Diagnosis, Treatment, and Prevention of Cancer-Associated Venous Thromboembolism
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.
1. Risk factor(s) for venous thromboembolism (VTE) in patients with cancer include which of the following characteristics?
2. Which of the following types of cancer is associated with the lowest risk of VTE?
3. Which of the follow regimens is recommended for prevention of central venous catheter (CVC)–associated deep venous thrombosis (DVT)?
4. Which of the following agents is preferred for the long-term management of VTE in patients with cancer?
5. What is the appropriate duration of therapy for a patient with cancer who has a DVT?
1. Answer: G. All of the characteristics listed increase the risk of VTE in patients with cancer. The risk of VTE varies among patients with cancer by organ site and disease extent. Types of cancer associated with a high risk of VTE include pancreatic cancer, brain tumors, and stomach cancer, whereas patients with head and neck cancer and breast cancer are at lower risk. Patients with metastatic cancer are at fourfold to twentyfold higher risk for VTE. Chemotherapy increases the risk of VTE by twofold, whereas cancer surgery is associated with a twofold higher risk of VTE than is surgery among patients without cancer.
2. Answer: A. Cervical cancer is associated with the lowest incidence of VTE (approximately 1.6%) among patients hospitalized with the tumor types listed. Pancreatic cancer is associated with a 20% risk of VTE in the first year after diagnosis for patients with metastatic disease. Gastric cancer is associated with a 10% incidence of VTE in the first year, whereas renal cell carcinoma is associated with a 6% incidence of VTE. Leukemia is associated with an annual incidence of 2% to 3% during the first year of treatment.
3. Answer: E. Prophylaxis against CVC-associated DVT is not recommended with any agent by any guideline. Although the initial randomized controlled trial of low-dose warfarin by Bern and colleagues noted a significant decrease in thrombosis, subsequent studies have not noted an beneficial effects with low-dose warfarin. Verso and colleagues conducted a large randomized controlled trial assessing the efficacy of enoxaparin and found no significant reduction in CVC-DVT compared with placebo. Dalteparin and low-dose heparin have not been shown to provide significant protection against CVC-associated thrombosis.
4. Answer: B. LMWH is preferred for acute and chronic management of VTE in patients with cancer. In the CLOT trial, dalteparin (200 units/kg daily for 1 month followed by 150 units/kg daily for months 2 to 6) was associated with a 50% reduction in the incidence of recurrent VTE compared with warfarin.
5. Answer: D. Anticoagulation should be continued for at least 3 months or as long as there is evidence of active cancer or active cancer therapy, whichever is longer. Prospective observational studies such as those conducted by Prandoni et al and Hutten et al. have demonstrated that patients with active cancer have a threefold to sixfold higher incidence of recurrent VTE compared with patients who do not have cancer. Therefore long-term therapy is appropriate.
