Total Neoadjuvant Therapy for Locally Advanced Rectal Cancer.

Importance: This was a clinical study of total neoadjuvant therapy (TNT) for rectal cancer. Objective: To assess the use and outcomes of TNT in routine practice. Design, Setting, and Participants: This international, multicenter study was conducted at 61 centers across 21 countries and included consecutive patients treated off trial with TNT for stage II/III rectal adenocarcinoma from September 2012 to December 2023. Data were analyzed between August and October 2024. Exposure: TNT, defined as the delivery of radiotherapy and nonradiosensitizing chemotherapy before surgery or watch and wait. Main Outcomes and Measures: The primary outcome was type of TNT administered. Secondary outcomes were patient characteristics, treatment adherence, safety, and efficacy overall and by type of TNT in the entire population and after propensity vector matching. Results: A total of 1585 patients (588 female [37.1%]; median [IQR] age, 61 [53-68] years) were included, 1260 (79.5%) of whom had 1 or more high-risk features (eg, cT4, cN2, extramural venous invasion, threatened/involved mesorectal fascia, and lateropelvic lymphadenopathy). Patients were treated with the PRODIGE 23-like regimen (FOLFIRINOX/FOLFOXIRI followed by long-course chemoradiotherapy) (271 [17.7%]), RAPIDO-like regimen (short-course radiotherapy followed by consolidation FOLFOX/CAPOX) (529 [33.4%]), OPRA induction-like (induction FOLFOX/CAPOX followed by long-course chemoradiotherapy) (190 [12.0%]), OPRA consolidation-like (long-course chemoradiotherapy followed by consolidation FOLFOX/CAPOX) (257 [16.2%]), and other regimens (360 [22.7%]). After TNT, 192 (12.1%) underwent watch and wait, and 30 (1.9%) underwent local excision. Pathological or clinical complete response was reported in 23.2% of cases. At treatment failure, 8.5% was local and 16.4% was distant progression. Three-year event-free survival (EFS) was 68% (95% CI, 64%-71%), and 5-year overall survival (OS) was 79% (95% CI, 75%-83%). In the overall population, patients treated with the PRODIGE 23-like regimen were most likely to have serious adverse events (61 [23.5%]) but had better local control and survival outcomes than those treated with the RAPIDO-like (EFS: hazard ratio [HR], 0.68; 95% CI, 0.49-0.95; P = .03; OS: HR, 0.51; 95% CI, 0.27-0.97; P = .04), OPRA induction-like (EFS: HR, 0.66; 95% CI, 0.44-0.98; P = .04; OS: HR, 0.35; 95% CI, 0.18-0.70; P = .003), and OPRA consolidation-like (EFS: HR, 0.64; 95% CI, 0.44-0.93; P = .02; OS: HR, 0.50; 95% CI, 0.25-1.00; P = .05) regimens. In the matched population (928 patients [58.5%]), no differences in survival outcomes were observed between the TNT regimens. Conclusions and Relevance: The findings of this case series study show substantial variation in the choice of the TNT regimen and were overall aligned with those reported in clinical trials, suggesting the efficacy of TNT in a clinical setting regardless of the specific regimen.