title: Complication probability models for radiation-induced heart valvular dysfunction: do heart-lung interactions play a role?
abstract: OBJECTIVE
  The purpose of this study is to compare different normal tissue complication probability (NTCP) models for predicting heart valve dysfunction (RVD) following thoracic irradiation.
  
  
  METHODS
  All patients from our institutional Hodgkin lymphoma survivors database with analyzable datasets were included (n = 90). All patients were treated with three-dimensional conformal radiotherapy with a median total dose of 32 Gy. The cardiac toxicity profile was available for each patient. Heart and lung dose-volume histograms (DVHs) were extracted and both organs were considered for Lyman-Kutcher-Burman (LKB) and Relative Seriality (RS) NTCP model fitting using maximum likelihood estimation. Bootstrap refitting was used to test the robustness of the model fit. Model performance was estimated using the area under the receiver operating characteristic curve (AUC).
  
  
  RESULTS
  Using only heart-DVHs, parameter estimates were, for the LKB model: D50 = 32.8 Gy, n = 0.16 and m = 0.67; and for the RS model: D50 = 32.4 Gy, s = 0.99 and γ = 0.42. AUC values were 0.67 for LKB and 0.66 for RS, respectively. Similar performance was obtained for models using only lung-DVHs (LKB: D50 = 33.2 Gy, n = 0.01, m = 0.19, AUC = 0.68; RS: D50 = 24.4 Gy, s = 0.99, γ = 2.12, AUC = 0.66). Bootstrap result showed that the parameter fits for lung-LKB were extremely robust. A combined heart-lung LKB model was also tested and showed a minor improvement (AUC = 0.70). However, the best performance was obtained using the previously determined multivariate regression model including maximum heart dose with increasing risk for larger heart and smaller lung volumes (AUC = 0.82).
  
  
  CONCLUSIONS
  The risk of radiation induced valvular disease cannot be modeled using NTCP models only based on heart dose-volume distribution. A predictive model with an improved performance can be obtained but requires the inclusion of heart and lung volume terms, indicating that heart-lung interactions are apparently important for this endpoint.
authors.affiliation: Institute of Biostructure and Bioimaging, National Council of Research (CNR), Naples, Italy; Department of Advanced Biomedical Sciences, Federico II University School of Medicine, Naples, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Cella
authors.affiliation: Institute of Biostructure and Bioimaging, National Council of Research (CNR), Naples, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Palma
authors.affiliation: Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Joseph O
authors.initials: JO
authors.lastname: Deasy
authors.affiliation: Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Jung Hun
authors.initials: JH
authors.lastname: Oh
authors.affiliation: Institute of Biostructure and Bioimaging, National Council of Research (CNR), Naples, Italy; Department of Advanced Biomedical Sciences, Federico II University School of Medicine, Naples, Italy.
authors.forename: Raffaele
authors.initials: R
authors.lastname: Liuzzi
authors.affiliation: Institute of Biostructure and Bioimaging, National Council of Research (CNR), Naples, Italy.
authors.forename: Vittoria
authors.initials: V
authors.lastname: D'Avino
authors.affiliation: Institute of Biostructure and Bioimaging, National Council of Research (CNR), Naples, Italy; Department of Advanced Biomedical Sciences, Federico II University School of Medicine, Naples, Italy.
authors.forename: Manuel
authors.initials: M
authors.lastname: Conson
authors.affiliation: Department of Clinical Medicine and Surgery, Federico II University School of Medicine, Naples, Italy.
authors.forename: Novella
authors.initials: N
authors.lastname: Pugliese
authors.affiliation: Department of Clinical Medicine and Surgery, Federico II University School of Medicine, Naples, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Picardi
authors.affiliation: Department of Advanced Biomedical Sciences, Federico II University School of Medicine, Naples, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Salvatore
authors.affiliation: Institute of Biostructure and Bioimaging, National Council of Research (CNR), Naples, Italy; Department of Advanced Biomedical Sciences, Federico II University School of Medicine, Naples, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Pacelli
mesh_terms: D016001:Confidence Intervals; D004307:Dose-Response Relationship, Radiation; D006351:Heart Valves / Q000503:physiopathology*; D006801:Humans; D016013:Likelihood Functions; D008168:Lung / Q000503:physiopathology*; D008955:Models, Cardiovascular; D011336:Probability; D012372:ROC Curve; D011832:Radiation Injuries / Q000150:complications*