Background and Objectives: Rectal cancer is a major cause of morbidity and mortality worldwide, and although current therapeutic protocols have improved survival, treatment-related toxicities may significantly affect patients’ daily functioning and emotional well-being. This study aimed to prospectively assess the impact of radiotherapy with concurrent capecitabine on functional and symptomatic outcomes in patients with rectal cancer, with a particular focus on the presence of a stoma and treatment strategy. Materials and Methods: From 165 patients initially assessed, 64 were included in this study after applying eligibility criteria. All received pelvic radiotherapy (50.4 Gy in 28 fractions); 62.5% also received CAPOX chemotherapy. The quality of life was assessed using EORTC QLQ-C30 and QLQ-CR29 questionnaires administered at three time points: before treatment, mid-treatment (day 15), and post-treatment. Results: A statistically significant deterioration was observed in physical, emotional, social, and role functioning over the course of treatment, along with an increase in symptom scores for fatigue, pain, gastrointestinal, and urinary complaints. The presence of a stoma was significantly associated with worse gastrointestinal symptoms and emotional functioning. No significant differences were noted between patients with or without chemotherapy. Despite symptom worsening, global quality-of-life scores remained relatively stable. Conclusions: These findings highlight the complex interplay between treatment toxicity and patient adaptation. The presence of a stoma and other clinical or demographic factors significantly influence patients’ experience during therapy. Integrating routine assessment of functional and symptomatic burden into clinical practice could support individualized interventions aimed at maintaining daily functioning and psychological resilience during treatment.

Background: 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. Objectives: To evaluate GI toxicity associated with TNT compared with CRT and to explore clinical predictors of these adverse events (AEs). Methods: This retrospective study included 201 patients with rectal cancer treated with TNT (n = 157) and CRT (n = 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. Results: 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; p = 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; p = 0.012), whereas vomiting (9.6% vs. 2.3%; p = 0.203) and diarrhea (17.8% vs. 9.1%; p = 0.242) did not reach statistical significance. In multivariable logistic regression, TNT (OR = 2.65; 95% CI 1.08–6.53; p = 0.032) and female sex (OR = 2.03; 95% CI 1.05–3.77; p = 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; p = 0.0089). Upper rectal tumor location was significantly associated with vomiting (p = 0.0054). No grade 3–4 GI AEs were observed in either treatment group. Conclusions: 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.