Vale Claire L, Burdett Sarah, Rydzewska Larysa H M, Albiges Laurence, Clarke Noel W, Fisher David, Fizazi Karim, Gravis Gwenaelle, James Nicholas D, Mason Malcolm D, Parmar Mahesh K B, Sweeney Christopher J, Sydes Matthew R, Tombal Bertrand, Tierney Jayne F
MRC Clinical Trials Unit at UCL, London, UK.
MRC Clinical Trials Unit at UCL, London, UK.
Lancet Oncol. 2016 Feb;17(2):243-256. doi: 10.1016/S1470-2045(15)00489-1. Epub 2015 Dec 21.
Results from large randomised controlled trials combining docetaxel or bisphosphonates with standard of care in hormone-sensitive prostate cancer have emerged. In order to investigate the effects of these therapies and to respond to emerging evidence, we aimed to systematically review all relevant trials using a framework for adaptive meta-analysis.
For this systematic review and meta-analysis, we searched MEDLINE, Embase, LILACS, and the Cochrane Central Register of Controlled Trials, trial registers, conference proceedings, review articles, and reference lists of trial publications for all relevant randomised controlled trials (published, unpublished, and ongoing) comparing either standard of care with or without docetaxel or standard of care with or without bisphosphonates for men with high-risk localised or metastatic hormone-sensitive prostate cancer. For each trial, we extracted hazard ratios (HRs) of the effects of docetaxel or bisphosphonates on survival (time from randomisation until death from any cause) and failure-free survival (time from randomisation to biochemical or clinical failure or death from any cause) from published trial reports or presentations or obtained them directly from trial investigators. HRs were combined using the fixed-effect model (Mantel-Haenzsel).
We identified five eligible randomised controlled trials of docetaxel in men with metastatic (M1) disease. Results from three (CHAARTED, GETUG-15, STAMPEDE) of these trials (2992 [93%] of 3206 men randomised) showed that the addition of docetaxel to standard of care improved survival. The HR of 0·77 (95% CI 0·68-0·87; p<0·0001) translates to an absolute improvement in 4-year survival of 9% (95% CI 5-14). Docetaxel in addition to standard of care also improved failure-free survival, with the HR of 0·64 (0·58-0·70; p<0·0001) translating into a reduction in absolute 4-year failure rates of 16% (95% CI 12-19). We identified 11 trials of docetaxel for men with locally advanced disease (M0). Survival results from three (GETUG-12, RTOG 0521, STAMPEDE) of these trials (2121 [53%] of 3978 men) showed no evidence of a benefit from the addition of docetaxel (HR 0·87 [95% CI 0·69-1·09]; p=0·218), whereas failure-free survival data from four (GETUG-12, RTOG 0521, STAMPEDE, TAX 3501) of these trials (2348 [59%] of 3978 men) showed that docetaxel improved failure-free survival (0·70 [0·61-0·81]; p<0·0001), which translates into a reduced absolute 4-year failure rate of 8% (5-10). We identified seven eligible randomised controlled trials of bisphosphonates for men with M1 disease. Survival results from three of these trials (2740 [88%] of 3109 men) showed that addition of bisphosphonates improved survival (0·88 [0·79-0·98]; p=0·025), which translates to 5% (1-8) absolute improvement, but this result was influenced by the positive result of one trial of sodium clodronate, and we found no evidence of a benefit from the addition of zoledronic acid (0·94 [0·83-1·07]; p=0·323), which translates to an absolute improvement in survival of 2% (-3 to 7). Of 17 trials of bisphosphonates for men with M0 disease, survival results from four trials (4079 [66%] of 6220 men) showed no evidence of benefit from the addition of bisphosphonates (1·03 [0·89-1·18]; p=0·724) or zoledronic acid (0·98 [0·82-1·16]; p=0·782). Failure-free survival definitions were too inconsistent for formal meta-analyses for the bisphosphonate trials.
The addition of docetaxel to standard of care should be considered standard care for men with M1 hormone-sensitive prostate cancer who are starting treatment for the first time. More evidence on the effects of docetaxel on survival is needed in the M0 disease setting. No evidence exists to suggest that zoledronic acid improves survival in men with M1 or M0 disease, and any potential benefit is probably small.
Medical Research Council UK.
关于多西他赛或双膦酸盐与激素敏感性前列腺癌标准治疗方案联合应用的大型随机对照试验结果已公布。为了研究这些治疗方法的效果并回应新出现的证据，我们旨在使用适应性荟萃分析框架对所有相关试验进行系统评价。
对于这项系统评价和荟萃分析，我们检索了MEDLINE、Embase、LILACS以及Cochrane对照试验中央登记库、试验注册库、会议论文集、综述文章以及所有相关随机对照试验（已发表、未发表和正在进行的）的试验出版物的参考文献列表，以比较标准治疗方案加或不加多西他赛或标准治疗方案加或不加双膦酸盐用于高危局限性或转移性激素敏感性前列腺癌男性患者的情况。对于每项试验，我们从已发表的试验报告或演示文稿中提取多西他赛或双膦酸盐对生存（从随机分组到任何原因导致的死亡时间）和无失败生存（从随机分组到生化或临床失败或任何原因导致的死亡时间）影响的风险比（HRs），或者直接从试验研究者处获取。使用固定效应模型（Mantel-Haenzsel）合并HRs。
我们确定了五项关于多西他赛用于转移性（M1）疾病男性患者的合格随机对照试验。其中三项试验（CHAARTED、GETUG-15、STAMPEDE）（3206名随机分组男性中的2992名[93%]）的结果显示，在标准治疗方案中添加多西他赛可改善生存。HR为0.77（95%CI 0.68 - 0.87；p<0.0001），这意味着4年生存率绝对提高了9%（95%CI 5 - 14）。标准治疗方案加用多西他赛还改善了无失败生存，HR为0.64（0.58 - 0.70；p<0.0001），这意味着4年绝对失败率降低了16%（95%CI 12 - 19）。我们确定了11项关于多西他赛用于局部晚期疾病（M0）男性患者的试验。其中三项试验（GETUG-12、RTOG 0521、STAMPEDE）（3978名男性中的2121名[53%]）的生存结果显示，添加多西他赛没有获益证据（HR 0.87 [95%CI 0.69 - 1.09]；p = 0.218），而其中四项试验（GETUG-12、RTOG 0521、STAMPEDE、TAX 3501）（3978名男性中的2348名[59%]）的无失败生存数据显示，多西他赛改善了无失败生存（0.70 [0.61 - 0.81]；p<0.0001），这意味着4年绝对失败率降低了8%（5 - 10）。我们确定了七项关于双膦酸盐用于M1疾病男性患者的合格随机对照试验。其中三项试验（3109名男性中的2740名[88%]）的生存结果显示，添加双膦酸盐可改善生存（0.88 [0.79 - 0.98]；p = 0.025），这意味着绝对改善率为5%（1 - 8），但该结果受一项氯膦酸钠试验的阳性结果影响，并且我们没有发现添加唑来膦酸有获益证据（0.94 [0.83 - 1.07]；p = 0.323），这意味着生存绝对改善率为2%（-3至7）。在17项关于双膦酸盐用于M0疾病男性患者的试验中，四项试验（6220名男性中的4079名[66%]）的生存结果显示，添加双膦酸盐（1.03 [0.89 - 1.18]；p = 0.724）或唑来膦酸（0.98 [0.82 - 1.16]；p = 0.782）没有获益证据。双膦酸盐试验的无失败生存定义对于正式的荟萃分析来说过于不一致。
对于首次开始治疗的M1激素敏感性前列腺癌男性患者，在标准治疗方案中添加多西他赛应被视为标准治疗。在M0疾病背景下，需要更多关于多西他赛对生存影响的证据。没有证据表明唑来膦酸能改善M1或M0疾病男性患者的生存，任何潜在益处可能都很小。
英国医学研究理事会。
