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© 2000 American Society for Clinical Oncology
Side Effects of ChemotherapyArthur Skarin, MDConsultant Editor
Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Harvard Medical School, Boston, MA CASE 3. ACUTE INTERSTITIAL PNEUMONITIS RELATED TO GEMCITABINE A 52-year-old man with stage IV non-small-cell lung cancer (NSCLC) presented with fevers and shortness of breath (SOB). He had a history of Hodgkin’s lymphoma at the age of 25 treated with cobalt-60 radiotherapy that included a mantle field. In 1997, at the age of 50 years, he developed SOB and was found to have a right-sided pleural effusion and small (1 to 2 mm) bilateral pulmonary nodules. Pleural biopsy and fluid analysis revealed poorly differentiated NSCLC. Results of a mediastinoscopy were positive for right-sided lymph node metastases. He was treated with six cycles of carboplatin and paclitaxel and experienced regression of the mediastinal adenopathy, effusion, and tiny lung nodules. One year later, he developed SOB. Computed tomography (CT) showed bilateral perihilar masses, recurrent mediastinal lymphadenopathy, and pulmonary nodules. Results of a bone scan were positive for diffuse bone metastases. He received six additional cycles of carboplatin and paclitaxel and experienced radiographic improvement of disease, but there were residual pulmonary nodules and intermittent SOB. Therefore, he was started on gemcitabine. His first two weekly courses of gemcitabine 850 mg/m2 were complicated by fevers and fatigue. His third dose was postponed for 3 weeks because of myelosuppression. He received his fourth dose 1 week after his third, and doses five and six were administered 3 weeks later. During the next 2 weeks, he developed episodes of SOB and fevers to 104°F. There were no night sweats, chills, or chest pain, but he had scant clear sputum production. Chest CT scanning revealed new, diffuse interstitial changes in both lungs with a ground glass appearance, especially in the left upper and lower lobes (Fig 1). He developed dyspnea and hypoxia and was admitted for management. He was started on co-trimoxazole and prednisone. Sputum showed grade 3+ polymorphonuclear neutrophils, moderate Gram-positive cocci, and grade 4+ oropharyngeal flora but was negative for Pneumocystis carinii and fungi. Blood cultures were also negative. Bronchoscopy and transbronchial biopsy showed only scant secretions, whereas four of four biopsies demonstrated nonspecific interstitial pneumonitis (Fig 2, A and B). The patient improved after 24 hours of therapy and was discharged on a corticosteroid taper with cotrimoxazole Pneumocystis carinii prophylaxis. Bacterial, viral, fungal, and acid-fast cultures were negative. A follow-up chest CT scan 2 months later showed resolution of the previous diffuse interstitial infiltrates.
The safety of gemcitabine was evaluated in 979 patients with a variety of malignancies by the United States Food and Drug Administration in May 1996. Doses ranged from 800 to 1,250 mg/m2 and were administered over a 30-minute weekly infusion. Dyspnea was reported in 23% of patients but was usually mild to moderate. Less than 1% of patients discontinued treatment as a result of the toxicity. Forty percent of patients had lung cancer or pulmonary manifestations of other tumors. An evaluation of the group of patients with pancreatic cancer (n = 242) found dyspnea in 10% of patients. Pulmonary and allergic toxicities were assessed in 565 patients in whom toxicities were assessed using World Health Organization recommended toxicity grading and deemed by the investigator as possibly being related to the study drug. Although 518 patients had no symptoms (grade 0), 25 (4.5%) had mild symptoms (grade 1), 10 (1.8%) had dyspnea on exertion, and seven (1.2%) had dyspnea at rest. Only one patient required complete bed rest. No change in allergic symptoms were reported in 542 patients (96.6%). However, 16 (2.9%) had edema, two (0.4%) had bronchospasm, and one (0.2%) had bronchospasm requiring intravenous therapy. No patients had anaphylaxis (data on file, Lilly Research Laboratories).1 Pulmonary toxicity during treatment with gemcitabine has previously been reported in three patients.2 They developed tachypnea, hypoxemia, and pulmonary edema with interstitial infiltrates on chest x-ray. In two patients, postmortem examination revealed acute respiratory distress syndrome; in the third patient, a transbronchial biopsy demonstrated interstitial pneumonitis. Three other fatal pulmonary complications during gemcitabine therapy have been reported in lung cancer patients (data on file, Lilly Research Laboratories, Indianapolis, IN). Another patient, a 68-year-old man without previous chemotherapy who had undergone pneumonectomy for lung cancer, was started on weekly gemcitabine 1,250 mg/m2 with 12.5 mg of prednisone daily. Six days after his sixth dose of gemcitabine, he developed fever, malaise, nonproductive cough, and progressive dyspnea. A chest x-ray showed a right basilar opacity. Sputum and blood cultures, Mycoplasma and Legionella titers, and viral serologies were negative. At autopsy, tissue stains for organisms were negative. Pathologic examination revealed diffuse alveolar damage.3 Gemcitabine structurally resembles cytarabine, which has been associated with noncardiogenic pulmonary edema. Symptoms occur during treatment or up to 28 days after cessation of therapy. In 13 (12%) of 103 patients treated with cytarabine for acute leukemia, acute respiratory failure developed and nine patients died. Of seven autopsies, six showed edema alone and one showed diffuse alveolar damage.4 These cases are not common but reinforce the need for careful attention to any new pulmonary complaints that occur in patients receiving gemcitabine. Prompt evaluation should be carried out owing to multiple etiologies in the differential diagnosis. Use of prednisone in our patient resulted in complete reversal of signs and symptoms. Copyright 2000 American Society of Clinical Oncology REFERENCES 1. Gemzar (gemcitabine HCL) for Injection. Indianapolis, IN, Eli Lilly and Co, 1996 (prescribing information) 2. Pavlakis N, Bell DR, Millward MJ, et al: Fatal pulmonary toxicity resulting from treatment with gemcitabine. Cancer 80:286-291, 1997[Medline] 3. Marruchella A, Fiorenzano G, Merizzi A, et al: Diffuse alveolar damage in a patient treated with gemcitabine. Eur Respir J 11:504-506, 1998[Abstract] 4. Andersson BS, Luna MA, Yee C, et al: Fatal pulmonary failure complicating high-dose cytosine arabinoside therapy in acute leukemia. Cancer 65:1079-1084, 1990[Medline]
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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