Defining the Optimal Radiation-induced Lymphopenia Metric to Discern Its Survival Impact in Esophageal Cancer

Purpose: A detrimental association between radiation-induced lymphopenia (RIL) and oncologic outcomes in patients with esophageal cancer has been established. However, an optimal metric for RIL remains undefined but is important for the application of this knowledge in clinical decision-making and trial designs. The aim of this study was to find the optimal RIL metric discerning survival. Methods and materials: Patients with esophageal cancer treated with concurrent chemoradiation therapy (CRT; 2004-2022) were selected. Studied metrics included absolute lymphocyte counts (ALCs) and neutrophil counts-and calculated derivatives-at baseline and during CRT. Multivariable Cox regression models for progression-free survival (PFS) and overall survival (OS) were developed for each RIL metric. The optimal RIL metric was defined as the one in the model with the highest c-statistic. Results: Among 1339 included patients, 68% received photon-based and 32% proton-based CRT (median follow-up, 24.9 months). In multivariable analysis, the best-performing models included "ALC in week 3 of CRT" (corrected c-statistic 0.683 for PFS and 0.662 for OS). At an optimal threshold of <0.5 x 10(3)/mu L (ie, grade >= 3 RIL), ALC in week 3 was significantly associated with PFS (adjusted hazard ratio, 1.64; 95% CI, 1.27-2.13) and OS (adjusted hazard ratio, 1.56; 95% CI, 1.15-2.08), with 5-year PFS of 29% vs 40% and OS of 38% vs 51%, respectively. Conclusions: Reaching grade >= 3 RIL in week 3 of CRT for esophageal cancer is the strongest RIL metric to distinguish survival outcomes. We suggest that this metric should be the target for lymphopenia-mitigating strategies and propose this metric to be included in future trials.