title: Brain metastases from renal cell carcinoma in the era of tyrosine kinase inhibitors.
abstract: BACKGROUND
  The effectiveness of tyrosine kinase inhibitors (TKI) in preventing brain metastases in patients with renal cell carcinoma is unclear.
  
  
  METHODS
  Preclinical studies were conducted to determine the steady-state brain and plasma concentrations of sorafenib and sunitinib in mice deficient in the drug efflux transporters; p-glycoprotein, and breast cancer resistance protein. A single-institution retrospective analysis of patients treated from 2008 to 2010 was conducted to assess the incidence of brain metastases before and during TKI treatment.
  
  
  RESULTS
  Transport of sorafenib and sunitinib across the blood-brain barrier was restricted. Retrospective analysis revealed that the median time to develop metastatic brain disease was 28 months (range, 1-108 months) while on TKI therapy and 11.5 months (range, 0-64 months) in patients who did not receive TKI therapy. The incidence of brain metastases per month in patients not treated with TKI therapy was 1.6 higher than the incidence in patients treated with TKI therapy.
  
  
  CONCLUSIONS
  Penetration of sorafenib or sunitinib through an intact blood-brain barrier to brain tissue is limited; however, the incidence of brain metastases per unit time is decreased in patients on TKI therapy in comparison with the "cytokine" era.
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA. dudek002@umn.edu
authors.forename: Arkadiusz Z
authors.initials: AZ
authors.lastname: Dudek
authors.forename: Ahmad
authors.initials: A
authors.lastname: Raza
authors.forename: Ming
authors.initials: M
authors.lastname: Chi
authors.forename: Meghali
authors.initials: M
authors.lastname: Singhal
authors.forename: Rajneet
authors.initials: R
authors.lastname: Oberoi
authors.forename: Rajendar K
authors.initials: RK
authors.lastname: Mittapalli
authors.forename: Sagar
authors.initials: S
authors.lastname: Agarwal
authors.forename: William F
authors.initials: WF
authors.lastname: Elmquist
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism; D001932:Brain Neoplasms / Q000188:drug therapy / Q000556:secondary*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000556:secondary; D005260:Female; D006801:Humans; D007211:Indoles / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000188:drug therapy*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000493:pharmacokinetics / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011758:Pyrroles / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012189:Retrospective Studies; D000077157:Sorafenib; D000077210:Sunitinib; D016896:Treatment Outcome
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C501412:Abcg2 protein, mouse; D000970:Antineoplastic Agents; D007211:Indoles; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D009536:Niacinamide; D000077157:Sorafenib; D000077210:Sunitinib