. BID, twice-daily dosing; INR, international normalized ratio; OD, once-daily dosing.
as cancer staging.54 Retrospective studies in unselected oncology patients have demonstrated incidental VTE rates of up to 6%,55,56 with thrombotic events evenly distributed between PE and/or DVT and intra-abdominal thrombosis.55 A prevalence of incidental PE of 3.1% was reported in a meta-analysis that included data from more than 6000 oncology patients.57 Incidental VTE also represents a signicant proportion of thrombotic complications in patients with cancer, comprising up to 60% in large series.58 Studies have suggested that, like suspected or symptomatic VTE, the occurrence of incidental VTE can have a negative impact on both patient quality of life and clinical outcomes. Patients with incidental PE often have symptoms such as fatigue and shortness of breath.59 In a retrospective case-control study comparing 51 unselected oncology patients with incidental PE and 144 patients with symptomatic PE, the 12-month rates of recurrent VTE, bleeding, and mortality were similar between the groups.60 A retrospective cohort of 135 consecutive patients with pancreatic cancer reported similar ndings.61 In another study, a comparison of cancer patients with and without incidental PE matched for age, cancer diagnosis, and stage of disease at the time of a restaging computed tomography scan of the chest found that patients with incidental PE had a higher mortality rate than those without PE.62 Whether anticoagulation is indicated or benecial in patients with incidental VTE remains controversial. Evidence is limited to 2 retrospective studies in patients with lung and pancreatic cancer. In a cohort of 113 patients with lung cancer and incidental PE, the 62 patients who did not receive anticoagulation had higher mortality
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rates compared with patients who were treated.63 Similarly, in patients with pancreatic cancer with incidental VTE, the use of anticoagulant therapy was associated with a 70% reduction in mortality rate.61 However, these studies are potentially biased to favor anticoagulation because anticoagulant therapy is likely to be withheld in those with a short life expectancy. Nonetheless, based on published literature to date, it is recommended that patients with incidental DVT and PE receive therapeutic anticoagulation if there are no contraindications.14,21 However, caution should be exercised in cases where the diagnosis of PE or DVT is questionable, especially for isolated subsegmental PE. Conrming the diagnosis with the appropriate testing (ie, computed tomographic pulmonary angiography or compression venous ultrasonography) is strongly encouraged in such cases.
Figure 3. Management algorithm of VTE in patients with cancer and thrombocytopenia. Management of acute VTE (,1 month) and subacute or chronic VTE ($1 month) are outlined in panels A and B, respectively.
the prolonged anticoagulant effect and unpredictable dose response. Figure 3 illustrates a reasonable approach to the treatment of cancerassociated thrombosis in patients with thrombocytopenia.65 Management of VTE in patients with intracranial malignancies is particularly challenging because of the fear of intracranial hemorrhage. No randomized controlled data exist for management of patients with primary or metastatic intracranial tumors and VTE; however, small retrospective studies indicate that anticoagulation can be safely used. Anticoagulation with intravenous UFH followed by VKA or subcutaneous UFH has been associated with rates of symptomatic intracranial hemorrhage between 0% and 7%.67-70 Similar results have been reported with LMWH in patients with glioma or metastatic brain tumors with a trend toward improved survival duration.71-73 The ASCO 2013 VTE Guideline recommends treating patients with intracranial malignancies with standard anticoagulation.14
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Table 2. Interactions between chemotherapeutic agents and immunosuppressants with NOACs based on known metabolic pathway activity
Dabigatran Interaction effect* Increases NOAC plasma levels P-glycoprotein Cyclosporine Tacrolimus Tamoxifen Lapatinib Nilotinib Sunitinib Reduces NOAC plasma levels Dexamethasone Doxorubicin Vinblastine Rivaroxaban P-glycoprotein CYP3A4 Cyclosporine Tacrolimus Tamoxifen Lapatinib Nilotinib Sunitinib Imatinib Dexamethasone Doxorubicin Vinblastine Apixaban P-glycoprotein CYP3A4 Cyclosporine Tacrolimus Tamoxifen Lapatinib Nilotinib Sunitinib Imatinib Dexamethasone Doxorubicin Vinblastine
the use of anticoagulant therapy.21 For patients with incidentally detected splanchnic vein thrombosis, there is no specic guidance on treatment. It is reasonable to withhold anticoagulation if the patient is truly asymptomatic, especially if radiologic evidence indicates that the thrombus is chronic in nature. Repeated imaging is prudent to detect thrombus progression if anticoagulation is not given.
CYP3A4, cytochrome P450 3A4. *Clinicians should consult with the pharmacist to determine if these and other drug interactions exist when NOACs are being considered. Drugs that inhibit P-glycoprotein transport or CYP3A4 pathway can increase NOAC levels. Drugs that induce P-glycoprotein transport or CYP3A4 pathway can lower NOAC levels.
short course of low-dose LMWH is effective and safe in treating catheter-related thrombosis in patients with severe thrombocytopenia.75 To date, published data and clinical experience suggest that catheter-related thrombosis is associated with a low risk for thrombosis recurrence and postthrombotic syndrome.76,77 Therefore, conservative treatment is recommended. A sensible approach is to remove the catheter only if (1) central venous access is no longer required; (2) the device is nonfunctional or defective; or (3) line-related sepsis is suspected or documented. Unless contraindicated, therapeutic anticoagulation should be given using either LMWH alone or LMWH followed by warfarin therapy. A short period of anticoagulation (3-5 days of LMWH) may even salvage some thrombosed catheters and obviate the need to remove and replace the line. Anticoagulation is recommended for a minimum of 3 months and while the catheter remains in place.
Authorship
Contribution: A.Y.Y.L. and E.A.P. wrote the manuscript.
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Conict-of-interest disclosure: A.Y.Y.L. reports receiving research funding from LEO Pharma and honoraria from Bayer, BoehringerIngelheim, Bristol-Myers Squibb, LEO Pharma, Pzer, and Sano Aventis. The remaining author declares no competing nancial interests.
Correspondence: Agnes Y. Y. Lee, University of British Columbia and Vancouver Coastal Health Diamond Health Care Centre, 2775 Laurel St, 10th Floor, Vancouver, BC, Canada; email: alee14@ bccancer.bc.ca.
References
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Available at: http://www.fda.gov/Drugs/DrugSafety/ PostmarketDrugSafetyInformationforPatientsand Providers/DrugSafetyInformationforHeathcare Professionals/ucm136254.htm. Accessed March 23, 2013. 36. Leizorovicz A, Siguret V, Mottier D, et al; Innohep in Renal Insufficiency Study Steering Committee. Safety profile of tinzaparin versus subcutaneous unfractionated heparin in elderly patients with impaired renal function treated for acute deep vein thrombosis: the Innohep in Renal Insufficiency Study (IRIS). Thromb Res. 2011;128(1): 27-34. 37. Eichinger S, Heinze G, Jandeck LM, Kyrle PA. Risk assessment of recurrence in patients with unprovoked deep vein thrombosis or pulmonary embolism: the Vienna prediction model. Circulation. 2010;121(14):1630-1636. 38. Tosetto A, Iorio A, Marcucci M, et al. Predicting disease recurrence in patients with previous unprovoked venous thromboembolism: a proposed prediction score (DASH). J Thromb Haemost. 2012;10(6):1019-1025. 39. 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