Chemotherapy-related delayed bilateral spontaneous pneumothorax and lung fibrosis: methotrexate or cyclophosphamide, or both?

A 27-year-old man was diagnosed with pre-T-cell acute lymphoblastic leukemia in November 2004 and underwent chemotherapy by German multicenter ALL (GMALL) protocol (including vincristine, daunorubicin, L-asparaginase, prednisolone, cyclophosphamide, Ara-C, intrathecal methotrexate (MTX), high dose MTX and mitoxantrone) between December 2004 and March 2005 with complete remission. Because the patient refused autologous stem cell transplantation, he received two cycles of high dose cyclophosphamide (2 g/m) and one cycle of high dose CEP (cyclophosphamide 3 g/m ¥ 2 days, etoposide 100 mg/m ¥ 4 days and cisplatin 50 mg/m ¥ 2 days) during July to September 2005 as intensive consolidation. Afterward, maintenance chemotherapy with weekly MTX (intravenous injection 40 mg) and daily mercaptopurine 50 mg was applied for 2 years. The last cycle of MTX was completed on 10 January 2008, and his disease status was determined in complete remission. The patient began to feel dyspnea since May 2008. His chest radiograph showed bilateral spontaneous pneumothorax and fibrotic change in the bilateral hilar area (Fig. 1). His chest computed tomography showed ground-glass appearance at the bilateral upper lung field (Fig. 2), and his pulmonary function test showed severe restrictive lung disease (forced vital capacity: 1.06 L; forced expiratory volume in 1 s: 0.78 L/s). Then the patient received video-assisted thoracoscopic surgery for bilateral wedge biopsy and pleurodesis. The pathology of lung tissue showed bilateral lung fibrosis without the evidence of microorganism involvement (Fig. 3). The etiology of bilateral pneumothorax with severe lung fibrosis was thought to be related to methotrexate or cyclophosphamide. The patient then received high dose prednisolone (60 mg daily), but his condition and pulmonary function responded poorly to steroid treatment. Now the patient is waiting for lung transplantation. Correspondence Chung-Jen Huang, MD, Division of Pulmonary and Intensive Care Medicine, Koo Foundation Sun Yat-Sen Cancer Center, 125 Lih-Der Road, Pei-Tou District, Taipei, Taiwan 11259. Tel: (886) 2-2897011 ext. 1720 Fax: (886) 2-8972233 email: huang600517@yahoo.com Figure 1. Chest radiograph showed bilateral pneumothorax, perihilar fibrosis and severe volume reduction. The Clinical Respiratory Journal FORUM