Updates in multidisciplinary management of resectable locally advanced esophageal and gastroesophageal cancer: a narrative review

Background and Objective: Esophageal and gastroesophageal junction (GEJ) cancers carry a poor prognosis, with a 5-year overall survival (OS) of 21.9%. Locally advanced, resectable disease represents a population in which curative-intent multimodality therapy is feasible yet requires complex multidisciplinary coordination. The treatment landscape for this population has undergone substantial transformation, driven by advances in molecular characterization and the introduction of novel perioperative and immunotherapy strategies. This narrative review aims to summarize recent practice-changing advances and provide a clinically actionable framework for the multidisciplinary management of locally advanced resectable esophageal and GEJ cancer.

Methods: A narrative review was conducted through structured searches of PubMed and National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines, covering publications from January 2000 through February 2026, using terms including esophageal cancer, GEJ cancer, perioperative chemotherapy, chemoradiation (CRT), immune checkpoint inhibition (ICI), microsatellite instability, and non-operative management (NOM). Phase III randomized controlled trials and practice-changing phase II studies were prioritized; institutional series were included when representing the best available evidence.

Key Content and Findings: This review synthesizes evidence spanning molecular classification, perioperative chemotherapy, CRT, immunotherapy, and emerging organ-preservation strategies. The ESOPEC and MATTERHORN trials established perioperative FLOT (5-fluorouracil, leucovorin, oxaliplatin, docetaxel) with or without durvalumab as the standard of care for resectable gastroesophageal adenocarcinomas (EACs), while neoadjuvant CRT remains standard for esophageal squamous cell carcinoma (ESCC). For mismatch repair deficiency (dMMR)/microsatellite instability-high (MSI-H) tumors, neoadjuvant ICI has yielded pathologic complete response (pCR) rates of 59–76%, with emerging evidence supporting NOM in clinical complete responders. Targeted therapy for human epidermal growth factor receptor 2 (HER2)-positive, CLDN18.2-positive, and FGFR2b-positive tumors continues to evolve.

Conclusions: Treatment paradigms for locally advanced esophageal and GEJ cancers are increasingly driven by histologic and molecular subtype. Perioperative FLOT with or without immunotherapy is now standard for EAC, while CRT remains foundational for squamous cell carcinoma. Immunotherapy has transformed outcomes for dMMR/MSI-H tumors, with NOM emerging as viable in select patients. Ongoing trials will further define total neoadjuvant therapy (TNT) and organ-preservation paradigms, with the potential to meaningfully reduce surgical morbidity in this complex patient population.