Pulmonary Toxicities of Gefitinib in Patients With Advanced Non-Small-Cell Lung Cancer

Gefitinib is a selective tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR) used to treat adults with EGFR mutation-positive non-small-cell lung cancer (NSCLC). Clinical benefits of gefitinib administration in NSCLC patients have been observed in clinical practice, but the extent of the pulmonary toxicity of gefitinib in patients with advanced NSCLC remains unclear. The aim of this systematic review was to evaluate the overall incidence and risk of gefitinib-related pulmonary toxicity in advanced NSCLC patients. Relevant trials were identified from the databases of Pubmed, Embase, Cochrane Library, and the clinicaltrials.gov of the U.S. National Institutes of Health. The outcomes included the overall incidence, odds ratios (ORs), and 95% confidence intervals (CIs). Fixed-effects models were used in the statistical analyses according to the heterogeneity of the included studies. According to the data from the included trials, the overall incidence of high-grade hemoptysis, pneumonia, pneumonitis, and interstitial lung disease (ILD) was 0.49% (95% CI: 0.24%–0.99%), 2.33% (95% CI: 1.47%–3.66%), 2.24% (95% CI: 1.34%–3.72%), and 1.43% (95% CI: 0.98%–2.09%), respectively. The pooled ORs of high-grade hemoptysis, pneumonia, pneumonitis, and ILD were 1.73 (95% CI: 0.46–6.52; P1⁄4 0.42), 0.99 (95% CI: 0.66–1.49; P1⁄4 0.95), 4.70 (95% CI: 1.48–14.95; P1⁄4 0.0087), and 2.64 (95% CI: 1.22–5.69; P1⁄4 0.01), respectively. Gefitinib was associated with a significantly increased risk of highgrade/fatal ILD and pneumonitis compared with the controls, whereas the risk of other high-grade pulmonary events (pneumonia and hemoptysis) was not significant. Careful surveillance of gefitinib-related gguo Zhang, PhD, and Xingguang Lian, PhD Abbreviations: BAL = broncho-alveolar lavage, CI = confidence interval, EGFR = epidermal growth factor receptor, ILD = interstitial lung disease, IPF = idiopathic pulmonary fibrosis, LPA = lysophosphatidic acid, NSCLC = non-small-cell lung cancer, OR = odds ratio, RCT = randomized controlled trial, ROR1 = receptor tyrosine kinase-like orphan receptor 1, TKI = tyrosine kinase inhibitor. INTRODUCTION G efitinib is a selective tyrosine kinase inhibitor (TKI) of the epidermal growth factor receptor (EGFR) used to treat adults with EGFR mutation-positive non-small-cell lung cancer (NSCLC). Clinical benefits of gefitinib administration in NSCLC patients have been observed in clinical practice. However, gefitinib is also associated with adverse events such as diarrhea, skin rash, and stomatitis. In addition, clinical trials have reported a broad range of gefitinib-related adverse pulmonary events, including interstitial lung disease (ILD) and pneumonia. The high incidence of adverse events is due to the characteristics and action mechanisms of gefitinib, which differs from those of conventional chemotherapy agents. Pulmonary toxicity has a poor prognosis because its pathophysiology is unclear, and therapeutic options are limited. Thus, the incidence of gefitinib-related pulmonary toxicity must be understood. Recently, gefitinib was shown to be more effective than placebo in increasing overall survival, and gefitinib was approved for NSCLC patients after the failure of chemotherapy. However, clinical trials have reported substantial variations in the incidence of pulmonary toxicity events, and death caused by pulmonary toxicity has been reported. Based on difficulties in interpreting and analyzing data from randomized controlled trials (RCTs), the extent of the pulmonary toxicity of gefitinib in patients with advanced NSCLC remains unclear. Furthermore, poor management of pulmonary toxicity may lead to serious lung injury or have life-threatening consequences. Therefore, this meta-analysis was conducted to investigate the pulmonary toxicity of gefitinib in advanced NSCLC patients.