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Multicenter Study
. 2025 Sep 1;11(9):1045-1054.
doi: 10.1001/jamaoncol.2025.2026.

Total Neoadjuvant Therapy for Locally Advanced Rectal Cancer

Alessandro Audisio  1   2 , Chiara Gallio  1 , Vaneja Velenik  3 , Hélène Meillat  4 , Erika Ruiz-Garcia  5 , Maria Carmen Riesco  6 , Javier Suárez Alecha  7 , Gertjan Rasschaert  8 , Carlos Carvalho  9 , Violaine Randrian  10 , Iva Kirac  11 , Jorge Hernando  12 , Mehmet Artaç  13 , Juan Manuel O'Connor  14 , Ithai Waldhorn  15 , Pètra M Braam  16 , Ali Shamseddine  17 , Roberto Moretto  18 , Carolina De la Pinta  19 , Francesca De Felice  20 , Audrius Dulskas  21 , David Páez López-Bravo  22 , Alexander Vanden Bulcke  23 , Felix Bock  24 , Amélie Deleporte  25 , Marc Van Den Eynde  26 , Karen P Geboes  27 , Mauro Loi  28 , Marco Messina  29 , Constance Houlzé-Laroye  30 , Alberto Puccini  31   32 , Alessandro Pastorino  33 , Demetris Papamichael  34 , Michele Fiore  35 , Daniel Sur  36 , Michal Eid  37 , Claire Antoun  38 , Massimiliano Salati  39 , Ingrid Garajovà  40 , Matas Jakubauskas  41 , Jirí Tomášek  42 , Cidália Maria Sousa Pinto  43 , Jerome Schwingel  44 , Federica Morano  45 , Richard A Adams  46 , Alexandre Dermine  47 , Amélie Chau  48 , Muhammad Ahsan Javed  49 , Michele Ghidini  50 , Francesco Fiorica  51 , Paola Montenegro  52 , Angelica Petrillo  53 , Gaya Spolverato  54 , Núria Mulet Margalef  55 , Marie Diaz  56 , Chiara Baratelli  57 , Francesco Puleo  58 , Athanasios Karampeazis  59 , Fatma Sert  60 , Quentin Gilliaux  61 , Alfonso De Stefano  62 , Gabriel Liberale  1 , Luigi Moretti  1 , Philippe Martinive  1 , Vaiva Deltuvaite Thomas  63 , Vincent Staggs  63 , Everardo D Saad  63 , Jean-Luc Van Laethem  1 , Francesco Sclafani  1 ; International Real-World TNT Study Consortium
Collaborators, Affiliations
Multicenter Study

Total Neoadjuvant Therapy for Locally Advanced Rectal Cancer

Alessandro Audisio et al. JAMA Oncol. .

Erratum in

  • Error in Author Affiliation.
    [No authors listed] [No authors listed] JAMA Oncol. 2025 Sep 1;11(9):1099. doi: 10.1001/jamaoncol.2025.3830. JAMA Oncol. 2025. PMID: 40965907 Free PMC article. No abstract available.

Abstract

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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Ruiz-Garcia reported personal fees from Roche/Genentech, Amgen, BMS, Astellas, and Merck Serono and nonfinancial support from Bayer and Gilead outside the submitted work. Dr Riesco-Martínez reported personal fees from Servier and Mundipharma and nonfinancial support from Amgen and Merck outside the submitted work. Dr Gertjan Rasschaert reported personal fees from Agenus, GSK, Medimix, MSD, and Neapolis Pharma, grants from GSK, and nonfinancial support from MSD, Ipsen, Esmo, and Servier outside the submitted work. Dr Randrian reported personal fees from Takeda, MSD, Merck Serono, Amgen, and Servier during the conduct of the study. Dr Moretto reported personal fees from Takeda and Amgen outside the submitted work. Dr Paez reported grants from Merck, personal fees from Amgen, Novartis Support, Esteve, and MSD outside the submitted work. Dr Deleporte reported personal fees from Servier and travel feeds from Amgen and Merckx outside the submitted work. Dr Geboes reported personal fees from BMS, MSD, Servier, Ipsen, Beigene, AstraZeneca, Amgen, and Meck Darmstadt and grants from Incyte outside the submitted work. Dr Piessen reported personal fees from BMS, Nestle, Astellas Pharma, Medtronic, MSD, Daiichi, Elivie, and Stryker outside the submitted work. Dr Puccini reported personal fees from GlaxoSmithKline, Takeda, Bayer, Daiichi Sankyo, MSD, Pierre Fabre, Servier, Amgen, and BMS and grants from GlaxoSmithKline and Amgen outside the submitted work. Dr Papamichael reported grants from Roche and Merck and institutional fees Merck Serono, Ipsen, and Servier outside the submitted work. Dr Eid reported personal fees from Merck, Ipsen, Roche, and Servier during the conduct of the study. Dr Borg reported grants from Bayer, Boehringer, and Merck Serono and personal fees from Molecular, Pierre Fabre, MSD, and Servier outside the submitted work. Dr Morano reported personal fees from Pierre Fabre, Accademia della Medicina, and Servier, grants from Incyte, and nonfinancial support from Amgen and Pierre Fabre outside the submitted work. Dr Petrillo reported personal fees from MSD, BMS, Merck Serono, Servier, Amgen, AstraZeneca, Roche, and Bayer outside the submitted work. Dr De Stefano reported nonfinancial support from Pierre Fabre and Servier outside the submitted work. Dr Sclafani reported personal fees from AMAL Therapeutics, Amgen, Bayer, BMS, Dragonfly Therapeutics, GKS, Nordic Pharma, Roche, and Servier; grants from Astellas, AstraZeneca, MSD, Pierre-Fabre, Sanofi, Amgen, Bayer, BMS, Merck, Roche, and Servier; and nonfinancial support from Lilly, Amgen, AstraZeneca, Bayer, Merck, Roche, and Servier outside the submitted work, as well as being the secretary of the European Organisation for Research and Treatment of Cancer Gastrointestinal Tract Cancer Group. No other disclosures were reported.

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