Overview
Venous thromboembolism (VTE) is a common and life-threatening condition in patients with cancer.1 Results from a 2021 population-based cohort study showed that the presence of cancer increased the risk of VTE by 9-fold.2 In a health claims database analysis of patients with cancer undergoing chemotherapy, VTE occurred in 12.6% of patients during the 12-month period from initiation of chemotherapy, compared with a rate of 1.4% among an age- and gender-matched control cohort without cancer.3 Chemotherapy, antiangiogenic therapy, protein kinase inhibitors, and immunotherapy have all been shown to increase the risk of VTE.2 More importantly, thrombosis is a leading cause of death in patients with cancer, found to be second only to cancer itself in a large prospective observational study.4 Multiple studies have reported significantly higher mortality and reduced overall survival among patients with cancer who developed VTE compared with those who did not.5–10 Specifically, the occurrence of VTE has been reported to increase the likelihood of death for patients with cancer by 2- to 6-fold.8–12 VTE has been reported to be the most common cause of death at 30-day follow-up among patients with cancer undergoing surgery.13
The underlying etiology of cancer-associated VTE is multifaceted and attributable to patient-related, cancer-related, and treatment-related factors. Stratification of these factors and accurate identification of patients with cancer at risk for developing VTE are important to prevent potentially deadly complications. It has also been acknowledged that patients with medical and surgical oncology needs, both hospitalized and ambulatory, are at increased risk of developing VTE.1,3,5,14,15 Therefore, appropriate use of VTE prophylaxis can bring about substantial benefits in patients at risk.16,17 The different subtypes of VTE, despite sharing similarities, can have vastly different symptoms and prognoses, requiring customized management plans with suitable diagnostic tools and therapeutics.18–22 There are many treatment options for VTE, encompassing anticoagulants, thrombolytics, mechanical devices, and surgical procedures, each with their own pros and cons.16,23 Careful selection of treatment methods with the optimal efficacy to safety consideration is instrumental in achieving the best outcomes. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Cancer-Associated Venous Thromboembolic Disease outline iterative implementations of therapeutic measures based on risk assessment, diagnoses of VTE subtypes, contraindications to therapeutic interventions, and cancer and treatment status of the patient.
Guidelines Update Methodology
The complete details of the Development and Update of the NCCN Guidelines are available at NCCN.org.
Literature Search Criteria
Prior to the update of the NCCN Guidelines for Cancer-Associated Venous Thromboembolic Disease, an electronic search of the PubMed database was performed to obtain key literature in cancer-associated venous thromboembolic disease since the previous guidelines update, using the following search terms: “cancer-associated venous thromboembolism” and “cancer thrombosis.” The PubMed database was chosen as it remains the most widely used resource for medical literature and indexes peer-reviewed biomedical literature.24
The search results were narrowed by selecting studies in humans published in English. Results were confined to the following article types: Clinical Trial, Phase II; Clinical Trial, Phase III; Clinical Trial, Phase IV; Guideline; Practice Guideline; Meta-Analysis; Randomized Controlled Trial; Systematic Reviews; Multicenter Studies; and Validation Studies.
The data from key PubMed articles as well as articles from additional sources deemed as relevant to these guidelines as discussed by the panel have been included in this version of the discussion section. Recommendations for which high-level evidence is lacking are based on the panel’s review of lower-level evidence and expert opinion.
Sensitive/Inclusive Language Usage
NCCN Guidelines strive to use language that advances the goals of equity, inclusion, and representation. NCCN Guidelines endeavor to use language that is person-first; not stigmatizing; antiracist, anticlassist, antimisogynist, antiageist, antiableist, and anti–weight-biased; and inclusive of individuals of all sexual orientations and gender identities. NCCN Guidelines incorporate nongendered language, instead focusing on organ-specific recommendations. This language is both more accurate and more inclusive and can help fully address the needs of individuals of all sexual orientations and gender identities. NCCN Guidelines will continue to use the terms “men,” “women,” “female,” and “male” when citing statistics, recommendations, or data from organizations or sources that do not use inclusive terms. Most studies do not report how sex and gender data are collected and use these terms interchangeably or inconsistently. If sources do not differentiate gender from sex assigned at birth or organs present, the information is presumed to predominantly represent cisgender individuals. NCCN encourages researchers to collect more specific data in future studies and organizations to use more inclusive and accurate language in their future analyses.
Evaluation and Treatment of VTE in Patients With Cancer
Evaluation and Treatment of Acute Superficial Vein Thrombosis
Even though few data are available on the incidence of acute superficial vein thrombosis (SVT) in patients with cancer, it has been estimated that the majority of SVT occur in the lower extremities (most often in the great saphenous vein) and external jugular veins.25,26 SVT is more likely than deep vein thrombosis (DVT) to be symptomatic, especially if occurring in the lower extremities. Intravenous catheter or peripherally inserted central catheter (PICC)-related SVT, sometimes referred to as infusion thrombophlebitis, is often associated with a palpable tender cord along the course of the affected vein. PICC-related SVT has been estimated to occur in 29% of patients who are hospitalized requiring intravenous therapy for more than 5 days.27
Although SVT does not generally have the same implications for morbidity and mortality as DVT, the OPTIMEV study in patients with cancer reported that patients with isolated SVT had similar risks of death and DVT/pulmonary embolism (PE) recurrence to patients with DVT. These risks were higher than those in patients with SVT without cancer.28 Furthermore, SVT and DVT can occur simultaneously and each predisposes the patient to the other condition.25,28,29 In a retrospective cohort study to determine the risk of arterial and venous complications after a spontaneous SVT in the leg, DVT was reported as the only primary outcome to show a significant relationship with SVT (odds ratio [OR], 10.2; 95% CI, 2.0–51.6).30 An extensive SVT in the saphenous vein can progress to involve the deep venous system at the saphenofemoral junction.31–33 Such clots can precipitate PE.32 An observational study of patients with symptomatic SVT reported that approximately 10% of patients developed thromboembolic complications at 3-month follow-up (DVT, PE, extension or recurrence of SVT) despite anticoagulation use in about 90% of individuals.25 In particular, male sex, active solid cancer, personal history of VTE, and saphenofemoral involvement have been reported among the factors significantly associated with concurrent or future DVT/PE in patients with SVT.29,34,35 In one study, the prevalence of malignancy was reported to be 18.8% among patients with SVT and concurrent DVT/PE, compared with 4.2% among those with isolated SVT (P<. 001).29
Evaluation
Diagnosis of SVT is made primarily on the basis of clinical symptoms, which consist of pain, erythema, and tenderness involving a superficial vein in the extremity. Workup consists of comprehensive history and physical (H&P), CBC with platelet count, prothrombin time (PT), activated partial thromboplastin time (aPTT), liver and kidney function tests, as well as venous ultrasound based on clinical judgment, especially if the possibility of proximal deep vein involvement exists (Figure 1). Progression of symptoms should be accompanied by follow-up imaging.
SVT-1. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Cancer-Associated Venous Thromboembolic Disease, Version 2.2024.
Citation: Journal of the National Comprehensive Cancer Network 22, 7; 10.6004/jnccn.2024.0046
Treatment
For SVT involving the upper extremity (median, basilic, and/or cephalic veins), if a peripheral catheter is involved and is no longer indicated, the first step is to remove the catheter. For patients with SVT associated with a PICC line, catheter removal may not be necessary, especially if the patient is treated with anticoagulation and/or if symptoms resolve. Whether a catheter is involved, symptomatic treatment involving warm compresses, nonsteroidal anti-inflammatory drugs, and elevation of the affected limb should be used as clinically indicated (Figute 1). Aspirin and nonsteroidal anti-inflammatory drugs by mouth should be avoided in patients with platelet counts less than 20,000 to 50,000/mcL or with severe platelet dysfunction. If there is symptomatic progression or progression on imaging, prophylactic dose anticoagulation is recommended. Anticoagulation at prophylactic doses, such as rivaroxaban 10 mg by mouth daily and fondaparinux 2.5 mg subcutaneous daily for 45 days, has been shown to be effective in some studies that included a limited number of patients with cancer.36–38 Specifically, in a small randomized trial, rivaroxaban was determined to be effective and safe in the treatment of SVT in the legs when compared with placebo based on parameters such as treatment “failure” (defined in the study as requirement for an alternative, nonstudy anticoagulant); development of proximal DVT or PE; or requirement for surgery for SVT (1 vs 5 patients; absolute risk reduction, 9.0%; 95% CI, −22% – 5.9%) and leg pain improvement (P=.011) by 90 days.37 In the much larger CALISTO trial, fondaparinux resulted in significantly reduced composite of death from any cause, symptomatic DVT/PE, symptomatic extension to the saphenofemoral junction, or symptomatic recurrence of SVT over placebo (0.9% vs 5.9%; relative risk [RR] reduction, 85%; 95% CI, 74–92; P<.001).38 In the randomized, phase 3b SURPRISE trial, rivaroxaban was noninferior to fondaparinux for the treatment of SVT in terms of symptomatic DVT/PE, progression or recurrence of SVT, and all-cause mortality (3% vs 2%; hazard ratio [HR], 1.9; 95% CI, 0.6–6.4; P=.0025).36
Therapeutic dose anticoagulation should be considered if the clot is in close proximity (defined as within approximately 3 cm) to the deep venous system (see “Therapeutic Anticoagulation for VTE,” Figures 2, 3, 4, and 5).
VTE-D 1 of 6. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Cancer-Associated Venous Thromboembolic Disease, Version 2.2024.
Citation: Journal of the National Comprehensive Cancer Network 22, 7; 10.6004/jnccn.2024.0046
VTE-D 2 of 6. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Cancer-Associated Venous Thromboembolic Disease, Version 2.2024.
Citation: Journal of the National Comprehensive Cancer Network 22, 7; 10.6004/jnccn.2024.0046
VTE-D 3 of 6. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Cancer-Associated Venous Thromboembolic Disease, Version 2.2024.
Citation: Journal of the National Comprehensive Cancer Network 22, 7; 10.6004/jnccn.2024.0046
VTE-D 4 of 6. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Cancer-Associated Venous Thromboembolic Disease, Version 2.2024.
Citation: Journal of the National Comprehensive Cancer Network 22, 7; 10.6004/jnccn.2024.0046
For SVT involving the lower extremity (great and small saphenous veins), prophylactic dose anticoagulation is recommended for at least 6 weeks if SVT is greater than 5 cm in length or if SVT extends above the knee. Therapeutic dose anticoagulation is recommended for at least 3 months if the SVT is within 3 cm of the saphenofemoral junction (see Figures 2, 3, 4, and 5). Additionally, repeat ultrasound should be considered in 7 to 10 days if the SVT is less than 5 cm in length or below the knee. If progression is indicated on ultrasound, prophylactic dose anticoagulation should be considered (Figure 1).
Evaluation and Treatment of Acute DVT
A limited number of investigations on the long-term sequelae of DVT have been performed, especially in patients with cancer. A prospective study in patients with symptomatic DVT showed that the cumulative incidence of recurrent VTE was 17.5% after 2 years of follow-up, 24.6% after 5 years, and 30.3% after 8 years. The cumulative incidence of the postthrombotic syndrome, a frequent complication of DVT, was 22.8%, 28.0%, and 29.1% after 2, 5, and 8 years, respectively.39 Some other studies have examined the prognostic significance of different subtypes of DVT. Data from OPTIMEV and the Cleveland Clinic examining isolated cancer-associated distal DVT and isolated proximal DVT individually came to the conclusion that the 2 conditions had similar prognoses; however, cancer-associated isolated distal DVT had dramatically poorer prognosis compared with those without cancer.40,41 The risk of VTE recurrence for patients with isolated distal DVT was reported in another study to be as high as 15.3% despite anticoagulant therapy in 99% of patients.42 A prospective, multicenter cohort study of 3,032 patients who had venous ports implanted reported the incidence of catheter-related thrombosis with or without PE at 12 months to be 3.8%.43 Recurrent VTE, bleeding complications, and mortality rates among patients with upper-extremity DVT were reported in a systematic review to average 5.1%, 3.1%, and 24% in prospective studies and 9.8%, 6.7%, and 35% in retrospective studies, respectively.44 According to data from the Computerized Registry of Patients with Venous Thromboembolism Registry, at presentation, patients with arm DVT often have less clinically overt PE than those with lower-limb DVT (9.0% vs 29%; OR, 0.24; 95% CI, 0.18–0.33), but their 3-month outcome is similar. Among patients with arm DVT, those with cancer had an increased incidence of major bleeding, recurrent VTE, and death compared with those with catheter-related DVT.45
Evaluation
Classic clinical symptoms are not present in all cases of acute DVT; however, clinical suspicion is warranted in case of swelling of the unilateral extremity; heaviness in the extremity distal to the site of the venous thrombosis; pain in the extremity; unexplained persistent calf cramping; swelling in the face, neck, or supraclavicular space; and catheter dysfunction (if a catheter is present) (Figure 6). DVT may also be an incidental finding. The most common presenting symptoms of DVT presented in the MASTER registry were extremity edema, pain, and erythema, which were observed in 80%, 75%, and 26% of patients with DVT, respectively.46 Diagnosis of DVT in adults with cancer should be tempered by an increased level of clinical suspicion on presentation of any clinically overt signs/symptoms that could represent an acute DVT. For patients for whom there is a high suspicion of DVT that do not have contraindications to anticoagulation, early initiation of anticoagulation should be considered while awaiting results from imaging studies.
DVT-1. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Cancer-Associated Venous Thromboembolic Disease, Version 2.2024.
Citation: Journal of the National Comprehensive Cancer Network 22, 7; 10.6004/jnccn.2024.0046
Workup consists of comprehensive medical H&P, CBC with platelet count, PT, aPTT±fibrinogen, and liver and kidney function tests (Figure 6). Venous ultrasound is the preferred imaging method for the initial diagnosis of DVT and has been shown to detect asymptomatic DVT of the lower extremities in 34% of patients who are nonambulatory with advanced cancer in a small prospective study.47 It has been reported that 2 normal ultrasound examinations obtained 1 week apart can be used to exclude progressive lower-extremity DVT.48
In cases of negative or indeterminate ultrasound results after repeat venous imaging and a continued high clinical suspicion of DVT, other venous imaging modalities are recommended and include repeat venous ultrasound, contrast-enhanced CT venography (CTV), and magnetic resonance venogram (MRV) with contrast. CTV has been reported to be as accurate as ultrasound, particularly in diagnosing femoropopliteal DVT.49,50 This method might be superior to ultrasound in detecting thrombus in large pelvis veins and the inferior vena cava (IVC).50 However, this method requires relatively high concentrations of contrast agent. Conversely, MRV with contrast allows enhanced venous signal and was reported in a meta-analysis to have higher sensitivity for proximal DVT than distal DVT, with equivalent sensitivity and specificity to ultrasound for diagnosing DVT.51 Some prospective studies suggested that MRV was more sensitive than ultrasound in the detection of lower-extremity DVT,52 and extension of DVT,53 and might be a valuable technique for assessing iliofemorocaval venous thrombosis.54 Drawbacks to this method include higher cost, longer imaging times, and limited availability in some practice settings.55 Standard invasive venography, once considered the gold standard for DVT diagnosis, has largely been replaced by less invasive methods such as ultrasound and MRV, which provide equivalent accuracies.54–56 Venography remains an important imaging modality when performed in conjunction with pharmacomechanical thrombectomy/thrombolysis. If all imaging tests are negative for DVT, reassurance should be provided and symptoms should be further evaluated for other causes.
The risk factors for upper-extremity DVT differ from those for lower-extremity DVT, as upper-extremity DVT is frequently related to the presence of a CVAD57–59 and associated with insertion attempts, previous insertion, or catheter placement.60,61 It must be noted that neither a clot within a catheter nor a simple fibrin sheath around a catheter represents a DVT. Clinical suspicion of catheter-related DVT is warranted when a patient presents with unilateral limb swelling, pain in the supraclavicular space or neck, or with catheter dysfunction. Workup for catheter-related DVT consists of venous ultrasound, CTV with contrast, MRV with contrast, and x-ray venogram with contrast. Venous ultrasound has been reported to accurately detect DVT in the peripheral upper extremity, in the brachial, distal subclavian, and axillary veins. In patients with catheters with isolated flow abnormalities, contrast venography may be preferred.59,62 Invasive venography for the detection of upper-extremity DVT should be performed through a peripheral vessel in the extremity, although venous access may be limited by edema. If no DVT is identified, symptoms should be evaluated for other causes and further diagnostic imaging/testing should be considered if initial testing is unrevealing or clinical suspicion remains high.
Treatment
DVT Involving the Proximal Lower Extremity
For patients with thrombosis in the pelvic and iliac veins, the IVC, and the femoral/popliteal veins, anticoagulation is recommended if no contraindication is present. Catheter-directed therapy (pharmacomechanical thrombolysis or mechanical thrombectomy) can be considered in appropriate candidates. Appropriate candidates for catheter-directed therapies include patients at risk for limb loss (eg, phlegmasia cerulea dolens), patients with central thrombus propagation in spite of anticoagulation, and those with severely symptomatic proximal DVT. If deemed appropriate for thrombolysis, the choice of regimen for thrombolysis should be made based on institutional expertise/preferences in conjunction with interventional radiology or vascular surgery colleagues (see “Thrombolytic Agents” and “Contraindications to Thrombolysis and Indications for Thrombolysis,” in these guidelines at NCCN.org). Graduated compress stockings (GCS) can be considered for symptom management if therapeutic anticoagulation is tolerated. Since the SOX trial reported that GCS did not reduce the incidence of postthrombotic syndrome after a first proximal DVT, routine prescription of GCS after DVT for the purpose of reducing postthrombotic syndrome is not recommended.63 If a contraindication to anticoagulation is present, an IVC filter, preferably retrievable, is recommended, as long as contraindication persists or is likely to recur. Patients should be re-evaluated regularly for change in the status of contraindication to anticoagulation until the contraindication is resolved, at which point anticoagulation should be initiated and IVC filter removed.
DVT Involving the Distal Lower Extremity
For patients with thrombosis in the peroneal, anterior and posterior tibial, and muscular (soleus and gastrocnemius) veins, anticoagulation is recommended unless contraindication is present. If a contraindication is present, follow-up with serial ultrasound is recommended. If ultrasound indicates progression of DVT to the popliteal vein, treatment should be initiated as outlined previously. Otherwise, local progression (but not to proximal deep vein) can be closely monitored for any change in status, in terms of both progression and contraindication to coagulation. If there is no progression of DVT, the patient should be followed as clinically indicated (Figure 7).
DVT-2. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Cancer-Associated Venous Thromboembolic Disease, Version 2.2024.
Citation: Journal of the National Comprehensive Cancer Network 22, 7; 10.6004/jnccn.2024.0046
DVT Involving the Upper Limb/Chest
For patients with thrombosis in the brachiocephalic, subclavian, axillary, internal jugular, and brachial veins, and the SVC, anticoagulation and catheter-directed therapy in appropriate candidates should be prescribed with the same caveats as DVT involving the proximal lower extremity. GCS are rarely considered in this setting (Figure 7). In the case of a contraindication to anticoagulation, patients should be followed until contraindication resolves or DVT progression occurs, at which point re-evaluation of the risk/benefit of anticoagulation is recommended (see “Elements for Consideration in Decision Not to Treat,” in these guidelines at NCCN.org).
Catheter-Related DVT
For patients with catheter-related DVT, in the absence of contraindication, anticoagulation is recommended. Anticoagulation without catheter removal is the preferred option for initial treatment, even for patients with asymptomatic DVT, provided that the catheter is necessary, functional, and free of infection. Catheter removal should be considered otherwise. Anticoagulation is continued for at least 3 months. If the catheter remains in place, then anticoagulation should continue as long as the catheter is present. However, it is important to recognize that there is very little clinical evidence regarding the appropriate duration of anticoagulation for catheter-associated DVT. The recommended duration of therapy also depends on tolerance of anticoagulation, response to anticoagulation, and catheter status. Longer duration of anticoagulation can be considered in patients with catheters with poor flow, persistent symptoms, or unresolved thrombus. Shorter duration of anticoagulation can be considered if the clot or symptoms resolve in response to anticoagulation and/or catheter removal. Catheter-directed thrombolysis (CDT) is rarely considered with the same caveats as DVT involving the proximal lower extremity. In the case of contraindication to anticoagulation, catheter removal is recommended, or the patient should be followed up with serial imaging until contraindication is resolved, at which point anticoagulation is recommended for at least 3 months. Otherwise, the patient should be re-evaluated for risk/benefit of anticoagulation (Figure 8).
DVT-3. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Cancer-Associated Venous Thromboembolic Disease, Version 2.2024.
Citation: Journal of the National Comprehensive Cancer Network 22, 7; 10.6004/jnccn.2024.0046
Anticoagulation for DVT
Several studies have supported the use of anticoagulation specifically for the treatment of DVT in the noncancer population. A meta-analysis comparing unfractionated heparin (UFH) and low molecular-weight heparins (LMWHs) found that LMWHs reduced mortality rates over 3 to 6 months of patient follow-up (OR, 0.71; 95% CI, 0.53–0.94; P=.02), as well as major bleeding complications (OR, 0.57; 95% CI, 0.33–0.99; P=.047), even though the absolute risk reduction was small and not statistically significant (0.61%; 95% CI, −0.04%–1.26%; P=.07).64 This comparison was also made in a systematic review that compiled 5 studies enrolling a total of 1,636 patients with proximal (above the knee) DVT. A subanalysis of these trials showed statistically significant reductions favoring LMWH in 3 areas: thrombotic complications; major hemorrhages; and overall mortality.65 Data from the Cancer-DACUS study suggest that LMWH for up to 6 months is just as effective as a 12-month course in preventing recurrence for patients with cancer-associated DVT of the lower limbs and subsequent residual vein thrombosis.66 The NCCN panel recommends a minimum anticoagulation duration of 3 months. The presence of active cancer, ongoing cancer treatment, an unprovoked DVT, or persistent thrombosis are reasons to consider continuation of anticoagulation. In a systematic review of 11 studies involving 3,019 patients with cancer-associated VTE, both rates of VTE recurrence and major bleeding were assessed to investigate the risk/benefit of continuing anticoagulation beyond 6 months.67 It was noted that VTE recurrence remains common between 6 to 12 months after a cancer-associated VTE, though the risk is lower in this time frame compared with the first 6 months after the event. For example, this study highlights the Hokusai-VTE Cancer study, which revealed a VTE recurrence rate of 7.6% in the first 6 months compared with 2.1% between 6 to 12 months in patients with cancer receiving extended anticoagulant therapy.67,68 This systematic review also noted an acceptable safety profile of extended anticoagulation between 6 to 12 months after a cancer-associated VTE, with major bleeding rates between 1%–4% in patients receiving anticoagulation compared with 0%–1% in those not receiving anticoagulation.67
No randomized controlled trials have reported the effects of particular therapeutic strategies on outcomes of catheter-related DVT. In one prospective study, patients with catheter-related thrombosis received anticoagulants alone, anticoagulants and catheter removal, or no treatment; none had recurrent thrombosis or symptomatic PE.60 Another study demonstrated that anticoagulation with dalteparin followed by warfarin was not associated with recurrent VTE or line removal due to infusion failure or recurrence/extension of DVT.69 In the Catheter 2 study, treatment with rivaroxaban for 12 weeks showed preservation of line function at 100% by study endpoint. The risk of recurrent VTE was 1.43%, with one episode of fatal PE.70 It must be noted that these studies enrolled a small number of patients and thus, their results should be interpreted with care.
The NCCN panel recommends that the effectiveness of anticoagulation in patients with established DVT be monitored clinically during and after treatment. Follow-up examinations and imaging evaluations allow physicians to detect clot progression in patients undergoing anticoagulation, detect DVT recurrence after successful treatment, and identify chronic injury to the venous system. These studies should be performed in response to symptoms.
Evaluation and Treatment of Pulmonary Embolism
Evaluation
Clinical suspicion of PE depends on the presence of current DVT or a recent history of DVT, or presentation of any clinically overt signs or symptoms of PE, including unexplained shortness of breath, chest pain—particularly pleuritic chest or back pain—tachycardia, apprehension or tachypnea, syncope, and hypoxemia. In the prospective multicenter MASTER registry, the most common presenting symptoms of PE were dyspnea, pain, and tachypnea, which were present in 85%, 40%, and 29% of patients with PE, respectively.46 In the International Cooperative Pulmonary Embolism Registry, the most common symptoms at PE diagnosis were dyspnea (82%), chest pain (49%), cough (20%), syncope (14%), and hemoptysis (7%).71 PE may also be an incidental finding.
Workup consists of a comprehensive medical H&P, CBC with platelet count, PT, aPTT, liver and kidney function tests, N-terminal prohormone B-type natriuretic peptide evaluation, chest x-ray, and electrocardiogram. In cases with a high suspicion of PE and no contraindications, early initiation of anticoagulation should be considered while waiting for imaging results. Chest x-rays may not be necessary if a CT angiography (CTA) is planned (Figure 9).
PE-1. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Cancer-Associated Venous Thromboembolic Disease, Version 2.2024.
Citation: Journal of the National Comprehensive Cancer Network 22, 7; 10.6004/jnccn.2024.0046
The preferred imaging technique for the initial diagnosis of PE is CTA, which allows for indirect evaluation of pulmonary vessels. Advantages of this method include accurate imaging of mediastinal and parenchymal structures; accurate visualization of emboli in many regions of the pulmonary vasculature; ability to be performed in conjunction with indirect CTV, which can detect DVT72,73; and ability to detect signs of right ventricular (RV) enlargement, which can be used in assessing risk for adverse clinical outcomes.74,75 Disadvantages of CTA include the associated radiation exposure and the need for large amounts of intravenous contrast, particularly when CTA is followed by indirect CTV.72
Alternative imaging modalities used for the diagnosis of PE include: (1) X-ray pulmonary angiography with contrast, which is infrequently used today because of its invasive nature. When used, this method is often combined with clot extraction or thrombolytic therapy; (2) MR angiography with contrast; and (3) ventilation-perfusion (VQ) scan if CTA is contraindicated (eg, renal insufficiency, contrast allergy refractory to anaphylaxis prophylaxis, and pregnancy, since a VQ scan is associated with less fetal radiation exposure than CTA). In a randomized, single-blind, noninferiority study, VQ scans identified significantly fewer PE than CTA (14.2% vs 19.2%; 95% CI, 1.1%–8.9%). However, there was no difference in the number of symptomatic VTE that occurred within 3 months in patients in whom PE was considered to be excluded (CTA 0.4% vs VQ scan 1.0%; 95% CI, 1.6%–0.3%).76 Patients older than 70 years of age are more likely than younger patients to be diagnosed with an intermediate-probability VQ scan result.77 Both intermediate- and low-probability VQ scan results lack diagnostic utility and should be considered indeterminate. In the setting of high clinical suspicion for PE, a high-probability VQ scan is diagnostic.
Clinical Prediction Tools for PE
Even though Wells criteria and d-dimer testing have been shown to be useful in the diagnosis of DVT/PE, with comparable results to conventional radiologic imaging strategies, patients with cancer made up a small number of patients in these studies.78,79 One study using the Wells criteria and d-dimer testing in the diagnosis of PE noted the performance of this strategy was comparable in patients with and without cancer; however, the number of patients with symptomatic VTE during follow-up was 4-fold higher than that in the total study population (2% vs 0.5%). In addition, the number needed to test to rule out PE in one patient was 3-fold higher in patients with cancer compared with patients without cancer.80 Results of a large prospective study of patients with suspected DVT in whom DVT had been excluded on radiologic testing showed that high d-dimer levels were present in a large percentage of patients with cancer.81 Other studies have supported that Wells criteria and d-dimer testing were less predictive of PE in patients with cancer.82–85 Therefore, most patients with cancer undergo imaging to exclude a diagnosis of PE.
The panel recommends risk stratification for patients with PE.86,87 Cardiac biomarkers such as troponin, which is released due to endomyocardial damage, and N-terminal prohormone B-type natriuretic peptide, as well as cardiac imaging results (ie, RV enlargement on echocardiography, CTA) and the presence of residual DVT on lower-extremity duplex imaging have demonstrated high predictive values for overall mortality in patients with PE.71,74,88–95 NCCN recommends the use of these tools, together with clinical judgment, in assessing risks in patients with PE. It has been demonstrated that combining the results from at least two of the previously discussed tests improved the specificity and positive predictive value compared with the use of individual tests alone in identifying patients at high risk for PE-related mortality.86 Since the 3-month mortality rate of patients with PE has been reported to be 15%,71 outpatient care of PE should be limited to individuals at low risk as identified by clinical, laboratory, and imaging assessment.
Clinical risk assessment tools have been developed to assess the advisability of outpatient treatment and intensity of initial follow-up and treatment. Generic scoring systems such as the Pulmonary Embolism Severity Index,96,97 the Hestia criteria,98 and the Geneva Prognostic Score99 are validated tools that can be used to determine risk for an adverse outcome associated with PE. However, it has been suggested that the Pulmonary Embolism Severity Index score might not be useful in patients with cancer.100 Conversely, scoring systems such as the Computerized Registry of Patients with Venous Thromboembolism, POMPE-C, as well as the EPIPHANY index, predict PE-related mortality risk and have been specifically developed for and externally validated in patients with cancer.101–105 One study postulated that cancer-specific prognostic scores performed better than generic scales in estimating PE mortality in patients with cancer.106 Other comparative studies, however, have not found such an association.107,108 Therefore, these scores can be included as an adjunct risk assessment tool, but should not be substituted for the previous risk-stratification procedures until data from large, prospective trials in patients with cancer are available.
Treatment
Once a diagnosis of PE is made, anticoagulation therapy is recommended for all patients with acute PE who do not have a contraindication to such therapy,109 including patients with incidental or subsegmental PEs (Figure 10). Anticoagulation should be continued after acute management of PE unless there is extension of VTE or new VTE while on recommended therapy (see “Progression or New Thrombosis on Therapeutic Anticoagulation,” available in these guidelines at NCCN.org). Outpatient care should be considered for PE in patients at low risk. After assessment of the cancer status, the physician should consider the use of systemic thrombolysis or CDT or embolectomy for hemodynamically unstable PE in patients with lower bleeding risk.109,110 Hemodynamically unstable PE is defined as acute PE with sustained hypotension (systolic blood pressure <90 mmHg for at least 15 minutes or requiring inotropic support, not due to a cause other than PE, such as arrhythmia, hypovolemia, sepsis, or left ventricular dysfunction), pulselessness, or persistent profound bradycardia (heart rate <40 bpm with signs or symptoms of shock).111 Rescue thrombolysis or thrombectomy can be considered in patients with hemodynamically stable PE who experience deterioration despite anticoagulation.109,110 For patients with hemodynamic compromise, venoarterial extracorporeal membrane oxygenation can be considered to optimize end-organ function as a bridge to recovery or intervention.112
PE-2. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Cancer-Associated Venous Thromboembolic Disease, Version 2.2024.
Citation: Journal of the National Comprehensive Cancer Network 22, 7; 10.6004/jnccn.2024.0046
In patients with a contraindication to anticoagulation, an IVC filter, preferably retrievable, should be strongly considered with or without embolectomy. The patient should be closely followed for a change in clinical status that would allow anticoagulation to be instituted. Permanent filters should only be considered for rare patients with chronic comorbidities or with permanent contraindication to anticoagulation. Filter placement should be considered if anticoagulation treatment is not possible within 1 month of symptomatic VTE onset.113
Embolectomy may be considered in patients with hemodynamic instability who have contraindications to thrombolytic therapy or those who remain unstable following thrombolysis (category 2B).109,110 Selection of thrombolytic agents and thrombectomy devices should be made based on local expertise and experience.
Thrombolytic Therapies/Thrombectomy for PE
Overall, favorable risk-versus-benefit profiles have not been clearly identified for systemic or CDT/catheter-directed thrombectomy for patients who are hemodynamically stable. In the MAPPET-3 trial, the addition of thrombolysis with alteplase to standard heparin treatment was associated with significantly decreased incidence of in-hospital mortality and clinical deterioration requiring treatment escalation (11% vs 25%; P=.006). However, this difference was due to a higher incidence of clinical instability in the placebo group, as in-hospital mortality rates were similar between treatment groups.114 The clinical endpoints and other aspects of the design of this trial have also been criticized.115,116 The PEITHO study, which included patients with cancer, reported significantly less death or hemodynamic decompensation (composite outcome) in patients receiving tenecteplase plus heparin versus placebo plus heparin (2.6% vs 5.6%; OR, 0.44; 95% CI, 0.23–0.87; P=.02). There was no difference in death between the 2 groups (1.2% vs 1.8%; P=.42), but there was significantly more frequent extracranial bleeding and stroke in the tenecteplase group (6.3% vs 1.2%; P<.001 and 2.4% vs 0.2%; P=.003, respectively).117 This benefit-to-risk profile is corroborated by results from a meta-analysis whereby the use of thrombolytic therapy was associated with lower all-cause mortality (OR, 0.53; 95% CI, 0.32–0.88) but higher risk of major bleeding (OR, 2.73; 95% CI, 1.91–3.91).118 Other meta-analyses reported no significant benefit with thrombolytic therapy compared with heparin alone in terms of recurrent PE or death, particularly for patients with hemodynamically stable PE.119–123 In the case of CDT, grade II clot lysis was achieved in a similar proportion of patients with cancer and those without cancer with no significant difference in bleeding risk in a retrospective consecutive case series.124 Reports from several studies evaluating the use of pulmonary embolectomy provide support for the use of this procedure in patients with hemodynamically stable or unstable acute PE characterized by RV dysfunction.125–127 It must be noted, however, that none of these studies specifically address patients with cancer. In a small, randomized trial, ultrasound-assisted CDT was shown to reverse RV dilatation in patients with hemodynamic stability. For PE, however, there was no difference in mortality or recurrent VTE.128 Larger randomized studies with clinical outcomes are needed to confirm the benefits of this approach.
IVC Filters for DVT/PE
IVC filter usage has increased substantially in the last few decades; however, due to the lack of randomized controlled trials evaluating their safety and efficacy, no particular filter should be considered superior.129–131 Moreover, IVC filters have been associated with an increased risk for recurrent DVT.132–134 The pivotal PREPIC trial, which compared permanent IVC filters in conjunction with anticoagulation with anticoagulant therapy alone, did not test the efficacy of IVC filters in the usual clinical scenario in which they are used, which is in patients without concomitant anticoagulation.132,133 In the PREPIC II study of retrievable IVC filters, there was no difference in recurrent PE between patients treated with anticoagulation and filters compared with anticoagulation alone (3% vs 1.5%; RR, 2.0; 95% CI, 0.51–7.89).135 In a multicenter trial of IVC filters in patients severely injured after major trauma, filters did not reduce the incidence of symptomatic PE or death compared with no filter (13.9% vs 14.4%; HR, 0.99; 95% CI, 0.51–1.94; P=. 98).136 Until further data are available, IVC filter placement should only be considered for patients with acute proximal lower-extremity DVT or PE who have absolute contraindications to anticoagulation. The benefit of placing an IVC filter in the absence of a lower-extremity IVC or pelvic DVT is unclear. IVC filters should only be used in patients in whom the benefits outweigh the risks, and filters should be retrieved as soon as possible.
Evaluation and Treatment of Splanchnic Vein Thrombosis
Splanchnic vein thrombosis (SPVT) refers to a relatively rare group of VTE within the splanchnic vasculature comprising the hepatic (characteristic of Budd-Chiari syndrome), portal, mesenteric, and splenic veins. The presence of SPVT has been associated with decreased survival in patients with cancer. In particular, portal vein thrombosis has been reported in about 20%–30% of patients with hepatocellular carcinoma at the time of diagnosis and is an independent predictor of poor survival.137–140 Thrombotic events may occur in multiple segments or in isolated segments within the splanchnic vasculature, with isolated portal vein thrombosis being the most common.141,142 Thrombosis in multiple segments has been associated with significantly decreased 10-year survival rate compared with thrombosis in a single/isolated segment (48% vs 68%; P<.001).142 In a retrospective study in patients with extrahepatic portal vein thrombosis, a concurrent diagnosis of mesenteric vein thrombosis was significantly predictive of decreased survival, as well as the presence of cancer.143 Several smaller retrospective studies have also reported adverse outcomes for patients with mesenteric vein thrombosis, with a 30-day mortality rate of 20%.144,145 Thromboses in the mesenteric vein can lead to intestinal infarction, which is frequently life-threatening.144,145 Intestinal infarction has been reported in 30%–45% of these patients at the time of diagnosis, of which up to 19% were fatal.141,144
Risk Factors
Risk factors for SPVT relevant to patients with cancer include recent abdominal surgery (eg, splenectomy),146–149 abdominal mass, pancreatitis,150 cirrhosis,143 paroxysmal nocturnal hemoglobinuria (PNH),151 myeloproliferative disorders,152 and JAK2V617F mutation with or without overt myeloproliferative disorders.153,154 In addition, the use of exogenous estrogen, such as oral contraceptives or hormone replacement therapy, has also been linked to SPVT.143,155 The presence of cancer itself, especially abdominal malignancies, is both a common risk factor for SPVT and a frequent cause of death in patients with SPVT.142–145 The JAK2V617F mutation is detected in a high proportion of patients with polycythemia vera, essential thrombocythemia, and primary myelofibrosis, and now constitutes a part of both diagnostic and prognostic assessment of these myeloproliferative disorders.156–159 In the absence of overt myeloproliferative disorders, JAK2V617F has been detected in approximately 20%–40% of patients with SPVT.160–162 Mutations in exon 12 of JAK2 may also be associated with SPVT in patients without JAK2V617F.163 PNH is a rare acquired clonal hematopoietic disorder resulting in chronic hemolysis, and has been associated with a high propensity for venous thrombosis, particularly in the splanchnic vasculature.164,165 In a post hoc analysis of patients with Budd-Chiari syndrome, those who had underlying PNH more frequently presented with additional SPVT at baseline compared with patients without PNH (47% vs 10%; P=.002).166
Evaluation
Clinical manifestations of acute SPVT typically include abdominal pain or midabdominal colicky pain, abdominal distention, rebound tenderness, guarding, fever, anorexia, nausea, vomiting, diarrhea, gastrointestinal bleeding, hepatomegaly, and ascites.167–171 SPVT may also be an incidental finding. Rebound tenderness, guarding, and fever may be indicative of progression to bowel infarction.167 Chronic SPVT may often be asymptomatic due to formation of collateral veins,167,168,172,173 although abdominal pain, nausea, vomiting, anorexia, lower-extremity edema, and splenomegaly have been reported with chronic presentations.168,171 Weight loss, abdominal distension, and postprandial abdominal pain may also be associated with chronic mesenteric vein thrombosis.172 Presence of splenomegaly and/or esophageal varices is a sign of portal hypertension associated with chronic SPVT, and complications may arise due to bleeding from varices.168,172,174,175 Acute SPVT is associated with presenting signs or symptoms of up to 8-week duration, with no portal cavernoma and no signs of portal hypertension.169
The diagnostic evaluation includes medical H&P, based on which further diagnostic testing involving both laboratory testing and imaging can be considered. Additional workup consists of CBC with platelet count and differential, PT, aPTT, basic metabolic profile, hepatic profile, and serum lactate levels. Imaging modalities include abdominal duplex ultrasound, CT abdomen/pelvis with contrast, and abdominal MRI with contrast. For suspected cases of SPVT involving the hepatic and/or portal veins, duplex ultrasonography is considered the initial choice of imaging.161,173–175 CT abdomen/pelvis with contrast is the preferred imaging study for patients with suspected mesenteric vein thrombosis as duplex ultrasound can be limited by overlying bowel gas.167,175 In the case of negative or indeterminate imaging results, other causes should be investigated. If there is continued suspicion of SPVT, repeat imaging is recommended, with consideration of consultation with radiology to optimize imaging techniques/modality (Figure 11).
SPVT-1. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Cancer-Associated Venous Thromboembolic Disease, Version 2.2024.
Citation: Journal of the National Comprehensive Cancer Network 22, 7; 10.6004/jnccn.2024.0046
Treatment
Acute Hepatic Vein Thrombosis
Acute hepatic vein thrombosis is defined by the presence of symptoms for 8 weeks or less. Patients with no contraindication to anticoagulation should undergo anticoagulant therapy with hepatology evaluation. Catheter-directed pharmacomechanical thrombectomy with or without transjugular intrahepatic portosystemic shunt (TIPS) should be considered (see “Thrombolytic Agents” and “Contraindications to Thrombolysis and Indications for Thrombolysis,” available in these guidelines, at NCCN.org). TIPs should be considered as one of the treatment options for patients with SPVT and severe symptoms or evidence of portal hypertension. If thrombectomy expertise is not available, consultation with a tertiary medical center is recommended. The decision to offer thrombolysis should be based on local availability/expertise, location of thrombus, and risk of bleeding. The choice of regimen should be made based on institutional expertise/preferences in conjunction with interventional radiology or vascular surgery colleagues. In the presence of contraindications to anticoagulants, patients should undergo hepatology evaluation, be considered for TIPS or surgical shunt, and regularly be reassessed for contraindications to anticoagulation (Figure 12).
SPVT-2. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Cancer-Associated Venous Thromboembolic Disease, Version 2.2024.
Citation: Journal of the National Comprehensive Cancer Network 22, 7; 10.6004/jnccn.2024.0046
Chronic Hepatic Vein Thrombosis
Chronic hepatic vein thrombosis is defined by the presence of symptoms for more than 8 weeks. Patients should undergo hepatology evaluation and be considered for TIPS (in the setting of portal hypertension) or surgical shunt and anticoagulation (Figure 12). It must be noted that risks/benefits of anticoagulation must be carefully weighed in patients with chronic thrombosis. The duration of anticoagulation should be at least 6 months for triggered events (eg, postsurgical) and indefinite if active cancer, persistent thrombophilic state, or unprovoked thrombotic event is present.
Acute Portal, Mesenteric, and/or Splenic Vein Thrombosis
An acute thrombotic event is defined by the presence of symptoms for 8 weeks or less, with no cavernous transformation/collaterals and no signs of portal hypertension. Anticoagulation and catheter-directed pharmacomechanical thrombectomy with or without TIPS is recommended for patients with no contraindication to anticoagulation with the same considerations as in those with acute hepatic vein thrombosis (Figure 12). Additionally, acute thrombosis involving the mesenteric veins is associated with high risks of intestinal infarction, which is life-threatening and requires immediate surgery to resect necrotic sections of the bowel.141,144 In the presence of contraindication to anticoagulants, patients should regularly be reassessed for contraindications to anticoagulation, similar to those with hepatic vein thrombosis, as well as gastrointestinal/surgery evaluation and subsequent surgery if bowel infarction is present.
Chronic Portal, Mesenteric, and/or Splenic Vein Thrombosis
Chronic thrombosis is defined by the presence of symptoms for longer than 8 weeks or cavernous transformation/collaterals or signs of portal hypertension at the time of diagnosis. Patients should be considered for gastronintestinal evaluation and surgery if bowel infarction is present, β blockers, variceal banding or sclerosis, and TIPS or surgical shunt and anticoagulation with the same considerations as those with chronic hepatic vein thrombosis (Figure 12).
Anticoagulation for SPVT
Anticoagulation as initial and long-term therapy in patients with SPVT has been reported in several studies.141,152,170,176 In a study of patients with acute SPVT primarily treated with anticoagulation (LMWH for 7–10 days followed by oral anticoagulation for 6 months), 45% of patients experienced complete recanalization. Patients requiring resection for intestinal infarction, experiencing incomplete recanalization of thrombus, or having inherited thrombophilia were given lifelong oral anticoagulation in this study. Recurrent VTE occurred in 18.5% of patients overall, and only in those who did not receive anticoagulation, and was significantly more frequent among patients with concurrent myeloproliferative disorders at presentation versus those without (70% vs 13%; P<.0001).141 In a prospective multicenter study in patients with acute portal vein thrombosis treated with anticoagulation (initial therapy with heparin followed by oral anticoagulation for 6 months or long-term in patients with permanent prothrombotic disorders or obstruction of mesenteric vein), the 1-year recanalization rates in the portal vein, mesenteric vein, and splenic vein were 38%, 61%, and 54%, respectively.170
Anticoagulation appears to lower the risk for recurrent thrombosis in patients with SPVT without increasing the risk for severe bleeding,141,152,170,176 including in patients with underlying prothrombotic states.152 An individual-patient meta-analysis of the effectiveness and safety of anticoagulation for SPVT revealed lower risks of VTE recurrence (HR, 0.42; 95% CI, 0.27–0.64), major bleeding (HR, 0.47; 95% CI, 0.30–0.74), and mortality (HR, 0.23; 95% CI, 0.17–0.31) during anticoagulation therapy compared with off-treatment periods.177 The study did include patients with cancer (32% of patients had solid cancers, 7.2% had myeloproliferative neoplasms, and 1.2% had leukemia, lymphoma, or multiple myeloma).
In contrast, a large, retrospective cohort study did not find evidence that anticoagulation was beneficial for the prevention of recurrent thrombosis in patients with SPVT. The rate of recurrent VTE was not significantly improved with oral warfarin in terms of 10-year recurrence-free survival rate (89% vs 77% in the control group; P=.38). Hormone therapy was the only independent predictor of recurrence in this study. Moreover, major bleeding events were reported more frequently among patients receiving anticoagulation compared with those who did not (26% vs 19%; P<.05), with gastroesophageal varices and anticoagulation as independent predictors of bleeding.142 In chronic SPVT, the presence of portal hypertension may increase the risk of bleeding from esophageal varices and splenomegaly may lead to decreased platelet counts, which can further increase the risks of bleeding events in patients treated with anticoagulation.178 Thus, in the absence of randomized controlled trials, the issue of long-term or lifelong anticoagulation remains somewhat controversial in patients with SPVT. An individual’s risk factor(s) for SPVT should be taken into consideration when weighing the risks and benefits of long-term anticoagulation.
Catheter-Directed Thrombolytic Therapy for SPVT
Thrombolytic therapy may be most suitable when administered locally for patients with recent thrombosis; however, this approach should be used with caution due to risks for major bleeding complications.179–182 TIPS may be appropriate for patients with an occluded IVC or a portacaval pressure gradient less than 10 mm Hg, and in those with refractory ascites and progressive hepatic dysfunction.183,184 This procedure is less invasive than surgical interventions, and has been successful in reducing portal hypertension, resolving ascites, and improving hepatic function in patients with Budd-Chiari syndrome.183–188 Although shunt dysfunction or stenosis is common during follow-up, TIPS is associated with promising long-term outcomes, with 5-year transplant-free survival rates of 74%–78%.183,188 On the other hand, surgical portosystemic shunts may be appropriate in patients without an occluded IVC, with a portacaval pressure gradient greater than 10 mm Hg, and with preservation of hepatic function.189 The impact of surgical shunts versus other interventions on long-term outcomes is unknown190; nevertheless, 5-year survival rates range from 75% to 87% in patients with Budd-Chiari syndrome undergoing successful surgical portosystemic shunts.191–193 This procedure may improve survival outcomes in patients with intermediate-risk prognostic factors as defined by Darwish Murad et al.194 Of note, surgical shunts appear to have now largely been replaced with TIPS.184
β-Blockers and Endoscopic Treatments for SPVT
Gastroesophageal varices may be seen in 35%–50% of patients with portal vein thrombosis at presentation and remain a significant independent risk factor for major bleeding in patients with SPVT.142 β-blockers and endoscopic treatments have been evaluated for variceal bleeding in patients at high risk of bleeding events. Even though one study showed visceral banding ligation to be more effective than propranolol in preventing visceral bleeding in patients with cirrhosis with high-risk gastroesophageal varices (7% vs 30%; P=.043),195 results from several prospective randomized studies found these options to be equally effective (12%–25% vs 24%–29%), with similar overall mortality rates.196–198 In one study, ligation was associated with a significantly decreased incidence of esophageal variceal bleeding compared with propranolol (5% vs 25%; P=.027) at the expense of a higher incidence of subcardial variceal bleeding (8% vs 0%; P=.027).196 Combining the 2 modalities did not significantly reduce the risks of bleeding (actuarial probability, 7% vs 11%; P=.72) or death (actuarial probability, 8% vs 15%; P=.37).199 In the context of secondary prophylaxis in patients with noncirrhotic portal hypertension, the incidence of recurrent variceal bleeding was similar between patients receiving ligation versus propranolol (24% vs 18%; P=.625).200 However, a meta-analysis of randomized studies demonstrated that the combined modality was significantly more effective than endoscopic treatment alone in preventing overall recurrent bleeding (OR, 2.20; 95% CI, 1.69–2.85; P<.0001) and in decreasing overall mortality (OR, 1.43; 95% CI, 1.03–1.98; P=.03). These data suggest that a combined regimen may be preferred as secondary prophylaxis for esophageal variceal bleeding.201
Therapeutic Anticoagulation for VTE in Patients With Cancer
The only placebo-controlled, randomized clinical trial on the use of anticoagulants, in particular heparin followed by warfarin, to treat VTE was performed in 1960.202 Although most of the subsequent clinical trials evaluating the use of anticoagulation therapy in the prevention and treatment of VTE have not been placebo-controlled, the evidence supporting the effectiveness of such therapies is strong.203–207
Anticoagulation agents used in the treatment of VTE are listed in “Therapeutic Anticoagulation for VTE” (Figures 2, 3, 4, and 5). The US FDA indications and NCCN recommendations for these therapies are listed in the NCCN Drugs & Biologics Compendium (NCCN Compendium) for Venous Thromboembolic Disease (for the latest version of the NCCN Compendium, visit NCCN.org). The panel recommends that agent selection be based on the presence of renal insufficiency, hepatic disease, inpatient/outpatient status, FDA approval, cost, patient preference, ease of administration, need for therapeutic monitoring, bleeding risk assessment, and reversibility (Figure 2). Suggested dosing schedules were established according to panel consensus and follow, with several exceptions, manufacturer recommendations. To avoid potential conflicts, users can consult dosing schedules listed in specific institutional standard operating procedure documents. Recommendations of the American College of Chest Physicians provide another legitimate source for anticoagulant dosing schedules.109,208–211
Direct Oral Anticoagulants
Apixaban is an orally administered direct factor Xa inhibitor approved by the FDA for a variety of indications, including the prevention and initial short- and long-term treatment of VTE.212–214 Since apixaban is primarily metabolized in the liver and renal elimination accounts for only about 27% of total drug clearance, the drug should be avoided in patients with severe hepatic impairment.214 Several clinical trials have found apixaban and LMWHs to be equivalent options for the treatment of VTE.215–218 In fact, apixaban led to lower or similar rates of recurrent VTE compared with dalteparin in the ADAM VTE trial and the Caravaggio study (0.7% vs 6.3%; HR, 0.099; 95% CI, 0.013–0.780; P=.0281 and 5.6% vs 7.9%; HR, 0.63; 95% CI, 0.37–1.07; P<.001 for noninferiority).216,217 Major bleeding was comparable in both studies and was not higher in the apixaban group.216–218 The AMPLIFY trial reported a similar rate of recurrent VTE and lower rate of major bleeding in the apixaban group compared with the enoxaparin/warfarin group (3.7% vs 6.4%; RR, 0.56; 95% CI, 0.13–2.37 and 2.3% vs 5.0%; RR, 0.45; 95% CI, 0.04–0.78).215
Edoxaban is an orally administered direct factor Xa inhibitor approved by the FDA for the treatment of DVT and PE after 5 to 10 days of initial therapy with a parenteral anticoagulant.219 Renal clearance accounts for approximately 50% of the total clearance of edoxaban.220 Clinical trial results indicated edoxaban to be noninferior to dalteparin with respect to the composite outcome of recurrent VTE or major bleeding (12.8% vs 13.5%; HR, 0.97; 95% CI, 0.70–1.36; P=.006 for noninferiority; P=.87 for superiority).221 It must be noted that edoxaban therapy is initiated after initial therapy with LMWH or UFH for at least 5 days. Dabigatran, another DOAC, follows a similar treatment regimen.222 Renal clearance of dabigatran is 80% of total clearance after oral administration.222 The clinical benefit of dabigatran in the treatment of cancer-associated VTE was found to be equivalent to warfarin in terms of both efficacy (HR, 0.75; 95% CI, 0.20–2.8 at baseline and HR 0.63; 95% CI, 0.20–2.0 for cancer diagnosed during the study) and safety (major bleeding HR, 4.1; 95% CI 2.2–7.5).223 However, unlike warfarin, concurrent administration with parenteral anticoagulants is not recommended when transitioning to edoxaban or dabigatran. Prescribing information must be consulted for transitioning protocols between agents.
Rivaroxaban is an orally administered direct factor Xa inhibitor approved by the FDA for a variety of indications, including the prevention and treatment of VTE.224–226 The drug is primarily eliminated via the kidneys; thus, rivaroxaban should be avoided in patients with severe renal impairment and used with caution in those with moderate impairment.226 Subgroup analysis of the EINSTEIN-DVT and EINSTEIN-PE trials in patients with active cancer concluded that rivaroxaban had similar efficacy to prevent VTE recurrence (5% vs 7%; HR, 0.67; 95% CI, 0.35–1.30) and reduce major bleeding events (2% vs 5%; HR, 0.42; 95% CI, 0.18–0.99) compared with enoxaparin and vitamin K antagonist.227 A prospective cohort study reported the 6-month cumulative incidence of new or recurrent VTE to be 4.4% and major bleeding to be 2.2% in patients on rivaroxaban, which were comparable to the EINSTEIN subgroup analysis.228 Another clinical trial comparing rivaroxaban and dalteparin had similar outcomes, with 6-month cumulative VTE recurrence rates of 4% and 11% (HR, 0.43; 95% CI, 0.19–0.99), as well as major bleeding rates of 6% and 4% (HR, 1.83; 95% CI, 0.68–4.96) in each respective group.229
Based on the quality of evidence presented on apixaban and edoxaban, which include data from large (n>1,000) prospective randomized controlled clinical trials,215,221 the NCCN panel assigns category 1 recommendations to these agents in the DVT/PE setting (Figures 3, 4, and 5). Although stage IV chronic kidney disease is not listed as a contraindication in the FDA-approved label for apixaban, the NCCN panel acknowledges that there are insufficient data to support safe apixaban dosing in this setting, especially in the setting of hemodialysis. It must be noted that patients with gastric and gastroesophageal tumors are at increased risk for hemorrhage with direct oral anticoagulants (DOACs) and thus, LMWHs are preferred in this setting. In the Hokusai VTE Cancer Study, the absolute rate of recurrent VTE was found to be 3.4% lower with edoxaban compared with dalteparin, whereas the absolute rate of major bleeding was 2.9% higher. In particular, the excess of major bleeding with edoxaban was confined to patients with gastrointestinal cancer.230 Conversely, results from the Caravaggio study demonstrated that major bleeding occurred in comparable proportions of patients treated with apixaban or dalteparin (3.8% vs 4.0%). Of note, major bleeding occurred in 9 patients with gastrointestinal cancer in each treatment group.218 Thus, the NCCN panel postulates that apixaban may be safer than edoxaban or rivaroxaban for patients with gastric or gastroesophageal lesions (category 2B recommendation).
A recent retrospective study compared the safety and efficacy of DOACs versus LMWH for treatment of VTE in patients with primary brain tumors or secondary metastases to the brain.231 No significant difference was seen in 6-month cumulative bleeding events, including intracranial hemorrhage, in the DOAC arm compared with the LMWH arm (14.3% vs 27.8%; P=.10). Similarly, rates of recurrent VTE events were similar between the DOAC and LMWH arms, at 5.6% and 6.6%, respectively (P=.96). These data suggest that DOACs may be a safe and effective treatment option for VTE in this patient population.
Low-Molecular-Weight Heparins
Dalteparin232 is approved for prevention and treatment of VTE and extended treatment of symptomatic VTE in patients with cancer, and enoxaparin233 is approved by the FDA for the immediate treatment of VTE. A Cochrane review found no significant differences in bleeding, thrombocytopenia, or survival outcomes with LMWH compared with oral vitamin K antagonists for the chronic treatment of VTE in patients with cancer. However, the incidence of VTE was significantly lower for patients receiving LMWH (RR, 0.58; 95% CI, 0.43–0.77).234 Although each of the 2 LMWHs has been studied in randomized controlled trials in patients with cancer, the efficacy of dalteparin in this population is supported by the highest quality evidence204,235 and is the only LMWH approved by the FDA for this indication. NCCN-recommended dosing regimens for dalteparin204,235,236 and enoxaparin203,233,237,238 in VTE treatment are based on the results of clinical studies and panel consensus. Dalteparin has been found to be more effective than a coumarin derivative regarding recurrent VTE (8.0% vs 15.8%; HR, 0.48; P=.002) without increasing the risk of bleeding in a large prospective randomized study.204 Its safety for cancer-associated VTE has also been monitored for a prolonged period (12 months).235 Conversely, the efficacy of enoxaparin for patients with cancer has been confirmed in a small study in comparison with warfarin (combined outcome including major bleeding or recurrent VTE: 10.5% vs 21.1%; 95% CI, 4.3%–20.3%; P=.09).203 In another study, enoxaparin was found to be a safe and effective option either by itself or in combination with warfarin.237 Additionally, enoxaparin at fixed dosages of 1.0 mg/kg twice daily or 1.5 mg/kg once daily was reported to be equivalent to dose-adjusted UFH in terms of both symptomatic VTE (2.9% and 4.4% vs 4.1%) and major hemorrhage (1.3% and 1.7% vs 2.1%) in a large, prospective, randomized trial. However, this study did not specifically enroll patients with cancer,238 and long-term treatment with enoxaparin dosing of 1.0 mg/kg subcutaneously every 12 hours has not yet been tested in patients with cancer. Thus, the NCCN panel assigns a category 1 recommendation to dalteparin for DVT/PE (Figures 3, 4, and 5).
Extended anticoagulation therapy with LMWHs may require dosage reduction after an initial period. In the CLOT study, the dalteparin dosing was lowered from 200 units/kg daily to 150 units/kg daily after 1 month.204 In addition, the ESMO clinical recommendations for management of VTE in patients with cancer specifies using 75%–80% of the initial dose of LMWH for extended anticoagulation therapy.239 Limited evidence exists concerning the safety and efficacy of LMWHs in special populations, such as patients with renal insufficiency, patients with body mass index >30 kg/m2, patients weighing <50 kg, patients ≥70 years of age, and patients with cancer.240 The NCCN panel suggests that each institution prepare a LMWH dosing algorithm tailored for these subsets of patients. Of the two LMWHs, specific dosing recommendations for patients with severe renal insufficiency (creatinine clearance [CrCl] <30 mL/min) are available only for enoxaparin.233,241 These recommendations are supported by results from multiple studies showing reduced renal clearance of enoxaparin and its association with a 2- to 3-fold increase in risk of bleeding when administered in standard, unadjusted therapeutic doses to patients with severe renal insufficiency.242–244 On the other hand, available data suggest dalteparin might be sufficiently cleared in patients with renal impairment245,246; however, monitoring of peak anti-Xa levels is still recommended in patients with CrCl <30 mL/min.232 Of the two LMWHs, a specific dosing recommendation for patients with a body mass index ≥40 kg/m2 is available only for enoxaparin.247 This recommendation is supported by a randomized controlled trial of enoxaparin 1 mg/kg versus reduced dose of 0.8 mg/kg every 12 hours in patients with a body mass index ≥40 kg/m2. A similar number of patients in both the reduced-dose arm and standard-dose arm reached goal anti-Xa levels, at 89.3% versus 76.9%, respectively (P=.29).247
Increased survival rates have been reported for subgroups of patients receiving chronic treatment with LMWH versus other VTE therapies or placebo.248,249 In the FAMOUS study of patients with advanced cancer without VTE, subgroup analysis of patients with better prognoses suggested that 2-and 3-year survival rates were higher for patients receiving dalteparin compared with those receiving placebo.248 A post hoc analysis of patients from the CLOT study also indicated that among patients without metastases, 1-year survival rates were higher for those receiving dalteparin versus an oral vitamin K antagonist.249 Other randomized studies and systematic reviews have provided evidence both for and against the purported survival benefits of LMWHs in patients with cancer.250–255 Of note, 2 large randomized prospective trials, as well as a systematic review, reported no overall survival advantage in patients with lung cancer receiving LMWH.253,255,256
Fondaparinux
Fondaparinux is a specific indirect factor Xa inhibitor for the treatment of VTE whose advantages include specific neutralization of factor Xa, elimination of the need to monitor anticoagulant response in most cases, and the lack of cross reactivity with the antibody associated with HIT.211,257,258 Subgroup analysis of data from the Matisse clinical trials supports the use of fondaparinux in patients with cancer. In these studies, fondaparinux led to a higher 3-month DVT recurrence rate (12.7% vs 5.4%; absolute difference 7.3%; 95% CI, 0.1–14.5) but a lower PE recurrence rate (8.9% vs 17.2%; absolute difference, −8.3; 95% CI, −16.7, 0.1) than enoxaparin, with no difference in bleeding or overall survival.259 The use of fondaparinux in patient populations with renal insufficiency or obesity has not been well-defined, although there is some evidence to support its safe and effective use in patients ≥60 years of age with a broad range of body weights.260 The NCCN panel recommends against the use of fondaparinux in patients with severe renal insufficiency and advises caution for use in patients with renal dysfunction (CrCl 30–50 mL/min) and patients >75 years of age (Figures 3, 4 and 5). The panel also recommends a reduced dose in patients weighing <50 kg and an increased dose in those weighing >100 kg.258,260
Unfractionated Heparin
UFH is approved by the FDA for a variety of indications, including the treatment of VTE.261 The initial dosing of UFH in the treatment of VTE is weight-based, with a recommended regimen of 80 units/kg bolus followed by 18 units/kg per hour infusion adjusted to target aPTT or per hospital standard operating procedures.262 Alternatively, fixed-dose, unmonitored, subcutaneous UFH (333 units/kg load, followed by 250 units/kg every 12 hours) has been reported to be comparable to LMWH in the treatment of patients with acute VTE (recurrent VTE, 3.8% vs 3.4%; absolute difference, 0.4%; 95% CI, −2.6%–3.3%).263 Patients receiving intravenous UFH must be hospitalized and monitored for anticoagulant response. The panel recommends UFH as the agent of choice in patients with CrCl <30 mL/min, because the liver is a main site of heparin biotransformation (Figures 3, 4, and 5).261 Some exceptions include patients with severe renal dysfunction but without intravenous access, and those with a new diagnosis of VTE despite therapeutic doses of UFH. In a meta-analysis of trials comparing outcomes with anticoagulants (UFH, LMWH, and fondaparinux) as initial treatment of VTE in patients with cancer, LMWH was associated with a significant reduction in mortality rate at 3-month follow-up compared with UFH (RR, 0.66; 95% CI, 0.40–1.10).264 However, no significant difference was found in VTE recurrence between LMWH and UFH. Furthermore, no statistically significant differences were found between UFH and fondaparinux in terms of mortality, VTE recurrence, or bleeding events.265
Warfarin
Warfarin is an option for long-term treatment of VTE in patients with cancer after initial treatment/bridging with UFH,261 LMWH,232,233 or fondaparinux.258 Warfarin can be safely administered to patients with renal insufficiency, although the response to warfarin is accentuated in patients with hepatic insufficiency.266 If warfarin is selected for chronic anticoagulation, the NCCN panel recommends initiating warfarin concurrently with the parenteral agent used for acute therapy (at previously recommended doses) and continuing both therapies for at least 5 days and until the International Normalized Ratio (INR) is ≥2 (Figures 3, 4, and 5). During the transition to warfarin monotherapy, the INR should be measured at least twice weekly. Once the patient is on warfarin alone, the INR should be measured initially at least once weekly. Once the patient is on a stable dose of warfarin with an INR of 2–3, INR testing can be gradually decreased to a frequency of no less than once monthly.
Summary
The intention for these guidelines is to provide a framework on which to prevent, diagnose, and treat cancer-associated VTE because cancer and cancer therapies have been shown to increase VTE risk. Moreover, thrombosis has been shown to be a leading cause of death in patients with cancer, second only to the cancer itself. VTE, as broadly defined in the NCCN Guidelines to include acute superficial vein thrombosis, acute deep venous thrombosis, acute pulmonary embolism, and splanchnic vein thrombosis, has a significant number of therapeutic options; thus, guidance for the careful selection of treatment methods that balance efficacy and safety is critical in achieving the best outcomes for patients.
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