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Journal of Clinical Oncology, Vol 23, No 10 (April 1), 2005: pp. 2423-2424 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.04.055
Side Effects and Good Effects from New Chemotherapeutic AgentsCASE 1. Gefitinib-Induced Interstitial FibrosisDepartment of Veterans Affairs VA, University of Medicine and Dentistry of New Jersey—New Jersey Medical School, New Jersey Health Care System, East Orange, NJ A 59-year-old man initially developed "cold" symptoms with persistent cough approximately 2 months before being diagnosed with non–small-cell lung cancer. He sought medical attention after the symptoms did not improve with over-the-counter medications and an empiric course of antibiotics. Radiographic findings showed a 2.0 x 3.5-cm right lower lobe mass with multiple pulmonary nodules and mediastinal lymphadenopathy. Bronchoscopy was and the biopsy was positive for malignant cells consistent with non–small-cell cancer of the lung. Approximately 2 months after diagnosis, the patient was started on carboplatin at an area under the plasma concentration–time curve 6 and paclitaxel 200 mg/m2. He received two cycles of treatment, but on repeat computed tomography (CT) scan, he was found to have disease progression. Subsequently, he enrolled on a clinical trial of docetaxel 75 mg/m2 and flavopiridol 60 mg/m2. He received six cycles of the second-line regimen, and had stable disease. A follow-up chest CT showed an increase in the size and number of lung nodules. He was offered treatment with gefitinib 250 mg per day as a third-line regimen. A repeat chest radiograph showed increase in tumor size, but no interstitial changes. Two months after starting gefitinib, he developed progressive fatigue and shortness of breath with difficulty in activities of daily living. Chest radiograph was consistent with an increase in the size of the mass, left lung consolidation, and possible postobstructive collapse of the right middle lobe. He was admitted with a working differential diagnosis of community-acquired interstitial pneumonia and was started on empiric antibiotics, nebulizer treatment, steroids, and supplemental oxygen. Further, gefitinib treatment was withheld. The patient continued to have worsening dyspnea despite medical management; arterial blood gas on 100% FiO2 showed, 7.45(7.34-7.45)/30(35-45)/48(70-100). Due to his continuing deterioration, he was intubated and transferred to the ICU. The patient underwent bronchoscopy with bronchiol alveolar lavage to rule out opportunistic infections. The lavage staining was positive for Candida albicans, and he was started on fluconazole. Chest CT showed new bilateral infiltrates and right lower lobe consolidation with interstitial involvement (Fig 1A). As his overall condition progressively deteriorated with worsening of his pulmonary status, it was decided by the family to withdraw life support and he expired. Consent for an autopsy was obtained. The autopsy revealed advanced bronchogenic adenocarcinoma involving both lungs along with diffuse alveolar damage with organization and early interstitial and intra-alveolar fibrosis (Fig 1B).
Gefitinib is regarded as a relatively safe agent,1 with the most frequently reported adverse events being diarrhea and rash. Rarely, it can cause fatigue and dyspnea.2 Cases of interstitial lung disease (ILD) have been observed in patients receiving gefitinib. During early trials of gefitinib, known as ZD 1839, studies showed that inhibition of epidermal growth factor receptor (EGFR) tyrosine kinase might augment pulmonary fibrosis.3,4 A recent hypothesis suggested that pulmonary fibrosis resulted from the alveolar epithelial injury by unidentified stimuli. The re-epithelization of the injured area by fibroblasts results in parenchymal fibrosis. In idiopathic pulmonary fibrosis (IPF), the alveolar epithelium undergoes focal hyperplasia in response to high levels of EGFR expression on alveolar type II cells, suggesting the cells are attempting to proliferate and regenerate the injured epithelium. Several studies have documented upregulation of EGFR ligands during pulmonary fibrogenesis in humans and rodents.3,4 The hypothesis of EGFR tyrosine kinase inhibition with ZD 1839 was tested in a study with murine models. The initial studies examined if ZD 1839 was capable of inhibiting the proliferation of alveolar type II-like cells in vitro. Results were conclusive and suggested that ZD 1839 selectively inhibited the proliferation of cells.5 As previous studies had shown expression of high levels of EGFR in fibrotic tissue, studies were conducted to determine whether the inhibition of EGFR by ZD 1839 affected bleomycin induced pulmonary fibrosis, a representative model of pulmonary fibrosis.6 It was found the mice treated with bleomycin and ZD 1839 exhibited a higher degree of fibrosis than mice treated with bleomycin and the vehicle alone, which was confirmed by histological analysis.5 The effects of ZD 1839 were also evaluated on EGFR phosphorylation using immunohistochemistry for detection of phosph-EGFR. In the mice receiving bleomycin and vehicle, staining was positive for phosph-EGFR in epithelial cells covering the surface of the fibrotic lesion, but negative in normal tissue, suggesting phosphorylation is required for regeneration of injured epithelium but not for the maintenance of normal epithelium. In contrast, the mice treated with bleomycin and ZD 1839 showed negative staining in all epithelial cells, even in the fibrotic area, confirming that ZD 1839 inhibited the phosphorylation of EGFR.5 The results of this study support a newly proposed hypothesis on the mechanism of pulmonary fibrosis from the original, which considered chronic inflammation to stimulate fibroblast migration, proliferation and production of parenchymal fibrosis. It suggests that the inappropriate regeneration of the sequentially injured epithelium is sufficient to stimulate fibroblasts, without the need of ongoing inflammation,7 implying that changes in the epithelial cells initiate the cascade of fibrogenesis. The results support this by showing that blockage of EGFR-dependent epithelial proliferation augments fibrosis and, the regenerated epithelium positively stained for phosph-EGFR suggesting EGFR is important for regeneration. These results suggest that ZD 1839 inhibits both activation of EGFR and the ability of regenerating epithelial cells to proliferate, leading to pulmonary fibrosis. ZD 1839 may also cause fibrosis by stimulating apoptosis in alveolar epithelial cells,8,9 by inhibiting epithelial differentiation,10 or inhibiting pulmonary angiogenesis. In a recent analysis by the US Food and Drug Administration, which included 50,500 patients (18,960 from marketed use in Japan), 408 cases of ILD (324 from Japan and 84 from United States/rest of world) were identified. The average time of onset for ILD was 24 days in Japan and 42 days in the US group. Worldwide, the incidence of ILD associated with gefitinib treatment was approximately 1% (2% in Japanese postmarketing experience and roughly 0.3% in approximately 23,000 patients in the US expanded-access program).11 Of the cases reported, 31% had prior radiation therapy, and 57% had prior chemotherapy. Patients often presented with the acute onset of dyspnea, with or without cough, or low-grade fever. The symptoms usually became severe in a short time usually requiring hospitalization with one third of cases being fatal. Patients on gefitinib or other EGFR tyrosine kinase inhibitors who develop pulmonary symptoms (fever, cough, and dyspnea) should be advised to seek medical attention promptly, and therapy should be interrupted. A thorough investigation of the symptoms should be done as soon as possible. Other specific causes such as pulmonary emboli, various types of infections, or lymphangitic spread of cancer should be ruled out, with possible lung biopsy if needed. If ILD is confirmed, then the patient should be treated, with consideration of corticosteroids.12 Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest.
REFERENCES 1. Inoue A, Saijo Y, Maemondo M, et al: Severe acute interstitial pneumonia and Gefitinib. Lancet 361:137-139, 2003[CrossRef][Medline] 2. Manufacturers' Prescribing Information in, Physicians' Desk Reference (ed 58). Montvale, NJ, Thomson PDR, 2004 3. Baughman RP, Lower EE, Miller MA, et al: Overexpression of transforming growth factor-alpha and epidermal growth factor receptor in idiopathic pulmonary fibrosis. Sarcoidosis Vasc Diffuse Lung Dis 16:57-61, 1999[Medline] 4. Madtes DK, Busby HK, Strandjord TP, et al: Expression of Transforming Growth Factor alpha and epidermal growth factor receptor is increased following bleomycin induced lung injury in rats. Am J Respir Cell Mol Biol 11:540-551, 1994[Abstract] 5. Suzuki H, Aoshiba K, Yokohori N, et al: Epidermal growth factor receptor tyrosine kinase inhibition augments a murine model of pulmonary fibrosis. Clin Cancer Res, 63:5054-5059, 2003 6. Thrall RS, Scalise PJ: Bleomycin, in Phan SH, Thrall RS (eds): Pulmonary Fibrosis, New York, NY, Marcel Dekker Inc, 1995, pp 231-292 7. Selmen M, King TE Jr, Pardo A: Idiopathic pulmonary fibrosis: Prevailing and evolving hypotheses about its pathogenesis and implications for therapy. Ann Intern Med 134:134-151, 2001
8. Ciardiello F, Caputo R, Bianco R, et al: Antitumor effect and potentiation of cytotoxic drugs activity in human cancer cells by ZD 1839 (Iressa), an epidermal growth factor receptor-selective tyrosine kinase inhibitor. Clin Cancer Res 6:2053-2063, 2000 9. Kuwano K, Hagimoto N, Kawaski M, et al: Essential roles of the Fas-Fas ligand pathway in the development of pulmonary fibrosis. J Clin Investig 104:13-19, 1999[Medline] 10. Yasui S, Nagai A, Oohira A, et al: Effects of anti-mouse EGF antiserum on the prenatal lung development in fetal mice. Pediatr Pulmonol 15:251-256, 1993[Medline]
11. Cohen MH, Williams GA, Sridhara R, et al: FDA Approval Summary: Gefitinib (ZD 1839) (Iressa) Tablets. Oncologist 8:303-306, 2003 12. Camus P, Fanton A, Bonniaud P, et al: Interstitial lung disease induced by drugs and radiation. Respiration 71:301-326, 2004[CrossRef][Medline] This article has been cited by other articles:
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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