Metformin in Chemotherapy-naive Castration-resistant Prostate Cancer: A Multicenter Phase 2 Trial (SAKK 08/09)
Metformin in Chemotherapy-naive Castration-resistant Prostate Cancer: A Multicenter Phase 2 Trial (SAKK 08/09)
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DOI：
10.1016/j.eururo.2013.12.057
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发表时间：
2014-09-01
期刊：
影响因子：
23.4
通讯作者：
Gillessen, Silke
中科院分区：
文献类型：
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作者：
Rothermundt, Christian;Hayoz, Stefanie;Gillessen, Silke
背景资料：有证据表明二甲双胍与改善前列腺癌（PCa）相关结局有关。目的：评估二甲双胍对去势抵抗性前列腺癌（CRPC）患者的治疗以及治疗对无进展生存期（PFS）和PSA的影响。倍增时间（PSA DT）。设计、设置和参与者：2010年12月至2011年12月期间，来自10家瑞士中心的44名进行性转移性CRPC男性患者被纳入该单臂II期试验。干预：患者接受二甲双胍1000 mg每日两次治疗，直至疾病进展。结果测量和统计分析：主要终点是12周时无疾病进展。采用Simon两阶段优化设计。在5%的显著性水平和90%的把握度下，44例患者需要在12 wk时测试PFS = 35%（H-1）.结果和局限性：36%的患者在12 wk时无进展，9.1%的患者在24 wk时无进展，在2例患者中证实了>= 50%的前列腺特异性抗原（PSA）下降。在23例患者（52.3%）中，我们观察到开始二甲双胍治疗后PSA DT延长。稳态模型评估指数从基线到12周下降了26%，表明胰岛素敏感性改善。胰岛素样生长因子1和胰岛素样生长因子结合蛋白3从基线到12周有显著变化。样本量和缺乏一个对照组是本试验的局限性，因此分析是explorative.Conclusions：二甲双胍治疗是安全的非糖尿病患者，它产生客观的PSA反应，并可能导致疾病稳定。二甲双胍在前列腺癌中的活性，沿着其低成本、有利的毒性特征和对代谢参数的积极作用，表明二甲双胍作为治疗前列腺癌患者的进一步研究是有意义的。我们发现一些患者的疾病稳定和前列腺特异性抗原倍增时间延长，以及对代谢参数的影响。(C)2013年欧洲泌尿外科协会。由Elsevier B出版。V.保留所有权利。
Background: There is evidence linking metformin to improved prostate cancer (PCa)-related outcomes.Objective: To evaluate treatment with metformin in patients with castration-resistant PCa (CRPC) and the effect of the treatment on progression-free survival (PFS) and PSA doubling time (PSA DT).Design, setting, and participants: Forty-four men with progressive metastatic CRPC from 10 Swiss centers were included in this single-arm phase 2 trial between December 2010 and December 2011.Intervention: Patients received metformin 1000 mg twice daily until disease progression. Outcome measurements and statistical analysis: The primary end point was the absence of disease progression at 12 wk. Simon two-stage optimal design was applied. With a 5% significance level and 90% power, 44 patients were required to test PFS at 12 wk = 35% (H-1).Results and limitations: Thirty-six percent of patients were progression-free at 12 wk, 9.1% were progression-free at 24 wk, and in two patients a confirmed >= 50% prostate-specific antigen (PSA) decline was demonstrated. In 23 patients (52.3%) we observed a prolongation of PSA DT after starting metformin. The homeostatic model assessment index fell by 26% from baseline to 12 wk, indicating an improvement in insulin sensitivity. There was a significant change in insulin-like growth factor-1 and insulin-like growth factor binding protein 3 from baseline to 12 wk. Sample size and lack of a control arm are the limitations of this trial; analyses are therefore exploratory.Conclusions: Treatment with metformin is safe in nondiabetic patients, and it yields objective PSA responses and may induce disease stabilization. The activity of metformin in PCa, along with its low cost, favorable toxicity profile, and positive effect on metabolic parameters, suggests that further investigation of metformin as therapy for patients with PCa is of interest.Patient summary: In this trial we assessed the use of the diabetes mellitus drug metformin in patients with advanced prostate cancer. We found disease stabilization and prolongation of prostate-specific antigen doubling time in some patients as well as effects on metabolic parameters. (C) 2013 European Association of Urology. Published by Elsevier B. V. All rights reserved.