**6. VTE Prophylaxis in cancer patients undergoing surgery**

Surgical interventions, both elective and emergency, increase VTE risk in cancer patients compared to similar interventions in non-cancer patients (Gallus, 1997; Kakkar et al., 2005; White et al., 2003;). Despite the utilization of VTE prophylaxis, one multicenter prospective study showed that VTE was the most frequent cause of 30-day mortality in cancer patients undergoing surgical procedures (Agnelli et al., 2006). Though low dose unfractionated heparin (LDUH) is effective in VTE prophylaxis, the drug should be given at the 5000 IU three times a day (not twice) in high risk surgical procedures like pelvic gynecological cancer procedures. LMWH, given once daily, is at least as effective as UFH for this indication (Clark-Pearson et al., 1990).

The issue of extended out-of-hospital prophylaxis in high risk surgical patients was addressed in major clinical trials (Gallus, 1997; Kakkar et al., 2005). In one double-blind, multicenter trial (ENOXACAN II), 322 patients undergoing planned curative open surgery for abdominal or pelvic cancer received enoxaparin (40 mg subcutaneously) daily for 6 to 10 days and were then randomly assigned to receive either enoxaparin (at the same dose) or placebo for another 21 days. Bilateral venography was performed between days 25 and 31, or sooner if symptoms of VTE occurred. In an intention-to-treat analysis and following the double-blind phase, VTE occurred in 4.8% in the extended enoxaparin group compared to 12.0% in the placebo group (P=0.02). This difference persisted at three months (13.8 % vs. 5.5%, P=0.01). There were no significant differences in the rates of bleeding or other complications during the double-blind or follow-up periods (Bergqvist et al., 2002).

In another open-label randomized trial designed to evaluate the efficacy and safety of thromboprophylaxis with dalteparin, another LMWH, administered for 28 days after major abdominal surgery compared to 7 days treatment. A total of 590 patients undergoing major abdominal surgery (60% for cancer) were recruited. The cumulative incidence of VTE was reduced from 16.3% with short-term (7days) thromboprophylaxis to 7.3% after prolonged thromboprophylaxis; a relative risk reduction (RR) of 55%; 95% confidence interval 15-76; P=0.012. The number that needed to be treated to prevent one case of VTE was 12 (95%

The concept of VTE prophylaxis for ambulatory cancer patients was tested in a recent double-blind study; patients with metastatic or locally advanced cancer of lung, colo-rectal, stomach, ovary, pancreas, or bladder who are initiating a new chemotherapy course, were randomized to receive subcutaneous semuloparin ( a new ultra low molecular weight heparin) or placebo. The drug was given at a dose of 20 mg subcutaneously and continued until change of chemotherapy. Twenty of the 1,608 patients treated with semuloparin (1.2%) and 55 of the 1,604 patients treated with placebo (3.4%) had a thromboembolic event, representing a 64% risk reduction in such event rate (hazard ratio [HR] = 0.36, 95% confidence interval [CI] 0.21–0.60, p<0.0001, intent-to-treat analysis). Nineteen of 1,589 patients (1.2%) in the semuloparin and 18 of the 1,583 patients (1.1%) in the placebo group

More work is needed before taking findings of these studies to clinical practice; as such ambulatory cancer patients on active chemotherapy may be considered for VTE prophylaxis

Surgical interventions, both elective and emergency, increase VTE risk in cancer patients compared to similar interventions in non-cancer patients (Gallus, 1997; Kakkar et al., 2005; White et al., 2003;). Despite the utilization of VTE prophylaxis, one multicenter prospective study showed that VTE was the most frequent cause of 30-day mortality in cancer patients undergoing surgical procedures (Agnelli et al., 2006). Though low dose unfractionated heparin (LDUH) is effective in VTE prophylaxis, the drug should be given at the 5000 IU three times a day (not twice) in high risk surgical procedures like pelvic gynecological cancer procedures. LMWH, given once daily, is at least as effective as UFH for this

The issue of extended out-of-hospital prophylaxis in high risk surgical patients was addressed in major clinical trials (Gallus, 1997; Kakkar et al., 2005). In one double-blind, multicenter trial (ENOXACAN II), 322 patients undergoing planned curative open surgery for abdominal or pelvic cancer received enoxaparin (40 mg subcutaneously) daily for 6 to 10 days and were then randomly assigned to receive either enoxaparin (at the same dose) or placebo for another 21 days. Bilateral venography was performed between days 25 and 31, or sooner if symptoms of VTE occurred. In an intention-to-treat analysis and following the double-blind phase, VTE occurred in 4.8% in the extended enoxaparin group compared to 12.0% in the placebo group (P=0.02). This difference persisted at three months (13.8 % vs. 5.5%, P=0.01). There were no significant differences in the rates of bleeding or other

complications during the double-blind or follow-up periods (Bergqvist et al., 2002).

In another open-label randomized trial designed to evaluate the efficacy and safety of thromboprophylaxis with dalteparin, another LMWH, administered for 28 days after major abdominal surgery compared to 7 days treatment. A total of 590 patients undergoing major abdominal surgery (60% for cancer) were recruited. The cumulative incidence of VTE was reduced from 16.3% with short-term (7days) thromboprophylaxis to 7.3% after prolonged thromboprophylaxis; a relative risk reduction (RR) of 55%; 95% confidence interval 15-76; P=0.012. The number that needed to be treated to prevent one case of VTE was 12 (95%

had a major bleeding (HR=1.05, 95%CI 0.55 to 1.99) (Agnelli et al., 2011).

**6. VTE Prophylaxis in cancer patients undergoing surgery** 

based on risk level and clinical judgment.

indication (Clark-Pearson et al., 1990).

confidence interval 7-44). Bleeding events were not increased with prolonged compared with short-term thromboprophylaxis (Rasmussen et al., 2006).

A recent meta-analysis of eligible clinical studies compared safety and efficacy of extended use of LMWH (for three to four weeks after surgery) versus conventional in-hospital prophylaxis among patients undergoing major abdominal surgeries. The indication for surgery was neoplastic disease in 70.6% (780/1104) of patients. The administration of extended LMWH prophylaxis significantly reduced the incidence of VTE, 5.93% versus 13.6%, RR 0.44 (CI 95% 0.28 - 0.7); DVT 5.93% versus 12.9%, RR 0.46 (CI 95% 0.29 - 0.74); proximal DVT 1% versus 4.72%, RR 0.24 (CI 95% 0.09 - 0.67). These superior efficacy results were obtained with no significant difference in major or minor bleeding between the two groups: 3.85% in the extended thrombo-prophylaxis group versus 3.48% in the conventional prophylaxis group; RR 1.12 (CI 95% 0.61 - 2.06) (Bottaro et al., 2008). Given the results of these studies, one can conclude that extended thromboprophylaxis with LMWH should be considered as a safe and useful strategy to prevent VTE in high-risk major abdominal and pelvic surgeries especially in cancer patients. Similar conclusions were reached in a more recent Cochrane database analysis (Rasmussen et al., 2009). Results of these studies are summarized in Figure-1.
