Towards Response ADAptive Radiotherapy for organ preservation for intermediate-risk rectal cancer (preRADAR): protocol of a phase I dose-escalation trial

Abstract

IntroductionOrgan 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.Methods and analysisThe 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.Ethics and disseminationThe 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.Trial registration numberWHO International Clinical Trials Registry (NL8997;https://trialsearch.who.int).

Quality of life and clinical outcomes in rectal cancer patients treated on a 1.5T MR-Linac within the MOMENTUM study

“…Our findings support the investigation of further dose escalation or boosting strategies with MR-guided RT systems, with the aim to enhance treatment efficacy and organ-preserving treatment approaches, while maintaining a good QoL. Several such studies are ongoing and the results are eagerly anticipated (e.g., NCT04808323, NCT05916040, NCT05108428, NCT05338866) [42] .…”

“…Therefore, it is expected that the use of MR-guided RT systems further reduces toxicity and improves patient outcomes, and enable dose escalation while preserving QoL. This is currently being investigated in the preRADAR trial [42] .…”

Flash Therapy for Cancer: A Potentially New Radiotherapy Methodology

“…Radiation-induced toxicity restricts the tumor's dose, thereby limiting the ability of radiotherapy to suppress tumor development. Furthermore, radiotherapy's prolonged toxicity critically impairs patients' mental and physical health [2]. Nevertheless, the main drawback of RT is that while it is intended to deliver a lethal dose to cancerous cells, exposure to those radiations can damage healthy tissues and cause serious health problems in the short and long term.…”