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.