External validation of an NTCP model for acute esophageal toxicity in locally advanced NSCLC patients treated with intensity-modulated 5 (chemo-)radiotherapy

Purpose: We externally validated a previously established multivariable normal-tissue complication probability (NTCP) model for Grade ≥2 acute esophageal toxicity (AET) after intensity-modulated (chemo-)radiotherapy or volumetric-modulated arc therapy for locally advanced non-small cell lung cancer.
Experimental design: A total of 603 patients from five cohorts within four different Dutch institutes were included. Using the NTCP model, containing predictors concurrent chemoradiotherapy, mean esophageal dose, gender and clinical tumor stage, the risk of Grade ≥2 AET was estimated per patient and model discrimination and (re)calibration performance was evaluated for all cohorts.
Results: Five validation cohorts experienced higher incidence of Grade ≥2 AET compared to the training cohort (49.3%-70.2% vs 35.6%; borderline significant for one cohort, highly significant for four cohorts). For three cohorts, discriminative performance was similar to the training cohort (area under the curve (AUC) 0.81-0.89 vs 0.84). In the two remaining cohorts the model showed poor discriminative power (AUC 0.64 and 0.63). Reasonable calibration performance was observed in two cohorts, and recalibration further improved performance in all three cohorts with good discrimination. Recalibration for the two poorly discriminating cohorts did not improve performance.
Conclusions: The NTCP model for AET prediction was successfully validated in three out of five patient cohorts. The model did not perform well in two cohorts, which included patients receiving substantially 105 different treatment.
Before applying the model in clinical practice validation of discrimination and calibration performance on a local cohort is recommended. Recalibration of the model is advised to match predicted probabilities to locally observed frequencies of AET.