Pulmonary drug toxicity in patients with primary breast cancer treated with high-dose combination chemotherapy and autologous bone marrow transplantation.

A protocol consisting of standard-dose adjuvant chemotherapy, high-dose combination alkylating agent chemotherapy, and autologous bone marrow transplant (ABMT) used at our institution for patients with primary breast cancer and extensive axillary lymph node involvement has been associated with a clinical syndrome of pulmonary drug toxicity in 23 of 59 patients (39%). In 10 patients in whom open-lung biopsies or transbronchial lung biopsies were obtained, we correlated the pulmonary pathology with the clinical features of the syndrome. These 10 patients presented with dyspnea, cough, fever, and hypoxemia at a mean time of 48 +/- 14 days after initiation of high-dose chemotherapy. Chest radiographs and CT scans showed interstitial and alveolar opacities. Pulmonary function tests revealed restrictive lung disease and reduced diffusing capacities. Open-lung and transbronchial lung biopsies showed alveolar septal thickening with fibrosis, atypical Type II pneumocytes, and pulmonary endothelial cell injury characteristic of drug toxicity. Corticosteroid therapy resulted in clinical improvement in 7 of 10 patients, but significant pulmonary function abnormalities remained. Local radiation therapy to the chest wall and regional lymph nodes appeared to exacerbate preexisting pulmonary drug toxicity in 4 patients. Two agents in the protocol, cyclophosphamide and carmustine (BCNU), can be implicated in the pathogenesis of this syndrome, and these agents most likely act synergistically to deplete reduced glutathione and impair antioxidant defenses. Since these drugs appear to contribute to the protocol in prolonging disease-free survival, prophylactic therapy of the lung should be investigated to reduce the high incidence of pulmonary toxicity.