What Is the Appropriate Treatment of Cancer-Associated Venous Thromboembolic Disease?
Case
A 70-year-old woman with recently diagnosed pancreatic cancer is admitted with worsening abdominal pain and new right-lower-extremity edema. A CT scan of the abdomen and pelvis reveals occlusive IVC and common iliac thromboses. A right-common-femoral DVT appears on Doppler ultrasound. A CT angiogram of her chest is negative for pulmonary emboli. What is the appropriate treatment for this patient’s thromboembolic disease?
Overview
VTE in the setting of malignancy is common, and the incidence of VTE among cancer patients is increasing for unclear reasons.1,2,3 VTE occurs in an estimated 4% to 20% of all malignancy patients. Overall, cancer patients are at a sixfold increased risk of developing VTE compared with the general population, and these patients represent approximately 20% of all VTE cases.4,5
VTE is a leading cause of mortality among hospitalized cancer patients; evidence of VTE exists in up to 50% of cancer patients at autopsy.3,4 VTE complications lead to significant morbidity, including recurrent VTE, pulmonary hypertension, post-thrombophlebitic syndrome, bleeding, and decreased quality of life.6,7
The risk is greatest for hospitalized cancer patients and those receiving active chemotherapy, particularly with such antiangiogenic agents as thalidomide and bevacizumab.4,6 Certain malignancies are more frequently associated with VTE; these include gastrointestinal, gynecologic, brain, lung, renal, and hematologic cancers.4 Table 1 (p. 50) summarizes risk factors associated with VTE in cancer patients.4
Patients with malignancy are hypercoagulable, primarily because of tumor-related alterations in the coagulation cascade.8 Tumors contain cell-surface proteins (e.g., tissue factor and cancer procoagulant) that lead to activation of the clotting cascade via interactions with factors IX and/or X. In addition, tumor-released cytokines cause prothrombotic changes in the vascular endothelium.8
This hypercoagulability is exacerbated by cancer-associated treatment events, including immobility, central venous catheters, erythropoiesis-stimulating agents, and packed red-blood-cell and platelet transfusions.5,9
Cancer-related therapy complications further confound VTE management. Drug interactions, chemotherapy-induced thrombocytopenia, malnutrition, bleeding risk from surgery or tumor location, and liver dysfunction make safe management of cancer-associated VTE a challenge.
Review of the Data
Low-molecular-weight heparin (LMWH) vs. vitamin K antagonists (VKA): There is significant evidence that LMWH is the preferred pharmacologic therapy for the initial and long-term treatment of cancer-related VTE. The most convincing data were published as the CLOT trial, and is supported by several smaller studies.10 Recommendations for the preferred use of LMWH are consistent among several national and international guidelines.6,7
In the CLOT (Randomized Comparison of Low-Molecular-Weight Heparin Versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer) trial, six months of treatment with an oral VKA preceded by five to seven days of LMWH was compared with six months of treatment with LMWH (dalteparin). Patients with the diagnosis of acute symptomatic VTE were evaluated. After six months of treatment, 53 of 336 patients in the oral anticoagulant group had recurrent VTE, compared with 27 of 336 patients in the LMWH group—a relative risk reduction of 52% and an absolute risk reduction of 8% (P=0.002). Complication rates (major and minor bleeding) and overall mortality were similar between the two groups.7,10
