Mayo Clin Proc, May 2003, Vol 78 BCNU-Associated Pulmonary Fibrosis 631 Figure 1. Chest radiograph of BCNU-treated patient, showing small right apical

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1 630 Case Report Upper Lobe Pulmonary Fibrosis Associated With High-Dose Chemotherapy Containing BCNU for Bone Marrow Transplantation JAMES M. PARISH, MD; JOHN R. MUHM, MD; AND KEVIN O. LESLIE, MD Upper lobe fibrotic lung disease is most often associated with sarcoidosis, Langerhans cell histiocytosis, silicosis, and other pneumoconioses but is usually not associated with drug-induced lung disease. Carmustine (BCNU) is a chemotherapeutic agent known to cause pulmonary toxicity. The radiographic pattern is usually diffuse bilateral lung disease predominantly in the lung bases. Upper lobe fibrotic disease associated with BCNU has been reported to occur in children treated for central nervous system gliomas. Often the lung disease occurs years after the exposure. Despite the widespread use of BCNU in the treatment of malignancy in adults, to our knowledge, the complication of upper lobe fibrotic disease has not been reported in adults. We describe a patient who presented with pneumothorax and bilateral upper lobe pulmonary fibrosis that we believe was due to BCNU given for bone marrow transplantation as part of therapy for breast cancer. Bilateral upper lobe pulmonary fibrosis can be associated with chemotherapeutic drugs. Mayo Clin Proc. 2003;78: CT = computed tomography; DLCO = diffusing capacity of the lung for carbon monoxide; FEV 1 = forced expiratory volume in 1 second; FVC = forced vital capacity More than 10 years ago, O Driscoll et al 1 described a group of patients treated with carmustine (BCNU) for central nervous system gliomas during childhood who developed upper lobe pulmonary fibrosis years after therapy. To our knowledge, bilateral upper lobe fibrotic lung disease has not been reported in adults receiving BCNU. 2 High-dose chemotherapy, which often includes BCNU, before bone marrow transplantation is known to produce pulmonary toxicity in adults, but the typical pattern is bilateral diffuse disease, predominantly in the lower lung zones and occurring weeks to months after therapy is administered. 3 We report a case of BCNU pulmonary toxicity presenting as progressive bilateral upper lobe pulmonary fibrosis in an adult who had received high-dose chemotherapy, including BCNU, preceding bone marrow transplantation for advanced breast cancer. REPORT OF A CASE A 57-year-old woman was referred to our institutuion for pulmonary consultation. She had experienced progressive dyspnea and cough for about 2 years, but her symptoms had become substantially worse during the 3 months before consultation. She had a 20-pack-year history of cigarette smoking but had quit smoking 17 years previously. She had no history of chronic obstructive pulmonary disease. From the Division of Pulmonary Medicine (J.M.P.), Department of Diagnostic Radiology (J.R.M.), and Department of Laboratory Medicine/Pathology (K.O.L.), Mayo Clinic, Scottsdale, Ariz. Address reprint requests and correspondence to James M. Parish, MD, Division of Pulmonary Medicine, Mayo Clinic, Shea Blvd, Scottsdale, AZ Four years before referral, she was diagnosed as having stage IIB breast cancer. She underwent local excision and radiation therapy localized to the left breast, left axilla, and left supraclavicular area. Over the next 3 months, she received 4 courses of doxorubicin (60 mg/ m 2 ) and cyclophosphamide (1200 mg/m 2 ). Four months after her initial diagnosis of breast cancer, she received high-dose chemotherapy preceding bone marrow stem cell transplantation. The chemotherapeutic regimen included 3 doses of cyclophosphamide (1875 mg/m 2 ), 3 doses of cisplatin (55 mg/m 2 ), and 1 dose of carmustine (450 mg/ m 2 ). She received methylprednisolone (1 mg/kg) for 7 days before bone marrow transplantation. Total body irradiation was not administered. Before transplantation, pulmonary function test results were normal, and computed tomography (CT) of the thorax showed no evidence of parenchymal disease. No pulmonary complications occurred during transplantation. On physical examination at our institution, the patient had no clinical evidence of recurrent breast cancer. Bronchial breath sounds were present in the upper lobes both anteriorly and posteriorly, but the lungs were otherwise clear on auscultation. Cardiovascular examination was notable only for tachycardia. The patient had no clubbing, cyanosis, edema, abnormal skin lesions, or abnormal lymphadenopathy. The remainder of the physical examination findings were unremarkable. Pulmonary function studies showed a restrictive pattern, with a total lung capacity of 3.6 L (71% of predicted), forced vital capacity (FVC) of 1.71 L (53% of predicted), forced expiratory volume in 1 second (FEV 1 ) of 1.62 L Mayo Clin Proc. 2003;78: Mayo Foundation for Medical Education and Research

2 Mayo Clin Proc, May 2003, Vol 78 BCNU-Associated Pulmonary Fibrosis 631 Figure 1. Chest radiograph of BCNU-treated patient, showing small right apical pneumothorax, bilateral apical pleural thickening, bilateral upper lobe fibrosis, and upward retraction of both hila. The pneumothorax was not evident on a radiograph obtained 1 year earlier. (62% of predicted), FEV 1 /FVC ratio of 94%, and diffusing capacity of the lung for carbon monoxide (DLCO) of 8.7 ml min 1 mm Hg 1 (39% of predicted). Chest radiography (Figure 1) showed a small right apical pneumothorax that was not evident on a radiograph obtained 1 year earlier. Bilateral apical pleural thickening, bilateral upper lobe fibrosis, and upward retraction of both hila were also noted. Thorax CT showed bilateral apical pleural thickening, bilateral upper lobe subpleural fibrosis, and a small, partially loculated right apical pneumothorax (Figure 2, top), multiple small subpleural bullae in the right apex (Figure 2, middle), and a small right pleural effusion (Figure 2, bottom). Aspiration was initially unsuccessful in resolving the pneumothorax. After several weeks of observation, the pneumothorax resolved, but the patient had persistent dyspnea and coughing. Bronchoscopy, cultures of bronchial washings, and transbronchoscopic lung biopsy were performed, but results were nondiagnostic. To establish a definite diagnosis, a thoracoscopic lung biopsy was performed. Microscopic evaluation of the wedge biopsy specimen revealed a distinctive pattern of pleural and subpleural parenchymal fibrosis (Figure 3, upper left). The pleural fibrosis appeared denser and less fibroblastic than that seen subpleurally and in other involved parenchymal areas (Figure 3, upper right). Fibrosis extended into the underlying lung tissue, following interlobular septae (Figure 3, lower left) with relative centrilobular sparing. Peribronchiolar fibrosis associated with mild bronchiolectasis and patchy mucostasis was also noted (Figure 3, lower right). Mild chronic parenchymal inflammation consisting of lymphocytes and scattered eosinophils was present, mainly in association with areas of fibrosis. The radiographic and microscopic findings lacked specific features of the diseases proposed in the clinical differential diagnosis (Langerhans cell histiocytosis, sarcoidosis, pneumoconioses, and granulomatous infections) and were most consistent with drug toxicity. Corticosteriods were administered, but dyspnea, cough, and exercise tolerance worsened over the course of the next year. Thorax CT showed resolution of the right apical lobe pneumothorax and progression of the bilateral apical pleural thickening and bilateral interstitial fibrosis (Figure 4). The patient s dyspnea and pulmonary function worsened further over the ensuing 2 years. Azathioprine was administered with no apparent clinical improvement. Lung transplantation was considered, but the patient developed a severe respiratory infection and died before the procedure could be performed. DISCUSSION Alkylating agents such as BCNU (part of the nitrosourea group) have been used for decades as chemotherapy for neoplastic disease. The most important action of the alkylating agents is disturbance of the fundamental mechanism of cell proliferation, DNA synthesis and cell division. BCNU was introduced for investigational clinical research in 1964 and became available commercially for clinical use in Initial experience with the drug identified myelosuppression and emesis as the major adverse effects, with mild hepatic and renal toxicities occurring less frequently. 5 Both BCNU and CCNU (lomustine) are highly lipophilic, allowing them to cross the blood-brain barrier. This property makes them important in the treatment of malignant brain tumors such as astrocytomas and metastatic tumors involving the brain. The nitrosoureas are also used in the treatment of Hodgkin disease and lymphomas. The first case of BCNU pulmonary toxicity in humans was reported by Holoye et al 6 in Durant et al 4 described 10 patients who developed pulmonary toxicity after BCNU therapy for malignancy, 9 of whom had also received cyclophosphamide, another drug known to be associated with pulmonary toxicity. In a report by Selker et al, 7 14 of 47 patients who had undergone chemotherapy, including BCNU, for primary intracranial glioma developed pulmonary toxicity, suggesting a prevalence of BCNU-related pulmonary toxicity as high as 30%. The exact mechanism of BCNU pulmonary toxicity is unknown, but several studies have noted a relationship between the dose of BCNU and this adverse reaction. 5,8 Weiss et al 5 found that a cumulative dose of 1200 to 1500 mg/m 2 significantly increased the risk of pulmonary toxicity. Other significant risk factors included preexisting lung disease, thoracic irradiation, concomitant administration of other drugs with known pulmonary toxicity, and exposure to high fractions of inspired oxygen.

3 632 Figure 2. Computed tomographic scans of the thorax in BCNUtreated patient, showing a small right apical pneumothorax, bilateral apical pleural thickening, and bilateral upper lobe subpleural fibrosis (top), multiple small right apical subpleural bullae (middle), and a small right pleural effusion (bottom). High-dose chemotherapy followed by autologous bone marrow transplantion has been used frequently in the past decade for the treatment of solid tumors and hematologic malignancies. A single high dose of BCNU has often been used in these regimens. Seiden et al 9 found that pulmonary toxicity occurred more commonly with chemotherapeutic protocols containing BCNU than with protocols that did not include this drug. A protocol containing both BCNU and cyclophosphamide had the highest prevalence of interstitial pneumonitis, defined by significant reductions in FEV 1 and DLCO. Ager et a 10 observed that high-dose chemotherapeutic regimens preceding autologous stem cell transplantation were associated with a 58% prevalence of pulmonary toxicity (identified by DLCO reductions of 20%) if the dose of BCNU was 600 mg/m 2 or higher compared with a prevalence of 8% with a 450-mg/m 2 dose. Chemotherapeutic regimens including high-dose BCNU can be associated with asymptomatic and subclinical decreases in DLCO that most likely represent a manifestation of pulmonary toxicity. Rubio et al 11 found that one of the main risk factors for idiopathic pneumonia syndrome in patients receiving high-dose chemotherapy for Hodgkin disease was a dose of BCNU greater than 475 mg/m 2. Frequently, treatment with corticosteroids can reverse this BCNU-associated decrease in DLCO. 12 In these reports of high-dose BCNU associated lung toxicity, diffuse interstitial infiltrates were observed most frequently. However, bilateral upper lobe fibrosis, as seen in our patient, has not been reported previously. Wilczynski et al 13 described a delayed pulmonary toxicity syndrome characterized by cough, dyspnea, and decreased DLCO (50%-60% of baseline) after high-dose chemotherapy (cyclophosphamide, cisplatin, BCNU) and autologous bone marrow transplantation. The mean onset of symptoms occurred 10.3 weeks after bone marrow transplantation, and the patients often responded to corticosteroid therapy. No relationship to BCNU dose was identified in these patients, suggesting that other factors were more relevant for development of pulmonary toxicity. Todd et al 14 reported pulmonary toxicity in patients with breast cancer who were treated with chemotherapy and bone marrow transplantation. In that study, 10 of 23 patients with pulmonary toxicity had open-lung or transbronchoscopic lung biopsies. The mean onset of symptoms was 48 weeks after induction chemotherapy. Three of the 10 patients died within 6 months, and 7 recovered with corticosteroid therapy within 8 months to 2 years. Five of the patients had upper lobe and lower lobe pulmonary interstitial abnormalities. In adults who had delayed-onset pulmonary toxicity after high-dose chemotherapy in association with autologous bone marrow transplantation, CT findings were predominantly peripheral, ground-glass, or consolidated opacities that occasionally appeared nodular or masslike. Occasionally, the CT pattern was suggestive of pulmonary edema with hazy opacification of the dependent portions of the lung with engorgement of the vessels and subpleural septal thicken-

4 Mayo Clin Proc, May 2003, Vol 78 BCNU-Associated Pulmonary Fibrosis 633 Figure 3. Photomicrographs of lung biopsy specimen from BCNU-treated patient. Upper left, Pleural and interlobular septal fibrosis with portions of the intervening parenchyma relatively spared. Delicate interstitial fibrosis is present to a variable degree throughout the sections. Some tractional dilatation of membranous bronchioles is evident. Upper right, High-magnification view showing laminated appearance of denser peripheral fibrosis interfacing with looser fibrosis beneath. P = pleural surface. Lower left, High-magnification view showing parenchymal fibrosis with associated mild chronic inflammation. Lower right, Cystic membranous bronchiole adjacent to area of fibrosis (hematoxylin-eosin, original magnification: upper left, 20; upper right, 40; lower left, 60; lower right, 40). ing. 2 Pleural effusions and adenopathy were uncommon. Bilateral upper lobe pulmonary fibrosis was not reported in these cases of idiopathic or delayed pulmonary toxicity after bone marrrow transplantation. In all these studies describing BCNU-associated pulmonary toxicity, radiographic abnormalities due to pulmonary fibrosis are typically described as diffuse and bilateral, involving predominantly the lower lobes. A review of adult patients with drug-induced lung disease associated with bleomycin, nitrofurantoin, penicillamine, BCNU, and amiodarone described 4 frequently observed patterns of lung disease: (1) fibrosis with or without consolidation, (2) ground-glass opacities, (3) widespread bilateral consolidation, and (4) bronchial wall thickening. 3 Upper lobe pulmonary fibrosis was not described. In contrast to the pattern of BCNU pulmonary toxicity described in adults, O Driscoll et al 1 described a distinctly different pattern of upper lobe pulmonary fibrosis in children. These investigators reported pulmonary fibrosis occurring up to 17 years after treatment with BCNU for brain tumors. Of 31 patients, 14 died of their tumor, but 6 died of pulmonary fibrosis. Of 8 survivors available for study, 6 had abnormal chest radiographic findings and chest CT scans that showed predominantly upper-zone pulmonary fibrosis. The pattern was patchy linear opacities with upward retraction of the pulmonary hila, a pattern that had not been described previously. Two patients had normal findings on chest radiography despite restrictive spirometry and histologic evidence of fibrosis. Taylor et al 15 reported upper lobe subpleural abnormalities in the same group of

5 634 Figure 4. Computed tomographic scans of the thorax in BCNU-treated patient 1 year after presentation, showing resolution of the right apical pneumothorax (left) and progression of the bilateral apical pleural thickening, bilateral subpleural fibrosis, and bilateral upper lobe fibrosis (left and right). patients studied by O Driscoll et al, 1 including one patient with bilateral spontaneous pneumothorax. Histologic changes included focal interstitial fibrosis and elastosis, prominent fibroblasts, and a focal lymphocytic infiltration. 16 One important difference between the children with upper lobe pulmonary fibrosis described by O Driscoll et al 1 and patients receiving conditioning regimens for bone marrow transplantation is the dose and frequency of the administration of BCNU. Patients undergoing high-dose chemotherapy before bone marrow transplantation typically receive a single dose of BCNU, whereas the patients reported by O Driscoll et al received BCNU at 100 mg/m 2 every 6 to 8 weeks for up to 2 years. Our patient received a single high dose of BCNU before bone marrow transplantation, rather than intermittent lower doses. In summary, delayed onset of upper lobe pulmonary fibrosis associated with BCNU therapy has been described in children treated for gliomas and occurs years after therapy. Pulmonary toxicity is commonly observed in adults after BCNU and high-dose chemotherapy, but to our knowledge, upper lobe pulmonary fibrosis has not been described in adults. The occurrence of upper lobe pulmonary fibrosis in adults is generally associated with sarcoidosis, Langerhans cell histiocytosis, silicosis, berylliosis, or other pneumoconioses. It can be progressive, unresponsive to treatment, and fatal. REFERENCES 1. O Driscoll BR, Hasleton PS, Taylor PM, Poulter LW, Gattameneni HR, Woodcock AA. Active lung fibrosis up to 17 years after chemotherapy with carmustine (BCNU) in childhood. N Engl J Med. 1990;323: Patz EF Jr, Peters WP, Goodman PC. Pulmonary drug toxicity following high-dose chemotherapy with autologous bone marrow transplantation: CT findings in 20 cases. J Thorac Imaging. 1994;9: Padley SP, Adler B, Hansell DM, Muller NL. High-resolution computed tomography of drug-induced lung disease. Clin Radiol. 1992;46: Durant JR, Norgard MJ, Murad TM, Bartolucci AA, Langford KH. Pulmonary toxicity associated with bischloroethylnitrosourea (BCNU). Ann Intern Med. 1979;90: Weiss RB, Poster DS, Penta JS. The nitrosoureas and pulmonary toxicity. Cancer Treat Rev. 1981;8: Holoye PY, Jenkins DE, Greenberg SD. Pulmonary toxicity in long-term administration of BCNU. Cancer Treat Rep. 1976;60: Selker RG, Jacobs SA, Moore PB, et al. 1,3-Bis(2-chloroethyl)-1- nitrosourea (BCNU)-induced pulmonary fibrosis. Neurosurgery. 1980;7: Weinstein AS, Diener-West M, Nelson DF, Pakuris E. Pulmonary toxicity of carmustine in patients treated for malignant glioma. Cancer Treat Rep. 1986;70: Seiden MV, Elias A, Ayash L, et al. Pulmonary toxicity associated with high dose chemotherapy in the treatment of solid tumors with autologous marrow transplant: an analysis of four chemotherapy regimens. Bone Marrow Transplant. 1992;10: Ager S, Mahendra P, Richards EM, Bass G, Baglin TP, Marcus RE. High-dose carmustine, etoposide and melphalan ( BEM ) with autologous stem cell transplantation: a dose-toxicity study. Bone Marrow Transplant. 1996;17: Rubio C, Hill ME, Milan S, O Brien ME, Cunningham D. Idiopathic pneumonia syndrome after high-dose chemotherapy for relapsed Hodgkin s disease. Br J Cancer. 1997;75: Kalaycioglu M, Kavuru M, Tuason L, Bolwell B. Empiric prednisone therapy for pulmonary toxic reaction after high-dose chemotherapy containing carmustine (BCNU). Chest. 1995;107: Wilczynski SW, Erasmus JJ, Petros WP, Vredenburgh JJ, Folz RJ. Delayed pulmonary toxicity syndrome following high-dose chemotherapy and bone marrow transplantation for breast cancer. Am J Respir Crit Care Med. 1998;157: Todd NW, Peters WP, Ost AH, Roggli VL, Piantadosi CA. Pulmonary drug toxicity in patients with primary breast cancer treated with high-dose combination chemotherapy and autologous bone marrow transplantation. Am Rev Respir Dis. 1993;147: Taylor PM, O Driscoll BR, Gattamaneni HR, Woodcock AA. Chronic lung fibrosis following carmustine (BCNU) chemotherapy: radiological features. Clin Radiol. 1991;44: Hasleton PS, O Driscoll BR, Lynch P, et al. Late BCNU lung: a light and ultrastructural study on the delayed effect of BCNU on the lung parenchyma. J Pathol. 1991;164:31-36.