Background and objective

Delivering radiotherapy to the bladder is challenging as it is a mobile, deformable structure. Dose-escalated adaptive image-guided radiotherapy could improve outcomes. RAIDER aimed to demonstrate the safety of such a schedule.

Methods

RAIDER is an international phase 2 noncomparative randomised controlled trial (ISRCTN26779187). Patients with unifocal T2-T4a urothelial bladder cancer were randomised (1:1:2) to standard whole bladder radiotherapy (WBRT), standard-dose adaptive radiotherapy (SART), or dose-escalated adaptive radiotherapy (DART). Two fractionation (f) schedules recruited independently. WBRT and SART dose was 55 Gy/20f or 64 Gy/32f, and DART dose was 60 Gy/20f or 70 Gy/32f. For SART and DART, a radiotherapy plan (small, medium, or large) was chosen daily. The primary endpoint was the proportion of patients with radiotherapy-related late Common Terminology Criteria for Adverse Events grade ≥3 toxicity; the trial was designed to rule out >20% toxicity with DART.

Key findings and limitations

A total of 345 patients were randomised between October 2015 and April 2020: 41/46 WBRT, 41/46 SART, and 81/90 DART patients in the 20f/32f cohorts, respectively. The median age was 72/73 yr; 78%/85% had T2 tumours, 46%/52% had neoadjuvant chemotherapy, and 70%/71% had radiosensitising therapy. The median follow-up was 42.1/38.2 mo. Sixty-six of 77 (86%) 20f and 74 of 82 (90%) 32f participants planned for DART met the mandatory medium plan dose constraints. Radiotherapy-related grade ≥3 toxicity was reported in one of 58 patients (90% confidence interval [CI] 0.1, 7.9) with 20f DART and zero of 56 patients with 32f DART. Two-year overall survival was 77% (95% CI 69, 82) for WBRT + SART and 80% (95% CI 73, 85) for DART (hazard ratio = 0.84, 95% CI 0.59, 1.21, p = 0.4). Thirteen of 345 (3.8%) participants had salvage cystectomy.

Conclusions and clinical implications

Grade ≥3 late toxicity was low. DART was safe and feasible to deliver, meeting preset toxicity thresholds. Disease-related outcomes are promising for dose-escalated treatments, with a low salvage cystectomy rate and overall survival similar to that seen in cystectomy cohorts.

中文翻译：

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膀胱癌剂量递增适应性放疗：2 期 RAIDER 随机对照试验的结果

 背景和目标

对膀胱进行放射治疗具有挑战性，因为它是一个可移动、可变形的结构。剂量递增的适应性图像引导放疗可以改善结局。RAIDER 旨在证明这种时间表的安全性。

 方法

RAIDER 是一项国际 2 期非比较随机对照试验 （ISRCTN26779187）。单灶性 T2-T4a 尿路上皮膀胱癌患者被随机 （1：1：2） 分配到标准全膀胱放疗 （WBRT） 、标准剂量适应性放疗 （SART） 或剂量递增适应性放疗 （DART） 组。独立招募两个分馏 （f） 时间表。WBRT 和 SART 剂量为 55 Gy/20f 或 64 Gy/32f，DART 剂量为 60 Gy/20f 或 70 Gy/32f。对于 SART 和 DART，每天选择放疗计划 （小型、中型或大型）。主要终点是放疗相关晚期不良事件通用术语标准 ≥3 级毒性患者的比例;该试验旨在排除 DART 的 >20% 毒性。

主要发现和局限性

2015 年 10 月至 2020 年 4 月期间，共有 345 名患者被随机分组：20f/32f 队列中分别为 41/46 WBRT、41/46 SART 和 81/90 DART 患者。中位年龄为 72/73 岁;78%/85% 的患者患有 T2 期肿瘤，46%/52% 的患者接受新辅助化疗，70%/71% 的患者接受放射增敏治疗。中位随访为 42.1/38.2 个月。计划接受 DART 的 77 名 （86%） 20f 参与者中有 66 名和 82 名 （90%） 32f 参与者中有 74 名符合强制性的中等计划剂量限制。58 例 20f DART 患者中有 1 例 （90% 置信区间 [CI] 0.1,7.9） 报告了放疗相关的 ≥ 级毒性，56 例 32f DART 患者中有 0 例报告了放疗相关的 3 级毒性。WBRT + SART 的两年总生存率为 77% （95% CI 69， 82），DART 为 80% （95% CI 73， 85） （风险比 = 0.84,95% CI 0.59， 1.21，p = 0.4）。 345 名参与者中有 13 名 （3.8%） 进行了挽救性膀胱切除术。

结论和临床意义

≥3 级晚期毒性较低。DART 给药安全且可行，符合预设的毒性阈值。剂量递增治疗的疾病相关结局很有希望，挽救性膀胱切除术率低，总生存期与膀胱切除术队列相似。