**3. Making the decision**

Despite its proven success, many registry studies have shown low compliance rates with published VTE prophylaxis guidelines. In a national Canadian multi-center survey study (the CURVE study), the medical records of patients in 20 teaching and 8 community hospitals were reviewed to assess the adherence to the established sixth American College of Chest Physicians (ACCP) consensus guidelines for VTE prophylaxis. In this study, 1894 eligible patients were included; thromboprophylaxis was administered only to 23% of all patients and to 37% of patients who were bedridden for more than 24 hours. However, only 16% of the patients had appropriate prophylaxis; in particular, patients with cancer had a significantly reduced likelihood of receiving prophylaxis (OR = 0.40, 95% CI (0.24–0.68)

Venous Thromboembolism Prophylaxis in Cancer Patients 115

Several clinical and scientific groups including the ACCP (Geerts et al., 2008), the American Society of Clinical Oncology (ASCO) (Lyman et al., 2007) and the National Comprehensive Cancer Network (NCCN) (Wagman et al., 2008) have established guidelines for VTE prophylaxis in cancer patients. All have different and somewhat conflicting recommendations but all lack a risk assessment model. While the ACCP guidelines were very conservative and advised prophylaxis for cancer patients who are bedridden with an acute medical illness, the NCCN, on the other hand, lowered their threshold for VTE prophylaxis; their most recent updated guidelines stated: ''The panel recommends prophylactic anticoagulation therapy for all inpatients with a diagnosis of active cancer (or for whom clinical suspicion of cancer exists) who do not have a contraindication to such therapy (category 1).'' Their recommendation was based on an assumption that ambulation in hospitalized cancer patients is inadequate to reduce VTE risk (Wagman et al., 2008). The ASCO guidelines published in 2007 have taken a more neutral position by stating in their summary conclusions: "Hospitalized patients with cancer should be considered candidates for VTE prophylaxis with anticoagulants in the absence of bleeding or other

Cancer patients treated in the outpatient setting can also be at high risk for VTE. Current guidelines do not recommend anticoagulant prophylaxis for ambulatory cancer patients. Khorana et al tried to establish a risk assessment model for VTE prophylaxis in ambulatory cancer patients after the initiation of chemotherapy. Five predictive variables were identified in a multivariate model: site of cancer (2 points for very high-risk site, 1 point for high-risk site), platelet count of 350 x 109/L or more, hemoglobin less than 100 g/L (10 g/dL) and/or use of erythropoiesis-stimulating agents, leukocyte count more than 11 x 109/L, and body mass index of 35 kg/m2 or more (1 point each). Rates of VTE in the validation part of their study were 0.3% in low-risk (score = 0), 2.0% in intermediate-risk (score = 1-2), and 6.7% in high-risk (score 3) category over a median of 2.5 months. The application of this model can identify patients with a nearly 7% short-term risk of symptomatic VTE and may be used to

select cancer outpatients for studies of thromboprophylaxis (Khorana et al., 2008).

also shown to be a risk factor for recurrent VTE (Kyrle et al., 2007).

More recently, researchers focused on biomarkers that can predict the occurrence of VTE. Pselectin, found in the α granules of platelets and endothelial cells and expressed on the cell surface on activation, mediates the adhesion of leukocytes, platelets, and cancer cells in inflammation, thrombosis, and cancer growth and metastasis ( Chen et al., 2006). Recent studies have demonstrated that high plasma levels of soluble P-selectin are strongly associated with VTE (Rectenwald et al., 2005). In a prospective cohort study, P-selectin was

In a recent study, the Vienna Cancer and Thrombosis Study (VCATS) group reported that elevated serum P-selectin levels predicts VTE in 687 newly diagnosed cancer patients. The cumulative probability of VTE after 6 months of follow up was 11.9% in patients with serum P-selectin above and 3.7% in those below the 75th percentile (P = 0.002). Authors postulated that such biomarker could identify cancer patient who may benefit from prophylaxis (Ay et

**4. Published guidelines** 

contraindications to anticoagulation" (Lyman et al., 2007).

**5. Ambulatory cancer patients** 

al., 2008).

(Kahn et al., 2007). Similar findings were also reported in the IMPROVE study in which only 45% of cancer patients who either met the ACCP criteria for requiring prophylaxis or were eligible for enrollment in randomized clinical trials that have shown the benefits of pharmacologic prophylaxis actually received prophylaxis [Tapson et al., 2007]. In another study conducted by our group, two hundred cancer patients with established diagnosis of VTE were identified; majority (91.8%) had advanced-stage cancer at time of VTE diagnosis. In addition to cancer, many patients had multiple coexisting risk factors for VTE with 137 (68.5%) patients had at least three, while 71 (35.5%) had four or more. Overall, 111(55.5%) patients developed lower-extremity DVT while 52 (26%) patients developed PE, other sites accounted for 18%. Almost three quarters of the patients (73.5%) had not received any antecedent prophylaxis. Prophylaxis rate was 23% among patients with >3 risk factors and 50% among the highest risk group with >5 risk factors (Abdel-Razeq et al., 2011).

Compared to surgical patients, decisions on when to offer prophylaxis in cancer patients admitted to medical units is difficult to make (Monreal et al., 2004); medical patients typically have many risk factors, the interaction of which is difficult to quantify. In a recent survey, The Fundamental Research in Oncology and Thrombosis (FRONTLINE), marked differences were seen in the use of thromboprophylaxis for surgical and medical cancer patients, with over 50% of surgeons reporting that they initiated thromboprophylaxis routinely, while most medical oncologists reported using thromboprophylaxis in less than 5% of medical cancer patients (Kakkar et al., 2003). These studies and many others (Chopard et al., 2005; Ageno et al., 2002), demonstrate that VTE prophylaxis in cancer patients is still underutilized.

Many factors may contribute to the low VTE prophylaxis rate in cancer patients. Obviously, concerns about bleeding especially in patients undergoing active treatment with chemotherapy that can lead to low blood counts is one of these reasons; this issue was evident in our study patients where 113 (18.6%) had prolonged PT and or PTT and another 92 (15.2%) had platelet counts < 100 K (Abdel-Razeq et al., 2001). While these may not represent absolute or even relative contraindications for using anticoagulants for VTE prophylaxis, nevertheless, such factors may prevent physicians from prescribing anticoagulant prophylaxis for cancer patients. Other reasons may include concerns about higher bleeding risks from tumor metastasis in vital structures like the brain. Such patients can be offered mechanical methods if anticoagulants deemed contraindicated. However, the absence of a suitable risk assessment model may also contribute to such low prophylaxis rate; such risk assessment model should take into account the additive or even the synergistic effect of the many other additional risk factors that cancer patients are typically admitted with.

Caprini et al. had established a risk assessment model to help health professionals in making the decision on when and how to prescribe VTE prophylaxis (Caprini et al., 2001 ; Motykie et al., 2000). Though we found it useful, we faced several limitations when we tried to apply such model in cancer patients. All cancer patients were given the same risk score; while in fact type of cancer, stage, nature of anti-cancer therapy and time since cancer diagnosis are, as discussed above, important factors that affect VTE rate in cancer patients (Abdel-Razeq et al., 2010).
