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 (V) and the UME mean dose (D) 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-D (R, 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-D emerged as a robust predictor across diverse treatment techniques and patient characteristics. These findings provide a foundation for clinical implementation of VBA.