title: Risk of interstitial lung disease with gefitinib and erlotinib in advanced non-small cell lung cancer: a systematic review and meta-analysis of clinical trials.
abstract: OBJECTIVE
  Gefitinib and erlotinib are oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) widely used in advanced non-small cell lung cancer (NSCLC). Interstitial lung disease (ILD) events have been described with these agents, although the overall risk remains unclear. We performed a systematic review and meta-analysis to determine the incidence and the relative risk (RR) associated with the use of gefitinib and erlotinib.
  
  
  METHODS
  PubMed databases were searched for articles published from January 2000 to October 2012, and abstracts presented at the American Society of Clinical Oncology and the European Society of Medical Oncology meetings held between 2000 and 2012 were searched for relevant studies. Eligible studies included randomized controlled trials with gefitinib and erlotinib in advanced NSCLC patients. Summary incidence rates, relative risks, and 95% CIs were calculated using fixed-effects or random-effects models, depending on the heterogeneity of the included studies.
  
  
  RESULTS
  15,618 patients from 29 randomized controlled trials were selected for this meta-analysis. The overall incidence for all-grade ILD events was 1.2% (95% CI, 0.9-1.6%) among patients receiving gefitinib and erlotinib, with a mortality of 22.8% (95% CI, 14.6-31.0%). Compared with controls, the RR of all-grade ILD events associated with gefitinib and erlotinib was 1.53 (95% CI, 1.13-2.08; P=0.006) using a fixed-effects model. The RR of fatal ILD events associated with EGFR TKIs treatment was 1.96 (95% CI, 1.03-3.72, P=0.041) compared with control patients. The analysis was also stratified for drug type, study location, treatment arm, and treatment line, but no significant differences in RRs were observed.
  
  
  CONCLUSIONS
  Treatment with EGFR TKIs gefitinib and erlotinib is associated with a significant increase in the risk of developing both all-grade and fatal ILD events in advanced NSCLC.
authors: Department of Oncology, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, Beijing, 101149 P. R. China.
authors: Liang
authors: L
authors: Shi
authors: Department of Oncology, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, Beijing, 101149 P. R. China.
authors: Junfang
authors: J
authors: Tang
authors: Department of Oncology, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, Beijing, 101149 P. R. China.
authors: Li
authors: L
authors: Tong
authors: Department of Oncology, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, Beijing, 101149 P. R. China. Electronic address: lza@vip.163.com.
authors: Zhe
authors: Z
authors: Liu
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000150:complications / Q000188:drug therapy* / Q000401:mortality; D002986:Clinical Trials as Topic; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D000069347:Erlotinib Hydrochloride; D000077156:Gefitinib; D006801:Humans; D015994:Incidence; D017563:Lung Diseases, Interstitial / Q000453:epidemiology* / Q000209:etiology / Q000401:mortality; D008175:Lung Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000401:mortality; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects; D012306:Risk; D016019:Survival Analysis
chemical_list: D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; D000077156:Gefitinib
keywords: Erlotinib; Gefitinib; Interstitial lung disease; Meta-analysis; Non-small cell lung cancer; Risk