The Evolution of Neoadjuvant Treatment for Resectable Esophageal Squamous Cell Carcinoma: Past Achievements, Current Standards, and Future Perspectives

Neoadjuvant treatment has become an integral component of multidisciplinary management for resectable esophageal squamous cell carcinoma (ESCC). Over recent decades, treatment has evolved from surgery alone to postoperative chemotherapy, neoadjuvant chemotherapy, intensified systemic therapy, neoadjuvant chemoradiotherapy, and, more recently, the incorporation of immune checkpoint inhibitors into curative-intent treatment. This evolution has been driven by persistent challenges including systemic recurrence, locoregional failure, treatment-related toxicity, and heterogeneous treatment response. This review traces the evolution of neoadjuvant treatment for resectable ESCC through landmark clinical trials that have shaped current practice. We discuss the transition from postoperative to neoadjuvant chemotherapy, the development of intensified chemotherapy and neoadjuvant chemoradiotherapy, and the emergence of immunotherapy, distinguishing the established role of adjuvant nivolumab from the emerging role of neoadjuvant immunochemotherapy. We then examine the unresolved relative roles of these strategies and the challenges in treatment selection. Finally, we discuss future directions centered on accurate response assessment, circulating tumor DNA-based molecular residual disease assessment, and response-adapted treatment, with particular emphasis on organ-preserving strategies after a clinical complete response. Although active surveillance has emerged as a potential alternative to immediate surgery in carefully selected patients, accurate identification of residual disease and appropriate surveillance remain essential. Future advances may therefore shift the focus from treatment intensification alone toward response-adapted strategies that can maintain oncological safety while potentially enabling organ preservation.