Evolution of Therapeutics for Locally Advanced Upper Gastrointestinal Adenocarcinoma

Upper gastrointestinal (GI) malignancies, including esophageal, gastroesophageal junction (GEJ), and gastric adenocarcinomas, remain a major global health concern, with poor overall survival and high recurrence rate despite aggressive treatment. Patients with very early tumors (cT1a) can benefit from endoscopic therapy. However, patients with locally advanced disease require multimodal therapies that may combine surgery, radiation, and systemic therapies. This review provides a comprehensive overview of recent advancements in the treatment of locally advanced upper GI adenocarcinomas. Surgical resection remains the cornerstone of curative treatment, with perioperative chemotherapy emerging as the standard of care. While preoperative chemoradiation has demonstrated some benefits in esophageal and GEJ cancers, recent data suggest a more limited role for radiation going forward. Immunotherapy has shown some promise in both the adjuvant and perioperative settings but has yet to establish definitive survival benefit. The integration of HER2-targeted therapies into treatment regimens for HER2-positive locally advanced gastroesophageal cancers has not yielded significant improvements, underscoring the need for more effective strategies. Ongoing research focuses on better predictive biomarkers, personalized treatment approaches, and potential organ preservation strategies for patients achieving a clinical complete response. Continued advancements in treatment modalities and precision medicine are critical to improving survival for patients with locally advanced upper GI adenocarcinomas.