title: Multivariate normal tissue complication probability modeling of heart valve dysfunction in Hodgkin lymphoma survivors.
abstract: OBJECTIVE
  To establish a multivariate normal tissue complication probability (NTCP) model for radiation-induced asymptomatic heart valvular defects (RVD).
  
  
  METHODS
  Fifty-six patients treated with sequential chemoradiation therapy for Hodgkin lymphoma (HL) were retrospectively reviewed for RVD events. Clinical information along with whole heart, cardiac chambers, and lung dose distribution parameters was collected, and the correlations to RVD were analyzed by means of Spearman's rank correlation coefficient (Rs). For the selection of the model order and parameters for NTCP modeling, a multivariate logistic regression method using resampling techniques (bootstrapping) was applied. Model performance was evaluated using the area under the receiver operating characteristic curve (AUC).
  
  
  RESULTS
  When we analyzed the whole heart, a 3-variable NTCP model including the maximum dose, whole heart volume, and lung volume was shown to be the optimal predictive model for RVD (Rs = 0.573, P<.001, AUC = 0.83). When we analyzed the cardiac chambers individually, for the left atrium and for the left ventricle, an NTCP model based on 3 variables including the percentage volume exceeding 30 Gy (V30), cardiac chamber volume, and lung volume was selected as the most predictive model (Rs = 0.539, P<.001, AUC = 0.83; and Rs = 0.557, P<.001, AUC = 0.82, respectively). The NTCP values increase as heart maximum dose or cardiac chambers V30 increase. They also increase with larger volumes of the heart or cardiac chambers and decrease when lung volume is larger.
  
  
  CONCLUSIONS
  We propose logistic NTCP models for RVD considering not only heart irradiation dose but also the combined effects of lung and heart volumes. Our study establishes the statistical evidence of the indirect effect of lung size on radio-induced heart toxicity.
authors.affiliation: Institute of Biostructures and Bioimaging, National Council of Research, Naples, Italy. laura.cella@cnr.it
authors.forename: Laura
authors.initials: L
authors.lastname: Cella
authors.forename: Raffaele
authors.initials: R
authors.lastname: Liuzzi
authors.forename: Manuel
authors.initials: M
authors.lastname: Conson
authors.forename: Vittoria
authors.initials: V
authors.lastname: D'Avino
authors.forename: Marco
authors.initials: M
authors.lastname: Salvatore
authors.forename: Roberto
authors.initials: R
authors.lastname: Pacelli
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D019540:Area Under Curve; D059248:Chemoradiotherapy / Q000009:adverse effects*; D005260:Female; D006321:Heart / Q000033:anatomy & histology / Q000528:radiation effects; D006349:Heart Valve Diseases / Q000209:etiology*; D006351:Heart Valves / Q000528:radiation effects*; D006689:Hodgkin Disease / Q000628:therapy*; D006801:Humans; D008168:Lung / Q000033:anatomy & histology; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D015999:Multivariate Analysis; D009929:Organ Size; D011336:Probability; D011832:Radiation Injuries / Q000150:complications*; D012189:Retrospective Studies; D017741:Survivors; D055815:Young Adult