Potential overtreatment in MRI-defined low-risk locally advanced rectal cancer in the era of neoadjuvant therapy: An international cohort study.

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Background: Multimodal neoadjuvant therapy, including chemoradiotherapy (CRT) and total neoadjuvant therapy, is the standard treatment for locally advanced rectal cancer (LARC). However, reliance solely on clinical staging may lead to overtreatment in biologically favorable tumors. Beyond oncological control, pelvic radiotherapy is associated with significant late toxicities, including chronic presacral sinus, secondary malignancies, and impaired bone marrow reserve, potentially compromising the tolerance to systemic therapy upon recurrence. For patients with favorable tumor biology, avoiding unnecessary pelvic irradiation can significantly impact on long-term outcomes and quality-of-life. From this perspective, we assessed the extent of potential overtreatment in MRI-defined low-risk LARC, using an international database from two tertiary centers in Japan and South Korea. Methods: Among 881 patients with clinically staged T2–3 node-positive or T3 node-negative LARC treated between 2013 and 2021, 298 who underwent upfront surgery were identified for this study. Clinical low-risk features were defined on preoperative MRI as the absence of N2 disease, mesorectal fascia involvement (≤1 mm), extramural venous invasion, or enlarged lateral pelvic lymph nodes. Of these, 169 patients (56.7%) were categorized as MRI-defined low risk and included in the analysis. Results: Within the cohort of 169 patients, pathological ≤T2N0 disease was identified in 24.3% (n=41), for whom no adjuvant treatment would typically be required. Pathological T3N0 was observed in 34.9% (n=59); in these cases, adjuvant therapy would generally be considered only in the presence of additional high-risk pathological features, such as lymphovascular invasion, non-well/moderately differentiated histology, or positive surgical margins. Notably, these high-risk features were absent in 45.5% of the pathological T3N0 patients. Overall, 40.2% of patients did not require adjuvant therapy based on the final pathology, indicating substantial clinical–pathological discordance. Conclusions: In addition to previously observed lower postoperative complication rates with upfront surgery than with neoadjuvant CRT, a considerable proportion of MRI-defined low-risk LARC demonstrated favorable pathological characteristics and low margin positivity despite clinically advanced staging. Therefore, routine preoperative intensive therapy may represent overtreatment in selected patients. These findings support MRI-guided, risk-adapted treatment strategies and warrant prospective validation.