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Journal of Clinical Oncology, Vol 25, No 23 (August 10), 2007: pp. 3543-3544 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.12.2218
Fatal Pulmonary Toxicity in Testis Cancer With Bleomycin-Containing ChemotherapyVrije Universiteit Medical Centre Amsterdam, Department of Oncology, Amsterdam, the Netherlands A 43-year-old man presented to the hospital with abdominal pain, weight loss, and a palpable tumor of his left testicle. Histology of the tumor after orchidectomy showed a mixed germ cell tumor, mainly embryonal carcinoma with a yolk sac component. Computed tomography scan of thorax and abdomen showed extensive metastasis with intrapulmonary lesions in both lungs, mediastinal and retroperitoneal lymphadenopathy, a large intra-abdominal tumor compressing the left ureter with hydronefrosis and ascites. No cerebral metastases were found. Laboratory testing revealed ß-human chorionic gonadotropin levels of 40 µ/L (normal range, 0 to 5 µ/L), alfa fetoprotein 89,622 µg/L (normal range, 0 to 10 µg/L), and lactate dehydrogenase 2,400 µ/L (normal range, 150 to 400 µ/L). Creatinine level was 108 µmol/L (creatinine clearance according to the Cockroft formula, 80 mL/min). He had no significant medical history except for a serious panic disorder, social phobia, and depressive episodes, for which he used medication consisting of alprazolam, risperdal, oxazepam, akineton, and anafranil. The patient was referred to our hospital for treatment of his poor prognostic nonseminoma testis. According to current standard, treatment was initiated with bleomycin, etoposide, and cisplatin chemotherapy (bleomycin USP, 30 U on days 1, 8, and 15; etoposide 100 mg/m2, and cisplatin 20 mg/m2 on days 1 to 5). The first course of chemotherapy was complicated by neutropenic fever without an evident focus for infection, for which he was treated with broad-spectrum antibiotics. A scrotal abscess for which he needed surgical incision and drainage complicated the second course, despite the addition of granulocyte colony-stimulating factor. He also developed deep vein thrombosis in his left iliac and femoral vein. The third course was unremarkable. On admittance for his fourth course of chemotherapy, he had no physical complaints besides the usual nervousness. On routine physical examination, however, crepitations were felt during palpation of the neck and lung auscultation disclosed diminished breath sounds over his right lower lobe. An x-ray of the thorax showed bilateral consolidations, pleural fluid in the right lower lobe, and mediastinal and subcutaneous emphysema (Fig 1A). Computed tomography scan of the thorax confirmed the diagnoses of a pneumomediastinum and subcutaneous emphysema without a pneumothorax (Fig 1B). After enteral contrast there was no leakage from the esophagus. Bronchoscopy excluded damage to the larger airways. Empirical treatment was started with broad-spectrum antibiotics after taking cultures of blood and sputum. However, his clinical condition deteriorated dramatically and he was transferred to the intensive care unit because of respiratory failure. High-pressure ventilation was necessary, suggesting stiff, fibrotic lungs. Bleomycin lung toxicity was suspected and because of the acute onset of symptoms, treatment with high-dose corticosteroids was commenced. Unfortunately, it was impossible to ventilate the patient adequately and he died several days later of respiratory failure.
Bleomycin is an antibiotic drug produced by Streptomyces verticillus. It has antitumor activity by breaking the DNA double helix by the production of free radicals, which is oxygen and iron dependent.1 It is mainly eliminated by the kidney and can be deactivated by the enzyme bleomycin hydrolase. This enzyme is missing in skin and lung, making those organs vulnerable to toxicity.2 The most feared and dose-limiting adverse effect of bleomycin is its induction of pulmonary toxicity.2 It has been reported in 2% to 40% of patients, depending on criteria used and the presence of risk factors. Death occurs in approximately 2% of patients.3 Diagnoses of bleomycin-induced pneumonitis is often one of exclusion, as symptoms and radiographic findings are nonspecific.2 Symptoms can consist of dry cough, shortness of breath, tachycardia, cyanoses, and sometimes fever. X-ray of the chest varies from no abnormalities to bilateral basal infiltrates, followed by diffuse interstitial and alveolar infiltrates.2 Pneumothorax with or without pneumomediastinum has been described in a few cases, where it was postulated that this complication occurred late in the disease when extensive architectural distortion led to rupture of subpleural cysts. Fatal pneumothorax is a rare but recognized complication, although pneumomediastinum was not encountered in those patients.4,5,6 Pneumomediastinum without pneumothorax has only been described in two patients with bleomycin-induced pneumonitis. It had no clinical implications and resolved spontaneously within weeks,4 in contrast to the patient described. The pathogenesis of bleomycin-induced pneumonitis is not exactly known, but endothelial damage due to cytokines and free radicals by forming a complex with Fe 3+ seem to play an important role.2,7 Age older than 40 years, reduced kidney function (glomerular filtration rate, < 80 mL/min), and cumulative dose of bleomycin higher than 300 mg are significantly associated with an increased risk of lung toxicity.7 Numerous methods have been evaluated to detect bleomycin-induced lung toxicity at an early stage to avoid development of more serious toxicity by withholding further treatment with bleomycin.2 Pulmonary function assessment appears to be the most proper tool. Several studies examined the predictive value of deterioration in transfer capacity of the lungs for carbon mono-oxide (TLCO) for the development of clinical significant bleomycin lung toxicity, with conflicting results.2,8,9,10 Although a decline in TLCO is not bleomycin specific and there is no direct association between pulmonary symptoms and decline of lung function tests, several authors advise stopping further bleomycin treatment when TLCO decreases more than 40% to 60% of the pretreatment value.2 To our knowledge, this is the first report of a fatal pneumomediastinum during bleomycin-combination chemotherapy. Remarkable is the presentation with a pneumomediastinum 12 weeks after the start of chemotherapy without preceding pulmonary symptoms. This is difficult to understand considering the earlier postulation that this was a late effect of bleomycin lung toxicity due to development of fibrosis with rupture of subpleural cysts. Apart from his older age, our patient had no specific risk factors for developing lung toxicity. He had no pre-existing pulmonary disease and his kidney function improved after the first cycle of chemotherapy to normal levels. Interaction between the patients neuroleptic comedication was considered, inducing the toxic effect of bleomycin. However, no evidence could be found to support this hypothesis. Lung function assessments or x-ray of the thorax were not used as routine monitoring test due to insufficient evidence to support its predictive value in the development of clinical significant bleomycin-induced lung toxicity. This case report illustrates a rare manifestation of bleomycin-associated pulmonary toxicity, which was unfortunately fatal. Awareness of pulmonary complications is very important as early recognition and subsequent interruption of bleomycin therapy is necessary to prevent morbidity and mortality in patients who are treated with curative intent. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.
REFERENCES 1. Azumbuja E, Fleck JF, Batista RG, et al: Bleomycin lung toxicity: Who are the patients with increased risk? Pulm Pharmacol Ther 18:363-366, 2005[CrossRef][Medline] 2. Sleijfer S: Bleomycin-induced pneumonitis. Chest 120:617-624, 2001[CrossRef][Medline] 3. Simpson AB, Paul J, Graham J, et al: Fatal bleomycin pulmonary toxicity in the west of Scotland 1991-1995: a review of patients with germ cell tumours. Br J Cancer 78:1061-1066, 1998[Medline] 4. Sikdar T, Macvicar D, Husband JE: Pneumomediastinum complicating bleomycin related lung damage. British J Rad 71:1202-1204, 1998 5. Doll DC: Fatal pneumothorax associated with bleomycin-induced pulmonary fibrosis. Cancer Chemother Pharmacol 17:294-295, 1986[Medline] 6. White DA, Stover DE: Severe bleomycin-induced pneumonitis, clinical features and response to corticosteroids. Chest 86:723-728, 1984[CrossRef][Medline] 7. O'Sullivan JM, Huddart RA, Norman AR, et al: Predicting the risk of bleomycin lung toxicity in patients with germ-cell tumours. Ann Oncol 14:91-96, 2003 8. McKeage MJ, Evans BD, Atkinson C, et al: Carbon monoxide diffusing capacity is a poor predictor of clinically significant bleomycin lung. J Clin Oncol 8:765-767, 1990[Medline] 9. Sorensen PF, Rossing N, Rorth M: Carbon monoxide diffusing capacity: A reliable indicator of bleomycin-induced pulmonary toxicity. Eur J Respir Dis 66:333-340, 1985[Medline] 10. Lucraft HH, Wilkinson PM, Stretton TB, et al: Role of pulmonary function tests in prevention of bleomycin pulmonary toxicity during chemotherapy for metastatic testicular teratoma. Eur J Cancer Clin Oncol 18:133-139, 1982[CrossRef][Medline]
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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