title: Risk of tyrosine kinase inhibitors-induced hepatotoxicity in cancer patients: a meta-analysis.
abstract: BACKGROUND
  Although existing evidence from clinical trials has demonstrated manifestation of hepatic adverse events (AEs) with the use of tyrosine kinase inhibitors (TKIs), overall risks have yet to be reported. Thus we conducted a meta-analysis to determine the risk of hepatotoxicity associated with the use of TKIs, by comparing the occurrence of hepatotoxicity of the TKI arms against that of comparison arms.
  
  
  METHODS
  A comprehensive literature search of randomized control trials involving TKIs was performed. Only randomized, double-blind and placebo-controlled phase 2 or phase 3 human trials were included. The included studies must involve the comparison of a TKI against placebo, or the comparison of TKI with chemotherapy agent against placebo with the same chemotherapy agent.
  
  
  RESULTS
  Twelve articles were included in the analysis. There was a significant overall increase in the odds of developing high-grade (grade 3 or above) hepatotoxicity with the use of TKIs compared to the control arms (Pooled OR 4.35, 95% CI 2.96-6.39). The odds of developing all-types all-grades (Pooled OR 2.42, 95% CI 1.52-3.85) and high-grade hepatotoxicity due to elevation in alanine transaminase (Pooled OR 5.22, 95% CI 2.88-9.46), aspartate transaminase (Pooled OR 6.15, 95% CI 3.09-12.25) and total bilirubin (Pooled OR 1.76, 95% CI 0.59-5.24) was higher with the use of TKI than compared to the controls.
  
  
  CONCLUSIONS
  This is the first meta-analysis to demonstrate a significantly increased risk of hepatic AEs associated with TKIs use. Clinicians should be aware of this risk and provide close monitoring in patients receiving these therapies.
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore, Singapore.
authors.forename: Yi Ling
authors.initials: YL
authors.lastname: Teo
authors.forename: Han Kiat
authors.initials: HK
authors.lastname: Ho
authors.forename: Alexandre
authors.initials: A
authors.lastname: Chan
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000970:Antineoplastic Agents / Q000009:adverse effects*; D001219:Aspartate Aminotransferases / Q000097:blood; D001663:Bilirubin / Q000097:blood; D006801:Humans; D008099:Liver / Q000187:drug effects*; D009369:Neoplasms / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000009:adverse effects*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D016032:Randomized Controlled Trials as Topic; D012306:Risk
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D011505:Protein-Tyrosine Kinases; D001663:Bilirubin