Neoadjuvant Chemoimmunotherapy versus Chemoradiotherapy in Resectable Locally Advanced Esophageal Squamous Cell Carcinoma: A Systematic Review and Reconstructed Individual Patient Data Meta-Analysis.

BACKGROUND: Neoadjuvant chemoradiotherapy (NCRT) plus surgery is standard for resectable locally advanced esophageal squamous cell carcinoma (LA-ESCC), but survival remains suboptimal. Neoadjuvant chemoimmunotherapy (NCIT) is an emerging alternative. This meta-analysis compared efficacy, safety, and survival between NCIT and NCRT. MATERIALS AND METHODS: Prospective trials on NCIT or NCRT for resectable LA-ESCC were searched up to 17 March 2026. Pathological complete response (pCR), major pathological response (MPR), overall survival (OS), and progression-free survival (PFS) were assessed. Survival data were reconstructed from Kaplan-Meier curves, and one-stage meta-analysis using shared-frailty Cox models was performed. RESULTS: A total of 34 studies (1275 NCIT, 1045 NCRT patients) were included. NCIT significantly improved OS (HR 0.63, 95% CI 0.47-0.84) and PFS (HR 0.69, 95% CI 0.51-0.93). The 3-year OS rates were 74.7% (NCIT) versus 63.2% (NCRT); 3-year PFS rates were 65.7% versus 54.6%. Adjuvant immunotherapy further improved survival (OS HR 0.51, 95% CI 0.32-0.83). pCR (31% versus 39%) and MPR (55% versus 64%) were lower with NCIT (P < 0.05). Among NCIT patients, MPR predicted better OS (HR 0.27, 95% CI 0.13-0.57). Neoadjuvant treatment with 3-4 cycles was associated with a significantly higher pCR rate compared with 2 neoadjuvant cycles (41% versus 26%, P < 0.001). Among studies using two neoadjuvant cycles, the nab-paclitaxel backbone improved pCR (32% versus 19%) and MPR (59% versus 34%) compared with paclitaxel. Postoperative anastomotic leakage was lower with NCIT (7% versus 12%), while pneumonia and 90-day mortality were comparable. CONCLUSIONS: NCIT provides superior survival and a manageable safety profile compared with NCRT in resectable LA-ESCC. Neodjuvant immunotherapy extending to 3-4 cycles and adding adjuvant immunotherapy may enhance outcomes. Long-term RCTs are warranted.