Antithrombotic Therapy in Cancer

There is increasing interest in the potential role of antithrombotic agents in the management of cancer patients. Low molecular weight heparins (LMWHs) have generated particular excitement because they have been validated in both the prevention and the treatment of thromboembolic disease in patients with malignancy. Retrospective analyses of clinical trials in which LMWH had been used to treat established thrombosis in cancer patients have suggested a survival advantage for the treated groups. The studies that formed the basis of these meta-analyses were not primarily designed to assess cancer outcomes, and little was known about the distribution of prognostic variables between groups of patients treated with different antithrombotic therapies in these trials. Thus, clear conclusions about the potential benefits of LMWH and long-term survival could not be established. Earlier this year, the first prospective, randomized, double-blind study designed to assess the potential value of long-term LMWH therapy to improve survival in cancer patients was reported. The study failed to achieve the predefined difference in mortality between groups of patients randomly assigned to placebo or LMWH, but did suggest a striking survival advantage for heparin treatment in a subgroup of patients with good-prognosis tumors. More recently, a second clinical trial in patients with small-cell lung carcinoma—again with random assignment to standard care with combination chemotherapy alone compared with LMWH plus standard care—showed advantages in terms of progression-free and overall survival for patients who received LMWH for 18 weeks. In this issue of the Journal of Clinical Oncology, two additional studies report on the potential benefits of longer term LMWH therapy for cancer patients. The first, by Lee et al, is the long-term follow-up patients in the Comparison of Low Molecular Weight Heparin Versus Oral Anticoagulant Therapy for Long Term Anticoagulation in Cancer Patients With Venous Thromboembolism (CLOT) trial. This study randomly assigned 676 patients to oral anticoagulant therapy or LMWH therapy for 6 months for treatment of acute, symptomatic, proximal vein thrombosis. The primary end point of the study was to determine rates of recurrent thromboembolic disease, but included a secondary end point of survival at 1 year. This trial showed that there is a survival benefit with LMWH therapy in the subgroup of patients without evident metastatic disease at the time of random assignment to treatment. A second study, by Klerk et al, showed the value of up to 6 weeks of LMWH therapy compared with placebo in patients with advanced malignant disease. A variety of tumor types were included in this study and for both the overall trial population and for a subgroup of patients with better prognosis at the time of random assignment, LMWH therapy was associated with a significant survival advantage. How might these interesting observations be explained? It could be that the administration of antithrombotic therapy to patients in these trials reduced the frequency of fatal pulmonary embolism. However, in the study by Klerk et al, the benefits of LMWH therapy were seen for months and years after the period of active administration (indeed, there was no obvious survival advantage in the acute treatment period), suggesting the mechanism is not purely an antithrombotic effect. This feature was also seen in other studies in which LMWH therapy was given to patients without underlying thromboembolic disease. It is more likely that the mechanism of this long-term benefit can be explained through effects on tumor cell biology. In this regard, there has been extensive evaluation of the potential role that the coagulation proteases play in tumorstromal interactions at a molecular level. Tissue factor (TF) is frequently overexpressed as a result of progression from benign to malignant phenotype, and that overexpression is associated with aggressive behavior and poor outcome in pancreatic cancer, among other tumors. TF, the physiological initiator of blood coagulation, is also known to have a strong structural homology with the class II cytokine receptor family. Identification of filamin A, as an JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 23 NUMBER 10 APRIL 1 2005