External Validation of Dose Patterns and Dosimetric Predictors for Radiation-Induced Esophagitis In Non-Small Cell Lung Cancer

Purpose: Radiation-induced esophagitis (RE) is a dose-limiting complication associated with chemo-radiation therapy for non-small cell lung cancer (NSCLC). We aimed to externally validate dose patterns and dosimetric predictors of grade ≥ 2 RE (RE2+) in an independent NSCLC cohort. Methods and Materials: We analyzed Radiation Therapy Oncology Group-0617 trial patient data. Patients received concurrent chemotherapy with or without cetuximab and 60- versus 74-Gy radiation doses. Voxel-based analysis (VBA) assessed spatial dose differences between patients with and without RE2+. The generalized linear model included dose maps and each nondosimetric variable selected by a least absolute shrinkage and selection operator regularized generalized linear model of RE2+. A nonparametric permutation test of the maximum threshold-free cluster-enhanced statistic accounting for multiple comparisons was performed, and the significance p-maps were generated and compared using the Dice-over-volume metric with previous VBA results. The external validity of esophageal predictors was also assessed in terms of discrimination (the area under the receiver's operating characteristic curve value) and calibration. Results: Out of 495 patients, 326 met the inclusion criteria for analysis. The RE2+ incidence (44%) was consistent with the development cohort. Clinical factors were not significantly correlated with RE2+. VBA identified the most significant regions of associations between biologically effective dose and RE2+ in the upper and middle thoracic esophageal (UME) segment, with satisfactory overlap with a prior study (Dice-over-volume metric = 0.7). The relative esophageal volume receiving ≥ 55 Gy (V55Gy) and the UME mean dose (Dmean) were both confirmed as good predictors in external validation with comparable discrimination (area under the curve value = 0.70; 95% CI: (0.61-0.72)). Calibration curves indicated superior risk prediction accuracy for UME-Dmean (Radj2, 0.80 vs 0.65). Conclusions: We successfully validated VBA findings on RE in an independent NSCLC cohort, reinforcing the role of the upper-middle esophagus as a critical region for RE2+ risk. The UME-Dmean emerged as a robust predictor across diverse treatment techniques and patient characteristics. These findings provide a foundation for clinical implementation of VBA.