Academic Urology Unit, Royal Marsden Hospital, London, UK; Institute of Cancer Research, London, UK.
Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
Lancet. 2018 Dec 1;392(10162):2353-2366. doi: 10.1016/S0140-6736(18)32486-3. Epub 2018 Oct 21.
Based on previous findings, we hypothesised that radiotherapy to the prostate would improve overall survival in men with metastatic prostate cancer, and that the benefit would be greatest in patients with a low metastatic burden. We aimed to compare standard of care for metastatic prostate cancer, with and without radiotherapy.
We did a randomised controlled phase 3 trial at 117 hospitals in Switzerland and the UK. Eligible patients had newly diagnosed metastatic prostate cancer. We randomly allocated patients open-label in a 1:1 ratio to standard of care (control group) or standard of care and radiotherapy (radiotherapy group). Randomisation was stratified by hospital, age at randomisation, nodal involvement, WHO performance status, planned androgen deprivation therapy, planned docetaxel use (from December, 2015), and regular aspirin or non-steroidal anti-inflammatory drug use. Standard of care was lifelong androgen deprivation therapy, with up-front docetaxel permitted from December, 2015. Men allocated radiotherapy received either a daily (55 Gy in 20 fractions over 4 weeks) or weekly (36 Gy in six fractions over 6 weeks) schedule that was nominated before randomisation. The primary outcome was overall survival, measured as the number of deaths; this analysis had 90% power with a one-sided α of 2·5% for a hazard ratio (HR) of 0·75. Secondary outcomes were failure-free survival, progression-free survival, metastatic progression-free survival, prostate cancer-specific survival, and symptomatic local event-free survival. Analyses used Cox proportional hazards and flexible parametric models, adjusted for stratification factors. The primary outcome analysis was by intention to treat. Two prespecified subgroup analyses tested the effects of prostate radiotherapy by baseline metastatic burden and radiotherapy schedule. This trial is registered with ClinicalTrials.gov, number NCT00268476.
Between Jan 22, 2013, and Sept 2, 2016, 2061 men underwent randomisation, 1029 were allocated the control and 1032 radiotherapy. Allocated groups were balanced, with a median age of 68 years (IQR 63-73) and median amount of prostate-specific antigen of 97 ng/mL (33-315). 367 (18%) patients received early docetaxel. 1082 (52%) participants nominated the daily radiotherapy schedule before randomisation and 979 (48%) the weekly schedule. 819 (40%) men had a low metastatic burden, 1120 (54%) had a high metastatic burden, and the metastatic burden was unknown for 122 (6%). Radiotherapy improved failure-free survival (HR 0·76, 95% CI 0·68-0·84; p<0·0001) but not overall survival (0·92, 0·80-1·06; p=0·266). Radiotherapy was well tolerated, with 48 (5%) adverse events (Radiation Therapy Oncology Group grade 3-4) reported during radiotherapy and 37 (4%) after radiotherapy. The proportion reporting at least one severe adverse event (Common Terminology Criteria for Adverse Events grade 3 or worse) was similar by treatment group in the safety population (398 [38%] with control and 380 [39%] with radiotherapy).
Radiotherapy to the prostate did not improve overall survival for unselected patients with newly diagnosed metastatic prostate cancer.
Cancer Research UK, UK Medical Research Council, Swiss Group for Clinical Cancer Research, Astellas, Clovis Oncology, Janssen, Novartis, Pfizer, and Sanofi-Aventis.
基于先前的研究结果，我们假设对前列腺进行放射治疗会改善转移性前列腺癌患者的总生存率，并且这种益处在转移性负担较低的患者中最大。我们旨在比较转移性前列腺癌的标准治疗方法，包括和不包括放射治疗。
我们在瑞士和英国的 117 家医院进行了一项随机对照的 3 期试验。符合条件的患者为新诊断的转移性前列腺癌。我们以 1:1 的比例将患者进行开放性标签随机分配至标准治疗（对照组）或标准治疗加放射治疗（放射治疗组）。随机分组按医院、随机分组时的年龄、淋巴结受累、世界卫生组织表现状态、计划的雄激素剥夺治疗、计划的多西他赛使用（自 2015 年 12 月起）和常规阿司匹林或非甾体抗炎药使用分层。标准治疗为终身雄激素剥夺治疗，自 2015 年 12 月起允许使用多西他赛。接受放射治疗的患者接受每日（55 Gy，20 次分割，4 周）或每周（36 Gy，6 次分割，6 周）计划，该计划在随机分组前指定。主要结局是总生存率，即死亡人数；该分析在单侧α为 2.5%的情况下具有 90%的效力，风险比（HR）为 0.75。次要结局是无失败生存率、无进展生存率、转移性无进展生存率、前列腺癌特异性生存率和有症状的局部无事件生存率。分析使用 Cox 比例风险和灵活参数模型进行调整，以适应分层因素。主要结局分析为意向治疗。两个预设的亚组分析按基线转移性负担和放射治疗方案检验前列腺放射治疗的效果。该试验在 ClinicalTrials.gov 注册，编号为 NCT00268476。
2013 年 1 月 22 日至 2016 年 9 月 2 日期间，2061 名患者接受了随机分组，1029 名患者被分配至对照组，1032 名患者被分配至放射治疗组。分配组之间平衡，中位年龄为 68 岁（IQR 63-73），中位前列腺特异性抗原水平为 97 ng/mL（33-315）。367（18%）名患者接受了早期多西他赛治疗。1082（52%）名参与者在随机分组前指定了每日放射治疗方案，979（48%）名参与者指定了每周放射治疗方案。819（40%）名男性有低转移性负担，1120（54%）名男性有高转移性负担，122（6%）名男性的转移性负担未知。放射治疗改善了无失败生存率（HR 0.76，95%CI 0.68-0.84；p<0.0001），但未改善总生存率（0.92，0.80-1.06；p=0.266）。放射治疗耐受性良好，放射治疗期间报告了 48 例（5%）不良事件（放射治疗肿瘤学组 3-4 级），放射治疗后报告了 37 例（4%）不良事件。安全性人群中，报告至少 1 例严重不良事件（不良事件通用术语标准 3 或更高级别）的比例在治疗组之间相似（对照组 398 例[38%]，放射治疗组 380 例[39%]）。
对新诊断的转移性前列腺癌患者进行前列腺放射治疗并未改善总生存率。
英国癌症研究中心、英国医学研究理事会、瑞士临床癌症研究组、安斯泰来、克洛维斯肿瘤学、杨森、诺华、辉瑞和赛诺菲-安万特。
