The impact of the effective dose to immune cells on lymphopenia and survival of esophageal cancer after chemoradiotherapy

Purpose: To test the hypothesis that effective dose to circulating immune cells (EDIC) impacts the severity of radiation-induced lymphopenia and clinical outcomes of esophageal cancer patients treated with concurrent chemoradiotherapy (CCRT). Material and methods: 488 esophageal cancer patients treated with CCRT with and without surgery were analyzed. The EDIC model considers the exposure of circulating immune cells as the proportion of blood flow to lung, heart, liver, and the volume of the exposed area of the body, with the basis of mean lung dose (MLD), mean heart dose (MHD), mean liver dose (MlD), and integral dose (ITD) of the body region scanned, calculated as: EDIC=0.12∗MLD+0.08∗MHD+0.15∗0.85∗MlD∗[Formula presented]^1/2+0.45+0.35∗0.85∗[Formula presented]^1/2∗[Formula presented] Where n is the fraction number. Correlations of EDIC with overall survival (OS), progression free survival (PFS), distant metastasis free survival (DMFS), and locoregional control (LRC) rates were analyzed using both univariable and multivariable Cox models. Lymphopenia during CCRT was graded according to Common Terminology Criteria for Adverse Events version 4.0. Results: Grade 4 lymphopenia resulted in inferior clinical outcomes, including OS, PFS, and DMFS. The median EDIC was 3.6 Gy (range, 0.8–6.0 Gy). Higher EDIC was strongly associated with severe lymphopenia, particularly when EDIC was above 4 Gy. Patients with EDIC > 4.0 Gy had more G4 lymphopenia than those with EDIC ≤ 4.0 Gy (67.3% vs. 40.8%; P < 0.001). On multivariate analysis, increasing EDIC was independently and inversely associated with worse OS, PFS, and DMFS. Conclusion: EDIC can be recommended as a useful tool to predict lymphopenia and inferior clinical outcomes, and it should be minimized below 4 Gy.