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. 2025 Nov 20.
doi: 10.1245/s10434-025-18777-6. Online ahead of print.

A Clinical Primer for Defining Time Zero in Rectal Cancer Studies of Nonoperative Management: Implications for Survival and Local Regrowth

Bailey K Hilty Chu  1 , Totadri Dhimal  2 , Megan Boyer  2 , Anthony Loria  2 , Samuel H Lai  3 , Xueya Cai  2   4 , Yue Li  2   5 , Paula Cupertino  2 , Virgilio George  6 , Christopher T Aquina  7 , Colleen Donahue  6 , Jon D Vogel  3 , Fergal J Fleming  2 ; United States Rectal Cancer Research Group
Collaborators, Affiliations

A Clinical Primer for Defining Time Zero in Rectal Cancer Studies of Nonoperative Management: Implications for Survival and Local Regrowth

Bailey K Hilty Chu et al. Ann Surg Oncol. .

Abstract

Background: Contemporary cancer research prioritizes clinical endpoints such as overall survival (OS) and disease-free survival (DFS). However, definition of the starting point, "time zero," for time-to-event analyses remains inconsistent in the rectal cancer nonoperative management (NOM) literature, affecting study comparisons. Moreover, the traditional definition of DFS for NOM is complicated given the success of salvage surgery for local regrowth (LR). Our aim was to evaluate how these definitions affect estimates of OS, LR, and DFS.

Methods: We analyzed both a single-institution and a multi-institution cohort of patients with rectal cancer on NOM, shifting time zero from diagnosis to the post-treatment response assessment and to the date of clinical complete response (cCR) determination.

Results: In the single-institution NOM cohort of 85 patients, shifting time zero from diagnosis to cCR determination led to a median 5-year OS decrease of 5% (87%→82%) and a 3-year LR rate increase of 4% (26%→30%). Importantly, the 5-year DFS increased by 23% (56%→79%) after excluding successful surgical disease salvage. In the multi-institutional dataset of 450 NOM patients, a shift of time zero from diagnosis to cCR determination led to a median 5-year OS decrease of 1.6% (94.2%→92.6%) and a 3-year LR rate increase of 1.1% (16.0%→17.1%). Five-year DFS increased by 8.3% (74.7%→83%) after excluding successfully salvaged disease.

Conclusions: The range of definitions of time zero and DFS affect oncologic estimates in NOM for rectal cancer, particularly in datasets with smaller sample sizes, which may misrepresent oncologic outcomes. This underscores the need for standardization to ensure accurate comparisons across studies and guide shared decision-making.

Keywords: Local regrowth; Nonoperative management; Overall survival; Rectal cancer; Time zero; Time-to-event analyses; Watch-and-wait.

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Conflict of interest statement

Disclosure: Fergal Fleming has received royalties from UpToDate for work unrelated to this study. The other authors have no disclosures to report.

References

    1. Delgado A, Guddati AK. Clinical endpoints in oncology - a primer. Am J Cancer Res. 2021;11(4):1121–31. - PubMed - PMC
    1. Habr-Gama A, Perez RO, Nadalin W, et al. Operative versus nonoperative treatment for stage 0 distal rectal cancer following chemoradiation therapy: long-term results. Ann Surg. 2004;240(4):711–7. https://doi.org/10.1097/01.sla.0000141194.27992.32 . - DOI - PubMed - PMC
    1. Garcia-Aguilar J, Patil S, Gollub MJ, et al. Organ preservation in patients with rectal adenocarcinoma treated with total neoadjuvant therapy. J Clin Oncol. 2022;40(23):2546–56. https://doi.org/10.1200/JCO.22.00032 . - DOI - PubMed - PMC
    1. Cercek A, Roxburgh CSD, Strombom P, et al. Adoption of total neoadjuvant therapy for locally advanced rectal cancer. JAMA Oncol. 2018;4(6):e180071. https://doi.org/10.1001/jamaoncol.2018.0071 . - DOI - PubMed - PMC
    1. Alvarez J, Shi Q, Dasari A, et al. ALLIANCE A022104/NRG-GI010: The Janus Rectal Cancer Trial: a randomized phase II/III trial testing the efficacy of triplet versus doublet chemotherapy regarding clinical complete response and disease-free survival in patients with locally advanced rectal cancer. medrxiv. 2024; https://doi.org/10.1101/2024.04.25.24306396

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