Chemoradiotherapy plus induction or consolidation chemotherapy as total neoadjuvant therapy for locally advanced rectal cancer: Pooled analysis of the CAO/ARO/AIO-12 and the OPRA randomized phase 2 trials.

Background: Total neoadjuvant therapy (TNT) has been used for patients with locally advanced rectal cancer. The optimal sequence of chemoradiotherapy (CRT) and chemotherapy (CT) is a matter of debate.
Methods: We performed a pooled analysis of the CAO/ARO/AIO-12 and OPRA multicenter, randomized phase 2 trials to identify patient subsets that could benefit from one TNT sequence over the other regarding disease-free survival (DFS). Patients with stage II/III rectal cancer were randomized to CRT (50.4-54 Gy) with either induction (INCT-CRT) or consolidation CT (CRT-CNCT) with fluorouracil, leucovorin, oxaliplatin (CAO/ARO/AIO-12 and OPRA) or capecitabine and oxaliplatin (OPRA) followed by mandatory total mesorectal excision (TME) (CAO/ARO/AIO-12) or selective watch-and-wait surveillance (OPRA). 311 and 324 patients were recruited from June 15, 2015 to January 31, 2018; and from April 12, 2014 to March 30, 2020 in the two trials, respectively. Pretreatment clinical and tumor characteristics included were age, sex, ECOG, cT-category, cN-category, clinical UICC stage, location from anal verge, and tumor grade.
Findings: In total, 628 eligible patients were included in the pooled analysis (CAO/ARO/AIO-12, n = 304; OPRA, n = 324). Of those, 313 were randomly assigned to the INCT-CRT group, and 315 to the CRT-CNCT group. Median follow-up was 43 months (IQR, 35-49) months in the CAO/ARO/AIO-12 trial and 61,2 months (IQR, 42-68,4) in the OPRA trial. Pooled analysis of baseline clinical and tumor characteristics did not identify any subgroups of patients that would benefit by the one TNT sequence over the other with regard to DFS.
Interpretation: To our knowledge, this is the first pooled analysis of two randomized trials after direct head-to-head comparison of both TNT sequences. Both trials reported higher rates of complete response with CRT-CNCT, and this should be considered the preferred TNT sequence if organ preservation is a priority.
Competing Interests: Declaration of Competing Interest The CAO/ARO/AIO-12 trial was supported by a grant from the German Cancer Aid (Deutsche Krebshilfe; funding number 110460). The OPRA trial was supported by grants from the National Cancer Institute of the United States R01CA182551, P30CA008748, and T32 CA009501. These were investigator-initiated trials and, hence, the funding organizations had no influence on and did not contribute to either the design and conduct of the study, collection, management, analysis, and interpretation of the data, preparation, review, or approval of the manuscript, and decision to submit the manuscript for publication. EF has received research funding from AstraZeneca and honoraria from Celgene, Merck and Akamis Bio UK. AJW has ownership Interests in Simphotek, had an advisory Role for AstraZeneca, MORE Health and NanoVi, and has received research funding and expenses from CivaTech Oncology. LBS had an advisory role for Genor, and has received research funding from Taiho Pharmaceutical. JJS received travel support for fellow education from Intuitive Surgical. He also served as a clinical advisor for Guardant Health and as a clinical advisor for Foundation Medicine. He served as a consultant and speaker for Johnson and Johnson and serves as a clinical advisor and consultant for GlaxoSmithKline. MW has served as consultant for Precisca, received funding from Clinical Genomics and is UpToDate Section Editor. TF reported receiving grants from German Cancer Aid (Deutsche Krebshilfe) and personal fees from Bayer Consultancies, Janssen Consultancies, Novartis Consultancies, Roche Consultancies, Vifor Consultancies, Fresenius Kabi Consultancies, CSL Behring Consultancies, and Minoryx Consultancies outside the submitted work. JGA owns stock in Intuitive Surgical and receives as Honoraria for Johnson & Johnson and Intuitive Surgical. He is also a consultant for Medtronic, Intuitive Surgical, and Johnson & Johnson. We thank the patients, investigators, and institutions involved in those two trials. All remaining authors have declared no conflicts of interest.
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