Department of Radiation-Oncology, University Medical Centre Utrecht, Utrecht, The Netherlands
Department of Surgery, University Medical Centre Utrecht, Utrecht, The Netherlands.
BMJ Open. 2023 Jun 15;13(6):e065010. doi: 10.1136/bmjopen-2022-065010.
Organ preservation is associated with superior functional outcome and quality of life (QoL) compared with total mesorectal excision (TME) for rectal cancer. Only 10% of patients are eligible for organ preservation following short-course radiotherapy (SCRT, 25 Gy in five fractions) and a prolonged interval (4-8 weeks) to response evaluation. The organ preservation rate could potentially be increased by dose-escalated radiotherapy. Online adaptive magnetic resonance-guided radiotherapy (MRgRT) is anticipated to reduce radiation-induced toxicity and enable radiotherapy dose escalation. This trial aims to establish the maximum tolerated dose (MTD) of dose-escalated SCRT using online adaptive MRgRT.
The preRADAR is a multicentre phase I trial with a 6+3 dose-escalation design. Patients with intermediate-risk rectal cancer (cT3c-d(MRF-)N1M0 or cT1-3(MRF-)N1M0) interested in organ preservation are eligible. Patients are treated with a radiotherapy boost of 2×5 Gy (level 0), 3×5 Gy (level 1), 4×5 Gy (level 2) or 5×5 Gy (level 3) on the gross tumour volume in the week following standard SCRT using online adaptive MRgRT. The trial starts on dose level 1. The primary endpoint is the MTD based on the incidence of dose-limiting toxicity (DLT) per dose level. DLT is a composite of maximum one in nine severe radiation-induced toxicities and maximum one in three severe postoperative complications, in patients treated with TME or local excision within 26 weeks following start of treatment. Secondary endpoints include the organ preservation rate, non-DLT, oncological outcomes, patient-reported QoL and functional outcomes up to 2 years following start of treatment. Imaging and laboratory biomarkers are explored for early response prediction.
The trial protocol has been approved by the Medical Ethics Committee of the University Medical Centre Utrecht. The primary and secondary trial results will be published in international peer-reviewed journals.
WHO International Clinical Trials Registry (NL8997; https://trialsearch.who.int).
与全直肠系膜切除术（TME）相比，器官保存可带来更好的功能结果和生活质量（QoL）。仅 10%的患者在接受短程放疗（SCRT，25Gy 分 5 次）和延长的反应评估间隔（4-8 周）后有资格进行器官保存。通过增加放疗剂量，有可能提高器官保存率。在线自适应磁共振引导放疗（MRgRT）有望降低放疗毒性，并能使放疗剂量升级。本试验旨在使用在线自适应 MRgRT 确定剂量递增 SCRT 的最大耐受剂量（MTD）。
预 RADAR 是一项多中心 I 期试验，采用 6+3 剂量递增设计。有器官保存意向的中危直肠癌（cT3c-d（MRF-）N1M0 或 cT1-3（MRF-）N1M0）患者符合条件。患者在标准 SCRT 后一周内，使用在线自适应 MRgRT，对大体肿瘤体积进行 2×5Gy（0 级）、3×5Gy（1 级）、4×5Gy（2 级）或 5×5Gy（3 级）的放疗增敏。试验从剂量水平 1 开始。主要终点是基于每个剂量水平的剂量限制毒性（DLT）发生率确定的 MTD。DLT 是指接受 TME 或局部切除治疗的患者中，9 种严重放射性毒性中最多 1 种和 3 种严重术后并发症中最多 1 种的复合事件，治疗开始后 26 周内。次要终点包括器官保存率、非 DLT、肿瘤学结果、治疗开始后 2 年内患者报告的 QoL 和功能结果。还对影像学和实验室生物标志物进行了探索，以预测早期反应。
试验方案已获得乌得勒支大学医学中心医学伦理委员会的批准。主要和次要试验结果将发表在国际同行评议期刊上。
世界卫生组织国际临床试验注册平台（NL8997；https://trialsearch.who.int）。
