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; E Fokas; M Diefenhardt; C Lee; F S Verheij; D M Omer; S T Lin; R F Dunne; J Marcet; P Cataldo; B Polite; P Piso; B Polat; H Dapper; M Ghadimi; R D Hofheinz; L-X Qin; L B Saltz; A J Wu; M J Gollub; J J Smith; M R Weiser; C Rödel; J Garcia-Aguilar; German Rectal Cancer Study Group; OPRA Consortium

doi:10.1016/j.annonc.2025.01.006

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

Ann Oncol. 2025 Jan 21:S0923-7534(25)00010-9. doi: 10.1016/j.annonc.2025.01.006. Online ahead of print.

Authors

H Williams¹, E Fokas², M Diefenhardt³, C Lee¹, F S Verheij¹, D M Omer¹, S T Lin⁴, R F Dunne⁵, J Marcet⁶, P Cataldo⁷, B Polite⁸, P Piso⁹, B Polat¹⁰, H Dapper¹¹, M Ghadimi¹², R D Hofheinz¹³, L-X Qin⁴, L B Saltz¹⁴, A J Wu¹⁵, M J Gollub¹⁶, J J Smith¹, M R Weiser¹, C Rödel¹⁷, J Garcia-Aguilar¹⁸; German Rectal Cancer Study Group; OPRA Consortium

Affiliations

¹ Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York, United States.
² Department of Radiotherapy and Oncology, University of Frankfurt, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany; German Cancer Consortium (DKTK), Partner Site: Frankfurt, Germany; Frankfurt Cancer Institute, Frankfurt, Germany; Department of Radiation Oncology, Cyberknife and Radiotherapy, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf (CIO ABCD), Faculty of Medicine Cologne, University Hospital Cologne, Cologne, Germany.
³ Department of Radiotherapy and Oncology, University of Frankfurt, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany; German Cancer Consortium (DKTK), Partner Site: Frankfurt, Germany; Frankfurt Cancer Institute, Frankfurt, Germany.
⁴ Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, United States.
⁵ Department of Medicine, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, United States.
⁶ Division of Colon and Rectal Surgery, Department of Surgery, University of South Florida, Tampa, Florida, United States.
⁷ Division of General Surgery, Department of Surgery, University of Vermont, Burlington, Vermont, United States.
⁸ Department of Medicine, Comprehensive Cancer Center, University of Chicago, Chicago, Illinois, United States.
⁹ Department of General and Visceral Surgery, Barmherzige Brüder Hospital, Regensburg, Germany.
¹⁰ Department of General and Visceral Surgery, University of Würzburg, Würzburg , Germany.
¹¹ Department of Radiation Oncology, Cyberknife and Radiotherapy, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf (CIO ABCD), Faculty of Medicine Cologne, University Hospital Cologne, Cologne, Germany.
¹² Department of General and Visceral Surgery, University Medical Center Göttingen, Göttingen, Germany.
¹³ Department of Medical Oncology, University Hospital Mannheim, Mannheim, Germany.
¹⁴ Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, United States.
¹⁵ Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, United States.
¹⁶ Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York, United States.
¹⁷ Department of Radiotherapy and Oncology, University of Frankfurt, Germany.
¹⁸ Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York, United States. Electronic address: [email protected].

PMID: 39848335
DOI: 10.1016/j.annonc.2025.01.006

Abstract

Background: Prospective data comparing watch-and-wait (WW) to mandatory total mesorectal excision (TME) in patients with locally advanced rectal cancer (LARC) remains 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 six 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 (IQR 1.13) 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.