Background: Clinical response following neoadjuvant therapy is paramount to identifying locally advanced rectal cancer (LARC) patients suitable for Watch and Wait (WW). A 3-tier schema was devised to stratify clinical response. Patients with a complete clinical response (cCR) are considered for WW, while those with an incomplete clinical response (iCR) are recommended for total mesorectal excision (TME). A near complete response (nCR) tier captures patients with significant, but not complete, response to be considered for WW. This schema’s efficacy has yet to be validated. We investigated survival and organ preservation (OP) rates based on this 3-tier clinical response assessment in patients with LARC who underwent total neoadjuvant therapy (TNT) in a prospective, multi-center clinical trial. Methods: Patients with MRI stage II and III rectal adenocarcinoma were randomized to either induction chemotherapy (FOLFOX or CAPEOX) followed by chemoradiation or chemoradiation followed by consolidation chemotherapy (FOLFOX or CAPEOX). At 8+/-4 weeks following TNT, response on digital rectal and endoscopic examinations was evaluated by the 3-tier schema. The date of this restaging clinical response assessment was used as time zero. The endpoints of rate of OP, disease-free survival (DFS), TME-free DFS, and overall survival (OS) were evaluated using the Kaplan-Meier method with differences analyzed by the log-rank test. Results: Clinical response assessments were available for 294 patients. The median time to assessment after neoadjuvant therapy was 7.9 weeks. Based on the 3-tier schema, 124 patients were categorized as cCR, 113 as nCR, and 57 as iCR. Baseline age, sex, average distance from the anal verge, clinical T classification, and clinical N classification were similar between the response groups. The table shows the 3-year rates of OP, DFS, TME-free DFS, and OS. The median follow-up was 2.36 years. Of the patients with a nCR, the 3-year TME rate was 48% compared with 21% in the cCR group. Conclusions: The 3-tier clinical response assessment has prognostic implications for OP and DFS in patients with LARC who underwent TNT. In patients with a nCR, more than half achieved OP at 3 years. This information should be utilized to counsel patients regarding their expected outcomes. Clinical trial information: NCT02008656

CI=Confidence Interval.