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

Introduction 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. Methods and analysis 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. Ethics and dissemination 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. Trial registration number WHO International Clinical Trials Registry (NL8997; https://trialsearch.who.int).</p

Postprandial metabolic responses to mixed versus liquid meal tests in healthy men and men with type 2 diabetes

AbstractAimsCompare metabolic responses after mixed versus liquid meals of similar caloric/nutritional content in healthy and type 2 diabetes (T2D) subjects.MethodsTen healthy men and 10 men with T2D received mixed and liquid meals after an overnight fast. Classical (insulinogenic index; insulin/glucose areas under curves, AUCinsulin/AUCglucose) and model-based (beta-cell glucose sensitivity; rate sensitivity; potentiation factor ratio, PFR) beta-cell function estimates were calculated. Between-meal differences in glucose, insulin, C-peptide, triglyceride (TG), beta-cell function and oral glucose insulin sensitivity (OGIS) and between-meal correlations for beta-cell function and OGIS were evaluated.ResultsAmong healthy subjects, beta-cell function and OGIS were similar between meals. C-peptide (p=0.03), insulin (p=0.002), AUCinsulin/AUCglucose (p=0.004) and insulin secretion (p=0.04) were higher after the liquid meal. Among T2D subjects, glucose, insulin, C-peptide, beta-cell function, and OGIS were similar. PFR was higher (p=0.004) and TG increased more slowly (p=0.002) after the liquid meal. OGIS and beta-cell function were correlated during both meals in both groups (r=0.66–0.98), except incremental AUCinsulin/AUCglucose, rate sensitivity, and, in healthy subjects, PFR.ConclusionsMetabolic responses after mixed or liquid meals of similar content were highly correlated in T2D and healthy subjects. In T2D, the liquid meal produced beta-cell function estimates generally similar to the mixed meal