Gastrointestinal Toxicity and Clinical Predictors of Total Neoadjuvant Therapy in Rectal Cancer: A Real-World Retrospective Study

<b>Background:</b> Total neoadjuvant therapy (TNT) is increasingly administered in rectal cancer, but compared with concurrent chemoradiotherapy (CRT), data regarding the gastrointestinal (GI) toxicity profile and clinical predictors remain limited. <b>Objectives:</b> To evaluate GI toxicity associated with TNT compared with CRT and to explore clinical predictors of these adverse events (AEs). <b>Methods:</b> This retrospective study included 201 patients with rectal cancer treated with TNT (<i>n</i> = 157) and CRT (<i>n</i> = 44). GI AEs (nausea, vomiting, diarrhea) were graded according to CTCAE v5.0. In the analysis of factors associated with GI AEs, multiple clinical and pathological variables were included using multivariable logistic regression. <b>Results:</b> The composite endpoint "any GI AEs grade ≥ 1" was more frequent in the TNT group compared with the CRT group (33.1% vs. 15.9%; RR = 2.08; 95% CI 1.02-4.25; <i>p</i> = 0.038). Nausea was significantly more frequent in the TNT group (28.7% vs. 9.1%; RR = 3.15; 95% CI 1.20-8.30; <i>p</i> = 0.012), whereas vomiting (9.6% vs. 2.3%; <i>p</i> = 0.203) and diarrhea (17.8% vs. 9.1%; <i>p</i> = 0.242) did not reach statistical significance. In multivariable logistic regression, TNT (OR = 2.65; 95% CI 1.08-6.53; <i>p</i> = 0.032) and female sex (OR = 2.03; 95% CI 1.05-3.77; <i>p</i> = 0.033) were identified as independent predictors of grade ≥ 1 GI AEs. For nausea, TNT remained significant (OR = 4.37; 95% CI 1.45-13.20; <i>p</i> = 0.0089). Upper rectal tumor location was significantly associated with vomiting (<i>p</i> = 0.0054). No grade 3-4 GI AEs were observed in either treatment group. <b>Conclusions:</b> TNT was associated with a higher incidence of mild GI AEs, predominantly driven by nausea, without an increase in severe toxicities. TNT and female sex were identified as independent clinical predictors of an increased risk of GI AEs, while tumor location in the upper third of the rectum was associated with a higher occurrence of vomiting.