title: Development of NTCP models for head and neck cancer patients treated with three-dimensional conformal radiotherapy for xerostomia and sticky saliva: the role of dosimetric and clinical factors.
abstract: OBJECTIVE
  The purpose of this multicentre prospective study was to investigate the significance of the radiation dose in the major and minor salivary glands, and other pre-treatment and treatment factors, with regard to the development of patient-rated xerostomia and sticky saliva among head and neck cancer (HNC) patients treated with primary (chemo-) radiotherapy ((CH)RT).
  
  
  METHODS
  The study population was composed of 167 consecutive HNC patients treated with three-dimensional conformal (3D-CRT) (CH) RT. The primary endpoint was moderate to severe xerostomia (XER6m) as assessed by the EORTC QLQ-H&N35 at 6 months after completing (CH)RT. The secondary endpoint was moderate to severe sticky saliva at 6 months (STIC6m). All organs at risk (OARs) potentially involved in salivary function were delineated on planning-CT, including the parotid, submandibular and sublingual glands and the minor glands in the soft palate, cheeks and lips. Patients with moderate to severe xerostomia or sticky saliva at baseline were excluded. The optimum number of variables for a multivariate logistic regression model was determined using a bootstrapping method.
  
  
  RESULTS
  The multivariate analysis showed the mean parotid dose, age and baseline xerostomia (none versus a bit) to be the most important predictors for XER6m. The risk of developing xerostomia increased with age and was higher when minor baseline xerostomia was present in comparison with patients without any xerostomia complaints at baseline. Model performance was good with an area under the curve (AUC) of 0.82. For STIC6m, the mean submandibular dose, age, the mean sublingual dose and baseline sticky saliva (none versus a bit) were most predictive for sticky saliva. The risk of developing STIC6m increased with age and was higher when minor baseline sticky saliva was present in comparison with patients without any sticky saliva complaints at baseline. Model performance was good with an AUC of 0.84.
  
  
  CONCLUSIONS
  Dose distributions in the minor salivary glands in patients receiving 3D-CRT have limited significance with regard to patient-rated symptoms related to salivary dysfunction. Besides the parotid and submandibular glands, only the sublingual glands were significantly associated with sticky saliva. In addition, reliable risk estimation also requires information from other factors such as age and baseline subjective scores. When these selected factors are included in predictive models, instead of only dose volume histogram parameters, model performance can be improved significantly.
authors.affiliation: Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands. i.beetz@rt.umcg.nl
authors.forename: Ivo
authors.initials: I
authors.lastname: Beetz
authors.forename: Cornelis
authors.initials: C
authors.lastname: Schilstra
authors.forename: Fred R
authors.initials: FR
authors.lastname: Burlage
authors.forename: Phil W
authors.initials: PW
authors.lastname: Koken
authors.forename: Patricia
authors.initials: P
authors.lastname: Doornaert
authors.forename: Henk P
authors.initials: HP
authors.lastname: Bijl
authors.forename: Olga
authors.initials: O
authors.lastname: Chouvalova
authors.forename: C René
authors.initials: CR
authors.lastname: Leemans
authors.forename: Geertruida H
authors.initials: GH
authors.lastname: de Bock
authors.forename: Miranda E M C
authors.initials: ME
authors.lastname: Christianen
authors.forename: Bernard F A M
authors.initials: BF
authors.lastname: van der Laan
authors.forename: Arjan
authors.initials: A
authors.lastname: Vissink
authors.forename: Roel J H M
authors.initials: RJ
authors.lastname: Steenbakkers
authors.forename: Johannes A
authors.initials: JA
authors.lastname: Langendijk
mesh_terms: D000368:Aged; D005260:Female; D006258:Head and Neck Neoplasms / Q000532:radiotherapy*; D006801:Humans; D008297:Male; D008954:Models, Biological; D011336:Probability; D011446:Prospective Studies; D011874:Radiometry; D020266:Radiotherapy, Conformal / Q000009:adverse effects*; D012044:Regression Analysis; D012463:Saliva; D014987:Xerostomia / Q000209:etiology*