title: Radiation pneumonitis as a function of mean lung dose: an analysis of pooled data of 540 patients.
abstract: OBJECTIVE
  To determine the relation between the incidence of radiation pneumonitis and the three-dimensional dose distribution in the lung.
  
  
  METHODS
  In five institutions, the incidence of radiation pneumonitis was evaluated in 540 patients. The patients were divided into two groups: a Lung group, consisting of 399 patients with lung cancer and 1 esophagus cancer patient and a Lymph./Breast group with 78 patients treated for malignant lymphoma, 59 for breast cancer, and 3 for other tumor types. The dose per fraction varied between 1.0 and 2.7 Gy and the prescribed total dose between 20 and 92 Gy. Three-dimensional dose calculations were performed with tissue density inhomogeneity correction. The physical dose distribution was converted into the biologically equivalent dose distribution given in fractions of 2 Gy, the normalized total dose (NTD) distribution, by using the linear quadratic model with an alpha/beta ratio of 2.5 and 3.0 Gy. Dose-volume histograms (DVHs) were calculated considering both lungs as one organ and from these DVHs the mean (biological) lung dose, NTDmean, was obtained. Radiation pneumonitis was scored as a complication when the pneumonitis grade was grade 2 (steroids needed for medical treatment) or higher. For statistical analysis the conventional normal tissue complication probability (NTCP) model of Lyman (with n=1) was applied along with an institutional-dependent offset parameter to account for systematic differences in scoring patients at different institutions.
  
  
  RESULTS
  The mean lung dose, NTDmean, ranged from 0 to 34 Gy and 73 of the 540 patients experienced pneumonitis, grade 2 or higher. In all centers, an increasing pneumonitis rate was observed with increasing NTDmean. The data were fitted to the Lyman model with NTD50=31.8 Gy and m=0.43, assuming that for all patients the same parameter values could be used. However, in the low dose range at an NTDmean between 4 and 16 Gy, the observed pneumonitis incidence in the Lung group (10%) was significantly (p=0.02) higher than in the Lymph./Breast group (1.4%). Moreover, between the Lung groups of different institutions, also significant (p=0.04) differences were present: for centers 2, 3, and 4, the pneumonitis incidence was about 13%, whereas for center 5 only 3%. Explicitly accounting for these differences by adding center-dependent offset values for the Lung group, improved the data fit significantly (p < 10(-5)) with NTD50=30.5+/-1.4 Gy and m=0.30+/-0.02 (+/-1 SE) for all patients, and an offset of 0-11% for the Lung group, depending on the center.
  
  
  CONCLUSIONS
  The mean lung dose, NTDmean, is relatively easy to calculate, and is a useful predictor of the risk of radiation pneumonitis. The observed dose-effect relation between the NTDmean and the incidence of radiation pneumonitis, based on a large clinical data set, might be of value in dose-escalating studies for lung cancer. The validity of the obtained dose-effect relation will have to be tested in future studies, regarding the influence of confounding factors and dose distributions different from the ones in this study.
authors.affiliation: Department of Radiotherapy, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Huis, Amsterdam.
authors.forename: S L
authors.initials: SL
authors.lastname: Kwa
authors.forename: J V
authors.initials: JV
authors.lastname: Lebesque
authors.forename: J C
authors.initials: JC
authors.lastname: Theuws
authors.forename: L B
authors.initials: LB
authors.lastname: Marks
authors.forename: M T
authors.initials: MT
authors.lastname: Munley
authors.forename: G
authors.initials: G
authors.lastname: Bentel
authors.forename: D
authors.initials: D
authors.lastname: Oetzel
authors.forename: U
authors.initials: U
authors.lastname: Spahn
authors.forename: M V
authors.initials: MV
authors.lastname: Graham
authors.forename: R E
authors.initials: RE
authors.lastname: Drzymala
authors.forename: J A
authors.initials: JA
authors.lastname: Purdy
authors.forename: A S
authors.initials: AS
authors.lastname: Lichter
authors.forename: M K
authors.initials: MK
authors.lastname: Martel
authors.forename: R K
authors.initials: RK
authors.lastname: Ten Haken
mesh_terms: D004307:Dose-Response Relationship, Radiation; D006801:Humans; D015994:Incidence; D008168:Lung / Q000528:radiation effects*; D017564:Radiation Pneumonitis / Q000453:epidemiology* / Q000473:pathology; D018570:Risk Assessment; D012720:Severity of Illness Index