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Locoregional and distant recurrence after neoadjuvant chemoimmunotherapy versus chemoradiotherapy in esophageal
Yingding Ruan1, Wenjun Cao2, Chuan Long1
1Department of Thoracic Surgery, The First People's Hospital of Jiande, No. 599, Yanzhou Street, Jiande, Zhejiang Province, 311600, China.
Background:
Neoadjuvant chemoimmunotherapy (NCIT) is used for locally advanced esophageal squamous cell carcinoma (ESCC), but its effect on postoperative recurrence patterns remains uncertain. We compared overall, locoregional, and distant recurrence after NCIT versus neoadjuvant chemoradiotherapy (NCRT).
Methods:
PubMed/MEDLINE, Embase, Web of Science Core Collection, Scopus, and the Cochrane Library were searched through 01 May 2026. Eligible studies included patients with resectable or potentially resectable locally advanced ESCC who received NCIT or NCRT followed by radical esophagectomy. Recurrence outcomes were pooled as risk ratios (RRs), and disease-free survival or recurrence-free survival (DFS/RFS) and overall survival (OS) as hazard ratios (HRs), using random-effects models. Post hoc sensitivity analyses excluded studies with marked between-group follow-up imbalance.
Results:
Twenty comparative studies, all conducted in China, were included; 19 were retrospective observational studies and one was a randomized phase 2 trial. Five studies contributed to the overall-recurrence analysis, and six studies contributed to each of the locoregional- and distant-recurrence analyses. NCIT was associated with lower overall recurrence (RR 0.68, 95% CI 0.49-0.95; P = 0.03) and distant recurrence/metastasis (RR 0.62, 95% CI 0.43-0.89; P = 0.009), whereas locoregional recurrence did not differ significantly (RR 1.02, 95% CI 0.67-1.55; P = 0.92). In post hoc analyses excluding studies with marked follow-up imbalance, the locoregional estimate remained nonsignificant (RR 0.87, 95% CI 0.66-1.15), and the distant-recurrence/metastasis estimate was attenuated and no longer significant (RR 0.65, 95% CI 0.36-1.17). Ten studies contributed to OS, which favored NCIT (HR 0.67, 95% CI 0.48-0.93; P = 0.02; I² = 77%), whereas eight contributed to DFS/RFS, which did not differ significantly (HR 0.82, 95% CI 0.59-1.13; P = 0.21; I² = 74%).
Conclusions:
Compared with NCRT, NCIT was associated with fewer overall recurrences after radical esophagectomy for locally advanced ESCC. The primary distant-recurrence signal was not robust after excluding studies with marked follow-up imbalance, and no locoregional advantage was demonstrated. These findings do not establish therapeutic superiority and should be interpreted cautiously given the predominance of retrospective evidence, risk of bias, and substantial heterogeneity in survival analyses.