title: Tyrosine kinase inhibitors directed against the vascular endothelial growth factor receptor (VEGFR) have distinct cutaneous toxicity profiles: a meta-analysis and review of the literature.
abstract: OBJECTIVE
  Inhibition of the vascular endothelial growth factor receptor (VEGFR) with tyrosine kinase inhibitors (TKIs) is associated with cutaneous adverse effects that increase patient morbidity. Our objective was to examine the skin toxicity profile of anti-VEGFR TKIs and determine the changing incidence in clinical trials.
  
  
  METHODS
  PubMed was queried for phase II or III trials of anti-VEGFR TKIs between 2000 and 2013 involving ≥50 patients. Adverse events were abstracted, with results presented in both fixed and random effects models. Odds ratios (OR) and 95 % confidence intervals (CIs) were estimated for studies with at least two arms.
  
  
  RESULTS
  Across 82 included studies, all grades rash (OR, 2.68; 95 % CI, 2.45-2.94), hand-foot skin reaction (HFSR) (OR, 2.70; 95 % CI, 2.43-3.00), and pruritus (OR, 1.25; 95 % CI, 1.12-1.39) were associated with anti-VEGFR TKIs. Vandetanib had the highest incidence of rash (41 %), while sorafenib was most commonly associated with HFSR (37 %) and pruritus (14 %). The incidence of HFSR from 2000 to 2013 showed an upward trend (r (2) = 0.042, p = 0.10) and in sunitinib therapy increased significantly (r (2) = 0.237, p = 0.04).
  
  
  CONCLUSIONS
  The incidence of HFSR, rash, and pruritus varies considerably by drug. Our data suggest a continued need to address skin toxicities and improve reporting strategies.
authors.affiliation: Dell Medical School, The University of Texas at Austin, 601 E. 15th Street, CEC 2.470, Austin, TX, 78701, USA, Prmassey@seton.org.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Massey
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Okman
authors.forename: Julia
authors.initials: J
authors.lastname: Wilkerson
authors.forename: Edward W
authors.initials: EW
authors.lastname: Cowen
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D006801:Humans; D015994:Incidence; D007211:Indoles / Q000009:adverse effects / Q000627:therapeutic use; D009536:Niacinamide / Q000009:adverse effects / Q000031:analogs & derivatives / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000009:adverse effects / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D011758:Pyrroles / Q000009:adverse effects / Q000627:therapeutic use; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*; D012867:Skin / Q000187:drug effects / Q000473:pathology*; D000077157:Sorafenib; D000077210:Sunitinib; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; D009536:Niacinamide; D000077157:Sorafenib; D017479:Receptors, Platelet-Derived Growth Factor; D040262:Receptors, Vascular Endothelial Growth Factor; D000077210:Sunitinib