Prognostic impact of dose to circulating blood cells in non-small cell lung cancer patients after chemoradiotherapy

Background: Severe radiation-induced lymphopenia (SRIL) is an adverse effect in which lymphocyte counts drop below a defined threshold after radiotherapy. This study aimed to identify key dosimetric factors associated with SRIL and survival in non-small cell lung cancer (NSCLC) patients undergoing chemoradiotherapy (CRT). Methods: A total of 241 NSCLC patients treated with definitive CRT were retrospectively analyzed. Baseline blood counts and dosimetric parameters of normal organs, including circulating blood, were assessed to identify predictors of SRIL and evaluate their impact on survival. SRIL was defined as an absolute lymphocyte count (ALC) nadir of <200/μL. Circulating blood dose was estimated using both stochastic and deterministic models: the hematological dose (HEDOS) model and the effective dose to immune cells (EDIC), respectively. Multivariate logistic regression identified predictors of SRIL, while multivariate Cox regression and Kaplan-Meier analyses evaluated prognostic effects on survival. Generalized additive models (GAM) assessed nonlinear associations. Results: SRIL occurred in 68 patients (28.2%) during treatment. The median overall survival (OS) and progression-free survival (PFS) for the entire cohort were 35.0 [95% confidence interval (CI): 29.0–41.0] and 10.0 months (95% CI: 8.0–12.0), respectively. Higher minimum blood dose [HEDOS D100, odds ratio (OR) 1.26, P=0.04], increased lung volume receiving ≥10 Gy (Lung V10, OR 1.03, P=0.02), lower baseline ALC (OR 1.00, P=0.02), and hemoglobin (OR 0.82, P=0.04) were significant predictors of SRIL. GAM identified a critical threshold of 8.29 Gy for HEDOS D100, above which survival outcomes were significantly worse, with shorter median OS (18.0 vs. 37.0 months) and PFS (5.0 vs. 10.0 months) compared to those below the threshold. Multivariate Cox analysis confirmed HEDOS D100 ≥8.29 Gy as an independent predictor of worse OS [hazard ratio (HR) 2.10, P=0.005] and PFS (HR 2.05, P=0.01). Conclusions: HEDOS D100 is a strong predictor of SRIL and survival, highlighting the importance of minimizing radiation exposure to circulating blood during CRT to improve clinical outcomes in NSCLC.