Randomized Phase III Trial of Standard Therapy Plus Low Molecular Weight Heparin in Patients With Lung Cancer: FRAGMATIC Trial

Abstract

Purpose Venous thromboembolism (VTE) is common in cancer patients. Evidence has suggested that low molecular weight heparin (LMWH) might improve survival in patients with cancer by preventing both VTE and the progression of metastases. No trial in a single cancer type has been powered to demonstrate a clinically significant survival difference. The aim of this trial was to investigate this question in patients with lung cancer. Patients and Methods We conducted a multicenter, open-label, randomized trial to evaluate the addition of a primary prophylactic dose of LMWH for 24 weeks to standard treatment in patients with newly diagnosed lung cancer of any stage and histology. The primary outcome was 1-year survival. Secondary outcomes included metastasis-free survival, VTE-free survival, toxicity, and quality of life. Results For this trial, 2,202 patients were randomly assigned to the two treatment arms over 4 years. The trial did not reach its intended number of events for the primary analysis (2,047 deaths), and data were analyzed after 2,013 deaths after discussion with the independent data monitoring committee. There was no evidence of a difference in overall or metastasis-free survival between the two arms (hazard ratio [HR], 1.01; 95% CI, 0.93 to 1.10; P = .814; and HR, 0.99; 95% CI, 0.91 to 1.08; P = .864, respectively). There was a reduction in the risk of VTE from 9.7% to 5.5% (HR, 0.57; 95% CI, 0.42 to 0.79; P = .001) in the LMWH arm and no difference in major bleeding events but evidence of an increase in the composite of major and clinically relevant nonmajor bleeding in the LMWH arm. Conclusion LMWH did not improve overall survival in the patients with lung cancer in this trial. A significant reduction in VTE is associated with an increase in clinically relevant nonmajor bleeding. Strategies to target those at greatest risk of VTE are warranted.

International clinical practice guidelines including guidance for direct oral anticoagulants in the treatment and prophylaxis of venous thromboembolism in patients with cancer

“…The updated search identifi ed eight meta-analyses (1669-9861 patients) [103][104][105][106][107][108][109][110] and six randomised clinical trials [111][112][113][114][115][116] comparing anticoagulant prophylaxis with no intervention or placebo in ambulatory patients receiving systemic anticancer therapy. Overall, a signifi cant 45·0% reduction in VTE occurrence was reported across the six meta-analyses assessing the safety and effi cacy of LMWH compared with no intervention or placebo.…”

“…Mortality was not diff erent between groups. The FRAGMATIC 111 multicentre, open-label, randomised trial assessed LMWH prophylaxis on 1-year survival in newly diagnosed patients with small-cell lung cancer or those with NSCLC of any stage. LMWH did not increase overall survival or metastasis-free survival.…”

Management of cancer-associated venous thromboembolism – a case-based practical approach

“…Furthermore, in patients with locally advanced or metastatic pancreatic cancer receiving gemcitabine-based chemotherapy, the effi cacy and safety of primary thromboprophylaxis with LMWH, albeit at (half-) therapeutic dosages, have been demonstrated in two randomized controlled trials [93,94]. In addition, patients with lung cancer, particularly those with small-cell lung cancer and limited disease, may benefi t from primary thromboprophylaxis with LMWH [95,96].…”

Antimetastatic Properties of Low Molecular Weight Heparin

“…Lung Cancer) trial reported by Macbeth et al 1 concluded that the addition of prophylactic doses of the low molecular weight heparin (LMWH) dalteparin for 24 weeks to standard of care in patients with lung cancer did not improve overall survival; the rate of venous thromboembolism was significantly reduced but at the cost of an increase in bleeding complications. There was also no significant effect on metastasis in the group that received dalteparin.…”

“…4,6 Although the authors should be congratulated for having chosen overall survival (and not only the occurrence of venous thromboembolism) as an end point, the FRAGMATIC trial was not designed to examine the antimetastatic properties of LMWHs. 1 Studies that test LMWHs with better antimetastatic properties such as tinzaparin should be conducted in a setting clearly defined for preventing metastasis. The best environment for testing an antimetastatic agent would be localized cancers that are being definitively treated by surgery or radiation together with chemotherapy.…”