Abstract
PURPOSE: To evaluate the prognostic role of pan-immune-inflammation value (PIV) in patients with oesophageal squamous cell carcinoma (ESCC) receiving chemoradiotherapy (CRT) combined with anti-programmed cell death 1 (PD-1) immunotherapy, and to explore the underlying mechanisms and dosimetric parameters that affect PIV zenith. METHODS: In this pooled analysis, 86 patients from two phase II trials who received toripalimab plus CRT were analysed. PIV was calculated as follows: (neutrophil count × platelet count × monocyte count)/lymphocyte count. The optimal cut-off value was determined using the receiver operating characteristic curve. Survival analysis was conducted using the Kaplan-Meier method and Cox regression models. Univariate and multivariable logistic regression analyses identified predictors of high PIV zenith. Pretreatment tumour samples from 46 patients were subjected to RNA and whole-exome sequencing (WES). Gene set enrichment analysis was performed on RNA sequencing (RNA-seq) data, and somatic mutations were assessed using WES to further explore molecular correlates. RESULTS: Significant changes in immuno-inflammatory biomarkers were observed during CRT, which gradually normalized post-radiotherapy. After a median follow-up of 35.5 months, patients with high PIV zenith during CRT exhibited significantly poorer progression-free survival (p = 0.007) and overall survival (p = 0.015). In multivariable analysis, high PIV zenith remained a significant prognostic indicator for survival. Mean lung dose (MLD) was identified as an independent predictor of high PIV zenith. Patients with high PIV zenith had decreased interferon α response, interferon γ response, transforming growth factor-β signalling and more frequent mutations in the Hippo pathway genes, resulting in pathway downregulation. CONCLUSIONS: High PIV zenith during CRT strongly predicts poorer survival outcomes in patients with ESCC treated with combined immunotherapy and CRT. These peaks are associated with higher MLD, reduced interferon α response, interferon γ response and increased prevalence of Hippo pathway mutations.