title: Radiation-induced craniofacial bone growth inhibition: efficacy of cytoprotection following a fractionated dose regimen.
abstract: BACKGROUND
  Severe craniofacial growth disturbances are noted in 66 to 100 percent of children with head and neck cancers who received radiotherapy during their growing years. The authors have previously demonstrated the prevention of radiation-induced craniofacial bone growth inhibition following single-dose orthovoltage radiation to the orbitozygomatic complex in an infant rabbit model through the administration of the cytoprotective agent amifostine (WR-2721) before radiation treatment. The purpose of this study was to investigate the efficacy of cytoprotection using a fractionated dose regimen that better approximates the clinical application of radiation therapy.
  
  
  METHODS
  Thirty 7-week-old male New Zealand rabbits were randomized into three groups (n = 10), each receiving six fractions of orthovoltage radiation to the right orbitozygomatic complex: group C, sham irradiation control; group F35, total dose of 35 Gy; and group F35A, total dose of 35 Gy with administration of amifostine 200 mg/kg intravenously 20 minutes before each fraction. Bone growth was evaluated up to skeletal maturity (age 21 weeks) with serial radiographs and computed tomography scans for cephalometric analysis, bone volume, and bone density measurements.
  
  
  RESULTS
  Fractionated radiation resulted in significant (p < 0.05) bone growth inhibition compared with sham radiation in 16 of 21 cephalometric parameters measured and significantly (p < 0.05) reduced bone volume of the rabbit orbitozygomatic complex. Pretreatment with amifostine before each radiation fraction prevented growth deformities in four cephalometric parameters and significantly (p < 0.05) attenuated these effects in another seven parameters compared with radiated animals. Bone volumes were also significantly (p < 0.05) improved in F35A animals compared with F35 animals.
  
  
  CONCLUSIONS
  This study establishes that fractionation of orthovoltage radiation does not prevent the development of growth disturbances of the rabbit craniofacial skeleton and also demonstrates that preirradiation administration of amifostine is highly effective in the prevention and attenuation of radiation-induced craniofacial bone growth inhibition.
authors.affiliation: Division of Plastic Surgery, The Hospital for Sick Children Center for Craniofacial Care and Research, Ontario, Canada.
authors.forename: Giorgio C
authors.initials: GC
authors.lastname: La Scala
authors.forename: David A
authors.initials: DA
authors.lastname: O'Donovan
authors.forename: Ivan
authors.initials: I
authors.lastname: Yeung
authors.forename: Johnson
authors.initials: J
authors.lastname: Darko
authors.forename: Patrick D
authors.initials: PD
authors.lastname: Addison
authors.forename: Peter C
authors.initials: PC
authors.lastname: Neligan
authors.forename: Cho Y
authors.initials: CY
authors.lastname: Pang
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Forrest
mesh_terms: D004999:Amifostine / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D002508:Cephalometry; D019610:Cytoprotection; D019583:Dose Fractionation, Radiation; D005147:Facial Bones / Q000187:drug effects / Q000254:growth & development* / Q000528:radiation effects*; D006128:Growth / Q000528:radiation effects; D006258:Head and Neck Neoplasms / Q000532:radiotherapy; D008297:Male; D008334:Mandible / Q000000981:diagnostic imaging; D009915:Orbit / Q000000981:diagnostic imaging / Q000254:growth & development / Q000528:radiation effects; D011817:Rabbits; D011837:Radiation-Protective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D011897:Random Allocation; D012886:Skull / Q000254:growth & development / Q000528:radiation effects; D014057:Tomography, X-Ray Computed; D015050:Zygoma / Q000000981:diagnostic imaging / Q000254:growth & development / Q000528:radiation effects
chemical_list: D011837:Radiation-Protective Agents; D004999:Amifostine