Administration of low molecular weight heparins for prolonging the survival of patients with cancer

Abstract

Thromboembolism represents one of the most common causes of mortality and morbidity in cancer patients, and thromboembolic events occur more often in patients with biologically more aggressive malignant disease. Therefore, low molecular weight heparins (LMWHs) are routinely administered to cancer patients. Importantly, in addition to the prophylactic activity against thromboembolism, LMWHs seem to decrease mortality in these patients. Improved clinical prognosis is independent of the antithrombotic efficacy, since vitamin K antagonists do not improve patient survival, and non-anticoagulant heparins exhibit a similar anti-cancer effect. This protective effect is primarily related to the prevention of spreading of the cancer through metastases. The mechanisms responsible for heparin-dependent inhibition of metastases comprise: inhibition of integrins, restraint of P-and L-selectin-mediated interactions of the platelets with circulating neoplastic cells, silencing of the chemokine CXCL12/CXCR4 axis, inhibition of heparanase activity, inhibition of neoangiogenesis within the tumour, and reduced local generation of thrombin. A combined effect of the above-described mechanisms is also possible. Although at the moment cancer patients are not recommended routine administration of LMWHs for survival improvement, such a recommendation might be expected in the future. It is possible that for this purpose, instead of currently available agents, some novel heparins or similarly structured chemical compounds will be used. In the FAMOUS trial, carried out on a subgroup of patients with good clinical prognosis, administration of LMWH significantly improved their survival [17]. In the MALT study, administration of LMWH resulted in improved survival in cancer patients with advanced malignancy with a life expectancy of more than six months [29]. Similarly, cancer patients with good clinical prognosis benefited from LMWH administration in the CLOT study [19]. Also, a post-hoc analysis of the results of the PROTECHT study revealed improved survival, but only in patients responding to chemotherapy [30], while this beneficial effect was not seen in those not responding to the treatment [31]. On the other hand, such an anti-cancer protective effect was not found in other clinical trials assessing the survival benefit of LMWH administration. However, these trials examined patients with an advanced malignancy and poor clinical prognosis [32,33].Analysis of the above-mentioned trials suggests that in selected groups of cancer patients LMWHs improve survival irrespective of the antithrombotic efficacy of the drug, since vitamin K antagonists did not improve clinical prognosis [19]. Besides, this anti-cancer effect did not result from an inhibition of primary tumours, but rather from anti-metastatic activity [34,35]. Consequently, two published meta-analyses [36,37] suggest that LMWHs can improve the survival of cancer patients, primarily those with non-metastatic disease. It is also possible that at least some patients with advance...