When to Offer Thromboprophylaxis to Patients With Advanced Pancreatic Cancer: Shedding Light on the Path Forward.

Abstract

The risk of venous thromboembolism (VTE) is increased substantially in patients with malignant disease, most notably cancers of the pancreas, stomach, kidney, ovary, lung, and CNS, as well as certain hematologic malignancies. The risk of VTE is further increased in patients with cancer and certain demographic-, diseaseand treatment-related characteristics. Patients with major medical comorbidities such as infection, pulmonary disease, and renal failure are notably at increased risk. In addition to hospitalized patients with cancer and those in the perioperative period, patients receiving systemic therapies including chemotherapy, hormonal therapy, and certain targeted agents are at several-fold increased risk for VTE compared with the general population. Even certain supportive care measures, such as the use of the erythroidstimulating agents and blood transfusions, have been associated with an increased risk of VTE. The identification of several factors associated with cancerassociated VTE has led to the development of multivariable risk models for cancer-associated risk. A VTE risk model was developed on the basis of a prospective cohort of 2,701 ambulatory patients during their initial three to four cycles of chemotherapy for cancer, and was validated in a separate group of 1,365 patients using five readily available clinical and laboratory risk factors that were identified. On the basis of this model, points were assigned and patients were classified as low, intermediate, and high risk for VTE according to cancer type, severe obesity (body mass index 35 kg/m), elevations in pretreatment platelet count ( 350,000/ L) and leukocyte count ( 11,000/ L), and either anemia ( 10 g/dL) or erythroid-stimulating agent use. The risk score has now been validated by a number of independent investigators in the United States and Europe. In a prospective cohort of 819 patients with cancer, Ay et al observed a cumulative risk of VTE at 6 months that ranged from 1.5% to 17.7% (1.5%, score 0; 3.8%, score 1; 9.4%, score 2; and 17.7%, score 3). It should be noted that in both the original model-development population and the various validation studies, high-risk patients represent approximately 10% of ambulatory patients receiving cancer chemotherapy. Current guidelines from both the American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network recommend an evaluation of VTE risk and encourage the use of a validated risk score in ambulatory patients receiving cancer chemotherapy. Patients with cancers of the pancreas and upper GI tract have recently received particular attention because of the apparent greater risk for VTE than in other cancer types. A retrospective observational study of ambulatory patients with common solid malignancies initiating cancer chemotherapy reported overall rates of VTE at 3.5 months and 1 year of 7.3% and 13.5%, respectively. The greatest risk of VTE was observed in patients with advanced pancreatic cancer (APC) and was determined to be 11.6% and 21.3% at 3.5 and 12 months, respectively. It may be noted that patients who developed VTE in this cohort experienced more than twice the risk of major bleeding and had approximately 50% greater health care expenditures than similar patients who did not develop VTE. Although the prognosis of most patients with APC is poor, those with VTE have a particularly poor survival. Although the role of anticoagulation is well supported in the treatment of established VTE and for prevention of VTE in hospitalized patients with cancer, the role of thromboprophylaxis in ambulatory patients has not been firmly established. Several randomized controlled trials (RCTs) of thromboprophylaxis in ambulatory patients with cancer have been published, including 11 that compared low–molecular weight heparins (LMWHs) with either placebo or no prophylaxis. A meta-analysis estimated an overall relative risk for symptomatic VTE across published trials of 0.47 (95% CI, 0.36 to 0.61; P .001) but generally low rates of VTE and an overall absolute reduction in VTE risk of only 2.8% (95% CI, 1.8% to 3.7%; P .001). The largest RCT of an LMWH for thromboprophylaxis in patients with solid malignancies demonstrated a hazard ratio for VTE of 0.36 (95% CI, 0.21 to 0.60; P .001) but observed absolute rates of VTE of only 3.4% and 1.2% among control and LMWH-treated patients, respectively. At the same time, the largest absolute rates of VTE were observed in trials of patients with APC. The long-awaited publication of CONKO-004 (Prospective Randomized Trial of Simultaneous Pancreatic Cancer treatment With Enoxaparin and Chemotherapy) that accompanies this article provides the opportunity to reconsider the risk of VTE in patients with JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 33 NUMBER 18 JUNE 2