BACKGROUND: Esophageal cancer remains one of the most aggressive and fatal malignancies worldwide. Historically, therapeutic strategies relied primarily on neoadjuvant chemotherapy or radiotherapy and surgery, but over the past two decades, randomized controlled trials have driven a major transformation in clinical practice. METHODS: This narrative review synthesizes the evolution of evidence-based management from early cytotoxic regimens to modern, histology-specific treatment pathways. We examine landmark trials establishing the roles of neoadjuvant chemoradiation and chemotherapy, along with emerging data on immunotherapy-including checkpoint inhibitors. Persistent challenges include optimizing treatment selection based on molecular profiling, improving response prediction, and managing toxicity in an aging population. CONCLUSIONS: We conclude by highlighting key gaps in current evidence and outlining future directions and ongoing clinical investigations.
