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

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Kaplan-Meier curves for the OS of clinical variables of metastatic SCLC patients.

<p>(A) age <70 yrs vs. ≥70yrs (p = 0.001), (B) ECOG PS 0–1 vs. ECOG PS >1 (p<0.001), (C) male (vs. female; p = 0.021), and (D) radiation therapy (RT) vs. patients not treated with RT (p<0.001).</p

Kaplan-Meier curves for the OS of metastatic SCLC patients. Effect of FDA approved drugs.

<p>(A) Aspirin (vs. control; p = 0.225), (B) doxazosin and prazosin (vs. control; p<0.479), (C) selective serotonin reuptake inhibitors (SSRIs) (vs. control; p = 0.195), (D) statin treatment vs. control (p = 0.002) and, (E) clomipramine (a tricyclic antidepressant; TCA) vs. control had no effect on OS.</p