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-dos e combination alkylating agent chemotherapy, and autologous bone marro w transplant (ABMT) used at our institution for patients with primary breast cancer and extensive axillary lymph nods involvement has been a ssociated with a clinical syndrome of pulmonary drug toxicity in 23 of 59 patients (39%). In 10 patients in whom open-lung biopsies or trans bronchial lung biopsies were obtained, we correlated the pulmonary pat hology with the clinical features of the syndrome. These 10 patients p resented with dyspnea, cough, fever, and hypoxemia at a mean time of 4 8 +/- 14 days after initiation of high-dose chemotherapy. Chest radiog raphs and CT scans showed interstitial and alveolar opacities. Pulmona ry function tests revealed restrictive lung disease and reduced diffus ing capacities. Open-lung and transbronchial lung biopsies showed alve olar septal thickening with fibrosis, atypical Type II pneumocytes, an d pulmonary endothelial cell injury characteristic of drug toxicity. C orticosteroid therapy resulted in clinical improvement in 7 of 10 pati ents, but significant pulmonary f unction abnormalities remained. Loca l radiation therapy to the chest wall and regional lymph nodes appeare d to exacerbate preexisting pulmonary drug toxicity in 4 patients. Two agents in the protocol, cyclophosphamide and carmustine (BCNU), can b e implicated in the pathogenesis of this syndrome, and these agents mo st likely act synergistically to deplete reduced glutathione and impai r 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 pulmon ary toxicity.