title: Safety and efficacy of addition of VEGFR and EGFR-family oral small-molecule tyrosine kinase inhibitors to cytotoxic chemotherapy in solid cancers: a systematic review and meta-analysis of randomized controlled trials.
abstract: BACKGROUND
  The approach of combining cytotoxic chemotherapy with oral small molecule tyrosine kinase inhibitors (TKIs) has been explored in a large number of randomized trials, in a variety of tumor. We performed a systematic review and meta-analysis to evaluate the safety and efficacy of this therapeutic approach.
  
  
  METHODS
  PubMed and the ASCO databases were searched up to March 2013. We included randomized trials in which the FDA approved vascular endothelial growth factor receptor (VEGFR) or epidermal growth factor receptor-family (EGFR)-targeted TKI in combination with chemotherapy was compared with chemotherapy alone in patients with any type of solid cancer. The endpoints included safety [fatal adverse events (FAEs), treatment discontinuation, any severe (grade 3 or 4) adverse events (AEs), and individual severe AEs] and efficacy [progression-free survival (PFS), and overall survival (OS)]. The pooled relative risk (RR) or hazard ratio (HR) were calculated.
  
  
  RESULTS
  A total of 16,011 patients from 43 trials were included. Compared with chemotherapy alone, the addition of a TKI significantly increased the risk of FAEs (RR, 1.63; 95% CI, 1.32-2.01), treatment discontinuation (RR, 1.80; 95% CI, 1.58-2.06), and any severe AE (RR, 1.25; 95% CI, 1.16-1.36). The addition of a TKI was associated with a significant improvement in PFS (HR, 0.82; 95% CI, 0.76-0.89), but not OS (HR, 0.99; 95% CI, 0.95-1.03).
  
  
  CONCLUSIONS
  It is important for physicians to weigh the risk of toxicity versus the modest PFS benefit associated with chemotherapy plus TKI in patients with solid cancers.
authors.affiliation: Department of Medicine, Beth Israel Medical Center, University Hospital and Manhattan Campus for the Albert Einstein College of Medicine, New York, United States. Electronic address: tfunakoshi@chpnet.org.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Funakoshi
authors.affiliation: Division of Hematology/Oncology, Tisch Cancer Institute, Mount Sinai School of Medicine, New York, United States. Electronic address: asma.latif@mountsinai.org.
authors.forename: Asma
authors.initials: A
authors.lastname: Latif
authors.affiliation: Division of Hematology/Oncology, Tisch Cancer Institute, Mount Sinai School of Medicine, New York, United States. Electronic address: matthew.galsky@mssm.edu.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Galsky
mesh_terms: D000284:Administration, Oral; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D004305:Dose-Response Relationship, Drug; D064420:Drug-Related Side Effects and Adverse Reactions / Q000453:epidemiology / Q000209:etiology*; D066246:ErbB Receptors / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D009369:Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D061214:Patient Safety; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic; D040262:Receptors, Vascular Endothelial Growth Factor / Q000187:drug effects* / Q000378:metabolism; D018570:Risk Assessment; D016896:Treatment Outcome
chemical_list: D047428:Protein Kinase Inhibitors; C512478:EGFR protein, human; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor
keywords: Epidermal growth factor receptor; Fatal adverse events; Overall survival; Progression free survival; Severe adverse events; Small-molecule tyrosine kinase inhibitor; Systematic review and meta-analysis; Treatment discontinuation; Vascular endothelial growth factor receptor