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Clinical Trial
. 2025 May;36(5):543-547.
doi: 10.1016/j.annonc.2025.01.006. Epub 2025 Jan 21.

Survival among patients treated with total mesorectal excision or selective watch-and-wait after total neoadjuvant therapy: a pooled analysis of the CAO/ARO/AIO-12 and OPRA randomized phase II trials

H Williams  1 , E Fokas  2 , M Diefenhardt  3 , C Lee  1 , F S Verheij  1 , D M Omer  1 , S T Lin  4 , R F Dunne  5 , J Marcet  6 , P Cataldo  7 , B Polite  8 , P Piso  9 , B Polat  10 , H Dapper  11 , M Ghadimi  12 , R D Hofheinz  13 , L-X Qin  4 , L B Saltz  14 , A J Wu  15 , M J Gollub  16 , J J Smith  1 , M R Weiser  1 , C Rödel  17 , J Garcia-Aguilar  18 ; German Rectal Cancer Study Group; OPRA Consortium
Affiliations
Clinical Trial

Survival among patients treated with total mesorectal excision or selective watch-and-wait after total neoadjuvant therapy: a pooled analysis of the CAO/ARO/AIO-12 and OPRA randomized phase II trials

H Williams et al. Ann Oncol. 2025 May.

Abstract

Background: Prospective data comparing watch-and-wait (WW) to mandatory total mesorectal excision (TME) in patients with locally advanced rectal cancer (LARC) remain limited, as randomized control trials assessing these two treatment approaches are considered impractical. This pooled analysis of the CAO/ARO/AIO-12 and OPRA trials analyzes survival outcomes among LARC patients managed with either a selective WW or mandatory TME strategy following total neoadjuvant therapy (TNT).

Patients and methods: The CAO/ARO/AIO-12 and OPRA trials were multicenter, phase II trials that randomized patients with stage II/III rectal cancer to receive either induction or consolidation chemotherapy as part of TNT. All patients in the CAO/ARO/AIO-12 trial underwent TME within 6 weeks of completing TNT. The OPRA trial allowed patients with a complete or near-complete response to enter WW while those with an incomplete response proceeded to TME. The primary endpoint of the present pooled analysis was disease-free survival (DFS). Secondary endpoints included distant recurrence-free survival (DRFS), local recurrence-free survival (LRFS) and overall survival (OS).

Results: This pooled analysis included 628 patients (n = 304 CAO/ARO/AIO-12; n = 324 OPRA). Median follow-up was 3.6 [interquartile range (IQR) 1.13] years and 5.1 (IQR 2.2) years, respectively. Patients in the CAO/ARO/AIO-12 trial were more likely to have cT3/4 and cN-positive disease while patients in the OPRA trial had tumors closer to the anal verge. Compliance to TNT and rates of grade 3+ adverse events were similar between studies. There were no differences in DFS, DRFS, LRFS or OS based on treatment strategy or TNT treatment arm.

Conclusions: This pooled analysis demonstrated equivalent oncologic outcomes between patients treated with mandatory TME and selective WW strategies following TNT. These results strengthen available evidence indicating that WW is a safe treatment option for patients with an excellent response to neoadjuvant therapy.

Keywords: locally advanced rectal cancer; nonoperative management; total neoadjuvant therapy; watch-and-wait.

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Conflict of interest statement

Disclosures: EF: research funding from AstraZeneca and honoraria from Celegne, Merck and Akamis Bio UK. RFD: Honoraria for consulting/advisory board for Helsinn Healthcare SA, Merck & Co., Exelixis Inc., and Toray Industries, Inc. RDH: Advisory role for Abbvie, Amgen, Astra Zeneca, Astellas, Bayer, BeiGene, BMS, Boehringer, Daiichi, GSK, Leo Pharma, Lilly, Merck, MSD, Nordic, Pierre Fabre, Roche, Saladax, Sanofi, Servier, WALA. Honoraria from Amgen, Roche, Merck, Sanofi, Daiichi, Bayer, medac, MSD, Boehringer, BMS, Saladax, Astra Zeneca, Lilly, Servier, Pierre Fabre, medupdate, Astellas, Nordic, WALA, Leo Pharma, Abbvie, Onkowissen, Falk Foundation. Research funding from German Cancer Aid. Review activities for German Cancer Aid JJS: travel support for fellow education from Intuitive Surgical. Clinical advisor for Guardant Health and Foundation Medicine. Consultant and speaker for Johnson and Johnson. Clinical advisor and consultant for GSK. CR: Research funding from German Cancer Aid and honoraria from Merck and GSK. JGA: honoraria from Medtronic, Johnson& Johnson, and Intuitive Surgical. All remaining authors have declared no conflicts of interest.

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