Low Molecular Weight Heparin, Therapy With Dalteparin, and Survival in Advanced Cander: The Fragmin Advanced Malignancy Outcome Study (FAMOUS)
Kakkar AK, Levine ML, Kadziola NR, Low V, Patel HK, Rustin G, Thomas M, Quigley M, Willimson RCN. Low molecular weight heparin, therapy with dalteparin, and survival in advanced cancer: The fragmin advanced malignancy outcome study (FAMOUS). JCO 2004;22:1944-1948.
ABSTRACT: Purpose: In experimental systems, interference with coagulation can affect tumor biology. Furthermore, it has been suggested that low molecular weight heparin therapy may prolong survival in patients with cancer. The primary aim of this study was to assess survival at 1 year of patients with advanced cancer. Patients and Methods: Patients with advanced malignancy (N = 385) were randomly assigned to receive either a once-daily subcutaneous injection of dalteparin (5,000 IU), a low molecular weight heparin, or placebo for 1 year. Results: The Kaplan-Meier survival estimates at 1, 2, and 3 years after randomization for patients receiving dalteparin were 46%, 27%, and 21%, respectively, compared with 41%, 18%, and 12% respectively, for patients receiving placebo (P = .19). In an analysis not specified a priori, survival was examined in a subgroup of patients (dalteparin, n = 55; and placebo, n = 47) who had a better prognosis and who were alive 17 months after randomization. In these patients, Kaplan-Meier survival estimates at 2 and 3 years from randomization were significantly improved for patients receiving dalteparin versus placebo (78% v 55% and 60% v 36%, respectively, P #.03). The rates of symptomatic venous thromboembolism were 2.4% and 3.3% for dalteparin and placebo, respectively, with bleeding rates of 4.7% and 2.7%, respectively. Conclusion: Dalteparin administration did not significantly improve 1-year survival rates in patients with advanced malignancy. However, the observed improved survival in a subgroup of patients with a better prognosis suggests a potential modifying effect of dalteparin on tumor biology.
Treating Cancer Patients Without Venous Thromboembolism With Low Molecular Weight Heparin To Improve Survival
Review by Ranjith Shetty, MD
This was the first, randomized, double blind, placebo-controlled trial to assess the efficacy and safety of long-term administration of low molecular weight heparin (LMWH) in cancer patients without underlying thrombosis. The idea was that LMWH might improve survival either by preventing venous thromboembolism or by having a direct anti-tumor effect, or by both mechanisms combined.
Patients with advanced stage III or IV malignant disease of the breast, lung, gastrointestinal tract, pancreas, liver, genitourinary tract, ovary, or uterus were randomly assigned to receive once-daily subcutaneous injections of either 5,000 IU of the LMWH, dalteparin, or placebo (0.9% normal saline). Therapy was scheduled for one year or until the patient died, whichever came first. The primary endpoint was mortality after 1 year of LMWH. Secondary endpoints included rates of symptomatic venous thromboembolic disease and bleeding complications.
374 patients were included in the analysis of the FAMOUS trial. 190 patients received dalteparin, and 184 patients received placebo. Baseline characteristics were similar in both groups.
Survival at 1 year was 46% (95% CI, 39 to 59%) in the dalteparin group and 41% (95% CI, 34 to 49%) in the placebo group (p = 0.19). At 2 years, the survival rate was 27% (95% CI, 20% to 34%) for patients receiving dalteparin versus 18% (95% CI, 11% to 25%) for patients receiving placebo. At 3 years, the survival rate was 21% (95% CI, 14% to 28%) in the dalteparin group and 12% (95% CI, 5% to 19%) in the placebo group. Despite lack of statistical significance, there was a trend toward improved survival in the LMWH group.
A subgroup, which was not defined prior to the study, of 55 patients in the dalteparin group and 47 patients in the placebo group survived beyond 17 months and was subsequently analyzed. The dalteparin group had a significant survival advantage (P = 0.03), with survival estimates at 2 and 3 years of 78% and 60%, respectively, versus 55% and 36% years, respectively. Rates of VTE were low in dalteparin and placebo groups, 2.4% and 3.3%, respectively. Bleeding rates were 4.7% (one major and eight minor bleeds) in the dalteparin group and 2.7% (5 minor bleeds) in the placebo group. The one major bleed was not thought to be because of dalteparin.
This trial did not show a difference in survival at 1 year after randomization between dalteparin and placebo in treatment of patients with advanced cancer without underlying thrombosis. The posthoc analysis of the subgroup of patients with less severe disease who survived beyond 17 months, however, did show a significant survival difference in the dalteparin group as compared to placebo. Though the study was not designed to assess this group, these intriguing results have paved the way for the further investigation of the possible tumor biology-modifying effects that low molecular weight heparins may have in the early stages of malignancy.About Ranjith Shetty, MD: Dr. Shetty completed his internship and residency in internal medicine at Georgetown University. In July of 2007, Dr. Shetty will begin his Cardiology fellowship at the Medical College of Virginia in Richmond, VA. He is currently involved with investigator initiated and multi-center trials at Brigham and Women’s hospital looking at novel anticoagulant treatment strategies for venous thromboembolism, as a Venous Thromboembolism Research Group Fellow.