Safety and early organ preservation outcomes after dose escalation with MR-guided radiotherapy for rectal cancer (preRADAR): A phase I trial

Abstract Background and purpose Organ preservation is a desirable goal for patients with rectal cancer. Magnetic resonance-guided radiotherapy (MRgRT) enables precise dose delivery and online adaptation. This phase I study (preRADAR) evaluated maximum tolerated dose (MTD) of short course radiotherapy (SCRT; 5x5 Gy) with a subsequent boost using MRgRT in intermediate-risk rectal cancer. Materials and methods the trial had a 6 + 3 dose-escalation design. Patients staged T3c-d(MRF-)N0M0 or T1-3(MRF-)N1M0 were treated on a 1.5 Tesla MR-linac with short-course radiotherapy (SCRT; 5 × 5 Gy) followed by 2–4 daily 5 Gy GTV boosts according to the dose level. Safety was assessed by incidence of acute and perioperative dose-limiting toxicities (DLTs) within prespecified time windows and stopping boundaries. Secondary endpoints included technical feasibility (boost PTV V95% > 90%) and organ preservation at six months. Results Out of 31 patients screened, sixteen were treated across three dose levels. All fractions were delivered as planned and all adaptive boost fractions achieved the predefined feasibility criterion (PTV V95% >90%). No acute DLTs occurred. Three perioperative DLTs were observed, including two anastomotic leaks requiring reoperation. The MTD was not identified; dose level 2 (SCRT + 4 × 5 Gy boosts) was the highest dose level completed within the DLT stopping boundaries, achieving a 26-week organ preservation rate of 56% (5/9). Conclusion MRgRT-based enables dose escalation following SCRT in intermediate-risk rectal cancer. The highest evaluated dose level, 4 × 5 Gy GTV boosts after SCRT, was considered safe within the predefined DLT boundaries and feasible for further evaluation.