title: Occurrence of hepatotoxicity with pazopanib and other anti-VEGF treatments for renal cell carcinoma: an observational study utilizing a distributed database network.
abstract: OBJECTIVE
  To quantify the hepatic safety of pazopanib and comparator anti-vascular endothelial growth factor (VEGF) therapies in clinical practice among renal cell carcinoma (RCC) patients.
  
  
  METHODS
  A population-based cohort study of new anti-VEGF users was conducted in two US healthcare databases, Department of Veterans Affairs (VA) and an oncology practice network (Altos), and the PHARMO Database Network in The Netherlands. A common protocol was used to collect liver chemistry (LC) data from anti-VEGF initiation through 4 years of follow-up. In the VA population, suspected drug-induced liver injury (DILI) outcomes were investigated via chart review, with adjudication by hepatologists.
  
  
  RESULTS
  In Altos and VA, respectively, the total RCC patients were: pazopanib (156, 243), bevacizumab (122, 99), sorafenib (82, 249) and sunitinib (285, 751). PHARMO contained too few patients to be included. Few cases of alanine aminotransferase (ALT) ≥8× the upper limit of normal were seen across the anti-VEGF cohorts; incidence rates (per 100 person-years) ranged from 0 (sunitinib) to 8.2 (pazopanib) in Altos and from 0 (bevacizumab and sorafenib) to 2.1 (pazopanib) among VA patients. No cases of Hy's law identified by combination LC elevations were seen in patients treated with pazopanib or bevacizumab; one case was observed in those treated with sorafenib, and two cases were found among sunitinib users. One case of adjudicated DILI was observed in a sunitinib-treated patient; none were found among patients treated with pazopanib, bevacizumab or sorafenib.
  
  
  CONCLUSIONS
  Severe liver injury occurred infrequently during exposure to pazopanib and other anti-VEGF therapies in a population-based setting.
authors.affiliation: Worldwide Epidemiology, R&D, GlaxoSmithKline, 150 Beach Road, #26-00 Gateway West, Singapore, 189720, Singapore. sumitra.y.shantakumar@gsk.com.
authors.forename: Sumitra
authors.initials: S
authors.lastname: Shantakumar
authors.affiliation: Center of Excellence in Epidemiology, Evidera, Lexington, MA, USA.
authors.forename: Beth L
authors.initials: BL
authors.lastname: Nordstrom
authors.affiliation: Department of Veteran's Affairs, Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), Boston VA Healthcare System, Boston, MA, USA.
authors.forename: Luc
authors.initials: L
authors.lastname: Djousse
authors.affiliation: New England Research Institutes, Inc., Watertown, MA, USA.
authors.forename: Susan A
authors.initials: SA
authors.lastname: Hall
authors.affiliation: Department of Veteran's Affairs, Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), Boston VA Healthcare System, Boston, MA, USA.|Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Gagnon
authors.affiliation: Center of Excellence in Epidemiology, Evidera, Lexington, MA, USA.
authors.forename: Kathy H
authors.initials: KH
authors.lastname: Fraeman
authors.affiliation: PHARMO Institute for Drug Outcomes Research, Utrecht, The Netherlands.
authors.forename: Myrthe
authors.initials: M
authors.lastname: van Herk-Sukel
authors.affiliation: Global Clinical Safety and Pharmacovigilance, GlaxoSmithKline, Collegeville, PA, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Chagin
authors.affiliation: Worldwide Epidemiology Department, R&D, GlaxoSmithKline, Research Triangle Park, NC, USA.
authors.forename: Jeanenne
authors.initials: J
authors.lastname: Nelson
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D000068258:Bevacizumab / Q000009:adverse effects / Q000627:therapeutic use; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000473:pathology; D056486:Chemical and Drug Induced Liver Injury / Q000453:epidemiology / Q000209:etiology*; D015331:Cohort Studies; D003195:Computer Communication Networks; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007191:Indazoles; D007211:Indoles / Q000009:adverse effects / Q000627:therapeutic use; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009536:Niacinamide / Q000009:adverse effects / Q000031:analogs & derivatives / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000009:adverse effects / Q000627:therapeutic use; D011743:Pyrimidines / Q000009:adverse effects / Q000627:therapeutic use*; D011758:Pyrroles / Q000009:adverse effects / Q000627:therapeutic use; D012189:Retrospective Studies; D000077157:Sorafenib; D013449:Sulfonamides / Q000009:adverse effects / Q000627:therapeutic use*; D000077210:Sunitinib; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors
chemical_list: D000970:Antineoplastic Agents; D007191:Indazoles; D007211:Indoles; D010671:Phenylurea Compounds; D011743:Pyrimidines; D011758:Pyrroles; D013449:Sulfonamides; D042461:Vascular Endothelial Growth Factor A; D009536:Niacinamide; D000068258:Bevacizumab; C516667:pazopanib; D000077157:Sorafenib; D000077210:Sunitinib
keywords: Anti-VEGF; Hepatotoxicity; Liver chemistry; Pazopanib; Renal cell carcinoma