Abstract
BACKGROUND: Esophageal cancer remains one of the most aggressive malignancies of the gastrointestinal tract, with high rates of recurrence and mortality despite curative-intent surgery and adjuvant therapies. Identifying factors associated with recurrence is crucial for improving outcomes and guiding personalized treatment. AIMS: The aim of this study was to evaluate pretreatment and treatment-related variables associated with recurrence in patients with esophageal cancer undergoing surgical resection. METHODS: This retrospective study analyzed data from patients with stage I-III esophageal carcinoma who underwent esophagectomy between 2000 and 2025, using the Fundação Oncocentro de São Paulo (FOSP) database. Clinical, histological, and treatment-related variables were evaluated. Disease-free survival and recurrence patterns were assessed using Cox proportional hazards models and Fine-Gray subdistribution hazard models. RESULTS: A total of 2,057 patients were included, with a mean follow-up of 36.5 months (±44.8). In the multivariate analysis, advanced tumor stage (stage II: HR 1.68, 95%CI 1.21-2.33; stage III: HR 3.23, 95%CI 2.29-4.56; both p<0.01), location (middle esophagus: HR 1.31, 95%CI 1.11-1.54; p=0.001; upper esophagus: HR 1.54, 95%CI 1.21-1.96; p<0.001), and histological subtype (rare histologies: HR 2.17, 95%CI 1.35-3.49; p=0.001) were associated with worse disease-free survival. Multimodal therapy improved disease-free survival (HR 0.40, 95%CI 0.24-0.66) in stage III tumors. Squamous cell carcinoma was independently associated with locoregional recurrence (SHR 1.52, 95%CI 1.05-2.20; p=0.027). For distant recurrence, squamous cell carcinoma showed a protective effect (SHR 0.52, 95%CI 0.31-0.88; p=0.015), while high tumor grade (grade II: SHR 3.65, 95%CI 1.98-6.72; p<0.001) was associated with an increased risk. Multimodal treatments influenced recurrence patterns but did not independently predict outcomes after adjustment. CONCLUSIONS: Tumor stage, location, and histology were strong predictors of disease-free survival after surgery for esophageal cancer. Histological subtypes significantly influenced recurrence patterns. Squamous cell carcinoma was associated with a higher risk of locoregional recurrence but a lower risk of distant metastasis compared to adenocarcinoma. Multimodal therapy demonstrated a protective effect in stage III disease.