Radiotherapy-Related Lung Fibrosis Enhanced by Tamoxifen

Abstract

BACKGROUND: Tamoxifen is an anti-estrogen with proven efficacy and low toxicity in the treatment of breast cancer. However, tamoxifen has been shown to exert a number of nonhormonal as well as hormonal effects. One nonhormonal effect of tamoxifen is the induction of transforming growth factor-beta (TGF-beta) secretion. TGF-beta has been implicated in the pathogenesis of radiation-induced fibrosis. PURPOSE: We investigated the development of lung fibrosis in breast cancer patients who were treated after mastectomy with radiotherapy, with or without simultaneous adjuvant treatment with tamoxifen. METHODS: Data from 196 women were included in the analysis. Eighty-four women were postmenopausal patients who participated in a randomized trial testing tamoxifen as an adjuvant to postmastectomy radiotherapy. The radiotherapy technique employed an 8-MV photon field covering the axillary and the infraclavicular and supraclavicular regions of the affected side of the chest; the chest wall was treated with an abutted electron field. Optical density changes in pretreatment and post-treatment chest x-ray films were used to monitor the development of lung fibrosis; lung reactions were assessed in the photon-irradiated field only. Logistic regression analysis was used to explore relationships between radiation dose and the development of lung fibrosis in patients either receiving or not receiving tamoxifen. All P values are from two-sided tests. RESULTS: Among the 84 women who participated in the randomized trial of radiotherapy plus tamoxifen (n = 38) versus radiotherapy alone (n = 46), there was a significant association between tamoxifen treatment and the incidence of marked lung fibrosis (relative risk = 2.0; 95% confidence interval [CI] = 1.2-3.5; P = .01). When logistic regression analysis was used to evaluate data from all 196 patients, a highly significant relationship was found between the incidence of lung fibrosis and total radiation dose (P = .0005). In the full analysis, an increased risk of marked lung fibrosis was found again for patients who received tamoxifen simultaneously with radiotherapy (with patients receiving radiotherapy alone as the referent, odds ratio = 2.9; 95% CI = 1.3-6.3; P = .007). Patient age and menopausal status did not significantly influence the results. CONCLUSION: Tamoxifen treatment during postmastectomy radiotherapy enhances the risk of radiation-induced lung fibrosis. IMPLICATIONS: In view of pre-existing data, we hypothesize that tamoxifen mediates the enhancement of radiation-induced lung fibrosis through the induction of TGF-beta secretion. If this hypothesis is correct, new strategies might be devised for preventing or reducing radiation-induced fibrosis. Because we studied a relatively small portion of the irradiated lung, we cannot recommend changes in current therapeutic measures; however, we strongly encourage additional studies of lung fibrosis in patients receiving tamoxifen and radiotherapy.