Targeted prophylaxis in cancer: the evidence accumulates

The association of cancer and hypercoagulability has been known for at least a century, but it is now increasingly clear that not all cancer patients are equally at risk for thrombotic events. The magnitude of risk varies widely by clinical risk factors such as type of malignancy, comorbid conditions, the clinical setting and therapeutic interventions. A post-menopausal woman with breast cancer receiving adjuvant endocrine therapy may have a very lowrisk of venous thromboembolism (VTE). In a meta-analysis of trials with a median follow-up time ranging from 51 to 100 months, rates of VTE range from 2 to 2.8 % with evidence of a protective effect for aromatase inhibitors (absolute risk difference -1.3 % vs. tamoxifen) [1]. In contrast, a patient with metastatic bladder cancer receiving cisplatin may have a very high-risk of VTE. In a retrospective cohort study of primarily solid tumor patients treated in 2008 with cisplatin-based chemotherapy, 18.1 % of patients developed thromboembolic events [2]. There is no doubt that VTE in cancer is consequential: it is the second leading cause of death, associated with short-term and long-term mortality, morbidity, with requirement for long-term anticoagulation with high-risk of bleeding and healthcare resource utilization. Thus, it is important to select high-risk patients for studies of thromboprophylaxis, and it is equally important to exclude low-risk patients where the magnitude of benefit is likely to be low. Patient selection and risk assessment are therefore crucial to optimize benefit for outpatient thromboprophylaxis in cancer. Several randomized studies have recently been published or presented. Although all have appropriately focused on cancer outpatients receiving chemotherapy, there are important differences in the types of patients included. In one corner are what might be called ‘‘generalist’’ studies: these include the two largest studies—PROTECHT which used nadroparin, a low-molecular-weight heparin (LMWH) as the prophylactic agent [3], and SAVE-ONCO, which used semuloparin, an ultra-LMWH [4]. Both studies included heterogeneous populations varying by the site of cancer, stage and chemotherapy. Both showed a significant reduction in VTE, but event rates were low (Fig. 1). Hence, study results have not been adopted into clinical practice. In the opposite corner are what might be termed ‘‘niche’’ studies: these trials are smaller, have focused on very highrisk sites of cancer such as pancreas or myeloma, populations that are homogenous and have high rates of VTE [5]. For instance, in the FRAGEM study of dalteparin thromboprophlyaxis in advanced pancreatic cancer, VTE during treatment (\100 days from randomization) was reduced from 23 to 3.4 % (p = 0.002), an 85 % risk reduction [5]. Such findings have led to ‘‘soft’’ recommendations for outpatient prophylaxis in high-risk patients. A criticism of these ‘‘niche’’ studies has been that the findings are applicabe only to a small percentage of cancer patients, and the impact on the public health burden of cancer-associated VTE is low. Is there a way to marry these two approaches to risk assessment? Can prophylaxis be targeted to high-risk patients and excluded for low-risk patients? In 2008, my colleagues and I developed and validated a risk score that includes five simple variables (Table 1) [6]. This model A. A. Khorana (&) James P. Wilmot Cancer Center, University of Rochester, 601 Elmwood Ave, Box 704, NY 14642 Rochester, USA e-mail: alok_khorana@urmc.rochester.edu