title: Growth plate abnormalities in pediatric cancer patients undergoing phase 1 anti-angiogenic therapy: a report from the Children's Oncology Group Phase I Consortium.
abstract: BACKGROUND
  Pre-clinical studies suggest that anti-angiogenic agents may be toxic to the developing growth plate. The purpose of this study was to evaluate the incidence of growth plate abnormalities in children with refractory cancer undergoing anti-angiogenic therapy.
  
  
  METHODS
  Targeted radiographic studies from 53 subjects enrolled on six separate Children's Oncology Group Phase 1 and Pilot Consortium clinical trials evaluating new anti-cancer agents interfering with angiogenesis were reviewed. Subjects received tyrosine kinase inhibitors with anti-angiogenic effects (n = 35), monoclonal antibodies targeting vascular endothelial growth factor (VEGF) (n = 13), or angiopoietin (n = 5). Radiographs of their distal femur/proximal tibia were obtained at baseline. Follow-up radiographs were obtained after odd-numbered treatment cycles in patients with open growth plates who did not experience disease progression prior to cycle 3.
  
  
  RESULTS
  Baseline and follow-up growth plate radiographs were acquired in 48/53 (90%) of patients. Five patients (9.4%), all of whom received a specific VEGF/VEGFR blocking agent (sunitinib [n = 1] or pazopanib [n = 4]), had growth plate abnormalities. Four patients had growth plate widening that was apparent on at least two successive radiographs, but was not confirmed by MRI. The fifth patient had progressive growth plate widening and evidence of physeal cartilage hypertrophy on MRI. Subsequent off treatment radiographs showed that the growth plate changes were reversible.
  
  
  CONCLUSIONS
  Growth plate abnormalities occur in a small, but relevant number of patients undergoing anti-angiogenic therapy. These results support the need for growth plate monitoring in children with open growth plates who are receiving anti-angiogenic therapy, and for improved methods to assess toxicity of anti-angiogenic agents to the developing skeleton.
authors.affiliation: Department of Radiology, Boston Children's Hospital Dana -Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Stephan D
authors.initials: SD
authors.lastname: Voss
authors.forename: Julia
authors.initials: J
authors.lastname: Glade-Bender
authors.forename: Sheri L
authors.initials: SL
authors.lastname: Spunt
authors.forename: Steven G
authors.initials: SG
authors.lastname: DuBois
authors.forename: Brigitte C
authors.initials: BC
authors.lastname: Widemann
authors.forename: Julie R
authors.initials: JR
authors.lastname: Park
authors.forename: Sarah E S
authors.initials: SE
authors.lastname: Leary
authors.forename: Marvin D
authors.initials: MD
authors.lastname: Nelson
authors.forename: Peter C
authors.initials: PC
authors.lastname: Adamson
authors.forename: Susan M
authors.initials: SM
authors.lastname: Blaney
authors.forename: Brenda
authors.initials: B
authors.lastname: Weigel
mesh_terms: D000293:Adolescent; D020533:Angiogenesis Inhibitors / Q000009:adverse effects*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D005500:Follow-Up Studies; D006132:Growth Plate / Q000187:drug effects* / Q000473:pathology*; D006801:Humans; D008297:Male; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000473:pathology; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D011379:Prognosis
chemical_list: D020533:Angiogenesis Inhibitors
keywords: anti-angiogenic therapy; developing growth plate; physeal toxicity