Randomized phase III trial of low-molecular-weight heparin enoxaparin in addition to standard treatment in small-cell lung cancer: the RASTEN trial

Abstract

BackgroundCoagulation activation and venous thromboembolism (VTE) are hallmarks of malignant disease and represent a major cause of morbidity and mortality in cancer. Coagulation inhibition with low-molecular-weight heparin (LMWH) may improve survival specifically in small-cell lung cancer (SCLC) patients by preventing VTE and tumor progression; however, randomized trials with well-defined patient populations are needed to obtain conclusive data. The aim of RASTEN was to investigate the survival effect of LMWH enoxaparin in a homogenous population of SCLC patients.Patients and methodsWe carried out a randomized, multicenter, open-label trial to investigate the addition of enoxaparin at a supraprophylactic dose (1 mg/kg) to standard treatment in patients with newly diagnosed SCLC. The primary outcome was overall survival (OS), and secondary outcomes were progression-free survival (PFS), incidence of VTE and hemorrhagic events.ResultsIn RASTEN, 390 patients were randomized over an 8-year period (2008–2016), of whom 186 and 191 were included in the final analysis in the LMWH and control arm, respectively. We found no evidence of a difference in OS or PFS by the addition of enoxaparin [hazard ratio (HR), 1.11; 95% confidence interval (CI) 0.89–1.38; P = 0.36 and HR, 1.18; 95% CI 0.95–1.46; P = 0.14, respectively]. Subgroup analysis of patients with limited and extensive disease did not show reduced mortality by enoxaparin. The incidence of VTE was significantly reduced in the LMWH arm (HR, 0.31; 95% CI 0.11–0.84; P = 0.02). Hemorrhagic events were more frequent in the LMWH-treated group but fatal bleedings occurred in both arms.ConclusionLMWH enoxaparin in addition to standard therapy did not improve OS in SCLC patients despite being administered at a supraprophylactic dose and despite resulting in a significant reduction in VTE incidence. Addition of LMWH cannot be generally recommended in the management of SCLC patients, and predictive biomarkers of VTE and LMWH-associated bleeding in cancer patients are warranted.

Glycosaminoglycans as Tools to Decipher the Platelet Tumor Cell Interaction: A Focus on P-Selectin

“…These effects were reflected in some clinical trials which exhibited an increased survival for heparin treated cancer patients [19,20]. Nonetheless, several recent clinical trials could not validate a potential survival benefit for heparinized patients [21,22]. Furthermore, direct oral anticoagulants (DOACs) are currently investigated for VTE prevention in cancer patients as compared with LMWHs.…”

“…The glycosaminoglycan heparin, which is routinely administered to cancer patients to prevent venous thrombosis, is currently critically considered to prolong patients' survival by attenuation of tumor metastasis [17,18]. A beneficial effect of low molecular weight heparin (LMWH) on cancer progression and patients' survival has been observed in clinical trials [19,20], whereas other studies could not identify a significant survival benefit [21,22]. For heparin, various different mechanisms have been identified which interfere with the metastatic spread of tumor cells such as inhibition of adhesion receptors or enzymes such as heparanase [23,24].…”

Low-molecular-weight heparin adherence and effects on survival within a randomised phase III lung cancer trial (RASTEN)

“…A complete description of the study design of RASTEN has been previously reported [7]. In brief, 377 patients were randomised 1:1 between a control arm receiving standard therapy and a treatment arm receiving standard therapy with the addition of enoxaparin.…”

“…We conducted an international, randomised phase 3 trial of the low-molecular-weight heparin (LMWH) enoxaparin as an adjunct to standard treatment in patients with SCLC (RASTEN trial), the results of which have been presented elsewhere [7]. The primary aim of the study was to determine whether the addition of LMWH could improve survival in SCLC.…”

Update in thrombosis and hemostasis: ASH meeting 2018

“…Different risk assessment models have been established to identify cancer patients at high risk for VTE ( [11][12][13]; Table 1). VTE prophylaxis in ambulatory cancer patients with LMWH using either a prophylactic or intermediate therapeutic dose was assessed in general cancer patients at high risk (Khorana score ≥3) or in specific cancer entities [14,15]. In line with the largest available meta-analysis [16], LMWH prophylaxis can significantly reduce the number of VTEs compared to no prophylaxis, but increases the bleeding rate and does not affect overall survival.…”