Radiation Dose-Volume Effects on Negative Tumor-Draining Lymph Nodes Impacted T-Cell Activation and Prognosis in Esophageal Cancer with Chemoradiotherapy

Abstract

Purpose: Preclinical model found that elective nodal irradiation (ENI) attenuated the efficacy of radiotherapy and radio-immunotherapy. However, limited clinical studies have explored the correlation between radiation dose-volume parameters of negative tumor draining lymph nodes (TDLNs) and T-cell activation/prognosis for cancer patients treated with definitive radio(chemo)therapy. Experimental Design: Patients with locally advanced esophageal cancer undergoing definitive chemoradiotherapy (CRT) were selected from two prospective trials. Dose-volume parameters of TDLN as well as other lymphocyte-related organs at risk (LOARs) and lymphocyte subsets such as CD3-CD19+ B cells, CD8+CD28+ T cells, and activated T cells (CD3+CD8+HLA-DR+) before and at the end of radiotherapy (RT) were collected. Logistic analysis was utilized to correlate dose-volume parameters with reductions in lymphocyte subsets. Prognosis of TDLN irradiation was investigated through Kaplan-Meier analysis and Cox hazards models. Results: Among 512 patients, the median mean dose of TDLN and negative non-TDLN was 25.6 Gy and 15.1 Gy, respectively. Multivariable analyses indicated TDLN V15 >50% was an independent predictor of poorer local-recurrence free survival (HR, 1.31; p=0.029) and distant-metastasis free survival (HR, 1.39; p<0.001), as well as greater reductions in CD3-CD19+ B cells (OR, 1.98; p=0.002), CD8+CD28+ T cells (OR, 3.42; p<0.001) and CD3+CD8+HLA-DR+ T cells (OR, 4.67; p=0.002) post-RT. Conclusions: A higher radiation dose-volume parameter of TDLNs in esophageal cancer patients undergoing CRT was significantly associated with suppression of T-cell activation and a worse prognosis. Limiting the percentage of TDLN V15 may be beneficial for improving the prognosis of CRT with or without PD-1 inhibitors.