Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial.
Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial.
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DOI：
10.1016/s0140-6736(15)01037-5
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发表时间：
2016-03-19
期刊：
影响因子：
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通讯作者：
STAMPEDE investigators
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作者：
James ND;Sydes MR;Clarke NW;Mason MD;Dearnaley DP;Spears MR;Ritchie AW;Parker CC;Russell JM;Attard G;de Bono J;Cross W;Jones RJ;Thalmann G;Amos C;Matheson D;Millman R;Alzouebi M;Beesley S;Birtle AJ;Brock S;Cathomas R;Chakraborti P;Chowdhury S;Cook A;Elliott T;Gale J;Gibbs S;Graham JD;Hetherington J;Hughes R;Laing R;McKinna F;McLaren DB;O'Sullivan JM;Parikh O;Peedell C;Protheroe A;Robinson AJ;Srihari N;Srinivasan R;Staffurth J;Sundar S;Tolan S;Tsang D;Wagstaff J;Parmar MK;STAMPEDE investigators
自20世纪40年代以来，长期激素治疗一直是晚期前列腺癌的标准治疗。STAMPEDE是一项采用多组、多阶段平台设计的随机对照试验。它招募了高风险，局部晚期，转移性或复发性前列腺癌的男性，他们正在开始一线长期激素治疗。我们报告了三项研究比较的主要生存结果，这些研究测试了在标准治疗基础上添加唑来膦酸、多西他赛或其联合治疗与单独使用标准治疗的比较。标准治疗为激素治疗至少2年; 2011年11月之前，鼓励N0M0疾病男性接受放疗，然后强制要求;淋巴结阳性非转移性（N + M0）疾病男性可选择放疗。分层随机化（通过最小化）将男性以2：1：1：1的比例分配至仅标准治疗组（仅SOC;对照组）、标准治疗+唑来膦酸组（SOC + ZA）、标准治疗+多西他赛组（SOC + Doc）或标准治疗+唑来膦酸+多西他赛组（SOC + ZA + Doc）。 唑来膦酸（4 mg）给药6个3周周期，然后4周1次，直至2年，多西他赛（75 mg/m2）给药6个3周周期，泼尼松龙每日10 mg。未对治疗分配设盲。主要结果指标是总生存率。研究组与对照组的成对比较在单侧α为2.5%时具有90%的把握度，风险比（HR）为0.75，需要大约400例对照组死亡。采用标准对数秩型方法对至事件发生时间数据进行统计分析，风险比（HR）和95% CI来自校正后的考克斯模型。本试验在www.example.com（NCT 00268476）和www.example.com（ISRCTN78818544）上注册。2962名男性在2005年10月5日至2013年3月31日期间被随机分配到四组。中位年龄为65岁（IQR 60 - 71）。1817例（61%）男性患有M+疾病，448例（15%）患有N +/X M0，697例（24%）患有N0M0。165例（6%）男性既往接受过局部治疗，中位前列腺特异性抗原为65 ng/mL（IQR 23 - 184）。中位随访时间为43个月（IQR 30 - 60）。对照组有415例死亡（347例[84%]前列腺癌）。中位总生存期为：仅SOC组71个月（IQR 32至未达到），SOC + ZA组未达到（32至未达到）（HR 0·94，95% CI 0·79 - 1·11; p = 0·450），SOC + Doc组81个月（41至未达到）（0·78，0·66 - 0·93; p = 0·006），SOC + ZA + Doc组76个月（39至未达到）（0·82，0·69 - 0·97; p = 0·022）。 在预先规定的亚组中，没有证据表明治疗效果（任何治疗）存在异质性。399例（32%）接受SOC治疗的患者、197例（32%）接受SOC + ZA治疗的患者、288例（52%）接受SOC + Doc治疗的患者和269例（52%）接受SOC + ZA + Doc治疗的患者报告了3 - 5级不良事件。 唑来膦酸未显示出生存改善的证据，不应作为该人群标准治疗的一部分。在长期激素治疗开始时给予多西他赛化疗，显示出生存率提高伴随不良事件增加的证据。多西他赛治疗应该成为开始长期激素治疗的适当健康男性护理标准的一部分。英国癌症研究、医学研究理事会、诺华、赛诺菲-安万特、辉瑞、杨森、安斯泰来、NIHR临床研究网络、瑞士临床癌症研究集团。
Long-term hormone therapy has been the standard of care for advanced prostate cancer since the 1940s. STAMPEDE is a randomised controlled trial using a multiarm, multistage platform design. It recruits men with high-risk, locally advanced, metastatic or recurrent prostate cancer who are starting first-line long-term hormone therapy. We report primary survival results for three research comparisons testing the addition of zoledronic acid, docetaxel, or their combination to standard of care versus standard of care alone. Standard of care was hormone therapy for at least 2 years; radiotherapy was encouraged for men with N0M0 disease to November, 2011, then mandated; radiotherapy was optional for men with node-positive non-metastatic (N+M0) disease. Stratified randomisation (via minimisation) allocated men 2:1:1:1 to standard of care only (SOC-only; control), standard of care plus zoledronic acid (SOC + ZA), standard of care plus docetaxel (SOC + Doc), or standard of care with both zoledronic acid and docetaxel (SOC + ZA + Doc). Zoledronic acid (4 mg) was given for six 3-weekly cycles, then 4-weekly until 2 years, and docetaxel (75 mg/m2) for six 3-weekly cycles with prednisolone 10 mg daily. There was no blinding to treatment allocation. The primary outcome measure was overall survival. Pairwise comparisons of research versus control had 90% power at 2·5% one-sided α for hazard ratio (HR) 0·75, requiring roughly 400 control arm deaths. Statistical analyses were undertaken with standard log-rank-type methods for time-to-event data, with hazard ratios (HRs) and 95% CIs derived from adjusted Cox models. This trial is registered at ClinicalTrials.gov (NCT00268476) and ControlledTrials.com (ISRCTN78818544). 2962 men were randomly assigned to four groups between Oct 5, 2005, and March 31, 2013. Median age was 65 years (IQR 60–71). 1817 (61%) men had M+ disease, 448 (15%) had N+/X M0, and 697 (24%) had N0M0. 165 (6%) men were previously treated with local therapy, and median prostate-specific antigen was 65 ng/mL (IQR 23–184). Median follow-up was 43 months (IQR 30–60). There were 415 deaths in the control group (347 [84%] prostate cancer). Median overall survival was 71 months (IQR 32 to not reached) for SOC-only, not reached (32 to not reached) for SOC + ZA (HR 0·94, 95% CI 0·79–1·11; p=0·450), 81 months (41 to not reached) for SOC + Doc (0·78, 0·66–0·93; p=0·006), and 76 months (39 to not reached) for SOC + ZA + Doc (0·82, 0·69–0·97; p=0·022). There was no evidence of heterogeneity in treatment effect (for any of the treatments) across prespecified subsets. Grade 3–5 adverse events were reported for 399 (32%) patients receiving SOC, 197 (32%) receiving SOC + ZA, 288 (52%) receiving SOC + Doc, and 269 (52%) receiving SOC + ZA + Doc. Zoledronic acid showed no evidence of survival improvement and should not be part of standard of care for this population. Docetaxel chemotherapy, given at the time of long-term hormone therapy initiation, showed evidence of improved survival accompanied by an increase in adverse events. Docetaxel treatment should become part of standard of care for adequately fit men commencing long-term hormone therapy. Cancer Research UK, Medical Research Council, Novartis, Sanofi-Aventis, Pfizer, Janssen, Astellas, NIHR Clinical Research Network, Swiss Group for Clinical Cancer Research.