Comparative efficacy and outcomes of different treatments for pathologically high-risk superficial esophageal cancer: a systematic review and network meta-analysis

He He, Hanlu Zhang, Haowen Lv, Ningying Ding, Wenping Wang

Background Endoscopic resection (ER) is increasingly used for superficial esophageal cancer (SEC), but pathological examination may reveal features associated with lymph-node metastasis or recurrence. The optimal management of patients with pathologically high-risk SEC remains uncertain because high-quality randomized evidence is lacking and direct comparisons among the available treatment strategies remain limited. Methods We performed a systematic review and frequentist network meta-analysis according to PRISMA (PROSPERO CRD420251164650). PubMed, Embase, Web of Science, and the Cochrane Library were searched from inception to December 17, 2025. Random-effects models were used as the primary analyses for overall survival (OS), recurrence-free survival (RFS), and disease-specific survival (DSS). Study-level subgroup analysis, network meta-regression, and sensitivity analyses were used to examine the robustness and comparability of the evidence. Results Thirty-four studies were included. The OS, RFS, and DSS networks contained 2,621, 2,173, and 1,274 participants, respectively. Compared with primary esophagectomy (ESO), ER followed by esophagectomy (ER+ESO) had an OS hazard ratio (HR) of 0.562 (95% CI 0.311-1.015; P = 0.056). The corresponding HRs were 0.480 for RFS (95% CI 0.235-0.983; P = 0.045) and 0.206 for DSS (95% CI 0.069-0.619; P = 0.005). No other strategy differed significantly from ESO. Global inconsistency was not detected for OS or DSS, whereas the RFS network showed significant between-design inconsistency. Study-level subgroup and network meta-regression analyses did not identify statistically significant effect modification by pathological-stage composition, T1b proportion, or lymphovascular invasion burden. Conclusions ER+ESO was associated with favorable RFS and DSS estimates in selected patients suitable for surgery, with a similar direction of effect for OS. These findings may support ER+ESO as an important post-ER treatment option when surgical tolerance is acceptable. ER followed by chemoradiotherapy may represent a clinically relevant organ-preserving strategy, particularly for patients in whom esophagectomy is not preferred or feasible. Systematic Review Registration https://www.crd.york.ac.uk/PROSPERO/view/CRD420251164650 , identifier CRD420251164650.