Safety and Survival Outcomes of Neoadjuvant Chemoradiotherapy Combined with Immunotherapy in Locally Advanced Esophageal Squamous Cell Carcinoma: A Multicenter Real-World Analysis (NEO-EC-01).

Abstract

Neoadjuvant chemoradiotherapy (nCRT) is the standard treatment for patients with locally advanced esophageal squamous cell carcinoma (LA-ESCC), although perioperative immunotherapy has shown considerable promise. The integration of immunotherapy with nCRT (nICRT) is an innovative treatment paradigm and early-phase studies have reported enhanced pathological complete response (pCR) rates. However, comprehensive evaluations of safety, long-term prognosis, and recurrence patterns are lacking. In this multicenter real-world study, the clinical efficacy, recurrence patterns, and potential prognostic biomarkers were evaluated in patients with LA-ESCC receiving nICRT followed by esophagectomy. Clinical data from patients with LA-ESCC who underwent nICRT followed by esophagectomy between September 2020 and February 2023 were retrospectively analyzed across three tertiary cancer centers. Baseline inflammatory markers (platelet-to-lymphocyte ratio [PLR] and neutrophil-to-lymphocyte ratio [NLR]) were calculated from pretreatment complete blood counts. Treatment-related adverse events (AEs), survival outcomes, and recurrence patterns were rigorously assessed. Among the 71 enrolled patients, all achieved R0 resection (100%). The pCR and major pathological response (mPR) rates were 50.7% (36/71) and 77.5% (55/71), respectively. Grade ≥ 3 AEs occurred in 25 patients (35.2%), predominantly neutropenia (31.0%, 22/71) and radiation oesophagitis (7.0%, 5/71). Postoperative complications included anastomotic leakage (4.2%, 3/71) and pneumonia (15.5%, 11/71). With a median follow-up of 36.5 months (95% CI: 29.8-43.2), the 2- and 3-year overall survival (OS) rates were 81.5 and 70.6%, and the disease-free survival (DFS) rates were 70.3 and 58.0%, respectively. Recurrences included locoregional (12/71, 16.9%; 11 nodal, 1 anastomotic) and distant metastases (23/71, 32.4%; lung [8], bone [5], pleura [5], liver/brain/adrenal gland/chest wall [2 each] and extra-nodal [5]). Multivariate analysis revealed that pathological N stage was an independent prognostic factor for both OS and DFS (P < 0.05), whereas elevated PLR was associated with worse DFS (P < 0.05). Notably, non-pCR patients receiving adjuvant therapy (n = 20) had superior 2-year OS (75% versus 53.3%) and DFS (54.5% versus 33.3%) than untreated patients did (n = 15; P < 0.05). nICRT demonstrates acceptable safety and efficacy in patients with LA-ESCC, with distant metastasis as the main recurrence pattern. The pretreatment PLR may serve as a prognostic biomarker, and adjuvant therapy improves survival in non-pCR patients. These findings warrant validation in prospective studies. The trial registration number is NCT06828718.