Efficacy and Safety of Combined Androgen Deprivation Therapy (ADT) and Docetaxel Compared with ADT Alone for Metastatic Hormone-Naive Prostate Cancer: A Systematic Review and Meta-Analysis

ObjectiveProstate cancer is the most common nonskin cancer and second most common cause of cancer mortality in older men in the United States (USA) and Western Europe. Androgen-deprivation therapy alone (ADT) remains the first line of treatment in most cases, for metastatic disease. We performed a systematic review and meta-analysis of all randomized controlled trials (RCT) that compared the efficacy and adverse events profile of a chemohormonal therapy (ADT ± docetaxel) for metastatic hormone-naive prostate cancer (mHNPC).MethodsSeveral databases were searched, including MEDLINE, EMBASE, LILACS, and CENTRAL. The primary endpoint was overall survival. Data extracted from the studies were combined by using the hazard ratio (HR) or risk ratio (RR) with their corresponding 95% confidence intervals (95% CI).ResultsThe final analysis included 3 trials comprising 2,264 patients (mHNPC). Patients who received the chemohormonal therapy had a longer clinical progression-free survival interval (HR = 0.64; 95% CI: 0.55 to 0.75; p2 = 0.64; df = 1 [p = 0.42]; I2 = 0%). The biochemical progression-free survival (bPFS) also was higher in patients treated with ADT plus docetaxel (HR = 0.63; 95% CI: 0.57 to 0.69; p2 = 0.48; df = 2 [p = 0.79]; I2 = 0%). Finally, the combination of ADT with docetaxel showed a superior overall survival (OS) compared with ADT alone (HR = 0.73; 95% CI: 0.64 to 0.84; p2 = 3.84; df = 2 [p = 0.15]; I2 = 48%). A random-effects model analysis was performed, and the results remained favorable to the use of ADT plus docetaxel (HR = 0.73; 95% CI: 0.60 to 0.89; p = 0.002). In the final combined analysis of the high-volume disease patients, the use of the combination therapy also favored an increased overall survival (HR = 0.67; 95% CI: 0.54 to 0.83; p = 0.0003). Regarding adverse events and severe toxicity (grade ≥3), the group receiving the combined therapy had higher rates of neutropenia, febrile neutropenia and fatigue.ConclusionThe combination of ADT with docetaxel improved the clinical progression-free survival, bPFS and OS of patients with mHNPC. A superior OS was seen especially for patients with metastatic and high-volume disease. This contemporary combination therapy may now be offered as a first-line treatment for selected patients.1. 研究目的：前列腺癌是美国（USA）及西欧老年男性最常见的非皮肤恶性肿瘤，亦是第二大癌症相关死亡病因。仅采用雄激素剥夺疗法（Androgen-deprivation therapy, ADT）仍是多数转移性前列腺癌患者的一线治疗方案。本研究针对比较化学内分泌治疗（ADT±多西他赛）用于转移性去势敏感性前列腺癌（metastatic hormone-naive prostate cancer, mHNPC）的疗效与不良事件特征的所有随机对照试验（randomized controlled trials, RCT）开展了系统评价与Meta分析。 2. 研究方法：本研究检索了MEDLINE、EMBASE、LILACS及CENTRAL等多个数据库。本研究的主要终点为总生存期。采用风险比（hazard ratio, HR）或相对危险度（risk ratio, RR）及其对应的95%置信区间（95% confidence intervals, 95% CI）合并各研究数据。 3. 研究结果：最终分析共纳入3项试验，共计2264例mHNPC患者。接受化学内分泌治疗的患者临床无进展生存期更长（HR=0.64；95%CI：0.55~0.75；p²=0.64；自由度df=1[p=0.42]；I²=0%）。采用ADT联合多西他赛治疗的患者，其生化无进展生存期（biochemical progression-free survival, bPFS）同样更优（HR=0.63；95%CI：0.57~0.69；p²=0.48；df=2[p=0.79]；I²=0%）。相较于单纯ADT治疗，ADT联合多西他赛方案可显著改善患者总生存期（overall survival, OS）（HR=0.73；95%CI：0.64~0.84；p²=3.84；df=2[p=0.15]；I²=48%）。采用随机效应模型进行分析，结果仍支持ADT联合多西他赛的治疗方案（HR=0.73；95%CI：0.60~0.89；p=0.002）。针对高瘤负荷患者的合并分析显示，联合治疗同样可提升患者总生存期（HR=0.67；95%CI：0.54~0.83；p=0.0003）。在不良事件与重度毒性（3级及以上）方面，联合治疗组患者的中性粒细胞减少症、发热性中性粒细胞减少症及疲劳发生率更高。 4. 研究结论：ADT联合多西他赛可改善mHNPC患者的临床无进展生存期、生化无进展生存期及总生存期，在转移性高瘤负荷患者中总生存期获益尤为显著。该新型联合治疗方案可作为特定人群的一线治疗选择。