Organ Preservation in Esophageal Cancer: Current Strategies, Challenges, and Future Directions.

Esophageal cancer (EC) continues to pose a major global health burden, ranking as the ninth most common malignancy and sixth leading cause of cancer mortality, with over 600,000 new cases and 500,000 deaths annually as of 2025. While esophagectomy has long been the standard for curative intent in resectable disease, organ preservation strategies have advanced significantly, offering viable alternatives for patients with locally advanced esophageal squamous cell carcinoma (ESCC) or those unsuitable for surgery due to comorbidities. These approaches encompass definitive chemoradiotherapy (dCRT), neoadjuvant chemoradiotherapy (nCRT) followed by active surveillance ("watch-and-wait"), and innovative integrations of immunotherapy and targeted therapies. This narrative review synthesizes evidence from recent clinical trials, systematic reviews, and international guidelines up to 2025, demonstrating that organ-sparing protocols can achieve comparable overall survival (OS) rates-often exceeding 50% at 5 years in selected cohorts-while substantially enhancing quality of life (QoL) by preserving esophageal function. For instance, the SANO trial (2025) confirmed non-inferiority of active surveillance post-nCRT, with 2-year OS of 74% versus 71% for standard surgery. Key challenges include imprecise response assessment, locoregional recurrences (20-30%), and treatment-related toxicities such as esophageal strictures. Emerging trials like ESOSTRATE and PALACE3 are evaluating immunotherapy-enhanced regimens, potentially expanding organ preservation to esophageal adenocarcinoma (EAC). With genomic biomarkers and novel modalities like proton therapy, personalized organ preservation promises to broaden applicability, reduce morbidity, and improve outcomes across histological subtypes. Additionally, recent studies emphasize the role of liquid biopsies, such as circulating tumor DNA (ctDNA), in monitoring treatment response and guiding surveillance, potentially reducing the need for invasive procedures and improving detection of minimal residual disease. The aim of this review is not only to summarize recent trials but to synthesize them into an operational framework that clinicians and researchers can apply: a decision algorithm for selecting organ preservation candidates. This is the novel element that distinguishes this work from prior narrative reviews.