Short-term androgen suppression and radiotherapy versus intermediate-term androgen suppression and radiotherapy, with or without zoledronic acid, in men with locally advanced prostate cancer (TROG 03.04 RADAR): an open-label, randomised, phase 3 factorial trial
Short-term androgen suppression and radiotherapy versus intermediate-term androgen suppression and radiotherapy, with or without zoledronic acid, in men with locally advanced prostate cancer (TROG 03.04 RADAR): an open-label, randomised, phase 3 factorial trial
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DOI：
10.1016/s1470-2045(14)70328-6
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发表时间：
2014-09-01
期刊：
影响因子：
51.1
通讯作者：
Steigler, Allison
中科院分区：
文献类型：
--
作者：
Denham, James W.;Joseph, David;Steigler, Allison
背景我们研究了雄激素抑制18个月加放疗（有或无唑来膦酸18个月）是否比新辅助雄激素抑制6个月加放疗（有或无唑来膦酸）更有效。局部晚期前列腺癌男性患者的2 × 2析因试验（前列腺特异性抗原[PSA] >= 10 μ g/L且Gleason评分>= 7的T2 a N 0 M0前列腺癌，或T2 b-4 N 0 M0肿瘤，无论PSA和Gleason评分如何）。我们通过计算机生成的最小化--按中心、基线PSA、肿瘤分期、Gleason评分和近距离放射治疗加强的使用分层--将患者以1：1：1：1的比例随机分配到四组中的一组。对照组患者接受亮丙瑞林新辅助雄激素抑制治疗（22.5 mg，每3个月一次，肌肉注射），持续6个月（短期）和单纯放疗（指定为STAS）;该手术后，使用亮丙瑞林进行另外12个月的雄激素抑制（中期; ITAS）或伴随18个月的唑来膦酸（4 mg，每3个月，持续18个月，静脉注射; STAS+唑来膦酸）或两者兼而有之（ITAS+唑来膦酸）。主要终点是前列腺癌特异性死亡率。该分析代表了治疗后5年肿瘤学终点的首次预先计划评估。研究结果在2003年10月20日至2007年8月15日期间，1071名男性被随机分配到STAS组（n=268）、STAS+唑来膦酸组（n = 268）、ITAS组（n = 268）和ITAS+唑来膦酸组（n=267）。ClinicalTrials.gov中位随访时间为74年（IQR 6.5-8.4）。STAS组、STAS+唑来膦酸组、ITAS组和ITAS+唑来膦酸组前列腺癌特异性死亡率的累积发生率分别为4.1%（95%CI 2.2-7.0）、7.8%（4.9-11.5）、7.4%（4.6-11.0）和4.3%（2.3-7.3）。全因死亡的累积发生率分别为17.0%（13.0-22.1）、18.9%（14.6-24.2）、19.4%（15.0-24.7）和13.9%（10.3-18.8）。无论是前列腺癌特异性死亡率还是全因死亡率在对照组和实验组之间都没有差异。STAS组PSA进展的累积发生率为34.2%（28.6-39.9），STAS+唑来膦酸组为39.6%（33.6-45.5），ITAS组为29.2%（23.8-34.8），ITAS+唑来膦酸组为26.0%（20.8-31.4）。与STAS相比，ITAS或STAS+唑来膦酸组PSA进展无差异;然而，ITAS+唑来膦酸组PSA进展减少（亚风险比[SHR] 0.71，95% CI 0.53-0.95; p=0.021）。STAS组局部进展的累积发生率为4.1%（2.2-7.0），STAS+唑来膦酸组为6.1%（3.7-9.5），ITAS组为1.5%（0.5-3.7），ITAS+唑来膦酸组为3.4%（1.7-6.1）;组间无差异。骨进展的累积发生率分别为7.5%（4.8-11.1）、14.6%（10.6-19.2）、8.4%（5.5-12.2）和7.6%（4.8-11.2）。与STAS相比，STAS加唑来膦酸增加了骨进展的风险（SHR 1 90，95%CI 1.14-3.17; p=0.012），但与其他两组无差异。远处进展的累积发生率在STAS组为14.7%（10.7-19.2），在STAS+唑来膦酸组为17.3%（13.0-22.1），在ITAS组为14.2%（10.3-18.7），在ITAS+唑来膦酸组为11.1%（7.6-15.2）;组间无差异。二次治疗干预的累积发生率分别为25.6%（20.5-30.9）、28.9%（23.5-34.5）、20.7%（16.1-25.9）和15.3%（11.3-20.0）。与STAS相比，ITAS+唑来膦酸减少了二次治疗干预的需要（SHR 0 67，95% CI 0. 48 - 0. 95; p= 0. 024）;与其他两组无差异。记录试验因素之间的相互作用，用于Gleason评分;因此，我们在所有组之间进行了成对比较。事后分析表明，PSA进展的减少和ITAS+唑来膦酸二次治疗干预需求的减少仅限于Gleason评分为8-10的肿瘤，在Gleason评分为7或更低的肿瘤中，ITAS优于STAS。长期发病率和生活质量评分没有受到不利影响，18个月的雄激素抑制或zoledronic acid.Interpretation相比，STAS，ITAS加zoledronic酸是更有效的治疗前列腺癌的Gleason评分为8-10，和ITAS单独是有效的肿瘤Gleason评分为7或更低。然而，这些结果是基于次要终点数据和事后分析，必须谨慎对待。长期随访是必要的，因为唑来膦酸和格里森评分之间的相互作用的外部验证。可以排除STAS加唑来膦酸作为潜在的治疗选择。
Background We investigated whether 18 months of androgen suppression plus radiotherapy, with or without 18 months of zoledronic acid, is more effective than 6 months of neoadjuvant androgen suppression plus radiotherapy with or without zoledronic acid.Methods We did an open-label, randomised, 2 x 2 factorial trial in men with locally advanced prostate cancer (either T2a N0 M0 prostatic adenocarcinomas with prostate-specific antigen [PSA] >= 10 mu g/L and a Gleason score of >= 7, or T2b-4 N0 M0 tumours regardless of PSA and Gleason score). We randomly allocated patients by computer-generated minimisation-stratified by centre, baseline PSA, tumour stage, Gleason score, and use of a brachytherapy boost-to one of four groups in a 1: 1: 1: 1 ratio. Patients in the control group were treated with neoadjuvant androgen suppression with leuprorelin (22.5 mg every 3 months, intramuscularly) for 6 months (short-term) and radiotherapy alone (designated STAS); this procedure was either followed by another 12 months of androgen suppression with leuprorelin (intermediate-term; ITAS) or accompanied by 18 months of zoledronic acid (4 mg every 3 months for 18 months, intravenously; STAS plus zoledronic acid) or by both (ITAS plus zoledronic acid). The primary endpoint was prostate cancer-specific mortality. This analysis represents the first, preplanned assessment of oncological endpoints, 5 years after treatment. Analysis was by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT00193856.Findings Between Oct 20, 2003, and Aug 15, 2007, 1071 men were randomly assigned to STAS (n=268), STAS plus zoledronic acid (n=268), ITAS (n=268), and ITAS plus zoledronic acid (n=267). Median follow-up was 7 4 years (IQR 6.5-8.4). Cumulative incidences of prostate cancer-specific mortality were 4.1% (95% CI 2.2-7.0) in the STAS group, 7.8% (4.9-11.5) in the STAS plus zoledronic acid group, 7.4% (4.6-11.0) in the ITAS group, and 4.3% (2.3-7.3) in the ITAS plus zoledronic acid group. Cumulative incidence of all-cause mortality was 17.0% (13.0-22.1), 18.9% (14.6-24.2), 19.4% (15.0-24.7), and 13.9% (10.3-18.8), respectively. Neither prostate cancer-specific mortality nor all-cause mortality differed between control and experimental groups. Cumulative incidence of PSA progression was 34.2% (28.6-39.9) in the STAS group, 39.6% (33.6-45.5) in the STAS plus zoledronic acid group, 29.2% (23.8-34.8) in the ITAS group, and 26.0% (20.8-31.4) in the ITAS plus zoledronic acid group. Compared with STAS, no difference was noted in PSA progression with ITAS or STAS plus zoledronic acid; however, ITAS plus zoledronic acid reduced PSA progression (sub-hazard ratio [SHR] 0.71, 95% CI 0.53-0.95; p=0.021). Cumulative incidence of local progression was 4.1% (2.2-7.0) in the STAS group, 6.1% (3.7-9.5) in the STAS plus zoledronic acid group, 1.5% (0.5-3.7) in the ITAS group, and 3.4% (1.7-6.1) in the ITAS plus zoledronic acid group; no differences were noted between groups. Cumulative incidences of bone progression were 7.5% (4.8-11.1), 14.6% (10.6-19.2), 8.4% (5.5-12.2), and 7.6% (4.8-11.2), respectively. Compared with STAS, STAS plus zoledronic acid increased the risk of bone progression (SHR 1 90, 95% CI 1.14-3.17; p=0.012), but no differences were noted with the other two groups. Cumulative incidence of distant progression was 14.7% (10.7-19.2) in the STAS group, 17.3% (13.0-22.1) in the STAS plus zoledronic acid group, 14.2% (10.3-18.7) in the ITAS group, and 11.1% (7.6-15.2) in the ITAS plus zoledronic acid group; no differences were recorded between groups. Cumulative incidence of secondary therapeutic intervention was 25.6% (20.5-30.9), 28.9% (23.5-34.5), 20.7% (16.1-25.9), and 15.3% (11.3-20.0), respectively. Compared with STAS, ITAS plus zoledronic acid reduced the need for secondary therapeutic intervention (SHR 0 67, 95% CI 0.48-0.95; p=0.024); no differences were noted with the other two groups. An interaction between trial factors was recorded for Gleason score; therefore, we did pairwise comparisons between all groups. Post-hoc analyses suggested that the reductions in PSA progression and decreased need for secondary therapeutic intervention with ITAS plus zoledronic acid were restricted to tumours with a Gleason score of 8-10, and that ITAS was better than STAS in tumours with a Gleason score of 7 or lower. Long-term morbidity and quality-of-life scores were not affected adversely by 18 months of androgen suppression or zoledronic acid.Interpretation Compared with STAS, ITAS plus zoledronic acid was more effective for treatment of prostate cancers with a Gleason score of 8-10, and ITAS alone was effective for tumours with a Gleason score of 7 or lower. Nevertheless, these findings are based on secondary endpoint data and post-hoc analyses and must be regarded cautiously. Longterm follow-up is necessary, as is external validation of the interaction between zoledronic acid and Gleason score. STAS plus zoledronic acid can be ruled out as a potential therapeutic option.