Normal tissue complication probability modelling and predicting for carbon-ion radiotherapy-induced symptomatic esophageal and tracheobronchial injuries in locally advanced non-small cell lung cancer

Radiation-induced injuries (RIs) to the esophagus (ESO) and proximal bronchial tree (PBT) represent one of the most frequently observed symptomatic adverse events in locally advanced non-small cell lung cancer (LA-NSCLC). The establishment of validated normal tissue complication probability (NTCP) models and subsequent dose constraint recommendations are especially essential in carbon-ion radiotherapy (CIRT), owing to its unique physical and biological properties. To establish NTCP models and derive corresponding dose constraints for symptomatic or severe RIs in ESO and PBT in LA-NSCLC treated with local effect model (LEM)-I-based CIRT. This retrospective study analyzed 184 LA-NSCLC patients treated with CIRT at a median prescription dose of 77 Gy (RBE) in 3.5 Gy (RBE) per fraction. Lyman-Kutcher-Burman (LKB) NTCP models were developed for acute esophagitis (ARI-ESO), late ESO reaction (LRI-ESO), and late PBT toxicity (LRI-PBT). Predictive performance was evaluated using the area under the receiver operating characteristic curve (AUC-ROC) by comparing single dosimetric parameters versus multivariate nomograms. For grade ≥ 2 (symptomatic) ARI-ESO and grade ≥ 2/≥3 (severe) LRI-PBT, low n values (0.053±0.097, 0.139 ± 0.085, 0.224 ± 0.135, respectively) indicated predominant dependence on high-dose regions. In contrast, higher n values (0.381/0.362) observed for grade ≥ 2/≥3 late ESO toxicities suggested the use of dual constraints incorporating both maximum dose (D max ) and mean dose (D mean ). The best equivalent uniform dose (EUD) thresholds (ROC‑derived) defined a low‑risk cohort with an actual incidence of ≤1.9% for each adverse event. The proposed D max thresholds of 78 Gy (RBE) for ESO and 80 Gy (RBE) for PBT are expected to limit toxicity risk below 5%. Multivariate nomograms integrating high-dose metrics and D mean achieved AUC-ROC values of 0.823–0.884. The first NTCP models for symptomatic toxicities of ESO and PBT were established in LA-NSCLC patients receiving LEM-I-based CIRT at ~3.5 Gy (RBE) per fraction with sequential systemic therapy. The ROC‑derived optimal EUD thresholds for discriminating NTCP risk were obtained with substantial AUC-ROC values. We also proposed NTCP-derived Dmax constraints and developed multivariate nomograms to facilitate routine clinical use. Further prospective studies in larger cohorts with extended follow-up were warranted.