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

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 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 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 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, 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.