Background: Total neoadjuvant therapy (TNT) has recently become a standard therapy for locally advanced rectal cancer (LARC). All nonsurgical interventions, including chemotherapy and concurrent chemoradiotherapy (CRT), are administered before either surgical resection of the rectum or non-operative management (NOM), depending on response to TNT. In the case of NOM, the impact of distant relapse on survival remains to be elucidated and circulating tumor DNA (ctDNA) monitoring has been proposed as a tool for early detection of relapse. Furthermore, predictive biomarkers of response to TNT are warranted for the early identification of patient candidates for NOM. In this regard, stromal contribution to sensitivity to pre-operative CRT is investigated by a transcriptomic signature on baseline tumor samples, as previously proposed by Isella C et al., Nature Genet, 2015. Methods: NO-CUT is a multicenter one-stage phase II trial aimed at assessing if a TNT approach with CAPOX followed by CRT can safely spare demolitive surgery in patients with LARC achieving a clinical complete response without increasing the risk of distant metastatic relapse. A Brookmeyer and Crowley approach was chosen to test the null hypothesis that the true distant relapse-free survival at 2.5 years rate is ≤75% against a one-sided alternative. The NOM cohort of the trial needs to accrue 44 evaluable patients and to be followed for at least 2.5 years. Such design yields a type I error rate of 10% and power of 80% when the true 2.5 years distant RFS proportion is 87%. Since it is assumed that the proportion of patients entering in the NOM cohort of the trial is at least 25%, a total of 180 patients are to be enrolled in NO-CUT study. Patients with medium-low LARC undergo TNT (4 cycles of CAPOX: capecitabine 1000 mg/m² bid days 1-14 q 3 weeks; oxaliplatin 130 mg/m² day 1 q 3 weeks) and 5 weeks of standard pelvic CT-RT, then restaging with imaging (MRI, CT-scan, and ultrasound endoscopy), and tumor biopsy. According to an algorithm defined for assessing tumor response, patients enter either NOM or surgery cohorts. During the follow-up phase of the trial, the NOM cohort is followed with intensive pelvic imaging and periodic blood samplings for 5 years. Tumor samples and ctDNA are studied at baseline, after TNT, and during follow-up. As of January 2023, 161 of planned 180 patients in 4 centers have been enrolled. Supported by grants from Associazione Italiana Ricerca Cancro (AIRC IG 2017-20685) and Fondazione Oncologia Niguarda. Clinical trial information: EudraCT 2017-003671-60.