Neoadjuvant Chemoimmunotherapy With Adaptive Radiotherapy for Esophageal Squamous Cell Carcinoma: Study Protocol for a Prospective Multicenter Phase Ii Trial

Abstract Background Neoadjuvant chemoradiotherapy (nCRT) followed by esophagectomy is the cornerstone of resectable esophageal squamous cell carcinoma (ESCC) management, yet outcomes remain suboptimal. Although the combination of immunotherapy enhances pathologic complete response (pCR), toxicity concerns limit broad adoption. Low-dose radiotherapy has been reported to synergize with chemoimmunotherapy by remodeling the tumor immune microenvironment, thereby bypassing the need for intensive CRT. This trial aims to explore an innovative strategy of a response-adapted neoadjuvant protocol combining LDRT, chemoimmunotherapy, and selective CRT escalation. Methods This is a prospective open-label, multicenter phase II trial with adaptive enrichment design, hypothesizing superiority in pCR rate compared to historical nCRT controls, while prioritizing CRT de-escalation for responders. All patients initiate therapy with low-dose radiotherapy (LDRT, 2Gy × 1f) followed by neoadjuvant chemoimmunotherapy (albumin-bound paclitaxel 260 mg/m2 + carboplatin AUC5 + tislelizumab 200 mg, q3w × 2 cycles). Patients achieving clinical complete response (cCR) proceed to esophagectomy within 4–6 weeks, while non-cCR patients receive intensified CRT (2Gy × 20f) followed by surgery. A target sample size of 61 patients is planned using a Simon’s two-stage design with a 20% attrition rate. Conclusion By tailoring treatment intensity to tumor response, this adaptive protocol aims to reduce overtreatment, spare toxicity, and improve survival outcomes, potentially redefining neoadjuvant paradigms for ESCC.