Radiotherapy Dose Escalation for Non-operative Management of Unresectable Locally Recurrent Rectal Cancer (STEP-UP)

Inclusion Criteria: * Age ≥ 18 years old. * Diagnosis of locally recurrent rectal cancer, defined as recurrent disease within the pelvis after surgical excision for primary rectal or distal sigmoidal cancer, diagnosed either by histopathology or clinically proven (evidence on imaging in combination with clinical findings, with consensus in MDT). A second recurrence is eligible if (chemo-)reirradiation is considered feasible, with consensus in MDT. * Recurrent disease is determined as unresectable where surgery has been ruled out by clinicians (or refused by patient), with consensus in MDT. Unresectable is defined as: expected gross incomplete resection with overt tumour remaining in the patient after resection, encasement of the ischiadic nerve and invasion of the cortex and/or neuroforamina from S2 and upwards. \- Either radiological absence of distant metastatic disease (M0), or, with (oligo)metastatic disease that does not require imminent start of systematic therapy at time of inclusion. If systematic chemotherapy was previously administered prior to inclusion, and there is a current indication for local treatment with radiotherapy, patients are still eligible. * WHO/ECOG performance score 0-2. * MR pelvis and thoracoabdominal CT with interpretation no longer than 6 weeks prior to inclusion. * Written informed consent according to the ICH-GCP and national/local regulations. Exclusion Criteria: * Radiological evidence of extensive metastatic disease (e.g., extensive liver or lung metastases) at time of inclusion, that requires imminent start of systemic therapy, with consensus in MDT. * Radiotherapy in the past 6 months. * Any contraindication for planned radiotherapy dose escalation, as determined by the radiation oncologist (e.g., residual grade 3 toxicity from previous radiotherapy). * Administration of bevacizumab/panitumumab/cetuximab \<6 weeks prior to start radiotherapy dose escalation. * Severe active morbidity, concomitant disease or active infections. * dMMR/MSI status