Background Coagulation 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 methods We 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. Results In 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. Conclusion LMWH 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.

中文翻译：

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小细胞肺癌标准治疗之外使用低分子量肝素依诺肝素的随机 III 期试验：RASTEN 试验。


背景凝血激活和静脉血栓栓塞（VTE）是恶性疾病的标志，也是癌症发病和死亡的主要原因。低分子量肝素 (LMWH) 的凝血抑制可通过预防 VTE 和肿瘤进展来改善小细胞肺癌 (SCLC) 患者的生存率；然而，需要对明确的患者群体进行随机试验才能获得结论性数据。 RASTEN 的目的是研究 LMWH 依诺肝素对同质 SCLC 患者群体的生存效果。患者和方法 我们进行了一项随机、多中心、开放标签试验，研究在新诊断 SCLC 患者的标准治疗中添加超预防剂量 (1 mg/kg) 的依诺肝素。主要结局是总生存期（OS），次要结局是无进展生存期（PFS）、VTE 发生率和出血事件。结果 在 RASTEN 中，390 名患者在 8 年期间（2008-2016）被随机分配，其中 186 名和 191 名患者分别纳入 LMWH 和对照组的最终分析。我们没有发现证据表明添加依诺肝素会导致 OS 或 PFS 存在差异[风险比 (HR)，1.11； 95%置信区间（CI）0.89-1.38； P = 0.36，HR，1.18； 95% CI 0.95-1.46； P = 0.14，分别]。对局限性和广泛性疾病患者的亚组分析并未显示依诺肝素可降低死亡率。 LMWH 组的 VTE 发生率显着降低（HR，0.31；95% CI 0.11-0.84；P = 0.02）。 LMWH 治疗组的出血事件更为频繁，但双臂均发生致命性出血。 结论 尽管使用超预防剂量并且导致 VTE 发生率显着降低，但标准治疗之外的 LMWH 依诺肝素并未改善 SCLC 患者的 OS。在 SCLC 患者的治疗中，一般不推荐添加 LMWH，并且需要在癌症患者中使用 VTE 和 LMWH 相关出血的预测生物标志物。