Normal tissue complication models for clinically relevant acute esophagitis (≥ grade 2) in patients treated with dose differentiated accelerated radiotherapy (DART-bid)

Franz Zehentmayr, Matthias Söhn, Ann-Katrin Exeli, Karl Wurstbauer, Almut Tröller, Heinz Deutschmann, Gerd Fastner, Christoph Fussl, Philipp Steininger, Manfred Kranzinger, Claus Belka, Michael Studnicka, Felix Sedlmayer

One of the primary dose-limiting toxicities during thoracic irradiation is acute esophagitis (AE). The aim of this study is to investigate dosimetric and clinical predictors for AE grade ≥ 2 in patients treated with accelerated radiotherapy for locally advanced non-small cell lung cancer (NSCLC). 66 NSCLC patients were included in the present analysis: 4 stage II, 44 stage IIIA and 18 stage IIIB. All patients received induction chemotherapy followed by dose differentiated accelerated radiotherapy (DART-bid). Depending on size (mean of three perpendicular diameters) tumors were binned in four dose groups: <2.5 cm 73.8 Gy, 2.5-4.5 cm 79.2 Gy, 4.5-6 cm 84.6 Gy, >6 cm 90 Gy. Patients were treated in 3D target splitting technique. In order to estimate the normal tissue complication probability (NTCP), two Lyman models and the cutoff-logistic regression model were fitted to the data with AE ≥ grade 2 as statistical endpoint. Inter-model comparison was performed with the corrected Akaike information criterion (AICc), which calculates the model's quality of fit (likelihood value) in relation to its complexity (i.e. number of variables in the model) corrected by the number of patients in the dataset. Toxicity was documented prospectively according to RTOG. The median follow up was 686 days (range 84-2921 days), 23/66 patients (35 %) experienced AE ≥ grade 2. The actuarial local control rates were 72.6 % and 59.4 % at 2 and 3 years, regional control was 91 % at both time points. The Lyman-MED model (D50 = 32.8 Gy, m = 0.48) and the cutoff dose model (Dc = 38 Gy) provide the most efficient fit to the current dataset. On multivariate analysis V38 (volume of the esophagus that receives 38 Gy or above, 95 %-CI 28.2-57.3) was the most significant predictor of AE ≥ grade 2 (HR = 1.05, CI 1.01-1.09, p = 0.007). Following high-dose accelerated radiotherapy the rate of AE ≥ grade 2 is slightly lower than reported for concomitant radio-chemotherapy with the additional benefit of markedly increased loco-regional tumor control. In the current patient cohort the most significant predictor of AE was found to be V38. A second clinically useful parameter in treatment planning may be MED (mean esophageal dose).