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Nitrosourea-induced pulmonary injury

Ronan O'Driscoll, BSc, MD, FRCP
Section Editors
Kevin R Flaherty, MD, MS
James R Jett, MD
Deputy Editors
Helen Hollingsworth, MD
Diane MF Savarese, MD


The nitrosourea drugs, a class of DNA alkylating agents related to nitrogen mustards, include carmustine (BCNU), lomustine (CCNU), semustine (methyl CCNU), and chloroethylnitrosourea (Sar-CNU). Nitrosourea drugs are used to treat lymphoma, brain tumors, melanoma, and other solid tumors including breast cancer. Carmustine is the most widely used nitrosourea, and is associated with acute and chronic pulmonary toxicity [1-4]. Pulmonary fibrosis has also followed treatment with semustine and chloroethylnitrosourea [5,6].

Most patients develop pulmonary fibrosis within three years of carmustine treatment; however, some patients develop breathlessness and aggressive fibrosis decades after exposure [1-4]. The reported incidence of carmustine-induced pulmonary toxicity has ranged from 20 to 30 percent in some studies, to as low as 1 percent in others [1]. The low incidence of pulmonary fibrosis in some series may be due to a short observation period, low dose carmustine therapy, or the short median survival of patients with aggressive tumors [7].

Carmustine is also used in the management of patients with lymphoma who require high dose chemotherapy in conjunction with hematopoietic stem cell support [8]. Patients who received carmustine as part of their preparative regimen for hematopoietic stem cell transplantation have a longer window for the development of pulmonary complications. In this setting the incidence of interstitial pneumonitis or idiopathic pneumonia has been reported to be 2 to 23 percent [9-11].

Some authors have suggested that this syndrome should be considered "idiopathic pneumonia syndrome" in the context of hematopoietic stem cell transplantation, because the etiology and histology of the lung abnormality are poorly characterized in many cases [12]. In addition, these patients are exposed to a single dose or short course of carmustine in combination with other chemotherapy agents, whereas use of carmustine for other disorders requires repeated cycles of chemotherapy over a period of up to two years. (See "Pulmonary complications after allogeneic hematopoietic cell transplantation", section on 'Idiopathic pneumonia syndrome'.)


Up to 25 percent of patients in whom carmustine is administered will develop pulmonary fibrosis during the ensuing 36 months, if they survive their malignancy [1-3,7,9,10,13,14]. Lung fibrosis is especially likely with very high doses (above 1500 mg per square meter), the concurrent administration of other agents with pulmonary toxicity (such as cyclophosphamide), and possibly by preexisting lung disease, localized chest wall radiotherapy, or atopy [11].

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Literature review current through: Nov 2017. | This topic last updated: Feb 02, 2017.
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  1. Weiss RB, Poster DS, Penta JS. The nitrosoureas and pulmonary toxicity. Cancer Treat Rev 1981; 8:111.
  2. Selker RG, Jacobs SA, Moore PB, et al. 1,3-Bis(2-chloroethyl)-1-nitrosourea (BCNU)-induced pulmonary fibrosis. Neurosurgery 1980; 7:560.
  3. Durant JR, Norgard MJ, Murad TM, et al. Pulmonary toxicity associated with bischloroethylnitrosourea (BCNU). Ann Intern Med 1979; 90:191.
  4. O'Driscoll BR, Hasleton PS, Taylor PM, et al. Active lung fibrosis up to 17 years after chemotherapy with carmustine (BCNU) in childhood. N Engl J Med 1990; 323:378.
  5. Wong RP, Baetz T, Krahn MJ, et al. SarCNU in recurrent or metastatic colorectal cancer: a phase II study of the National Cancer Institute of Canada Clinical Trials Group. Invest New Drugs 2006; 24:347.
  6. Webster M, Cairncross G, Gertler S, et al. Phase II trial of SarCNU in malignant glioma: unexpected pulmonary toxicity with a novel nitrosourea: a phase II trial of the national cancer institute of canada clinical trials group. Invest New Drugs 2005; 23:591.
  7. Weinstein AS, Diener-West M, Nelson DF, Pakuris E. Pulmonary toxicity of carmustine in patients treated for malignant glioma. Cancer Treat Rep 1986; 70:943.
  8. Alessandrino EP, Bernasconi P, Colombo A, et al. Pulmonary toxicity following carmustine-based preparative regimens and autologous peripheral blood progenitor cell transplantation in hematological malignancies. Bone Marrow Transplant 2000; 25:309.
  9. Wadhwa PD, Fu P, Koc ON, et al. High-dose carmustine, etoposide, and cisplatin for autologous stem cell transplantation with or without involved-field radiation for relapsed/refractory lymphoma: an effective regimen with low morbidity and mortality. Biol Blood Marrow Transplant 2005; 11:13.
  10. Wong R, Rondon G, Saliba RM, et al. Idiopathic pneumonia syndrome after high-dose chemotherapy and autologous hematopoietic stem cell transplantation for high-risk breast cancer. Bone Marrow Transplant 2003; 31:1157.
  11. Frankovich J, Donaldson SS, Lee Y, et al. High-dose therapy and autologous hematopoietic cell transplantation in children with primary refractory and relapsed Hodgkin's disease: atopy predicts idiopathic diffuse lung injury syndromes. Biol Blood Marrow Transplant 2001; 7:49.
  12. Clark JG, Hansen JA, Hertz MI, et al. NHLBI workshop summary. Idiopathic pneumonia syndrome after bone marrow transplantation. Am Rev Respir Dis 1993; 147:1601.
  13. Shen YC, Chiu CF, Chow KC, et al. Fatal pulmonary fibrosis associated with BCNU: the relative role of platelet-derived growth factor-B, insulin-like growth factor I, transforming growth factor-beta1 and cyclooxygenase-2. Bone Marrow Transplant 2004; 34:609.
  14. Cao TM, Negrin RS, Stockerl-Goldstein KE, et al. Pulmonary toxicity syndrome in breast cancer patients undergoing BCNU-containing high-dose chemotherapy and autologous hematopoietic cell transplantation. Biol Blood Marrow Transplant 2000; 6:387.
  15. Schmitz N, Diehl V. Carmustine and the lungs . Lancet 1997; 349:1712.
  16. Rubio C, Hill ME, Milan S, et al. Idiopathic pneumonia syndrome after high-dose chemotherapy for relapsed Hodgkin's disease. Br J Cancer 1997; 75:1044.
  17. Ager S, Mahendra P, Richards EM, et al. High-dose carmustine, etoposide and melphalan ('BEM') with autologous stem cell transplantation: a dose-toxicity study. Bone Marrow Transplant 1996; 17:335.
  18. Chastagner P, Kalifa C, Doz F, et al. Outcome of children treated with preradiation chemotherapy for a high-grade glioma: results of a French Society of Pediatric Oncology (SFOP) Pilot Study. Pediatr Blood Cancer 2007; 49:803.
  19. Chap L, Shpiner R, Levine M, et al. Pulmonary toxicity of high-dose chemotherapy for breast cancer: a non-invasive approach to diagnosis and treatment. Bone Marrow Transplant 1997; 20:1063.
  20. Kalaycioglu M, Kavuru M, Tuason L, Bolwell B. Empiric prednisone therapy for pulmonary toxic reaction after high-dose chemotherapy containing carmustine (BCNU). Chest 1995; 107:482.
  21. Parish JM, Muhm JR, Leslie KO. Upper lobe pulmonary fibrosis associated with high-dose chemotherapy containing BCNU for bone marrow transplantation. Mayo Clin Proc 2003; 78:630.
  22. Lind PA, Marks LB, Jamieson TA, et al. Predictors for pneumonitis during locoregional radiotherapy in high-risk patients with breast carcinoma treated with high-dose chemotherapy and stem-cell rescue. Cancer 2002; 94:2821.
  23. McGaughey DS, Nikcevich DA, Long GD, et al. Inhaled steroids as prophylaxis for delayed pulmonary toxicity syndrome in breast cancer patients undergoing high-dose chemotherapy and autologous stem cell transplantation. Biol Blood Marrow Transplant 2001; 7:274.
  24. Damon LE, Wolf JL, Rugo HS, et al. High-dose chemotherapy (CTM) for breast cancer. Bone Marrow Transplant 2000; 26:257.
  25. O'Driscoll BR, Kalra S, Gattamaneni HR, Woodcock AA. Late carmustine lung fibrosis. Age at treatment may influence severity and survival. Chest 1995; 107:1355.
  26. Lohani S, O'Driscoll BR, Woodcock AA. 25-year study of lung fibrosis following carmustine therapy for brain tumor in childhood. Chest 2004; 126:1007.
  27. Taylor PM, O'Driscoll BR, Gattamaneni HR, Woodcock AA. Chronic lung fibrosis following carmustine (BCNU) chemotherapy: radiological features. Clin Radiol 1991; 44:299.
  28. 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.
  29. Mertens AC, Yasui Y, Liu Y, et al. Pulmonary complications in survivors of childhood and adolescent cancer. A report from the Childhood Cancer Survivor Study. Cancer 2002; 95:2431.