Pleiotropic effects of heparins: does anticoagulant treatment increase survival in cancer patients?

Abstract

The association between venous thromboembolism (VTE) and cancer has been recognized for more than 100 years. Numerous studies have been performed to investigate strategies to decrease VTE incidence and to establish whether treating VTE impacts cancer progression and overall survival. Accordingly, it is important to understand the role of the hemostatic system in tumorigenesis and progression, as there is abundant evidence associating it with cell survival and proliferation, tumor angiogenesis, invasion, and dissemination, and metastasis formation. In attempts to further the scientific evidence, several studies examine survival benefits in cancer patients treated with anticoagulant therapy, specifically treatment with vitamin K antagonists, unfractionated heparin, and low-molecular-weight heparin. Several studies and meta-analyses have been conducted with a special focus on brain tumors. However, no definitive conclusions have been obtained, and more well-designed clinical trials are needed.

SEOM clinical guideline of venous thromboembolism (VTE) and cancer (2019)

“…Different clinical trials designed to study the prevention role of anticlotting treatments in the progression or relapse of VTE in cancer patients, which confirmed a potential survival benefit, larger than the one expected from VTE-risk reduction [82].…”

Unfractionated and Low Molecular Weight Heparin Reduce Platelet Induced Epithelial-Mesenchymal Transition in Pancreatic and Prostate Cancer Cells

“…Stem cell properties can apparently support tumor cell survival, extravasation, and finally seeding in a distant organ and make the inefficient process of metastasis more efficient. Nonetheless the positive clinical effects of heparin for cancer patients beyond anticoagulation are far from being clear since several prospective trials could determine a heparin related pro-survival benefit whereas other trials could not ascertain any beneficial outcomes [ 32 , 33 , 59 , 60 ]. Obviously, patients at an early stage of disease seem to profit from heparin administration, in contrast, cancer patients at a late stage with severe progression do not benefit from heparin treatment.…”

“…Therefore, cancer patients are routinely treated with low-molecular-weight heparin (LMWH) to prevent cardiovascular events. Besides the anticoagulant properties, some clinical trials also revealed prosurvival effects of heparin whereas other trials could not substantiate an impact of heparin on patients’ survival [ 32 , 33 , 34 , 35 ]. Notwithstanding, in several in vitro approaches, a multitude of antimetastatic effects for heparin became apparent including blockade of adhesion receptors (like P-and L-selectin or integrin α IIb β III ) or of heparanase, which is expressed by different tumor entities [ 36 , 37 ].…”

Necuparanib, A Multitargeting Heparan Sulfate Mimetic, Targets Tumor and Stromal Compartments in Pancreatic Cancer

“…Heparins and other anticoagulants have been prescribed to oncology patients for decades to prevent venous thromboembolism (VTE), a comorbidity of cancer. As the hemostatic system has also been shown to play a role in tumor development and progression, multiple clinical trials have examined whether heparin therapy adds to the efficacy of chemotherapeutics beyond VTE prevention; although there has been some evidence of benefit, dosing has been limited due to heparin's anticoagulant activity (41). Necuparanib was designed, in part, to build upon the clinical benefit of heparin therapy, with reduced anticoagulation properties to enable higher dosing levels.…”