Clinical outcome after total neoadjuvant treatment (CAO/ARO/AIO-12) versus intensified neoadjuvant and adjuvant treatment (CAO/ARO/AIO-04) a comparison between two multicenter randomized phase II/III trials

•Intertrial comparison between intensified neoadjuvant chemoradiotherapy and adjuvant chemotherapy (CAO/ARO/AIO-04) vs Total Neoadjuvant Therapy (CAO/ARO/AIO-12)•Total Neoadjuvant Therapy improves rates of pathological complete remission compared to intensified neoadjuvant chemoradiotherapy.•But Total Neoadjuvant Therapy did not improve oncological outcome compared to intensified neoadjuvant chemoradiotherapy and adjuvant chemotherapy.•Oncologic outcomes were not significantly different among subgroups and after propensity score matching analysis.•Total mesorectal excision quality or rates of post-surgical complications did not deteriorate after prolonged time to surgery. Total neoadjuvant therapy (TNT) can enhance local tumor regression, but its survival benefits compared to intensified chemoradiotherapy (CRT) followed by adjuvant chemotherapy (CT) remain unclear. This is a secondary comparison between 607 patients treated with intensified 5-FU/Oxaliplatin neoadjuvant CRT and adjuvant CT within the experimental arm of the CAO/ARO/AIO-04 phase III trial, and 306 patients treated with TNT within the CAO/ARO/AIO-12 phase II trial. Comparison between clinical-pathological characteristics, surgical quality, and post-surgical complications were analyzed using the Pearson’s Chi-squared or Mann-Whitney U test. Oncological outcome was examined with log-rank, Gray’s test, and multivariate cox regression. In addition, further subgroup analyses and propensity score matching were performed to optimize the balance of baseline covariates. Patients treated with CRT followed by consolidation CT had a significantly higher rate of pathological complete remission (pCR) compared to patients treated within the experimental arm of the CAO/ARO/AIO-04 trial (25.3 % vs 17.3 %, P = 0.04). Post-surgical complications were less common in the CAO/ARO/AIO-12 trial. After a median follow-up of 46 months, clinical outcome did not differ significantly in the overall cohort, in any subgroup or after propensity score matching. In multivariate analysis, disease-free survival (DFS) was similar between the experimental arm of the CAO/ARO/AIO-04 trial and treatments arms of the CAO/ARO/AIO-12 trial (vs arm A: HR 0.92 [95 % CI 0.62–1.37], P = 0.69; vs arm B: HR 1.06 [95 % CI 0.72–1.58], P = 0.76). Notwithstanding the limitations of intertrial comparison, TNT did not improve long term oncological outcome in our study compared to the intensified neoadjuvant CRT and adjuvant CT treatment in the CAO