Department of Radiation Oncology, Royal North Shore Hospital, Sydney, NSW, Australia; Sydney Medical School, University of Sydney, Sydney, NSW, Australia.
Auckland Hospital, Auckland, New Zealand.
Lancet Oncol. 2020 Oct;21(10):1331-1340. doi: 10.1016/S1470-2045(20)30456-3.
Adjuvant radiotherapy has been shown to halve the risk of biochemical progression for patients with high-risk disease after radical prostatectomy. Early salvage radiotherapy could result in similar biochemical control with lower treatment toxicity. We aimed to compare biochemical progression between patients given adjuvant radiotherapy and those given salvage radiotherapy.
We did a phase 3, randomised, controlled, non-inferiority trial across 32 oncology centres in Australia and New Zealand. Eligible patients were aged at least 18 years and had undergone a radical prostatectomy for adenocarcinoma of the prostate with pathological staging showing high-risk features defined as positive surgical margins, extraprostatic extension, or seminal vesicle invasion; had an Eastern Cooperative Oncology Group performance status of 0-1, and had a postoperative prostate-specific antigen (PSA) concentration of 0·10 ng/mL or less. Patients were randomly assigned (1:1) using a minimisation technique via an internet-based, independently generated allocation to either adjuvant radiotherapy within 6 months of radical prostatectomy or early salvage radiotherapy triggered by a PSA of 0·20 ng/mL or more. Allocation sequence was concealed from investigators and patients, but treatment assignment for individual randomisations was not masked. Patients were stratified by radiotherapy centre, preoperative PSA, Gleason score, surgical margin status, and seminal vesicle invasion status. Radiotherapy in both groups was 64 Gy in 32 fractions to the prostate bed without androgen deprivation therapy with real-time review of plan quality on all cases before treatment. The primary endpoint was freedom from biochemical progression. Salvage radiotherapy would be deemed non-inferior to adjuvant radiotherapy if freedom from biochemical progression at 5 years was within 10% of that for adjuvant radiotherapy with a hazard ratio (HR) for salvage radiotherapy versus adjuvant radiotherapy of 1·48. The primary analysis was done on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, NCT00860652.
Between March 27, 2009, and Dec 31, 2015, 333 patients were randomly assigned (166 to adjuvant radiotherapy; 167 to salvage radiotherapy). Median follow-up was 6·1 years (IQR 4·3-7·5). An independent data monitoring committee recommended premature closure of enrolment because of unexpectedly low event rates. 84 (50%) patients in the salvage radiotherapy group had radiotherapy triggered by a PSA of 0·20 ng/mL or more. 5-year freedom from biochemical progression was 86% (95% CI 81-92) in the adjuvant radiotherapy group versus 87% (82-93) in the salvage radiotherapy group (stratified HR 1·12, 95% CI 0·65-1·90; p=0·15). The grade 2 or worse genitourinary toxicity rate was lower in the salvage radiotherapy group (90 [54%] of 167) than in the adjuvant radiotherapy group (116 [70%] of 166). The grade 2 or worse gastrointestinal toxicity rate was similar between the salvage radiotherapy group (16 [10%]) and the adjuvant radiotherapy group (24 [14%]).
Salvage radiotherapy did not meet trial specified criteria for non-inferiority. However, these data support the use of salvage radiotherapy as it results in similar biochemical control to adjuvant radiotherapy, spares around half of men from pelvic radiation, and is associated with significantly lower genitourinary toxicity.
New Zealand Health Research Council, Australian National Health Medical Research Council, Cancer Council Victoria, Cancer Council NSW, Auckland Hospital Charitable Trust, Trans-Tasman Radiation Oncology Group Seed Funding, Cancer Research Trust New Zealand, Royal Australian and New Zealand College of Radiologists, Cancer Institute NSW, Prostate Cancer Foundation Australia, and Cancer Australia.
辅助放疗已被证明可使高危疾病患者根治性前列腺切除术后生化进展的风险减半。早期挽救性放疗可能会导致类似的生化控制，同时毒性较低。我们旨在比较接受辅助放疗和接受挽救性放疗的患者之间的生化进展。
我们在澳大利亚和新西兰的 32 个肿瘤中心进行了一项 3 期随机对照非劣效性试验。符合条件的患者年龄至少为 18 岁，并且接受了根治性前列腺切除术治疗前列腺腺癌，病理分期显示高危特征，包括阳性手术切缘、前列腺外扩展或精囊侵犯；东部合作肿瘤学组表现状态为 0-1 级，并且术后前列腺特异性抗原（PSA）浓度为 0.10ng/ml 或更低。患者通过互联网独立生成的最小化技术随机分配（1:1），随机分配至根治性前列腺切除术后 6 个月内接受辅助放疗或 PSA 为 0.20ng/ml 或更高时接受早期挽救性放疗。从研究者和患者那里隐藏了分配序列，但未对个别随机分配进行治疗分配掩盖。根据放疗中心、术前 PSA、Gleason 评分、手术切缘状态和精囊侵犯状态对患者进行分层。两组放疗均为前列腺床 64Gy/32 次，不伴雄激素剥夺治疗，所有病例在治疗前均进行实时计划质量审查。主要终点是无生化进展。如果挽救性放疗与辅助放疗相比，5 年无生化进展的比例在辅助放疗的 10%以内，并且挽救性放疗与辅助放疗的风险比（HR）为 1.48，则挽救性放疗被认为不劣于辅助放疗。主要分析基于意向治疗进行。本研究在 ClinicalTrials.gov 注册，NCT00860652。
2009 年 3 月 27 日至 2015 年 12 月 31 日期间，333 名患者被随机分配（166 名接受辅助放疗；167 名接受挽救性放疗）。中位随访时间为 6.1 年（IQR 4.3-7.5）。一个独立的数据监测委员会建议因预计事件发生率过低而提前关闭入组。挽救性放疗组中有 84 名（50%）患者的 PSA 为 0.20ng/ml 或更高时接受放疗。辅助放疗组 5 年无生化进展率为 86%（95%CI 81-92），挽救性放疗组为 87%（82-93）（分层 HR 1.12，95%CI 0.65-1.90；p=0.15）。挽救性放疗组（90[54%]）的 2 级或更高级别的泌尿生殖系统毒性发生率低于辅助放疗组（116[70%]）。挽救性放疗组（16[10%]）和辅助放疗组（24[14%]）的 2 级或更高级别的胃肠道毒性发生率相似。
挽救性放疗未达到试验规定的非劣效性标准。然而，这些数据支持使用挽救性放疗，因为它可导致与辅助放疗相似的生化控制，使一半左右的男性免于骨盆放疗，并且与明显较低的泌尿生殖系统毒性相关。
新西兰健康研究委员会、澳大利亚国家健康医学研究委员会、维多利亚癌症委员会、新南威尔士癌症委员会、奥克兰医院慈善信托基金、跨塔斯曼放射肿瘤学组种子基金、新西兰癌症研究信托基金、皇家澳大利亚和新西兰放射科医师学院、新南威尔士癌症研究所、前列腺癌基金会澳大利亚和澳大利亚癌症协会。
