title: Normal tissue complication models for clinically relevant acute esophagitis (≥ grade 2) in patients treated with dose differentiated accelerated radiotherapy (DART-bid).
abstract: BACKGROUND
  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).
  
  
  METHODS
  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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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).
authors.affiliation: Univ.-Klinik für Radiotherapie und Radio-Onkologie, Landeskrankenhaus Salzburg, Univ.-Klinikum der Paracelsus Medizinischen Privatuniversität, Müllner Hauptstr. 48, 5020, Salzburg, Austria. f.zehentmayr@salk.at.|Institute for Research and Development of Advanced Radiation Technologies (radART), Paracelsus Medizinische Privatuniversität, Müllner Hauptstr. 48, 5020, Salzburg, Austria. f.zehentmayr@salk.at.
authors.forename: Franz
authors.initials: F
authors.lastname: Zehentmayr
authors.affiliation: Department of Radiotherapy and Radiation Oncology, Ludwig-Maximilians-Universität Munich, Marchioninistr. 15, 81377, Munich, Germany. matthias.soehn@med.uni-muenchen.de.
authors.forename: Matthias
authors.initials: M
authors.lastname: Söhn
authors.affiliation: Univ.-Klinik für Radiotherapie und Radio-Onkologie, Landeskrankenhaus Salzburg, Univ.-Klinikum der Paracelsus Medizinischen Privatuniversität, Müllner Hauptstr. 48, 5020, Salzburg, Austria. a.exeli@salk.at.
authors.forename: Ann-Katrin
authors.initials: AK
authors.lastname: Exeli
authors.affiliation: Institute for Research and Development of Advanced Radiation Technologies (radART), Paracelsus Medizinische Privatuniversität, Müllner Hauptstr. 48, 5020, Salzburg, Austria. k.wurstbauer@salk.at.
authors.forename: Karl
authors.initials: K
authors.lastname: Wurstbauer
authors.affiliation: Department of Radiotherapy and Radiation Oncology, Ludwig-Maximilians-Universität Munich, Marchioninistr. 15, 81377, Munich, Germany. almut.troeller@med.uni-muenchen.de.|Department of Radiation Oncology, William Beaumont Health System, 3601 W. Thirteen Mile Road, Royal Oak, MI, 48073, USA. almut.troeller@med.uni-muenchen.de.
authors.forename: Almut
authors.initials: A
authors.lastname: Tröller
authors.affiliation: Univ.-Klinik für Radiotherapie und Radio-Onkologie, Landeskrankenhaus Salzburg, Univ.-Klinikum der Paracelsus Medizinischen Privatuniversität, Müllner Hauptstr. 48, 5020, Salzburg, Austria. h.deutschmann@salk.at.|Institute for Research and Development of Advanced Radiation Technologies (radART), Paracelsus Medizinische Privatuniversität, Müllner Hauptstr. 48, 5020, Salzburg, Austria. h.deutschmann@salk.at.
authors.forename: Heinz
authors.initials: H
authors.lastname: Deutschmann
authors.affiliation: Univ.-Klinik für Radiotherapie und Radio-Onkologie, Landeskrankenhaus Salzburg, Univ.-Klinikum der Paracelsus Medizinischen Privatuniversität, Müllner Hauptstr. 48, 5020, Salzburg, Austria. g.fastner@salk.at.
authors.forename: Gerd
authors.initials: G
authors.lastname: Fastner
authors.affiliation: Univ.-Klinik für Radiotherapie und Radio-Onkologie, Landeskrankenhaus Salzburg, Univ.-Klinikum der Paracelsus Medizinischen Privatuniversität, Müllner Hauptstr. 48, 5020, Salzburg, Austria. c.fussl@salk.at.
authors.forename: Christoph
authors.initials: C
authors.lastname: Fussl
authors.affiliation: Institute for Research and Development of Advanced Radiation Technologies (radART), Paracelsus Medizinische Privatuniversität, Müllner Hauptstr. 48, 5020, Salzburg, Austria. philipp.steininger@pmu.ac.at.
authors.forename: Philipp
authors.initials: P
authors.lastname: Steininger
authors.affiliation: Univ.-Klinik für Radiotherapie und Radio-Onkologie, Landeskrankenhaus Salzburg, Univ.-Klinikum der Paracelsus Medizinischen Privatuniversität, Müllner Hauptstr. 48, 5020, Salzburg, Austria. m.kranzinger@salk.at.
authors.forename: Manfred
authors.initials: M
authors.lastname: Kranzinger
authors.affiliation: Department of Radiotherapy and Radiation Oncology, Ludwig-Maximilians-Universität Munich, Marchioninistr. 15, 81377, Munich, Germany. claus.belka@med.uni-muenchen.de.
authors.forename: Claus
authors.initials: C
authors.lastname: Belka
authors.affiliation: Univ.-Klinik für Pneumologie, Landeskrankenhaus Salzburg, Univ.-Klinikum der Paracelsus Medizinischen Privatuniversität, Müllner Hauptstr. 48, 5020, Salzburg, Austria. m.studnicka@salk.at.
authors.forename: Michael
authors.initials: M
authors.lastname: Studnicka
authors.affiliation: Univ.-Klinik für Radiotherapie und Radio-Onkologie, Landeskrankenhaus Salzburg, Univ.-Klinikum der Paracelsus Medizinischen Privatuniversität, Müllner Hauptstr. 48, 5020, Salzburg, Austria. f.sedlmayer@salk.at.|Institute for Research and Development of Advanced Radiation Technologies (radART), Paracelsus Medizinische Privatuniversität, Müllner Hauptstr. 48, 5020, Salzburg, Austria. f.sedlmayer@salk.at.
authors.forename: Felix
authors.initials: F
authors.lastname: Sedlmayer
mesh_terms: D000208:Acute Disease; D000230:Adenocarcinoma / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001317:Austria / Q000453:epidemiology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy; D059248:Chemoradiotherapy / Q000009:adverse effects*; D019583:Dose Fractionation, Radiation; D004941:Esophagitis / Q000453:epidemiology / Q000209:etiology* / Q000473:pathology; D005260:Female; D006801:Humans; D015994:Incidence; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D009367:Neoplasm Staging; D058958:Organs at Risk / Q000528:radiation effects*; D011379:Prognosis; D011832:Radiation Injuries / Q000453:epidemiology / Q000209:etiology* / Q000473:pathology; D011878:Radiotherapy / Q000009:adverse effects*