Diagnosis, Treatment, and Prevention of Cancer-Associated Venous Thromboembolism

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Diagnosis, Treatment, and Prevention of Cancer-Associated Venous Thromboembolism

Amer M. Zeidan, Patrick M. Forde and Michael B. Streiff

Summary of Key Points

• Venous thromboembolism (VTE) is a common complication in patients with cancer, affecting approximately 15% of patients during their clinical course. VTE is fivefold to sevenfold more likely to develop in patients with cancer than in patients without cancer.

• The incidence of VTE varies by cancer type and extent of disease. High-risk cancers include pancreatic, brain, and gastric tumors, whereas breast, head and neck, and prostate cancers are associated with a lower risk. Metastatic cancer is associated with a twofold increased risk of VTE.

• Lymphoma and myeloma are also associated with a high risk of VTE.

• VTE is the second most common cause of mortality among patients with cancer and is associated with a threefold increased risk of death compared with patients without cancer.

• Surgery, chemotherapy, hormonal therapy, erythropoietic stimulatory agents, and central venous catheters (CVCs) increase the risk of cancer-associated VTE.

• Risk factors for CVC-associated VTE include left-sided insertion, CVC outer diameter and number of lumens, and catheter tip position above or below the superior vena cava–right atrial junction.

• Pharmacologic VTE prophylaxis is recommended in all surgical and medical oncology patients without contraindications. Optimally managed mechanical prophylaxis should be used when pharmacologic prophylaxis is contraindicated.

• An adjusted dose of warfarin (international normalized ratio 1.3-1.9), a prophylactic dose of nadroparin and semuloparin, and a therapeutic dose of dalteparin have been shown to reduce the risk of VTE in ambulatory patients with cancer who are receiving chemotherapy, although none has improved survival.

• The Khorana risk score that is calculated on the basis of tumor type, prechemotherapy platelet count, and white blood cell count, hemoglobin, use of erythropoietic stimulatory agents, and body mass index can be used to assess the risk of VTE among ambulatory patients with cancer who are starting chemotherapy. This score may help to identify ambulatory medical oncology patients in whom outpatient VTE prophylaxis may be beneficial.

• Enoxaparin, 40 mg daily, and dalteparin, 5000 units daily for 28 days, have been shown to reduce the incidence of VTE compared with prophylaxis for 6 to 10 days in patients with cancer who have undergone surgery.

• In a prospective observational study of more than 2300 patients with cancer who underwent surgery, VTE was responsible for 46% of deaths, making it the most common cause of death within the first 30 days after surgery.

• Extended outpatient pharmacologic VTE prophylaxis should be considered for high-risk surgical oncology patients. Risk factors for VTE in surgical oncology patients include age >60 years, anesthesia time exceeding 2 hours, bed rest exceeding 3 days, advanced cancer stage, and a previous history of VTE.

• Prospective studies have noted that symptomatic central venous catheter thrombosis occurs in 4% of patients with cancer.

• A prophylactic dose of low-molecular-weight heparin and low-dose warfarin are ineffective for CVC-associated deep venous thrombosis (DVT) and should not be prescribed. Adjusted-dose warfarin (international normalized ratio 1.5 to 2) was associated with a reduced incidence of CVC thrombosis at a cost of increased bleeding.

• Diagnosis of VTE in patients with cancer relies primarily on objective imaging with duplex ultrasonography and computed tomography (CT) angiography. In patients with negative duplex studies in whom there is a high suspicion of DVT, CT venography should be considered.

• Low molecular weight heparin is recommended for the initial and long-term treatment of VTE in most patients with cancer who have VTE. Anticoagulation should be continued for at least 3 months or until there is no evidence of active cancer and therapy is completed.

• Catheter-directed pharmacomechanical thrombolysis is a consideration in patients with cancer who do not have contraindications to its use and who have extensive or limb- or life-threatening DVT. Catheter-directed pharmacomechanical thrombolysis is associated with an increased risk of bleeding.

• Systemic thrombolytic therapy should be considered for patients with hemodynamically significant pulmonary embolism (PE).

• Vena cava filters are effective for prevention of PE but are also associated with an increased risk of DVT and inferior vena cava thrombosis. Therefore inferior vena cava filters are primarily recommended for patients who are not candidates for anticoagulation.

• Common causes of recurrent VTE in patients with cancer include local vascular compression, therapeutic resistance (Trousseau syndrome, particularly with vitamin K antagonists) and heparin-induced thrombocytopenia.

• CVC-associated thrombosis generally can be managed by anticoagulation alone without CVC removal. Anticoagulation should be continued for at least 3 months or as long as the CVC is in place.

• Patients with primary and metastatic brain tumors without evidence of hemorrhage generally can be treated safely with anticoagulation for VTE. Metastatic central nervous system tumors at high risk for bleeding include metastatic melanoma, renal cell carcinoma, thyroid carcinoma, and choriocarcinoma.

• Patients with cancer who have stable PE and no signs of hemodynamic compromise can be safely treated as outpatients in the absence of other contraindications to outpatient management. Assessment of right ventricular overload by echocardiography or CT angiography and/or biomarkers can assist with decision making.

• Patients with unsuspected PE should be managed in a similar fashion as patients with symptomatic PE because their outcomes appear to be similar.

Introduction

The seminal description of the association between cancer and venous thromboembolism (VTE) by Trousseau was made almost 150 years ago.1 Consequently, the combination of the cancer and VTE is still commonly referred to as Trousseau syndrome.2 In addition to deep venous thrombosis (DVT) and pulmonary embolism (PE), a wide range of clinically significant thromboembolic events have been observed in patients with cancer, including visceral thrombosis, catheter-related thrombosis, arterial thromboembolism, nonbacterial (marantic) thrombotic endocarditis, migratory thrombophlebitis, hepatic venoocclusive disease (VOD), and disseminated intravascular coagulation (DIC).3 Since the pivotal observation by Trousseau in 1865, our understanding of the prevalence and pathophysiology of VTE in patients with cancer has significantly improved, novel and advanced diagnostic techniques have become readily available for daily clinical use, and effective preventive and therapeutic interventions have been incorporated into standard clinical practice. Nonetheless, the intimate complex bidirectional relationship between VTE and cancer has not been completely deciphered, and VTE continues to be an important and a commonly underrecognized contributor to morbidity and mortality in patients with cancer. In this chapter we will discuss the epidemiology, pathogenesis, diagnosis, prevention, and treatment of cancer-associated VTE.

Epidemiology of Cancer-Associated VTE

Cancer-Associated VTE Is Common

Since the early observations by Trousseau and others, the strong association between malignancy and development of VTE has been confirmed in multiple retrospective and observational prospective studies.4-11 The estimated annual incidence of VTE in patients with cancer is 0.5%, compared with 0.1% in the general population.12 During the clinical course of cancer, the cumulative incidence of symptomatic VTE has been reported to be approximately 15%, with a range of 3.8% to 30.7%.13,14 It has been estimated that up to one fifth of all patients with VTE have an underlying cancer.11,15,16 As a group, malignancies are associated with a fourfold to sevenfold increase in VTE, with a twenty-eightfold increase in risk of VTE in certain types of cancer.5,7,17 Researchers from the Netherlands observed a sevenfold increase in risk of VTE among patients with malignancy compared with persons without cancer.5 In a large population-based study, the presence of a malignant neoplasm was associated with an odds ratio (OR) of 6.5 for VTE compared with control subjects without cancer.17 In addition, incidental asymptomatic VTE is noted on routine imaging in 1.5% to 6.3% of patients.2020

The incidence of VTE is not uniformly distributed among different cancer types.5,21 In general, pancreatic, gastric, brain, ovarian, renal, and hematologic malignancies have been associated with a higher risk of VTE, whereas cancers of the head and neck, breast, prostate, and esophagus are associated with lower VTE rates (Fig. 35-1).4,5,2124 However, because of the higher incidence and prevalence of lung, colon, prostate, and breast cancers, these malignancies are associated with the highest absolute number of VTEs.21 The histologic type and extent of the malignancy also influence VTE risk. For example, lung adenocarcinoma is associated with a greater risk of VTE than is squamous cell carcinoma of the lung.25 Metastatic cancers are more likely to be associated with VTE than are localized malignancies.4,5,21,25 For the most common cancer types, the relative risk (RR) of symptomatic VTE has been estimated to be fourfold to more than twentyfold higher for metastatic malignancies.4,21,25A Even within the same patient with cancer, VTE risk varies throughout the course of the person’s disease because of effects of other intrinsic and extrinsic factors such as cancer stage, surgery and length of anesthesia, chemotherapeutic and hormonal therapies, age, the presence of indwelling central venous catheters, immobilization, inherited thrombophilia, a previous personal history of VTE, and infections.5,7,8,17,21,26,27 The first year after cancer diagnosis, and especially the first few months, is particularly associated with the development of VTE, although the risk of VTE remains elevated for many years after the initial cancer diagnosis.5 Blom et al.5 noted an adjusted OR for VTE of 53.5 (95% confidence interval [95% CI], 8.6-334.3) during the first 3 months after cancer diagnosis, with a subsequent reduction to 14.3 (95% CI, 5.8-35.2) 3 to 12 months after diagnosis, and a reduction to 3.6 (95% CI, 2.0-6.5) 1 to 3 years after diagnosis, but the increased VTE risk persisted for 15 years after cancer diagnosis.5

Similar to solid tumors, hematologic malignancies are also associated with an increased incidence of cancer-associated VTE.4,5,21,23,24,2830 In fact, in a population-based study, patients with hematologic malignancies had the highest risk of VTE among different tumor types (OR 28; 95% CI, 4-200).5,8 Among patients with hematologic malignancies, patients with multiple myeloma (MM) are at a higher risk for VTE due to cancer and treatment-related factors.31,32 It has been reported that cancer-associated VTE complicates the course of MM in at least 10% of patients.27,31 In an analysis from the California Cancer Registry, the 1-year cumulative incidence of VTE in persons with acute myeloid leukemia, lymphoma, chronic lymphocytic leukemia, acute lymphoblastic leukemia, and chronic myeloid leukemia were 3.7%, 2.8%, 2.7%, 2.6%, and 1.5%, respectively.11

The Bidirectional Relationship Between Cancer and VTE

The relationship between cancer and VTE is bidirectional; VTE, especially idiopathic VTE, can be a harbinger of an occult malignancy.2 Population-based observational studies have documented an increased risk of malignancy after a first episode of idiopathic VTE.33,34 In an analysis of the Swedish Cancer Registry,33 Baron et al.33 found that at the time of VTE diagnosis or during the first year of follow-up, there was a large increase in the risk for virtually all cancers (standardized incidence ratio of 4.4; 95% CI, 4.2-4.6) The increased risk of future cancer diagnosis in patients with VTE compared with those without VTE persisted for 2 through 25 years after admission to hospital with the index VTE.33 In a large analysis of the Danish Cancer Registry, an increased standardized incidence ratio of 1.3 (95% CI, 1.21-1.33) for cancer diagnosis was found for patients with a VTE episode.34 The risk was substantially elevated only during the first 6 months of follow-up and declined rapidly thereafter to a constant level slightly above 1.0 one year after the VTE episode.34 The risk of cancer was twofold higher for patients diagnosed with idiopathic versus triggered VTE.34 The association was most pronounced for cancers of the pancreas, ovary, liver, and brain.34 Unfortunately, extensive cancer screening at the time of VTE diagnosis is not associated with improved outcome because most cancers associated with VTE are metastatic at the time of VTE diagnosis.35,36 Consequently, the possibility of an underlying cancer among patients presenting with an idiopathic VTE always should be taken into consideration, but cancer screening should be limited to age-appropriate screening procedures in the absence of obvious signs of an underlying malignancy.34

VTE is Associated with Worse Outcomes in Patients with Cancer

Studies have shown that diagnosis of VTE in patients with malignancy is associated with worse outcomes and shortened survival.24,25,2830,3639 VTE is the second most common cause of mortality after cancer itself among patients with malignancy.25,40 In fact, 15% of deaths occurring in hospitalized patients with cancer are attributable to PE.15,41 Chew et al.21 analyzed approximately 235,000 patients with cancer in the California Cancer Registry who were linked to the California Patient Discharge Data Set and found in a multivariate analysis that diagnosis of VTE during the first year of follow-up was a significant predictor of death and decreased survival for most cancer types and stages. The 1-year survival of patients with cancer who were diagnosed with VTE is one third (12% versus 36%) that of patients with cancer who do not have VTE.36 Levitan et al.23 noted a threefold increase in 6-month mortality among patients with cancer who had VTE compared with those without VTE.

In addition to symptomatic VTE, unsuspected asymptomatic PE found on routine cancer staging computed tomography (CT) imaging was found to adversely affect survival in patients with cancer.37,39,42 In a retrospective matched cohort study, the hazard ratio (HR) for death among patients who had cancer with unsuspected PE detected on staging CT was 1.51 (95% CI, 1.01-2.27), with the risk attributable to proximal rather than subsegmental unsuspected PE.37 Another retrospective study showed that patients with cancer who were diagnosed with and treated for incidental PE have similar rates of recurrent VTE, bleeding, and mortality compared with patients with cancer who had symptomatic PE.38 Moreover, several studies in patients with cancer have correlated increases in biomarkers of thrombin generation, even in absence of documented VTE, with more aggressive cancer biology and worse outcomes.4245 Despite ongoing anticoagulation therapy, patients with cancer have a 3.2-fold increased risk of recurrent VTE compared with patients without cancer (12-month cumulative VTE incidence 20.7% vs. 6.8%).46 Additionally, the incidence of major bleeding is 2.2-fold higher in patients with cancer compared with patients without cancer (12.4% vs. 4.9%).46 The risks of recurrent VTE and bleeding appear to correlate with the extent of the malignancy.46 As expected, the development of VTE in patients with cancer is associated with a significant increase in the consumption of health care resources.47

Pathogenesis of Cancer-Associated VTE

Multiple factors contribute to the hypercoagulable state associated with malignancy (Box 35-1). In general terms, these factors can be divided into three broad categories: factors intrinsic to the cancer (tumor-specific factors), patient-related factors (host-specific factors), and environmental factors.

Tumor-Specific Factors

Malignancy is characterized by a bidirectional interrelationship connecting cancer growth, progression, and metastasis with activation of the coagulation cascade and subsequent thrombin generation and inflammation.7,4850 As discussed earlier, tumor-associated factors such as site, histology, and stage all influence the risk of thrombosis. Cancer cells can disrupt the hemostatic balance via several different pathways, including production of procoagulant, profibrinolytic, proproteolytic, and proaggregating activities, expression of adhesion molecules that mediate direct interactions with host vascular and blood cells, and secretion of proinflammatory and proangiogenic cytokines.7,27,40,50,51 Figure 35-2 depicts some of the tumor-specific factors that contribute to the hypercoagulable state of cancer. Cancer procoagulant is a cysteine protease expressed only by malignant cells that can directly activate factor X independent of factor VII.5454 In addition, cancer procoagulant has been demonstrated to activate platelets, further adding to its prothrombotic potential.55 Cancer procoagulant has been identified in a wide variety of cancer types and has been noted to have increased activity at disease onset with a subsequent slow decline.7,5256

Tissue factor (TF) is the principal initiator of the coagulation protease cascade and is normally expressed as a transmembrane glycoprotein on vascular subendothelial cells.3,7,48,49 Therefore TF is not normally in contact with blood unless vascular endothelial integrity is compromised or if its expression is induced on endothelial cells by inflammatory stimuli.3,7,48,49 Many types of cancer cells such as pancreatic adenocarcinoma and malignant glioma express high levels of TF, which can subsequently lead to activation of both factor X and factor IX, thrombin formation, and ultimately, fibrin clot formation.7,57 TF, which can also be produced by cells in the cancer microenvironment depending on cancer type and context, has been associated with cancer initiation, metastasis, progression, and angiogenesis, in addition to activation of coagulation.49,5863 Laboratory studies have demonstrated a correlation between increasing TF expression in glioma cells and histologic grade, progression, and the risk of intravascular thrombosis.64,65 In pancreatic adenocarcinoma, it has been shown that fibrinogen and plasminogen activator inhibitors (PAIs) 1, 2, and 3 exist throughout the tumor stroma and that tumor cells stain for TF, PAI, prothrombin, and several other coagulation factors.66 In another study, expression of TF was found to correlate strongly with the degree of histologic differentiation in pancreatic adenocarcinoma. Tumors with stronger immunoreactivity for TF were more poorly differentiated.60 Based on these observations, it has been theorized that local coagulation activation may regulate growth and progression of pancreatic adenocarcinoma.65,66 TF can drive cancer progression by coagulation-dependent and coagulation-independent mechanisms.49,67 The circulating form of TF has been proposed to contribute more significantly to the pathogenesis of cancer-associated VTE than TF expressed on primary cancer cells.49 In a retrospective study, patients with cancer who had circulating TF-expressing microparticles had a 1-year cumulative incidence of VTE of 34.8% versus 0% in those without detectable TF-bearing microparticles.68 This and other similar observations suggest that cancer-derived TF-bearing microparticles are thrombogenic in vivo and are likely to play a central role in the pathogenesis of cancer-associated VTE.49 The clinical utility of this assay has not been demonstrated yet, and it remains an investigational tool at the current time.

Most patients with cancer have been found to exhibit increased levels of coagulation factors V, VIII, IX, XI, and biomarkers of thrombin generation such as prothrombin fragment 1+2 and D dimer.48,59 As mentioned previously, elevated biomarkers of thrombin generation have been associated with aggressive cancer biology and worse clinical outcomes.4245 The fibrinolytic system can also be significantly dysregulated in patients with cancer.69 Malignant cells can express different proteins in the fibrinolytic system, including urokinase-type and tissue-type plasminogen activators (UPA and TPA, respectively) and PAIs.7,69,70 For example, acute promyelocytic leukemia is often associated at onset with a life-threatening coagulopathy associated with hypofibrinogenemia, increased thrombin generation and fibrin degradation, and prolonged prothrombin and thrombin times.27 The leukemic cells in acute promyelocytic leukemia can express the UPA receptor on their surface, which activates UPA and TPA, contributing to the fibrinolytic state characteristic of the disease.71 Other leukemic cells are also capable of expressing various fibrinolytic and proteolytic enzymes that can mediate the bleeding complications seen in some patients with acute leukemia.27,51,69 Similarly, plasminogen activators, PAIs, and other proteins that regulate the fibrinolytic system are also expressed by solid tumor cells, and the resulting imbalance in fibrinolysis may contribute to the hypofibrinolytic and procoagulant state seen in some affected patients.7,69,70 Additionally, cancers can be associated with deficiencies in the natural anticoagulants, antithrombin, protein C, and protein S, further promoting the cancer-associated thrombogenic state.72,73 The degree of activation of the coagulation cascade and fibrinolysis differs between various tumor types. As noted earlier, some patients with cancer will exhibit clinically evident manifestations of activated coagulation such as DIC and/or venous or arterial thromboembolism, whereas many other patients with cancer will only have laboratory markers of a procoagulant state such as elevated D dimer.74,75

Cancer cells can also modulate the hemostatic balance in an indirect fashion through their interaction with host immune cells such as monocytes and macrophages, leading to activation of platelets and factors X and XII.2 Tumor cells can directly produce inflammatory cytokines or indirectly stimulate their production by host cells (leukocytes and endothelial cells), promoting a hypercoagulable state.2,3 These inflammatory cytokines, such as tumor necrosis factor–alpha (TNF-α), interleukin-1 (IL-1), and vascular endothelial growth factor (VEGF) can induce TF production by endothelial cells and monocytes, stimulate PAI-1 production, and downregulate expression of the natural anticoagulant protein, thrombomodulin, on endothelial cells.3,4A,76,77 In addition, these cytokines can lead to vascular endothelial cell damage and conversion of vascular lining into a thrombogenic surface.2 In addition to activation of TF production by endothelial cells and monocytes, the effects of VEGF include induction of angiogenesis and increased local vascular permeability, therefore increasing the exposure of TF and promoting cancer-associated thrombogenesis.78 The acute phase reactants induced by inflammatory cytokines in patients with cancer include procoagulants such as von Willebrand factor (vWF), factor VIII, and fibrinogen, therefore favoring a thrombogenic hemostatic milieu. Tumor cells can also promote nonenzymatic activation of factor X through the sialic acid moieties of mucin produced by adenocarcinomas.2 Although increased levels of factor VIII, vWF, fibrinogen, PAI, and markers of thrombin generation and fibrin degradation have been associated with more advanced cancers and worse outcomes, these biomarkers have not shown any benefit to date in selecting patients with cancer who might benefit from primary anticoagulant VTE prophylaxis.14,4245,79

Tumor cells can also directly aggregate platelets and secrete important platelet aggregation agonists such as thrombin and adenosine diphosphate.80 In addition to these biochemical procoagulant mechanisms, direct cell-cell interactions and the local mass effect of tumors contribute to VTE pathogenesis in patients with cancer. Vascular invasion and physical compression by the tumor can mechanically obstruct venous blood flow, leading to venous stagnation, endothelial lining damage, and local activation of the coagulation cascade, all of which predispose to VTE.14,81,82 In patients with myeloma, increased plasma viscosity, elevated levels of circulating immunoglobulins, autoantibodies targeting natural anticoagulants, and secretion of inflammatory mediators with procoagulant activity have all been proposed to contribute to the pathogenesis of VTE.31,32,83

Host-Specific Factors

Studies have shown that some host-specific factors can also modify the risk of VTE. Older age (≥65 years) has been modestly associated with cancer-associated VTE in hospitalized patients.84 Poor performance status in patients with lung cancer who are receiving chemotherapy, which might be a surrogate for limited mobility, has been prospectively associated with increased VTE risk.85 Patient race (African Americans have a higher risk, whereas Asians have a lower risk) and comorbidities such obesity and renal disease have also been associated with increased risk of cancer-associated VTE, whereas gender does not significantly influence risk.5,8,84,86 ABO blood group status, which was found to affect the risk of VTE in the general population, has also been found to modify the risk of VTE in patients with malignant glioma.87,88 Although the pathophysiology of the ABO blood group’s association with VTE is not fully clarified, ABO blood group status does influence factor VIII and vWF levels, which might mediate this effect.89,90

The presence of prothrombotic genetic alterations has been also shown to influence the risk of VTE in patients with cancer. In a large population-based, case-control study of 3220 consecutive patients aged 18 to 70 years in the Netherlands, patients with cancer who were carriers of factor V Leiden or the prothrombin gene 20210A mutation had a fourfold increased risk of VTE compared with patients with cancer who did not have these mutations.5 In contrast, a smaller study from Brazil found no significant difference in the prevalence of four thrombophilic genetic mutations/polymorphisms (factor V Leiden, prothrombin gene 20210A mutation, FXIII Val34Leu polymorphism, and methylenetetrahydrofolate reductase [MTHFR] C677T polymorphism) in patients with cancer who did and did not have VTE.91 A third study in patients with gastrointestinal adenocarcinoma found a significant association between VTE and factor V Leiden mutation but not with prothrombin gene 20210A mutation or the MTHFR C677T polymorphism.92 A matched nested, case-control study of breast cancer prevention using tamoxifen found no significant association between the factor V Leiden mutation or the prothrombin gene 20210A mutation and VTE risk.93

Environmental Factors

Environmental factors significantly modulate VTE risk in patients with cancer. As expected, many modifiable VTE risk factors increase VTE risk in patients with and without cancer.

Surgery, Radiation Therapy, and Cancer-Associated VTE

Major surgery, a well-recognized VTE risk factor, has been associated with a twofold increased risk of VTE in patients with cancer compared with patients without cancer.94 Furthermore, patients with cancer have a fourfold increased risk of fatal PE after undergoing surgery compared with patients without cancer.15 Factors such as the duration of anesthesia and the procedure, the complexity of the surgery, increasing age, and late mobilization can all modify the risk of postoperative VTE in patients with cancer.3 In contrast to surgery, conflicting data exist regarding the contribution of radiation therapy to the risk of cancer-associated VTE. For example, adjuvant radiation therapy in combination with surgery or chemotherapy was associated with an increased incidence of VTE in patients with glioma or rectal carcinoma, whereas no increased VTE risk was found in otherwise healthy patients with early-stage uterine cervical cancer who received radiation therapy.9797 In a large observational database study by Blom et al.,4 no additional risk of VTE was conferred by radiation therapy in patients with cancer. These data suggest that radiotherapy is inconsistently associated with VTE8 and that the impact of radiotherapy on VTE risk may be influenced by tumor type and treatment context.

Chemotherapy, Hormonal Therapy, and Cancer-Associated VTE

Chemotherapy, hormonal therapy, and hematopoietic growth factors have all been associated with an increased risk of VTE.2 Patients with cancer who undergo chemotherapy have been found to have a higher risk of VTE and recurrent VTE when compared with patients with cancer who do not undergo chemotherapy.17,98,99 As described earlier, the risk of VTE after cancer therapy depends on the interaction between therapeutic agents, the type and stage of malignancy, and the presence of other VTE risk factors such as advanced age, surgery, immobilization, and the use of central venous catheters.100 Although the causal role of cancer therapies in VTE is well recognized, the pathogenic mechanisms underlying the augmented prothrombotic state and increased risk of VTE are poorly understood despite many years of active research.2,3,100 Multiple mechanisms are likely to be involved depending on the specific chemotherapeutic agent and its interaction with other patient variables. These mechanisms can involve direct vascular endothelial cell damage, increased endogenous procoagulant and decreased anticoagulant levels, altered fibrinolytic activity, platelet activation and aggregation, and increased TF expression by direct and indirect effects.3,100112 Prechemotherapy platelet count and chemotherapy-associated neutropenia in hospitalized patients with cancer also have been associated with increased VTE risk.9,29,98

The causal relationship between chemotherapy and VTE in patients with cancer has been most studied in the context of breast cancer clinical trials.100 When treated with adjuvant chemotherapy, the risk of DVT in patients with early-stage breast cancer increases from a baseline risk of less than 1% to 2% to 10%.113 In a study of adjuvant epirubicin and cyclophosphamide, a 10% incidence of VTE was found.104 Saphner et al.114 reviewed the records of 2673 patients for the occurrence of vascular complications; these patients received treatment as part of seven consecutive Eastern Cooperative Oncology Group studies of adjuvant therapy for breast cancer. The authors found a significantly higher risk of thrombosis (venous and arterial combined) of 5.4% among patients who received adjuvant therapy in comparison with 1.6% among patients who did not receive adjuvant therapy. Premenopausal patients who received chemotherapy with tamoxifen had a significantly higher rate of VTE than did those who received chemotherapy without tamoxifen (2.8% vs. 0.8%). Postmenopausal patients who received tamoxifen and chemotherapy had a significantly higher rate of VTE than did those who received tamoxifen alone (8% vs. 2.3%) or those who were observed (8% vs. 0.4%). The authors concluded that combining chemotherapy with tamoxifen was associated with more venous and arterial thromboembolic complications than chemotherapy alone in premenopausal patients and with more venous thrombi than tamoxifen alone among postmenopausal patients.114 Other studies confirmed a higher risk of VTE with chemotherapy-hormonal therapy combinations compared with tamoxifen alone in adjuvant therapy for postmenopausal patients with breast cancer.115 In a randomized trial comparing a chemotherapy-hormonal therapy regimen for 12 weeks versus 36 weeks of chemotherapy in patients with stage II breast cancer, VTE developed in 6.8% of treated patients, all during therapy.116 Although aromatase inhibitors such as anastrozole have been associated with a lower risk of VTE than tamoxifen, anastrozole has been associated with a 1% to 2% incidence of VTE as first-line therapy for advanced hormone-receptor positive breast cancer in postmenopausal women.117 In the “Arimidex, tamoxifen, alone or in combination” (ATAC) study evaluating adjuvant endocrine treatment for postmenopausal women with hormone-receptor–positive early breast cancer, the rate of VTE after almost 5.5 years of follow-up was 4.5% for patients who received tamoxifen versus 2.8% for those who received anastrozole.118

The agent 5-fluorouracil, which has been associated with VTE in one out of every seven patients with colorectal cancer who have been treated with the drug, has been proposed to induce a prothrombotic state by decreasing protein C levels, increasing fibrinogen proteolysis, and possibly causing vascular endothelial toxicity.3,119L-asparaginase has been associated with a 4% to 14% incidence of VTE in adults with acute lymphoblastic leukemia.100,120L-asparaginase is associated with reductions in fibrinogen, protein C, protein S, antithrombin, plasminogen, and factors IX and XI, whereas it increases levels of factors V and VIII.121,122 Platinum-based regimens have been associated with increased VTE risk in patients with germ cell tumors, non–small cell lung cancer, cervical cancer, and ovarian cancer.85,123125 Other agents such as bleomycin, mitomycin C, and the use of high-dose chemotherapy conditioning for hematopoietic stem cell transplantation (HSCT) have all been also associated with VTE.126 Corticosteroids, a class of drugs commonly used in cancer therapy, especially for lymphoid malignancies and MM, can increase the risk of VTE, especially when high doses are used in patients with germ cell tumors and MM.123,127 Glucocorticoids have been found to increase factor VII, VIII, XI, and fibrinogen levels, which may contribute to the reported increased risk of VTE in patients using glucocorticoids on a chronic basis.128

Immunomodulatory Agents and Cancer-Associated VTE

In addition to traditional chemotherapy and hormonal therapy, some newer antineoplastic agents have also been associated with increased VTE risk. The immunomodulatory and antiangiogenic agents thalidomide and lenalidomide, which are used for treatment of various cancers, have both been associated with VTE. Thalidomide use in MM as a single agent, whether in newly diagnosed or relapsed/refractory disease, has not been associated with a significantly increased risk of VTE (an incidence of 2% to 4%).31,129131 In contrast, combinations of thalidomide with dexamethasone or chemotherapy have been associated with an increased risk of VTE in newly diagnosed patients with MM (an incidence of 14% to 26%).31,132 Interestingly, VTE incidence is not increased to the same degree with thalidomide and dexamethasone in patients with relapsed/refractory MM (an incidence of 2% to 8%).133

Similarly, lenalidomide has also been associated with increased VTE risk in patients with MM when used in combination with dexamethasone or chemotherapy, especially in newly diagnosed patients.31,134 In newly diagnosed patients with MM, lenalidomide and high-dose dexamethasone (480 mg/month) have been associated with a 12% to 26% VTE rate compared with 6% to 12% when lenalidomide is used with low-dose dexamethasone (160 mg/kg).134,135 Most cases of VTE associated with lenalidomide occur in the first 3 months of therapy.135 VTE rates as high as 17% have been reported in patients with relapsed or refractory MM who have received treatment with lenalidomide.31,136,137 The etiology of thalidomide- and lenalidomide-associated VTE is not fully understood, although direct vascular endothelial toxicity, acquired protein C resistance, and upregulation of the potent platelet activator cathepsin G have been implicated.31,32,138

Molecularly Targeted Therapies and Cancer-Associated VTE

Some molecularly targeted antineoplastic agents have also been associated with increased VTE risk. The novel antiangiogenic agent bevacizumab, a humanized monoclonal antibody to VEGF that is used in the treatment of several types of cancer, has been variably associated with an increased risk of VTE, arterial thromboembolism, and bleeding.139 In a metaanalysis of 15 randomized trials that included 7956 patients with a variety of advanced solid cancers, patients who received bevacizumab had an incidence of all-grade and high-grade VTE of 11.9% and 6.3%, respectively.140 Therapy with bevacizumab was associated with an RR of VTE of 1.33 (95% CI, 1.13-1.56) compared with control subjects, and that risk was increased for both all-grade and high-grade VTE.140 In contrast, Hurwitz et al.141 found no added risk of VTE among patients treated with regimens containing bevacizumab compared with patients receiving regimens that did not contain bevacizumab (10.9% vs. 9.8%, (OR, 1.14; 95% CI, 0.96 to 1.35; P = .13). Axitinib, an oral receptor tyrosine kinase inhibitor of VEGF and platelet-derived growth factor receptors commonly used in patients with advanced renal cell carcinoma, has been also associated with mesenteric vein thrombosis.142 In a systematic review, two other oral agents targeting angiogenesis, sunitinib and sorafenib, were found to be associated with an increased risk of arterial but not venous thrombosis.143 The safety of continuing VEGF inhibitors in patients who have sustained a VTE while receiving therapy and subsequently undergo anticoagulation is currently unknown.139

Hematopoietic Growth Factors and Cancer-Associated VTE

Hematopoietic growth factor therapy plays an important role in the supportive care of patients with cancer. Erythropoiesis-stimulating agents (ESAs) can reduce the severity of anemia and transfusion requirements in patients with cancer, whereas granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) can reduce neutropenic complications. The use of ESAs has been associated with an increased risk of thrombotic complications in patients with cancer.146-146 Several recent studies have demonstrated an association with tumor progression, mortality, and thrombotic complications, especially VTE, in some patients with solid tumor malignancies who received ESAs.145,146 In a systematic review of 27 randomized trials involving 3287 adult patients with cancer who received darbepoetin or epoetin, Bohlius et al.147 noted that the RR of thromboembolic complications was 1.7 (95% CI, 1.4-2.1) compared with untreated control subjects. In a randomized study of healthy volunteers, G-CSF administration enhanced platelet aggregation by 75% as measured by circulating soluble P-selectin, suggesting that G-CSF use may increase thrombotic risk in patients with cancer.148 Nonetheless, there is currently no conclusive evidence of an association of myeloid growth factor administration with VTE.149 In a retrospective analysis, transfusion of blood products was independently associated with an elevated risk of VTE, arterial thrombosis, and in-hospital mortality in hospitalized patients with cancer.150

Indwelling Venous Catheters and Cancer-Associated VTE

Another important factor that contributes to the predisposition of patients with cancer to VTE is the frequent use of indwelling central venous catheters (CVCs) and peripherally inserted central catheters (PICCs). These catheters facilitate blood sampling and the administration of chemotherapy, intravenous fluids, blood products, and parenteral antibiotics. Thrombosis of the upper extremities has been found to be more common in patients with malignancy and a CVC.151,152 Reported rates of symptomatic CVC-associated VTE in patients with cancer have ranged between 0.3% and 28.3%; recent data from large prospective trials have identified rates of 4% to 8%.153,154 Nonetheless, the majority of CVC- and PICC-associated thrombosis in patients with cancer are actually asymptomatic: one metaanalysis reported that only 12% of CVC-associated VTEs were symptomatic.152,153,155 Several risk factors for CVC-associated thrombosis in patients with cancer have been described. Some of these risk factors include the number of lumens and the outer diameter of the catheter (thrombosis is more common with larger catheter diameter and an increased number of lumens), insertion site (with a higher thrombosis risk for left-sided CVCs), catheter tip position (the right atrial–superior vena caval junction tip position has a lower risk of thrombosis compared with more central or peripheral positions), the material of the catheter, the method of insertion, CVC-related infections, prior personal history of CVC thrombosis, elevated platelet counts, and inherited prothrombotic genetic mutations.152,153,156,157 Tumor type (ovarian carcinoma and lung adenocarcinoma are associated with a higher risk) and the extent of disease (metastatic disease is associated with a higher risk) can also modify the risk of CVC-associated thrombosis in patients with cancer.152,153,156159 In addition, therapy-related factors can affect the risk of CVC-associated thrombosis in patients with cancer. For example, infusion of sclerosing chemotherapeutic agents and chest radiotherapy have both been associated with increased risk.156,160 Close attention to modifiable risk factors can help to minimize the risk of CVC-associated VTE (see Chapter 26).

Prevention of Cancer-Associated VTE

Prevention of VTE in Hospitalized Medical Oncology Patients

Hospitalized medical oncology patients are at high risk for VTE. Therefore patients with cancer should always receive some form of VTE prophylaxis, preferably pharmacologic prophylaxis given the variable compliance with mechanical prophylaxis in routine care settings.161,162 The American Society of Clinical Oncology (ASCO), the European Society of Medical Oncology (ESMO), and the National Comprehensive Cancer Network (NCCN) all recommend pharmacologic VTE prophylaxis in all hospitalized medical oncology patients, and the American College of Chest Physicians (ACCP) recommend pharmacologic prophylaxis if patients have at least one additional risk factor for VTE.163168 Because no dedicated randomized trials have been conducted to evaluate VTE prophylaxis in hospitalized medical oncology patients,86 these recommendations are based on the high risk of VTE in this patient population and the supportive data from three large randomized controlled trials in hospitalized general medical patients that included some oncology patients.86,169171 Although none of these studies reported specific bleeding rates for the subgroup of oncology patients, there was no increase in the overall risk of major bleeding compared with the control arm in any of these trials.86,167,169171 Therefore until specific data for hospitalized medical oncology patients are available, strategies used for VTE prophylaxis in hospitalized general medical inpatients should be applied to medical oncology patients as well. Box 35-2 describes some of the commonly used pharmacologic thromboprophylaxis regimens, and Box 35-3 lists relative and absolute contraindications to pharmacologic and mechanical VTE prophylaxis. When using graduated compression stockings (GCS) for mechanical prophylaxis in patients with cancer, it is important to fit patients with the correct stocking size and monitor patients closely for skin complications. In a randomized trial of the use of GCS in patients who had a stroke, GCS were associated with a fourfold increased risk of skin ulceration.172

To identify risk factors for VTE among hospitalized patients with cancer, Khorana and colleagues29 examined the University Health System discharge database. Venous thromboembolism occurred in 4.1% of patients, DVT developed in 3.4%, and PE developed in 1.1%. African American patients had the highest rate of VTE (5.1%), whereas white and Hispanic patients had an intermediate rate (4%) and Asians Americans had the lowest rate (3.3%). Patients with pancreatic cancer had the highest rate of VTE (8.1%), followed by other intraabdominal noncolorectal cancers (6.6%), ovarian cancer (5.6%), kidney cancer (5.6%), and myeloma (5%). The lowest VTE rates were found in patients with head and neck cancer (1.4%), prostate cancer (1.9%), and breast cancer (2.3%). Patients receiving chemotherapy were at higher risk (4.9%) than patients not receiving chemotherapy (4%). Medical comorbid conditions such as infections (OR 1.77), renal disease (OR 1.53), pulmonary disease (OR 1.37), and anemia (OR 1.35) were associated with greater risk, as was female gender (1.14) and transfusions (1.35). Mortality was significantly higher among patients who sustained VTE (16.3% vs. 6.3%, P < .0001).29 These factors may be useful for generating a risk stratification model for hospitalized medical oncology patients.

Prevention of VTE in Ambulatory Medical Patients with Cancer

Because most episodes of VTE in patients with cancer occur in the outpatient setting, prevention of VTE in ambulatory medical oncology patients has been the focus of extensive investigation. In 1994, Levine and coworkers173 reported a double-blind, randomized study of very low dose warfarin thromboprophylaxis in patients with stage IV breast cancer. In this study, 152 patients received very low dose warfarin (1 mg adjusted to achieve an INR of 1.3-1.9), whereas 159 patients received placebo. Seven cases of VTE (six DVT and one PE) occurred in the placebo group and one PE occurred in the warfarin group (P = .031), representing an 85% risk reduction. Major bleeding occurred in two placebo recipients and one patient treated with warfarin.173 In the Prophylaxis of Thromboembolism During Chemotherapy Trial (PROTECHT), Agnelli et al.174 randomly assigned 1166 patients in a double-blind fashion to evaluate the clinical benefit of prophylactic-dose nadroparin for thromboprophylaxis in ambulatory patients with cancer who were actively receiving chemotherapy for metastatic or locally advanced solid tumors. Participants with lung, gastrointestinal, pancreatic, breast, ovarian, or head and neck cancers were randomly assigned in a 2 : 1 schema to receive either nadroparin (3800 IU subcutaneously daily, n = 779) or placebo (n = 387) for the duration of chemotherapy up to a maximum of 4 months. The primary end point was a composite of independently adjudicated symptomatic VTE or arterial thromboembolism. In total, 1150 patients (769 patients in the nadroparin arm and 381 patients in the placebo arm) were evaluated for the primary efficacy and safety analyses using a modified intention-to-treat approach. In the nadroparin arm, the primary outcome developed in 15 patients (2%), compared with 15 patients (3.9%) in the placebo group (single-sided P = .02). There was no statistically significant difference in the rates of major bleeding events (0.7% for the nadroparin group vs. 0% in the placebo group, two-sided P = .18) or minor bleeding (7.4% in the nadroparin group compared with 7.9% in placebo arm). In total, 15.7% serious adverse events occurred in the nadroparin group versus 17.6% in the placebo group. The authors concluded that nadroparin reduces the incidence of thromboembolic events in ambulatory patients with metastatic or locally advanced malignancies who are receiving chemotherapy.174 It is worth noting that breast and head and neck cancers are not usually considered high risk for VTE development, and the inclusion of these patients in this study may have accounted for the observed low thromboembolic event rates.86

In another prospective study, the UK-FRAGEM trial, 123 patients with advanced pancreatic carcinoma were randomly assigned to receive either gemcitabine or gemcitabine plus a weight-adjusted therapeutic dose of dalteparin for 12 weeks (200 IU/kg daily × 1 month and then 150 IU/kg daily for months 2 and 3).175 The primary end point was the reduction of all-type VTE during the study period. The incidence of the primary outcome was decreased from 23% to 3.4% (P = .002) in favor of the dalteparin group, with a risk ratio of 0.15 (95% CI, 0.035-0.61), corresponding to an 85% risk reduction. At the end of follow-up, all instances of VTE were also reduced significantly from 28% to 12% (P = .039), with a risk ratio of 0.42 (95% CI, 0.19-0.94), a 58% risk reduction. Lethal VTE occurring earlier than 100 days was seen only in the control arm (8.3% compared with 0%, P = .057, with a risk ratio of 0.092, 95% CI, 0.005-1.635). No difference in overall survival was found. The authors concluded that weight-adjusted dalteparin used as primary VTE prophylaxis for 12 weeks in patients with advanced pancreatic carcinoma who receive gemcitabine is safe and is associated with a significant reduction of all VTEs during the prophylaxis period.175 It should be noted the PROTECHT study used prophylactic-dose nadroparin, whereas the UK-FRAGEM trial used therapeutic-dose dalteparin.86

In the SAVE-ONCO trial, a recently published, double-blind, multicenter randomized study, investigators evaluated the efficacy and safety of the new ultra low molecular weight heparin, semuloparin, for VTE prophylaxis in patients with cancer who were undergoing chemotherapy.176 In this study, 3212 patients with metastatic or locally advanced solid tumors who were starting chemotherapy were randomly assigned to receive subcutaneous semuloparin, 20 mg once daily, or placebo until there was a change of chemotherapy regimen. The primary efficacy outcome of the study was a composite of any symptomatic DVT, any nonfatal PE, and death related to VTE, whereas the primary safety outcome was the incidence of clinically relevant bleeding. The median duration of therapy was 3.5 months. In the semuloparin arm, VTE occurred in 1.2% in comparison with 3.4% in the placebo arm (HR, 0.36; 95% CI, 0.21-0.60; P < .001), with consistent efficacy among subgroups defined based on origin and stage of cancer and the baseline risk of VTE. There was no significant difference in clinically relevant bleeding between the two groups (2.8% vs. 2% in the semuloparin and placebo groups, respectively; HR, 1.40; 95% CI, 0.89-2.21). The authors concluded that semuloparin reduces the incidence of VTE in patients with cancer receiving chemotherapy without a significant increase in major bleeding episodes.176

As discussed earlier, thalidomide and lenalidomide therapy in patients with MM has been associated with an increased incidence of VTE, especially in combination with chemotherapy or high-dose corticosteroids. The 2008 International Myeloma Working Group issued a consensus statement on the prevention of VTE associated with thalidomide and lenalidomide with specific recommendations based on type of therapy and individual VTE and bleeding risks.177 The group developed a risk assessment model based on patient-related (e.g., obesity), myeloma-related (e.g., hyperviscosity) and therapy-related (e.g., high-dose dexamethasone) risk factors for VTE. The panel recommended aspirin for patients with ≤1 VTE risk factor and low molecular weight heparin (LMWH, equivalent to enoxaparin, 40 mg daily) for patients with ≥2 individual or myeloma-related risk factors (Table 35-1).177 LMWH has been recommended for all patients receiving concurrent high-dose dexamethasone or doxorubicin. Full-dose warfarin (INR goal of 2 to 3) has been listed as an alternative to LMWH. The panel acknowledged the limited high-quality data in the literature.177 Subsequent to this consensus statement, two large randomized studies of VTE prophylaxis in patients with MM who were treated with lenalidomide- or thalidomide-based combination regimens have been published.178,179 The first study was a prospective, open-label, randomized study comparing the efficacy and safety of VTE prophylaxis with low-dose aspirin or LMWH in patients with newly diagnosed MM who were treated with lenalidomide and low-dose dexamethasone induction and melphalan-prednisone-lenalidomide consolidation.178 A total of 342 patients without clinical indications or contraindications to antiplatelet or anticoagulant therapy were randomly assigned to receive aspirin, 100 mg daily (n = 176), or enoxaparin, 40 mg daily (n = 166). There was no statistically significant difference in the incidence of VTE between the two groups (2.27% in the aspirin group vs. 1.2% in the LMWH group, corresponding to an absolute risk difference of 1.07%; 95% CI, −1.69-3.83; P = .452). Although PE was observed in 1.7% of patients in the aspirin arm compared with none in the LMWH group, no arterial thrombosis, acute cardiovascular events, major bleeding complications, or sudden deaths were reported. The authors concluded that in newly diagnosed patients with MM who are receiving lenalidomide in conjunction with low-dose dexamethasone, aspirin can offer an effective and less-expensive alternative to LMWH for VTE prophylaxis.178

MYELOMA-ASSOCIATED RISK FACTORS MYELOMA THERAPY

image

BMI, Body mass index; ESA, erythropoiesis-stimulating agent; INR, international normalized ratio; LMWH, low molecular weight heparin; VTE, venous thromboembolism.

Adapted from Palumbo A, Rajkumar SV, Dimopoulos MA, Richardson PG, San Miguel J, Barlogie B, et al. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia 2008;22:414–23.

In the second study, aspirin or fixed low-dose warfarin was compared with enoxaparin for VTE prophylaxis in patients with MM who were treated with thalidomide-based regimens.179 In this randomized, open-label, multicenter trial, 667 patients with previously untreated MM with no clinical indication or contraindication for a specific antiplatelet or anticoagulant therapy were randomly assigned to receive low-dose aspirin, 100 mg daily; fixed-dose warfarin, 1.25 mg daily; or enoxaparin, 40 mg daily. The primary outcome was a composite of serious thromboembolic events, acute cardiovascular events, or sudden deaths during the first 6 months of therapy. In total, 659 patients were analyzed, of whom 43 (6.5%) experienced the primary outcome (6.4% in the aspirin group, 8.2% in the warfarin group, and 5% in the enoxaparin group). Compared with enoxaparin, the absolute differences were +1.3% (95% CI, −3%-5.7%; P = .544) in the aspirin group and +3.2% (95% CI, –1.5%-7.8%; P = .183) in the warfarin group. VTE risk was noted to be 1.38 times higher in patients treated with thalidomide without bortezomib. In total, three major (0.5%) and 10 minor (1.5%) bleeding events were recorded. The authors concluded that in patients with MM who were treated with thalidomide-based regimens, aspirin and warfarin showed similar efficacy in reducing serious thromboembolic events, acute cardiovascular events, and sudden deaths compared with enoxaparin, except in elderly patients, in whom warfarin showed less efficacy than enoxaparin.179 It is important to note that none of the patients received highly thrombogenic myeloma regimens, which would presumably be more likely to demonstrate a benefit for more intensive thromboprophylaxis.

Although two large randomized studies of thromboprophylaxis in ambulatory medical oncology patients (PROTECHT and SAVE-ONCO) have demonstrated significant reductions in VTE without an increase in bleeding complications, only the ACCP guidelines recommend thromboprophylaxis for outpatients with cancer if they have other VTE risk factors such as a previous VTE, immobilization, or treatment with an angiogenesis inhibitor.165 The ASCO, ESMO, and NCCN guidelines do not recommend routine prophylaxis in medical oncology outpatients receiving chemotherapy except for high-risk patients with MM who are being treated with thalidomide- or lenalidomide-based combination chemotherapy regimens.8,163,167,168 The NCCN made this decision on the basis of several factors, including the number of patients who need to undergo treatment to prevent one symptomatic VTE, the expense and inconvenience of therapy and its impact on quality of life, and a lack of impact on mortality.168 The NCCN Guideline Committee believes that targeting thromboprophylaxis to the patients at highest risk may make the risk: benefit equation more favorable.168

Assessment of Risk of Cancer-Associated VTE

In addition to the previously mentioned clinicopathological VTE risk factors in patients with cancer, several promising predictive biomarkers have been reported.8,11 Elevated prechemotherapy platelet count (≥350,00/µL), elevated white blood cell count (>11,000/µL), low hemoglobin levels (<10 g/dL), elevated D-dimer and prothrombin fragment 1+2 levels, increased C-reactive protein levels, increased plasma levels of the soluble form of the platelet adhesion molecule P-selectin, increased levels of factor VIII, and elevated levels of TF have all been associated with an increased risk of cancer-associated VTE.125,180187

Given the highly variable incidence of VTE among ambulatory patients with cancer, identification of the patients at highest risk would maximize the benefit of thromboprophylaxis. To facilitate risk-adaptive VTE thromboprophylaxis, Khorana and colleagues86,180 developed and validated a VTE risk stratification model in medical oncology patients receiving chemotherapy on an outpatient basis using readily available clinical and laboratory data (Table 35-2). The Khorana Risk model was developed in a cohort of 2701 ambulatory patients with cancer in whom chemotherapy was initiated, and it was subsequently validated in an independent cohort of 1365 patients.180 In a stage-adjusted multivariate predictive model, five variables present before chemotherapy initiation were identified: primary site (or type) of malignancy, prechemotherapy platelet count ≥350,000/µL, hemoglobin <10 g/dL and/or the use of ESAs, white blood cell count >11,000/µL, and a body-mass index ≥35 kg/m2.8,180,188 To calculate the score, two points were assigned to very high-risk cancer types (e.g., stomach and pancreas), one point was assigned for high-risk cancers (e.g., lung, lymphoma, gynecologic, testicular, and bladder), and one point was assigned for each of the other four predictive risk factors in the model. Based on the total score, each patient was assigned to a low-risk (score = 0), intermediate-risk (score = 1-2), or a high-risk (score ≥3) category.8,180,188 Over a median of 2.5 months, the rates of VTE in the derivation and validation cohorts were, respectively, 0.8% and 0.3% in the low-risk group, 1.8% and 2% in the intermediate-risk group, and 7.1% and 6.7% in the high-risk group.8,180,188 Using the threshold for the high-risk category (score of 3 points), the model had a negative predictive model of 98.5% for identifying patients at low risk for VTE and was associated with high rate of short-term development of symptomatic VTE (approximately 7%), similar to the VTE rates observed in surgical or hospitalized patients for whom VTE prophylaxis has been demonstrated to be an effective and a safe therapeutic strategy.8,169,180,188 Since it was initially proposed, the Khorana Risk Model has been independently validated by other studies.86,167,189191

Table 35-2

The Khorana Predictive Model for Risk of Cancer-Associated Venous Thromboembolism in Ambulatory Outpatients Beginning Chemotherapy

VTE Risk Factor Points
SITE OF CANCER  
Very high risk (pancreas, stomach) 2
High risk (lung, lymphoma, gynecologic, bladder, testicular) 1
PRECHEMOTHERAPY PLATELET COUNT
>350,000/µL 1
PRECHEMOTHERAPY WHITE BLOOD CELL COUNT
>11,000/µL 1
HEMOGLOBIN LEVEL  
<10 g/dL or use of erythropoiesis-stimulating agents 1
BODY MASS INDEX  
≥35 kg/M2 1

image

VTE, Venous thromboembolism.

Based on the total point score, three risk levels are identified: low risk (score = 0), intermediate risk (score = 1-2), or high risk (score ≥3). Over a median of 2.5 months, the rates of VTE in the derivation and validation cohorts were, respectively, 0.8% and 0.3% in low-risk, 1.8% and 2% in intermediate-risk, and 7.1% and 6.7% in high-risk groups.

Adapted from Khorana AA, Kuderer NM, Culakova E, Lyman GH, Francis CW. Development and validation of a predictive model for chemotherapy-associated thrombosis. Blood 2008;111:4902–7.

Ay et al.189 prospectively validated the Khorana Risk Model in 819 outpatients with cancer. In their study, VTE developed in 61 patients (7.4%) during a median follow-up of 656 days. The cumulative VTE probability in the Khorana model after 6 months was 17.7% in patients in the high-risk category (score ≥3, n = 93), 9.6% for intermediate risk patients with a score of 2 (n = 221), 3.8% for those with a score of 1 (n = 229), and 1.5% among low-risk patients (score of 0, n = 276).189 Ay and colleagues189

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