Radiation pneumonitis as a function of mean lung dose: an analysis of pooled data of 540 patients

Abstract

Purpose: To determine the relation between the incidence of radiation pneumonitis and the three-dimensional dose distribution in the lung. Methods and Materials: 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 α/β 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, NTD mean, 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, NTD mean, 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 NTD mean. The data were fitted to the Lyman model with NTD 50 = 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 NTD mean 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 NTD 50 = 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, NTD mean, is relatively easy to calculate, and is a useful predictor of the risk of radiation pneumonitis. The observed dose–effect relation between the NTD mean 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.