How Long to Treat Acute Venous Thrombosis in Cancer: Can Treatment Be Personalized?

Venous thromboembolism (VTE) is a common occurrence in patients with malignant disease. Standard treatment for acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE) is usually initial subcutaneous weight-adjusted low molecular weight heparin (LMWH), which is continued for approximately 6 months. The treatment of acute DVT and/or PE is to prevent recurrent thromboembolism. In one prospective study, the cumulative incidence of recurrent VTE at 12 months was approximately 20% in patients with cancer with acute VTE compared with 7% in noncancer patients with acute VTE. Conversely, the risk of anticoagulant-associated bleeding in patients with cancer was increased 2-fold compared with that for noncancer patients. The duration of anticoagulant therapy in patients with cancer is an important unanswered question. Clinical practice guidelines recommend continuation for as long as the cancer is active (eg, patient with symptomatic metastatic disease receiving chemotherapy and prolonged immobility). However, in truth, these guidelines are based on extrapolations from patients without cancer and clinical experience. The DACUS (Duration of Anticoagulation Based on Ultrasonography) investigators are to be congratulated for conducting a prospective randomized trial to address the question of the optimal duration of anticoagulant therapy in patients with malignant disease. They used a test, residual vein thrombosis (RVT), measured by compression ultrasound to guide the duration of therapy. The presence of RVT reflects venous stasis and vessel wall damage, which are two important components in the pathogenesis of venous thrombosis. Previous prospective studies in patients with acute VTE but without cancer demonstrated a relationship between RVT and recurrent VTE. In the DACUS trial, 347 patients with active cancer and DVT were treated with LMWH for 6 months and then underwent compression ultrasound for RVT. Subjects with no evidence of RVT stopped their LMWH and were followed for 12 months after discontinuation of LMWH. Seventy percent of the cohort had RVT and were randomly assigned to receive 6 more months of LMWH or no further treatment. In the group with no RVT who stopped treatment at 6 months, the rate of recurrent VTE was 2.8%. In the RVT-positive group, the rate of recurrent VTE from the time of random assignment was 18% in patients who received longer LMWH treatment (18 months of followup) compared with 22% in those who stopped treatment (12 months of follow-up). Although these results appear to favor longer term treatment, the difference was not statistically significant. When patients with no RVT at 6 months who did not receive extended treatment are compared with those with presence of RVT at 6 months who did not receive extended treatment, there was a statistically significant different in recurrence. There are several points related to the study design that should be considered. The primary outcome measure as defined in the study protocol was recurrent VTE after discontinuation of LMWH. In the initial submission to Journal of Clinical Oncology (JCO), the VTE and bleeding events during the first 6 months after random assignment were not counted for the extended LMWH treatment group. In a randomized trial, events are counted from the point of random assignment. As this is JCO policy and to avoid confusion for the reader, the authors were asked by the Editors to count events from the time of random assignment. The authors do report in Figure 3 the number of VTE events (four) and major bleeds (two) during the 6 months after random assignment. Table 3 takes these events into consideration. We can only speculate why the authors defined the follow-up period as starting from the point of stopping the LMWH. Thrombosis physicians are very interested in the period after stopping anticoagulants in patients with idiopathic VTE where rebound thrombosis is a major issue. Although we agree that this is of interest, it may not be germane to patients with cancer and VTE because of their shortened life span. The design of this study is similar to one that the McMaster group did many years ago in noncancer patients where impedance plethysmography (IPG) was used to guide the duration of anticoagulant therapy in patients presenting with idiopathic proximal DVT. IPG, similar to RVT, was used as a marker of poor venous flow. Similar to the current study, a positive IPG was associated with an increased risk of recurrence. RVT can be considered in a similar way to how oncologists think about a biomarker test to guide treatment in patients with breast cancer. A prognostic test describes the clinical course of the disease, that is, who will develop recurrent cancer and who will not, whereas a predictive test determines whether the treatment will work. In patients with estrogen receptor–positive breast cancer who receive endocrine treatment and are being considered for chemotherapy, tests such as Oncotype Dx that define a low risk group for recurrence are used to spare patients chemotherapy. In the DACUS study, the RVT was prognostic but not predictive. The absence of RVT in patients who received 6 months of LMWH was associated with only a 2.9% risk of JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 32 NUMBER 32 NOVEMBER 1

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