From Anatomy to Biology: Tumor Location has Limited Independent Value in Predicting Pathological Complete Response After Neoadjuvant Chemoradiotherapy

Abstract

Background Neoadjuvant therapy is the standard treatment for locally advanced rectal cancer; however, treatment response remains heterogeneous, and research has increasingly shifted from isolated anatomical predictors toward biologically integrated response assessment. This study evaluated whether anatomical tumor location was independently associated with pathological response to neoadjuvant therapy. Materials and Methods This multicenter retrospective study included 179 patients with stages II-III rectal adenocarcinoma undergoing long-course neoadjuvant chemoradiotherapy followed by total mesorectal excision between January 2023 and January 2026. Tumor location was categorized as upper (>10 cm), mid (5-10 cm), or low (<5 cm) rectum. Pathological response was assessed using the modified Ryan system, and major response was defined as TRG 0-1. Multivariable binary logistic regression evaluated factors associated with major pathological response, with multinomial regression as a secondary exploratory analysis. Results In the primary multivariable analysis, tumor location was not independently associated with major pathological response (global P = .358). Major response occurred in 47.5% of patients without lymphovascular invasion but in only 3.3% of those with lymphovascular invasion, which was associated with lower odds of major response (OR 0.05, 95% CI 0.01-0.15; P < .001). Conclusion Anatomical tumor location was not independently associated with pathological response following neoadjuvant chemoradiotherapy. These findings suggest that response assessment should extend beyond simple anatomical variables and be interpreted within the broader context of tumor biology and integrated clinicopathological assessment.