ABSTRACT
The close relationship between hypercoagulability and cancer was fi rst identifi ed in 1865 (1), and has been extensively studied since (2). Heparin is a highly sulfated glycosaminoglycan that has been in clinical use as an anticoagulant for many years (3-5). Many retrospective
analyses of clinical data implicate heparin in improving survival of cancer patients (6-10), as do studies using various mouse models of cancer (see below). In contrast, clinical trials using oral vitamin K antagonists, another type of anticoagulant, showed no signifi cant improvement of survival in most cancers (11-14). This suggests that the anticoagulant effects of heparin are not primarily responsible for the antimetastatic effect. Based on encouraging observations with heparin treatment, several recent prospective clinical trials have been performed to evaluate this phenomenon (14-18). The CLOT clinical trial, in which patients with a solid tumor and venous thromboembolism were treated with dalteparin or a vitamin K antagonist, demonstrated no effect on survival (15). However, analysis of a subset of patients who were metastasis-free at the beginning of the trial demonstrated a signifi cant increase in survival with dalteparin in that population (14). The Fragmin Advanced Malignancy Outcome Study (FAMOUS) trial evaluated the effect of the low-molecular-weight heparin (LMWH) dalteparin on the survival of patients with advanced carcinoma (16). No improvement in survival was seen in patients with an originally poor prognosis, but those with a better prognosis demonstrated a statistically signifi cant increase in survival. A trial of patients with small cell lung cancer also demonstrated increased survival in patients who were given dalteparin in combination with traditional chemotherapy, compared to patients who received traditional chemotherapy alone, regardless of the initial stage of the patients (17). Finally, the Malignancy and Low-Molecular-Weight Heparin Therapy (MALT) trial of patients with advanced solid tumors demonstrated an improvement in survival in patients who received the LMWH nadroparin compared to those who received a placebo (18).
