Background: A Watch and Wait (W&W) strategy has been advocated for selected patients with a locally advanced rectal cancer (LARC) and a clinical complete response (cCR) after neoadjuvant treatment (NAT). In this context, total neoadjuvant therapy (TNT) has emerged as a strategy to enhance treatment response. Currently, TNT has reported higher rates of pathological complete response (pCR) and organ preservation when compared to long course radiotherapy (LCRT). However, the best TNT strategy is still unknown. We therefore hypothesize that in LARC patients, the use of a TNT strategy based on short course radiotherapy (SCRT) followed by consolidation chemotherapy is associated with a higher rate of pCR and sustained (>1year) cCR when compared to an historic cohort treated with LCRT. Methods: This is a prospective, single arm, phase II study that is currently enrolling patients with LARC (AJCC TNM cT3-T4 w/wo secondary lymph nodes according to clinical staging) > 18 years old from a tertiary hospital from Santiago, Chile. We included patients with biopsy proven palpable (<7cm from anal verge) adenocarcinoma from the middle-lower rectum. We excluded patients with contraindications to SCRT and/or chemotherapy. All patients receive SCRT (5x5 Gy) followed by systemic consolidation chemotherapy 7-14 days after last dose of SCRT, using either 9 cycles of FOLFOX or 6 cycles of CAPOX. Patients will be evaluated to determine the degree of response at 3 time points during TNT: baseline, mid-TNT (9 weeks after TNT beginning) and post-TNT (18 weeks after TNT beginning). At each time point, patients will be clinically evaluated with a DRE, flexible sigmoidoscopy (photos & video) and a magnetic resonance image of the rectum. CT scan will be performed at baseline and complete TNT. Treatment response will be categorized as cCR, near-cCR and incomplete response (IR) according to the Memorial Sloan Kettering Regression Schema previously validated in the OPRA Trial. Patients with an IR will be offered TME. Patients with a cCR will be offered a W&W strategy, if accepted. Patients with a near-cCR will be evaluated again in 4 weeks to define cCR versus IR. In cases of TME, surgical specimens will be processed in a standardized manner and tumor regression grade will be assessed using the American College of Pathologist’s Scale. Additionally, validated quality of life questionnaires will be administered at the baseline, post-NAT and at 6,12 and 24 months of follow-up. Finally, a repository for endoscopic/MRI imaging, tumoral tissue and serum will be obtained. For statistical analysis, an α level of error of 5% will be set. For sample size calculation, a pCR rate of 12% was used based in historic data. Using a previously reported design and considering a 30% of combined pCR/sustained cCR, sample size to prove statistical significance with β power of 80% and error of 10% will be 73 patients. Clinical trial information: NCT04864067.