Timing of androgen-deprivation therapy in patients with prostate cancer with a rising PSA (TROG 03.06 and VCOG PR 01-03 [TOAD]): a randomised, multicentre, non-blinded, phase 3 trial
Timing of androgen-deprivation therapy in patients with prostate cancer with a rising PSA (TROG 03.06 and VCOG PR 01-03 [TOAD]): a randomised, multicentre, non-blinded, phase 3 trial
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DOI：
10.1016/s1470-2045(16)00107-8
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发表时间：
2016-06-01
期刊：
影响因子：
51.1
通讯作者：
Turner, Sandra
中科院分区：
文献类型：
--
作者：
Duchesne, Gillian M.;Woo, Henry H.;Turner, Sandra
雄激素剥夺治疗适用于治疗后前列腺特异性抗原升高（PSA复发）或认为不适合治疗的前列腺癌患者;然而，其引入的最佳时机尚不确定。我们的目的是评估是否立即雄激素剥夺治疗提高总生存率相比，延迟therapy.Methods在这个随机，多中心，3期，非盲法试验，我们通过29个肿瘤中心在澳大利亚，新西兰和加拿大招募男性。如果前列腺癌男性患者在既往尝试治愈性治疗（放疗或手术，伴或不伴术后放疗）后PSA复发，或者如果认为他们不适合治愈性治疗（由于年龄、合并症或局部晚期疾病），则他们符合资格。我们使用了一种嵌入数据库的、动态平衡的随机化算法，由癌症理事会维多利亚协调，将受试者（1：1）随机分配至立即雄激素剥夺治疗（立即治疗组）或延迟雄激素剥夺治疗（延迟治疗组），建议间隔至少2年，除非有临床禁忌。PSA复发受试者的随机化按既往治疗类型、无复发间期和PSA倍增时间分层;非治愈性疾病受试者的随机化按转移状态分层;两组的随机化按计划治疗方案（连续或间歇）和治疗中心分层。临床医生可以规定任何形式和时间表的雄激素剥夺治疗和组分配不设盲。主要结局是意向治疗人群的总生存率。在独立数据监查委员会审查后，试验于2012年关闭，但数据收集持续了18个月，直至2014年2月26日。它在澳大利亚新西兰临床试验注册处（ACTRN 12606000301561）和ClinicalTrials.gov（NCT 00110162）注册。结果在2004年9月3日至2012年7月13日期间，我们招募了293名男性（261名PSA复发，32名不可治愈的疾病）。我们将142名男性随机分配到立即治疗组，151名分配到延迟治疗组，从随机分配之日起，中位随访时间为5年（IQR 3.3-6.2）。立即治疗组中有16例（11%）男性死亡，延迟治疗组中有30例（20%）男性死亡。延迟治疗组的5年总生存率为86.4%（95%CI 78.5-91.5），而立即治疗组为91.2%（84.2-95.2）（对数秩p=0.047）。考克斯回归后，即刻与延迟组分配的总生存期的未校正HR为0.55（95% CI 0.30-1.00; p=0.050）。23例患者发生3级治疗相关不良事件。105例（36%）男性发生需要住院的不良事件;这些事件均不归因于治疗或治疗时间组之间存在差异。最常见的严重不良事件是心血管疾病，发生在9名（6%）延迟治疗组和13名（9%）立即治疗arm.Interpretation雄激素剥夺治疗的患者中，与PSA复发或不可治愈的前列腺癌患者延迟干预相比，立即接受雄激素剥夺治疗显著改善了总生存率。这些结果提供了生存率和发病率的基准证据，以便在考虑男性治疗方案时与他们讨论。
Background Androgen-deprivation therapy is offered to men with prostate cancer who have a rising prostate-specific antigen after curative therapy (PSA relapse) or who are considered not suitable for curative treatment; however, the optimal timing for its introduction is uncertain. We aimed to assess whether immediate androgen-deprivation therapy improves overall survival compared with delayed therapy.Methods In this randomised, multicentre, phase 3, non-blinded trial, we recruited men through 29 oncology centres in Australia, New Zealand, and Canada. Men with prostate cancer were eligible if they had a PSA relapse after previous attempted curative therapy (radiotherapy or surgery, with or without postoperative radiotherapy) or if they were not considered suitable for curative treatment (because of age, comorbidity, or locally advanced disease). We used a database-embedded, dynamically balanced, randomisation algorithm, coordinated by the Cancer Council Victoria, to randomly assign participants (1: 1) to immediate androgen-deprivation therapy (immediate therapy arm) or to delayed androgen-deprivation therapy (delayed therapy arm) with a recommended interval of at least 2 years unless clinically contraindicated. Randomisation for participants with PSA relapse was stratified by type of previous therapy, relapse-free interval, and PSA doubling time; randomisation for those with non-curative disease was stratified by metastatic status; and randomisation in both groups was stratified by planned treatment schedule (continuous or intermittent) and treatment centre. Clinicians could prescribe any form and schedule of androgen-deprivation therapy and group assignment was not masked. The primary outcome was overall survival in the intention-to-treat population. The trial closed to accrual in 2012 after review by the independent data monitoring committee, but data collection continued for 18 months until Feb 26, 2014. It is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12606000301561) and ClinicalTrials.gov (NCT00110162).Findings Between Sept 3, 2004, and July 13, 2012, we recruited 293 men (261 with PSA relapse and 32 with non-curable disease). We randomly assigned 142 men to the immediate therapy arm and 151 to the delayed therapy arm. Median follow-up was 5 years (IQR 3.3-6.2) from the date of randomisation. 16 (11%) men died in the immediate therapy arm and 30 (20%) died in the delayed therapy arm. 5-year overall survival was 86.4% (95% CI 78.5-91.5) in the delayed therapy arm versus 91.2% (84.2-95.2) in the immediate therapy arm (log-rank p=0.047). After Cox regression, the unadjusted HR for overall survival for immediate versus delayed arm assignment was 0.55 (95% CI 0.30-1.00; p=0.050). 23 patients had grade 3 treatment-related adverse events. 105 (36%) men had adverse events requiring hospital admission; none of these events were attributable to treatment or differed between treatment-timing groups. The most common serious adverse events were cardiovascular, which occurred in nine (6%) patients in the delayed therapy arm and 13 (9%) in the immediate therapy arm.Interpretation Immediate receipt of androgen-deprivation therapy significantly improved overall survival compared with delayed intervention in men with PSA-relapsed or non-curable prostate cancer. The results provide benchmark evidence of survival rates and morbidity to discuss with men when considering their treatment options.