Comparative efficacy and safety of neoadjuvant immunochemotherapy, chemoradiotherapy, and chemotherapy in resectable locally advanced esophageal squamous cell carcinoma: A network meta-analysis of randomized controlled trials.

Abstract

e16140 Background: Neoadjuvant chemoradiotherapy (NCRT) followed by surgery is currently the standard of care for resectable locally advanced esophageal squamous cell carcinoma (LA-ESCC). Recently, neoadjuvant immunochemotherapy (NICT) has emerged as a highly promising strategy, demonstrating potent antitumor activity and a manageable safety profile. Due to the lack of large-scale, head-to-head randomized controlled trials (RCTs) directly comparing NICT with NCRT, the optimal neoadjuvant strategy remains clinically debated. This network meta-analysis aims to compare the survival outcomes, pathological responses, and safety profiles among NICT, NCRT, and neoadjuvant chemotherapy (NCT) to guide individualized treatment decisions. Methods: We systematically searched PubMed, Embase, and the Cochrane Library for eligible RCTs published from January 2000 to December 2025. Study quality was assessed using the Cochrane Risk of Bias tool 2.0. A frequentist network meta-analysis based on a random-effects model was performed to comprehensively evaluate overall survival (OS), pathological complete response (pCR), and grade ≥3 treatment-related adverse events (TRAEs). Treatment ranking probabilities were estimated using P-scores. Results: Seven RCTs involving 1,362 patients were included. For OS, compared with surgery alone (S), NICT demonstrated the most pronounced survival benefit (HR 0.36, 95% CI 0.17 – 0.76), followed by NCRT (HR 0.62, 95% CI 0.50 – 0.78) and NCT (HR 0.75, 95% CI 0.58 – 0.98). The P-score ranking indicated that NICT had the highest probability of being the optimal treatment for improving OS (P-score 0.97). In contrast, pCR rates were highest with NCRT (OR 10.07 vs. NCT, 95% CI 4.51–22.48), followed by NICT (OR 4.14, 95% CI 2.01–8.55). Both OS and pCR showed low heterogeneity (I² = 0%). Regarding safety, NICT showed a grade ≥3 TRAE profile comparable to that of NCT (P-score: 0.47 vs. 0.53). Conclusions: NICT and NCRT offer distinct therapeutic advantages in LA-ESCC. While NCRT remains superior for achieving pathological complete response, NICT provides a more pronounced long-term survival benefit and favorable systemic tolerability. These findings suggest that NICT may be the preferred neoadjuvant strategy for maximizing OS in LA-ESCC, whereas NCRT retains value for local tumor downstaging. Nevertheless, further well-designed randomized studies are warranted to validate these results, given the limitied number of included trials.