Clinical Research Directory

Inclusion criteria: * Age 18 years or older. * Eastern Cooperative Oncology Group performance status 0-1. * Fit for combination chemotherapy. * Biopsy-verified primary locally advanced rectal adenocarcinoma. * At least one high-risk feature: cT3c, cT4a, or cT4b disease; tumour or lymph node 1 mm or less from the mesorectal fascia; enlarged lateral pelvic lymph nodes; or extramural vascular invasion on MRI. * Laboratory values adequate for chemotherapy according to local guidelines. * Able to understand the study information and provide written informed consent. * Willing to receive dose-escalated short-course proton radiotherapy. * Willing and able to travel to the Danish Centre for Particle Therapy for planning and treatment. Exclusion criteria: * Rectal tumour invading cranial sacral bone or lumbosacral nerve roots. * Distant metastatic disease at baseline (M1). * Mismatch repair-deficient or microsatellite instability-high tumour. * Recurrent rectal cancer. * Previous pelvic radiotherapy. * Serious comorbidity or other condition making total neoadjuvant therapy unsafe in the investigator's judgement. * Pregnancy or breastfeeding. * Inability to comply with study procedures or follow-up. * Implant, including an artificial hip, that precludes proton therapy. * Contraindication to MRI, including an incompatible cardiac implantable electronic device.