From Bench to Bedside: Attempt to Evaluate Repositioning of Drugs in the Treatment of Metastatic Small Cell Lung Cancer (SCLC)

Backgrounds
Based on in vitro data and results of a recent drug repositioning study, some medications approved by the FDA for the treatment of various non-malignant disorders were demonstrated to have anti-SCLC activity in preclinical models. The aim of our study is to confirm whether use of these medications is associated with survival benefit.
Methods
Consecutive patients with pathologically confirmed, stage 4 SCLC were analyzed in this retrospective study. Patients that were prescribed statins, aspirin, clomipramine (tricyclic antidepressant; TCA), selective serotonin reuptake inhibitors (SSRIs), doxazosin or prazosin (α1-adrenergic receptor antagonists; ADRA1) were identified.
Results
There were a total of 876 patients. Aspirin, statins, SSRIs, ADRA1, and TCA were administered in 138, 72, 20, 28, and 5 cases, respectively. A statistically significant increase in median OS was observed only in statin-treated patients when compared to those not receiving any of the aforementioned medications (OS, 8.4 vs. 6.1 months, respectively; p = 0.002). The administration of SSRIs, aspirin, and ADRA1 did not result in a statistically significant OS benefit (median OS, 8.5, 6.8, and 6.0 months, respectively). The multivariate Cox model showed that, besides age and ECOG PS, radiotherapy was an independent survival predictor (Hazard Ratio, 2.151; 95% confidence interval, 1.828–2.525; p <0.001).
Conclusions
Results of drug repositioning studies using only preclinical data or small numbers of patients should be treated with caution before application in the clinic. Our data demonstrated that radiotherapy appears to be an independent survival predictor in stage 4 SCLC, therefore confirming the results of other prospective and retrospective studies.

研究背景
基于体外实验数据与近期一项药物重定位研究的结果，若干获美国食品药品监督管理局（Food and Drug Administration, FDA）批准用于治疗多种非恶性疾病的药物，在临床前模型中被证实具有抗小细胞肺癌（Small Cell Lung Cancer, SCLC）活性。本研究旨在明确上述药物的使用是否与生存获益相关。

研究方法
本项回顾性研究连续纳入经病理确诊的IV期小细胞肺癌患者进行分析，并筛选出接受以下药物治疗的受试者：他汀类药物、阿司匹林、氯米帕明（三环类抗抑郁药, TCA）、选择性5-羟色胺再摄取抑制剂（SSRIs）、多沙唑嗪或哌唑嗪（α1肾上腺素能受体拮抗剂, ADRA1）。

研究结果
本研究共纳入876例患者。其中接受阿司匹林、他汀类药物、SSRIs、ADRA1及TCA治疗的病例数分别为138例、72例、20例、28例及5例。与未接受上述任一药物治疗的患者相比，仅他汀类药物治疗组患者的中位总生存期（Overall Survival, OS）存在统计学意义的显著延长（中位OS分别为8.4个月与6.1个月，p=0.002）。接受SSRIs、阿司匹林及ADRA1治疗并未获得具有统计学意义的OS获益（中位OS分别为8.5个月、6.8个月与6.0个月）。多因素Cox模型分析显示，除年龄与ECOG体能状态评分（Eastern Cooperative Oncology Group Performance Status, ECOG PS）外，放疗是独立的生存预测因子（风险比=2.151；95%置信区间=1.828~2.525；p<0.001）。

研究结论
仅基于临床前数据或小样本患者队列的药物重定位研究结果，在应用于临床实践前应谨慎评估。本研究数据证实，放疗是IV期小细胞肺癌患者的独立生存预测因子，这一结果与其他前瞻性及回顾性研究的结论相符。