Neoadjuvant immunochemotherapy and surgical innovation reshape multimodal management of esophageal cancer

Abstract Esophageal cancer requires multimodal management that accounts for histology, resectability and operative fitness. This narrative review examines selected literature published through December 2025 on neoadjuvant systemic therapy, minimally invasive esophagectomy and perioperative decision-making. Neoadjuvant chemotherapy and chemoradiotherapy have established roles, but their relative benefits depend on the population and regimen. CROSS demonstrated a survival benefit over surgery alone, whereas ESOPEC favored perioperative FLOT over CROSS chemoradiotherapy in resectable esophageal adenocarcinoma. For esophageal squamous cell carcinoma, randomized phase III trials have demonstrated higher pathological complete response rates with selected chemoimmunotherapy regimens than with chemotherapy alone. However, pathological response should not be equated with an established survival benefit, and mature comparisons against chemoradiotherapy remain important. Evidence from gastric and gastroesophageal junction adenocarcinoma also requires careful interpretation before extrapolation to esophageal primary tumors. The TIME, MIRO and ROBOT randomized trials support reductions in postoperative pulmonary morbidity with the minimally invasive approaches evaluated compared with open esophagectomy. These European trials assessed different operations and do not directly establish their effects specifically after neoadjuvant immunochemotherapy. Retrospective studies of the interval to surgery report conflicting associations and do not establish a universal optimal window. Biomarkers, including circulating tumor DNA, remain promising but require prospective validation before directing perioperative treatment. Future trials should integrate survival, surgical safety, patient-reported outcomes and histology-specific treatment selection.