Low Molecular Weight Heparins Prolong Survival in Cancer Patients

NEW YORK APR 15, 2005 (Reuters Health) - Low molecular weight heparins (LMWH) appear to have direct anti-cancer activity, especially in patients with nonmetastatic tumors and patients with a predicted survival that exceeds 6 months, according to two reports in the April 1st issue of the Journal of Clinical Oncology.

Previous research has suggested a survival advantage when LMWHs are administered to cancer patients, but the data were inconclusive, Dr. Clara P. W. Klerk of the University of Amsterdam and her team note.

To further investigate, they conducted a randomized, double-blind, placebo-controlled study of 302 patients with metastasized or locally advanced solid tumors and no venous thromboembolism.

Active treatment consisted of subcutaneous injections of nadroparin, twice daily for 14 days then once a day for the next 4 weeks. Metastatic disease was present in approximately 90% of patients.

During mean follow-up of 12 months, median survival was 6.6 months in the placebo group and 8.0 months in the nadroparin group, for a hazard ratio (HR) of 0.75 (p = 0.021).

The advantage was even more pronounced among patients with a life expectancy of 6 months or longer (median survival 9.4 months versus 15.4 months, HR 0.64, p = 0.010).

Risk of major bleeding was not significantly increased.

Dr. Klerk"s group suggests that LMWH "can interfere with angiogenesis, adhesion of cancer cells to vascular endothelium, and invasion."

In the second study, Dr. Mark N. Levine at Henderson Hospital in Hamilton, Ontario, and colleagues conducted a post hoc analysis of data from the CLOT trial (Comparison of Low Molecular Weight Heparin Versus Oral Anticoagulant Therapy for Long Term Anticoagulation in Cancer Patients with Venous Thromboembolism).

Patients with cancer and acute venous thromboembolism (n=602) were randomized to 6 months treatment with dalteparin alone 200 U/kg for 1 month followed by 150 U/kg for 5 months, or dalteparin for 1 week followed by an oral coumarin derivative for 6 months. 

Among the patients without metastases (75 in each group), the probability of death at 12 months was 36% in the coumarin group and 20% in the dalteparin group (HR 0.50, p = 0.03).

Among the 221 patients with metastatic disease assigned to dalteparin and 231 allocated to oral anticoagulant, there was no significant difference according to treatment group (HR 1.1, p = 0.46).

Dr. Levine"s group theorizes that "in patients with disseminated cancer, tumor-related vasculature is sufficiently developed so that an antiangiogenic agent would have minimal impact, whereas impairing the establishment of such vasculature by an antiangiogenic agent could exert an inhibitory effect on tumor growth even beyond the time of drug exposure."

In a related editorial, Dr. Nicholas R. Lemoine at Queen Mary University of London comments that "much work needs to be done to identify the mechanisms involved, but there are already indications that the interface between the coagulation system and the cancer cell will be a rewarding area for cell biology and cancer therapeutics."

SOURCE:

• Journal of Clinical Oncology 2005;23:2119-2120,2123-2135.