Neoadjuvant chemoimmunotherapy cycles in locally advanced Esophageal squamous cell carcinoma: a retrospective comparison of three versus two cycles

Esophageal squamous cell carcinoma is a major global health challenge in its locally advanced stages. Neoadjuvant chemoimmunotherapy aims to downstage tumors before surgery, but the optimal number of cycles remains uncertain. We performed a single-institution retrospective study of 208 consecutive patients with resectable, locally advanced esophageal squamous cell carcinoma treated between March 2020 and April 2024. Patients received either two (n = 84) or three (n = 124) cycles of platinum-based chemotherapy plus a programmed death-1 inhibitor, followed by esophagectomy without planned radiotherapy. Primary outcomes were pathologic complete response and disease-free survival; safety and clinical-to-pathologic downstaging were prespecified secondary end points. Three cycles yielded higher objective response (75.0% vs. 60.7%) and a higher pathologic complete response of the primary tumor (27.4% vs. 11.9%) than two cycles. Disease-free survival favored three cycles (hazard ratio, 0.52). Treatment-related adverse events occurred more often with three cycles, driven mainly by bone-marrow suppression (32.3% vs. 11.9%) but were generally manageable and compatible with timely surgery. Overall survival did not differ within the current median follow-up of 21 months. This retrospective analysis suggests that three cycles of neoadjuvant chemoimmunotherapy may provide greater tumor response and improved disease-free survival compared with two cycles in operable esophageal squamous cell carcinoma, with acceptable toxicity. However, neoadjuvant chemoradiation-which typically achieves higher pathologic complete response rates-remains the standard of care. Longer follow-up and prospective, stratified trials are needed to validate these findings and to define the role of a radiation-free strategy in appropriately selected patients.