Radiation-induced craniofacial bone growth inhibition: Efficacy of cytoprotection following a fractionated dose regimen

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 or, bitozgomatic 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.