Cyclophosphamide in the treatment of idiopathic pulmonary fibrosis: a prospective study in patients who failed to respond to corticosteroids.

STUDY OBJECTIVES To prospectively examine the role of cyclophosphamide in patients with idiopathic pulmonary fibrosis that is unresponsive to or intolerant of high-dose steroid treatment. DESIGN Prospective study. SETTING Tertiary referral center. PATIENTS Nineteen patients with biopsy specimen-proven usual interstitial pneumonia who failed to respond (n = 16) or experienced adverse effects (n = 3) from corticosteroid treatment (1 mg/kg/d for 3 months). INTERVENTION Steroid therapy was tapered quickly, and oral cyclophosphamide, 2 mg/kg/d, was prescribed (mean duration of treatment, 6.0 +/- 0.9 months). MEASUREMENTS AND RESULTS In 10 patients, response to therapy was determined by pretreatment and posttreatment clinical (dyspnea), radiographic (chest radiograph), and physiologic (pulmonary function, including exercise saturation) scores (CRP). Response was defined as a > 10-point drop in CRP; stable as +/- 10-point change in CRP; and nonresponders as > 10-point rise in CRP. In nine patients, physiologic criteria were used to assess response; significant changes in pulmonary function were defined as follows: total lung capacity, +/- 10% of baseline value; FVC, +/- 10% of baseline value, diffusion capacity of the lung for carbon monoxide, +/- 20% of baseline value; and resting pulse oximetry, +/- 4% of baseline value. Patients who died while receiving or shortly after discontinuing cyclophosphamide were classified as nonresponders (n = 2). Among 19 patients treated with cyclophosphamide, only 1 patient demonstrated sustained response; 7 patients remained stable and 11 deteriorated while receiving the drug. Toxicity associated with cyclophosphamide was substantial; more than two thirds of the patients developed drug-related adverse effects, and almost half discontinued the drug prematurely due to side effects. In the remaining patients, cyclophosphamide therapy was discontinued due to lack of improvement or progressive deterioration. CONCLUSIONS Cyclophosphamide therapy is of limited efficacy in patients with idiopathic pulmonary fibrosis who fail to respond or who experience adverse effects from corticosteroid treatment, and adverse effects often complicate its use.

[1]  A H Morris,et al.  Standardized single breath normal values for carbon monoxide diffusing capacity. , 2015, The American review of respiratory disease.

[2]  M. Schmidt,et al.  Cyclophosphamide pulse therapy in idiopathic pulmonary fibrosis. , 1998, The European respiratory journal.

[3]  M A Schork,et al.  Idiopathic pulmonary fibrosis: predicting response to therapy and survival. , 1998, American journal of respiratory and critical care medicine.

[4]  R. Hubbard,et al.  Survival in patients with cryptogenic fibrosing alveolitis: a population-based cohort study. , 1998, Chest.

[5]  B. Hoen,et al.  A prospective, multicenter, randomized trial comparing steroids and pulse cyclophosphamide versus steroids and oral cyclophosphamide in the treatment of generalized Wegener's granulomatosis. , 1997, Arthritis and rheumatism.

[6]  F. Martinez,et al.  Thin-section CT obtained at 10-mm increments versus limited three-level thin-section CT for idiopathic pulmonary fibrosis: correlation with pathologic scoring. , 1997, AJR. American journal of roentgenology.

[7]  J. Lynch,et al.  Immunosuppressive and cytotoxic pharmacotherapy for pulmonary disorders. , 1997, American journal of respiratory and critical care medicine.

[8]  J. Samet,et al.  Corticosteroids and the treatment of idiopathic pulmonary fibrosis. Past, present, and future. , 1996, Chest.

[9]  Guy Hoffman,et al.  Cyclophosphamide-Induced Cystitis and Bladder Cancer in Patients with Wegener Granulomatosis , 1996, Annals of Internal Medicine.

[10]  F. Martinez,et al.  Influence of sample number and biopsy site on the histologic diagnosis of diffuse lung disease. , 1995, The Annals of thoracic surgery.

[11]  C. Kwoh,et al.  Effects of cyclophosphamide on the development of malignancy and on long-term survival of patients with rheumatoid arthritis. A 20-year followup study. , 1995, Arthritis and rheumatism.

[12]  R. Wu,et al.  Changes in pulmonary function test results after 1 year of therapy as predictors of survival in patients with idiopathic pulmonary fibrosis. , 1995, Chest.

[13]  J. Lafitte,et al.  Determinants of response to immunosuppressive therapy in idiopathic pulmonary fibrosis. , 1994, The European respiratory journal.

[14]  D. Schwartz,et al.  Determinants of progression in idiopathic pulmonary fibrosis. , 1994, American journal of respiratory and critical care medicine.

[15]  D. Schwartz,et al.  Determinants of survival in idiopathic pulmonary fibrosis. , 1994, American journal of respiratory and critical care medicine.

[16]  J. Roca,et al.  Interstitial pulmonary fibrosis with and without associated collagen vascular disease: results of a two year follow up. , 1992, Thorax.

[17]  R. Baughman,et al.  Use of intermittent, intravenous cyclophosphamide for idiopathic pulmonary fibrosis. , 1992, Chest.

[18]  N L Müller,et al.  Fibrosing alveolitis: chest radiography and CT as predictors of clinical and functional impairment at follow-up in 26 patients. , 1992, Radiology.

[19]  Guy Hoffman,et al.  Wegener Granulomatosis: An Analysis of 158 Patients , 1992, Annals of Internal Medicine.

[20]  G. Raghu,et al.  Azathioprine combined with prednisone in the treatment of idiopathic pulmonary fibrosis: a prospective double-blind, randomized, placebo-controlled clinical trial. , 1991, The American review of respiratory disease.

[21]  J. Darbyshire,et al.  Randomised controlled trial comparing prednisolone alone with cyclophosphamide and low dose prednisolone in combination in cryptogenic fibrosing alveolitis. , 1989, Thorax.

[22]  R. Crystal,et al.  Pharmacologic suppression of the neutrophil component of the alveolitis in idiopathic pulmonary fibrosis. , 1987, The American review of respiratory disease.

[23]  A. Degraff,et al.  Adverse effects of cyclophosphamide in idiopathic pulmonary fibrosis. , 1985, Connecticut medicine.

[24]  R. Rudd,et al.  Cryptogenic fibrosing alveolitis. Relationships of pulmonary physiology and bronchoalveolar lavage to response to treatment and prognosis. , 1981, The American review of respiratory disease.

[25]  B. Burrows,et al.  Cryptogenic fibrosing alveolitis: response to corticosteroid treatment and its effect on survival , 1980, Thorax.

[26]  A. Salsbury,et al.  Bronchoalveolar lavage fluid cell counts in cryptogenic fibrosing alveolitis and their relation to therapy. , 1980, Thorax.

[27]  J. Allen,et al.  Diffuse interstitial pneumonitis. Clinicopathologic correlations in 20 patients treated with prednisone/azathioprine. , 1978, The American journal of medicine.

[28]  G. Meuret,et al.  Early stage of fulminant idiopathic pulmonary fibrosis cured by intense combination therapy using cyclophosphamide, vincristine, and prednisone. , 1978, Respiration; international review of thoracic diseases.

[29]  M. Turner‐Warwick,et al.  The treatment of cryptogenic fibrosing alveolitis with immunosuppressant drugs. , 1971, The Quarterly journal of medicine.

[30]  Goldman Hi,et al.  Respiratory function tests; normal values at median altitudes and the prediction of normal results. , 1959 .

[31]  H. Reynolds,et al.  Diagnostic and management strategies for diffuse interstitial lung disease. , 1998, Chest.

[32]  T. Schaberg,et al.  Lung function tests in patients with idiopathic pulmonary fibrosis. Are they helpful for predicting outcome? , 1997, Chest.

[33]  I. D. Johnston,et al.  British Thoracic Society study of cryptogenic fibrosing alveolitis: current presentation and initial management. Fibrosing Alveolitis Subcommittee of the Research Committee of the British Thoracic Society. , 1997, Thorax.

[34]  G. Raghu,et al.  Idiopathic Pulmonary Fibrosis: Current Clinical Concepts and Challenges in Management , 1994 .

[35]  D. Schwartz,et al.  Outcome of subjects with idiopathic pulmonary fibrosis who fail corticosteroid therapy. Implications for further studies. , 1993, Chest.

[36]  D. Heimer,et al.  Desquamative interstitial pneumonitis causing acute respiratory failure, responsive only to immunosuppressants. , 1991, Respiration; international review of thoracic diseases.

[37]  M. Turner-Warwick,et al.  The value of serial bronchoalveolar lavages in assessing the clinical progress of patients with cryptogenic fibrosing alveolitis. , 1987, The American review of respiratory disease.

[38]  M. Schwarz,et al.  A clinical, radiographic, and physiologic scoring system for the longitudinal assessment of patients with idiopathic pulmonary fibrosis. , 1986, The American review of respiratory disease.

[39]  H. Kazemi,et al.  Interstitial lung disease resistant to corticosteroid therapy. Report of three cases treated with azathioprine or cyclophosphamide. , 1975, Chest.