title: Is There a Survival Benefit of First-Line Epidermal Growth Factor Receptor Tyrosine-Kinase Inhibitor Monotherapy Versus Chemotherapy in Patients with Advanced Non-Small-Cell Lung Cancer?: A Meta-Analysis.
abstract: BACKGROUND
  Tyrosine-kinase inhibitors (TKIs) markedly improve progression-free survival (PFS) of patients with advanced non-small-cell lung cancer (NSCLC) mutated for epidermal growth factor receptor (EGFR). Results on overall survival (OS) are less clear-cut. We performed a publication-based meta-analysis to address further this issue.
  
  
  METHODS
  We did a PubMed query using keywords simultaneously (lung neoplasm, tyrosine kinase inhibitors, epidermal growth factor receptor mutation, survival, and randomized controlled trials). We also searched for relevant abstracts in annual proceedings of ASCO, ESMO, and WCLC meetings. We cross-checked all references from all eligible articles. Only phase III randomized controlled trials comparing TKI monotherapy and platinum-based doublet chemotherapy in first-line treatment of metastatic or advanced NSCLC were included. We used EasyMA software to perform statistical analyses. A random effect model was used in case of heterogeneity between studies (and a fixed effect model in absence of heterogeneity).
  
  
  RESULTS
  The eight eligible studies included 2962 patients (780 males, 2182 females, mostly Asian, median age 60 years), 2909 adenocarcinomas (98 %), 1739 mutated tumors (897 exon 19 deletion, 699 L858 mutation), 448 stage IIIB, and 2222 stage IV (75 %) tumours and 2453 never smokers (83 %). Four studies assessed gefitinib, two studies assessed erlotinib, and two studies assessed afatinib. Chemotherapies were doublets including a platinum salt. All studies included patients with EGFR mutations, but six studies included only EGFR mutated patients. OS was similar among patients who first received TKI or chemotherapy (HR 0.98, 95 % CI 0.87-1.10, fixed effect model). Conversely, compared with chemotherapy, EGFR TKIs significantly improved PFS in patients with EGFR-mutated tumours (HR 0.37, 95 % CI 0.29-0.49, random effect model). Concerning side effects, rash (RR 6.29, 95 % CI 4.05-9.77), diarrhoea (RR 3.51, 95 % CI 2.15-5.75), stomatitis (RR 3.57, 95 % CI 1.81-7.04), and interstitial lung disease (RR 6.07, 95 % CI 1.66-22.2) were significantly more frequent after TKIs. As expected, fatigue (RR 0.38, 95 % CI 0.32-0.45), nausea/vomiting (RR 0.19, 95 % CI 0.11-0.32), and haematological disorders, including thrombocytopenia (RR 0.18, 95 % CI 0.09-0.35), anaemia (RR 0.22, 95 % CI 0.15-0.33), and grade 3-4 neutropenia (RR 0.06, 95 % CI 0.04-0.08), were significantly more frequent after chemotherapy.
  
  
  CONCLUSIONS
  The major discrepancy between a similar OS and a markedly improved PFS after first-line TKI compared with chemotherapy could be related to the high level of crossing-over between both groups.
authors.affiliation: Department of Oncology, Avicenne Hospital, HUPSSD, AP-HP, 125 route de Stalingrad, 93009, Bobigny, France.
authors.forename: Gaetan Des
authors.initials: GD
authors.lastname: Guetz
authors.affiliation: Unité de Coordination en Onco-Gériatrie (UCOG), HUPSSD, AP-HP, Sevran, France. thierry.landre@rmb.aphp.fr.|Department of Geriatric Oncology, René Muret hospital, HUPSSD, AP-HP, Avenue du Dr Schaeffner, 93270, Sevran, France. thierry.landre@rmb.aphp.fr.
authors.forename: Thierry
authors.initials: T
authors.lastname: Landre
authors.affiliation: Department of Pharmacology, Avicenne Hospital, HUPSSD, AP-HP, Bobigny, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Uzzan
authors.affiliation: Department of Oncology, Avicenne Hospital, HUPSSD, AP-HP, 125 route de Stalingrad, 93009, Bobigny, France.
authors.forename: Kader
authors.initials: K
authors.lastname: Chouahnia
authors.affiliation: Department of Pharmacology, Avicenne Hospital, HUPSSD, AP-HP, Bobigny, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Nicolas
authors.affiliation: Department of Oncology, Avicenne Hospital, HUPSSD, AP-HP, 125 route de Stalingrad, 93009, Bobigny, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Morere
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000401:mortality*; D002986:Clinical Trials as Topic; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000401:mortality*; D008297:Male; D058990:Molecular Targeted Therapy; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D015996:Survival Rate
chemical_list: D047428:Protein Kinase Inhibitors; C512478:EGFR protein, human; D066246:ErbB Receptors