Efficacy of Gefitinib in a Patient with Lung Cancer Associated with Idiopathic Pulmonary Fibrosis

Lung cancer frequently develops in patients with idiopathic pulmonary fibrosis (IPF).1Daniels CE Jett JR Does interstitial lung disease predispose to lung cancer?.Curr Opin Pulm Med. 2005; 11: 431-437Crossref PubMed Scopus (120) Google Scholar However, there is no established or standardized chemotherapy to date for advanced lung cancer associated with IPF. Gefitinib, an oral inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase domain, is effective for selected patients with advanced non-small cell lung cancer (NSCLC).2Thackcher N Chang A Parikh P et al.Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomized, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer).Lancet. 2005; 366: 1527-1537Abstract Full Text Full Text PDF PubMed Scopus (2001) Google Scholar However, the incidence of interstitial lung disease (ILD) caused by gefitinib is as high as 5% in Japan, and preexisting pulmonary fibrosis is considered to be a risk factor for developing ILD.3Takano T Ohe Y Kusumoto M et al.Risk factors for interstitial lung disease and predictive factors for tumor response in patients with advanced non-small cell lung cancer treated with gefitinib.Lung Cancer. 2004; 45: 93-104Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar, 4Hotta K Kiura K Tabata M et al.Interstitial lung disease in Japanese patients with non-small cell lung cancer receiving gefitinib: an analysis of risk factors and treatment outcome in Okayama Lung Cancer Study Group.Cancer J. 2005; 11: 417-424Crossref PubMed Scopus (69) Google Scholar We report the case of a patient with stage IV adenocarcinoma associated with IPF who was successfully treated with gefitinib. A 77-year-old man was admitted to our hospital for the evaluation of a mass lesion on chest radiograph. He had smoked one pack of cigarettes daily for 59 years. On examination, fine crackles were heard at both lung bases. A chest computed tomography (CT) scan revealed a lobulated mass, 66 × 50 mm in diameter, in the right upper lobe with enlargement of paratracheal, pretracheal, and subcarinal lymph nodes (Figure 1A). In addition, honeycombing was observed in the lung base bilaterally (Figure 1B). A diagnosis of adenocarcinoma was made by transbronchial biopsy. Brain CT disclosed a metastatic lesion, 5 mm in diameter, in the right parietal lobe. The patient was diagnosed as having stage IV (cT2N2M1) NSCLC associated with IPF. At first, the brain metastasis was treated by stereotactic radiosurgery (gamma knife). Subsequently, the patient preferred gefitinib for the first-line therapy to intravenous chemotherapy, and informed consent was obtained. After 3 weeks' treatment with gefitinib 250 mg/day, a chest CT scan revealed substantial regression of both the primary tumor and mediastinal lymph node metastases without worsening of IPF. This response lasted for 7 months, and gefitinib was discontinued. The size of both the primary tumor and the mediastinal lymph nodes increased again after 3 months' discontinuation of gefitinib. Re-treatment with gefitinib was begun, and a significant response was observed within 2 weeks. Partial response continued for 5 months, but gefitinib was discontinued because right hemiplegia resulting from multiple brain metastases developed. After whole brain irradiation, the patient received supportive care alone and was referred to a hospital near his home. The prevalence of lung cancer in IPF varies from 4.4% to 48.2% by the type of studies.1Daniels CE Jett JR Does interstitial lung disease predispose to lung cancer?.Curr Opin Pulm Med. 2005; 11: 431-437Crossref PubMed Scopus (120) Google Scholar The pathogenesis of lung cancer remains unclear, but recurrent injury and inflammation of IPF would result in genetic alterations in airway epithelial cells that predispose patients to lung cancer.1Daniels CE Jett JR Does interstitial lung disease predispose to lung cancer?.Curr Opin Pulm Med. 2005; 11: 431-437Crossref PubMed Scopus (120) Google Scholar Chemotherapy for advanced lung cancer associated with IPF is limited. New chemotherapeutic agents such as gemcitabine, irinotecan, paclitaxel, docetaxel, and gefitinib can cause severe pulmonary toxicity.1Daniels CE Jett JR Does interstitial lung disease predispose to lung cancer?.Curr Opin Pulm Med. 2005; 11: 431-437Crossref PubMed Scopus (120) Google Scholar The efficacy and toxicity of these novel drugs for patients with lung cancer associated with IPF remain unknown, because most of the prospective clinical studies do not include patients with co-morbid or poor performance status. Pretreatment clinical factors that can predict gefitinib efficacy are: being of East Asian origin, a non-smoker, a woman, and having adenocarcinoma.2Thackcher N Chang A Parikh P et al.Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomized, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer).Lancet. 2005; 366: 1527-1537Abstract Full Text Full Text PDF PubMed Scopus (2001) Google Scholar Recent studies have shown that mutations in the tyrosine kinase domain of EGFR are associated with sensitivity to gefitinib,5Paez JG Janne PA Lee JC et al.EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy.Science. 2004; 304: 1497-1500Crossref PubMed Scopus (8465) Google Scholar although EGFR mutations of tumor specimens of the patient were not studied. The reported incidence and mortality of ILD caused by gefitinib is approximately 2% to 5% in Japan.3Takano T Ohe Y Kusumoto M et al.Risk factors for interstitial lung disease and predictive factors for tumor response in patients with advanced non-small cell lung cancer treated with gefitinib.Lung Cancer. 2004; 45: 93-104Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar, 4Hotta K Kiura K Tabata M et al.Interstitial lung disease in Japanese patients with non-small cell lung cancer receiving gefitinib: an analysis of risk factors and treatment outcome in Okayama Lung Cancer Study Group.Cancer J. 2005; 11: 417-424Crossref PubMed Scopus (69) Google Scholar However, the incidence of ILD is reportedly less than 0.5% outside Japan.1Daniels CE Jett JR Does interstitial lung disease predispose to lung cancer?.Curr Opin Pulm Med. 2005; 11: 431-437Crossref PubMed Scopus (120) Google Scholar Predicted risk factors for the development of ILD are: preexisting pulmonary fibrosis, poor performance status, prior radiation therapy, and Japanese ethnicity.3Takano T Ohe Y Kusumoto M et al.Risk factors for interstitial lung disease and predictive factors for tumor response in patients with advanced non-small cell lung cancer treated with gefitinib.Lung Cancer. 2004; 45: 93-104Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar, 4Hotta K Kiura K Tabata M et al.Interstitial lung disease in Japanese patients with non-small cell lung cancer receiving gefitinib: an analysis of risk factors and treatment outcome in Okayama Lung Cancer Study Group.Cancer J. 2005; 11: 417-424Crossref PubMed Scopus (69) Google Scholar Gefitinib can be administered to patients with co-morbid conditions or poor performance status. Because treatment for advanced NSCLC associated with IPF is limited, gefitinib still remains one of the therapeutic options for such patients if administered under careful observation for lung damage.