title: The role of smoking status on the progression-free survival of non-small cell lung cancer patients harboring activating epidermal growth factor receptor (EGFR) mutations receiving first-line EGFR tyrosine kinase inhibitor versus platinum doublet chemotherapy: a meta-analysis of prospective randomized trials.
abstract: BACKGROUND
  Univariate analyses from several randomized phase III trials seemed to suggest ever-smokers with advanced mutated epidermal growth factor receptor (EGFRm) non-small cell lung cancer (NSCLC) did not seem to benefit from EGFR tyrosine kinase inhibitors (TKIs) as first-line treatment when compared with platinum-doublet chemotherapy as measured by progression-free survival (PFS).
  
  
  METHODS
  A literature-based meta-analysis of PFS outcomes as measured by log-transformed pooled hazard ratio (HR) was performed using a random-effect model. Pooled HRs for smoking status, age, gender, ethnicity, type of EGFR mutation, and EGFR TKI were obtained. Comparison of the pooled HR was performed by metaregression analysis.
  
  
  RESULTS
  Among the 1,649 EGFRm NSCLC patients analyzed from 7 prospective randomized trials (WJTOG3405, NEJ002, EURTAC, OPTIMAL, LUX Lung-3, LUX Lung-6, and ENSURE), 83.7% were Asians, and 30.0% were ever-smokers. An equal percentage of ever-smokers received doublet chemotherapy (30.2%) or EGFR TKI (30.0%). The pooled HR for PFS was 0.29 (95% confidence interval [CI]: 0.21-0.39) for never-smokers and 0.54 (95% CI: 0.38-0.76) for ever-smokers (p < .007 by metaregression). The pooled PFS HR for exon 19 deletion was 0.25 (95% CI: 0.19-0.31) and 0.44 for exon 21 substitution (95% CI: 0.34-0.57) (p < .001 by metaregression analysis). The pooled PFS HR was 0.33 (95% CI: 0.24-0.46) for Asians and 0.48 for non-Asians (95% CI: 0.28-0.84) (p = .261 by metaregression analysis).
  
  
  CONCLUSIONS
  EGFRm NSCLC patients derived significant PFS benefit from TKI over platinum-doublet chemotherapy as first-line treatment regardless of smoking status; however, PFS benefit is significantly better in never-smokers by metaregression analysis.
authors: Izumi Municipal Hospital, Osaka, Japan; Nagoya University Hospital, Nagoya, Aichi, Japan; Miyagi Cancer Center, Miyagi, Japan; University of Kansas Cancer Center, Kansas City, Kansas, USA; National Hospital Organization Kinki-Chuo Chest Medical Center, Osaka, Japan; National Hospital Organization Nagoya Medical Center, Aichi, Japan; Aichi Medical University School of Medicine, Nagoya, Aichi, Japan; Graduate School of Medicine, Osaka City University, Osaka, Japan; Koyo Hospital, Wakayama, Japan; Catalan Institute of Oncology, Barcelona, Spain; Kansai Medical University Hirakata Hospital, Osaka, Japan; Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Orange, California, USA.
authors: Yoshikazu
authors: Y
authors: Hasegawa
authors: Izumi Municipal Hospital, Osaka, Japan; Nagoya University Hospital, Nagoya, Aichi, Japan; Miyagi Cancer Center, Miyagi, Japan; University of Kansas Cancer Center, Kansas City, Kansas, USA; National Hospital Organization Kinki-Chuo Chest Medical Center, Osaka, Japan; National Hospital Organization Nagoya Medical Center, Aichi, Japan; Aichi Medical University School of Medicine, Nagoya, Aichi, Japan; Graduate School of Medicine, Osaka City University, Osaka, Japan; Koyo Hospital, Wakayama, Japan; Catalan Institute of Oncology, Barcelona, Spain; Kansai Medical University Hirakata Hospital, Osaka, Japan; Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Orange, California, USA Ignatius.ou@uci.edu mando@med.nagoya-u.ac.jp.
authors: Masahiko
authors: M
authors: Ando
authors: Izumi Municipal Hospital, Osaka, Japan; Nagoya University Hospital, Nagoya, Aichi, Japan; Miyagi Cancer Center, Miyagi, Japan; University of Kansas Cancer Center, Kansas City, Kansas, USA; National Hospital Organization Kinki-Chuo Chest Medical Center, Osaka, Japan; National Hospital Organization Nagoya Medical Center, Aichi, Japan; Aichi Medical University School of Medicine, Nagoya, Aichi, Japan; Graduate School of Medicine, Osaka City University, Osaka, Japan; Koyo Hospital, Wakayama, Japan; Catalan Institute of Oncology, Barcelona, Spain; Kansai Medical University Hirakata Hospital, Osaka, Japan; Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Orange, California, USA.
authors: Makoto
authors: M
authors: Maemondo
authors: Izumi Municipal Hospital, Osaka, Japan; Nagoya University Hospital, Nagoya, Aichi, Japan; Miyagi Cancer Center, Miyagi, Japan; University of Kansas Cancer Center, Kansas City, Kansas, USA; National Hospital Organization Kinki-Chuo Chest Medical Center, Osaka, Japan; National Hospital Organization Nagoya Medical Center, Aichi, Japan; Aichi Medical University School of Medicine, Nagoya, Aichi, Japan; Graduate School of Medicine, Osaka City University, Osaka, Japan; Koyo Hospital, Wakayama, Japan; Catalan Institute of Oncology, Barcelona, Spain; Kansai Medical University Hirakata Hospital, Osaka, Japan; Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Orange, California, USA.
authors: Satomi
authors: S
authors: Yamamoto
authors: Izumi Municipal Hospital, Osaka, Japan; Nagoya University Hospital, Nagoya, Aichi, Japan; Miyagi Cancer Center, Miyagi, Japan; University of Kansas Cancer Center, Kansas City, Kansas, USA; National Hospital Organization Kinki-Chuo Chest Medical Center, Osaka, Japan; National Hospital Organization Nagoya Medical Center, Aichi, Japan; Aichi Medical University School of Medicine, Nagoya, Aichi, Japan; Graduate School of Medicine, Osaka City University, Osaka, Japan; Koyo Hospital, Wakayama, Japan; Catalan Institute of Oncology, Barcelona, Spain; Kansai Medical University Hirakata Hospital, Osaka, Japan; Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Orange, California, USA.
authors: Shun-Ichi
authors: S
authors: Isa
authors: Izumi Municipal Hospital, Osaka, Japan; Nagoya University Hospital, Nagoya, Aichi, Japan; Miyagi Cancer Center, Miyagi, Japan; University of Kansas Cancer Center, Kansas City, Kansas, USA; National Hospital Organization Kinki-Chuo Chest Medical Center, Osaka, Japan; National Hospital Organization Nagoya Medical Center, Aichi, Japan; Aichi Medical University School of Medicine, Nagoya, Aichi, Japan; Graduate School of Medicine, Osaka City University, Osaka, Japan; Koyo Hospital, Wakayama, Japan; Catalan Institute of Oncology, Barcelona, Spain; Kansai Medical University Hirakata Hospital, Osaka, Japan; Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Orange, California, USA.
authors: Hideo
authors: H
authors: Saka
authors: Izumi Municipal Hospital, Osaka, Japan; Nagoya University Hospital, Nagoya, Aichi, Japan; Miyagi Cancer Center, Miyagi, Japan; University of Kansas Cancer Center, Kansas City, Kansas, USA; National Hospital Organization Kinki-Chuo Chest Medical Center, Osaka, Japan; National Hospital Organization Nagoya Medical Center, Aichi, Japan; Aichi Medical University School of Medicine, Nagoya, Aichi, Japan; Graduate School of Medicine, Osaka City University, Osaka, Japan; Koyo Hospital, Wakayama, Japan; Catalan Institute of Oncology, Barcelona, Spain; Kansai Medical University Hirakata Hospital, Osaka, Japan; Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Orange, California, USA.
authors: Akihito
authors: A
authors: Kubo
authors: Izumi Municipal Hospital, Osaka, Japan; Nagoya University Hospital, Nagoya, Aichi, Japan; Miyagi Cancer Center, Miyagi, Japan; University of Kansas Cancer Center, Kansas City, Kansas, USA; National Hospital Organization Kinki-Chuo Chest Medical Center, Osaka, Japan; National Hospital Organization Nagoya Medical Center, Aichi, Japan; Aichi Medical University School of Medicine, Nagoya, Aichi, Japan; Graduate School of Medicine, Osaka City University, Osaka, Japan; Koyo Hospital, Wakayama, Japan; Catalan Institute of Oncology, Barcelona, Spain; Kansai Medical University Hirakata Hospital, Osaka, Japan; Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Orange, California, USA.
authors: Tomoya
authors: T
authors: Kawaguchi
authors: Izumi Municipal Hospital, Osaka, Japan; Nagoya University Hospital, Nagoya, Aichi, Japan; Miyagi Cancer Center, Miyagi, Japan; University of Kansas Cancer Center, Kansas City, Kansas, USA; National Hospital Organization Kinki-Chuo Chest Medical Center, Osaka, Japan; National Hospital Organization Nagoya Medical Center, Aichi, Japan; Aichi Medical University School of Medicine, Nagoya, Aichi, Japan; Graduate School of Medicine, Osaka City University, Osaka, Japan; Koyo Hospital, Wakayama, Japan; Catalan Institute of Oncology, Barcelona, Spain; Kansai Medical University Hirakata Hospital, Osaka, Japan; Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Orange, California, USA.
authors: Minoru
authors: M
authors: Takada
authors: Izumi Municipal Hospital, Osaka, Japan; Nagoya University Hospital, Nagoya, Aichi, Japan; Miyagi Cancer Center, Miyagi, Japan; University of Kansas Cancer Center, Kansas City, Kansas, USA; National Hospital Organization Kinki-Chuo Chest Medical Center, Osaka, Japan; National Hospital Organization Nagoya Medical Center, Aichi, Japan; Aichi Medical University School of Medicine, Nagoya, Aichi, Japan; Graduate School of Medicine, Osaka City University, Osaka, Japan; Koyo Hospital, Wakayama, Japan; Catalan Institute of Oncology, Barcelona, Spain; Kansai Medical University Hirakata Hospital, Osaka, Japan; Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Orange, California, USA.
authors: Rafael
authors: R
authors: Rosell
authors: Izumi Municipal Hospital, Osaka, Japan; Nagoya University Hospital, Nagoya, Aichi, Japan; Miyagi Cancer Center, Miyagi, Japan; University of Kansas Cancer Center, Kansas City, Kansas, USA; National Hospital Organization Kinki-Chuo Chest Medical Center, Osaka, Japan; National Hospital Organization Nagoya Medical Center, Aichi, Japan; Aichi Medical University School of Medicine, Nagoya, Aichi, Japan; Graduate School of Medicine, Osaka City University, Osaka, Japan; Koyo Hospital, Wakayama, Japan; Catalan Institute of Oncology, Barcelona, Spain; Kansai Medical University Hirakata Hospital, Osaka, Japan; Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Orange, California, USA.
authors: Takayasu
authors: T
authors: Kurata
authors: Izumi Municipal Hospital, Osaka, Japan; Nagoya University Hospital, Nagoya, Aichi, Japan; Miyagi Cancer Center, Miyagi, Japan; University of Kansas Cancer Center, Kansas City, Kansas, USA; National Hospital Organization Kinki-Chuo Chest Medical Center, Osaka, Japan; National Hospital Organization Nagoya Medical Center, Aichi, Japan; Aichi Medical University School of Medicine, Nagoya, Aichi, Japan; Graduate School of Medicine, Osaka City University, Osaka, Japan; Koyo Hospital, Wakayama, Japan; Catalan Institute of Oncology, Barcelona, Spain; Kansai Medical University Hirakata Hospital, Osaka, Japan; Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Orange, California, USA Ignatius.ou@uci.edu mando@med.nagoya-u.ac.jp.
authors: Sai-Hong Ignatius
authors: SH
authors: Ou
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D016190:Carboplatin / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D002945:Cisplatin / Q000627:therapeutic use*; D018450:Disease Progression; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D011379:Prognosis; D011446:Prospective Studies; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic; D012907:Smoking / Q000009:adverse effects*; D015996:Survival Rate
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D016190:Carboplatin; D066246:ErbB Receptors; D002945:Cisplatin
keywords: Afatinib; EGFR TKIs; EGFR mutant non-small cell lung cancer; Erlotinib; Gefitinib; Meta-analysis; Smoking status
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