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Abstract: Purpose: Radiation-induced pathologic fractures (Fx) of the mandible are well documented and can have devastating effects on a patient's quality of life. Treatment of these pathologic fractures can be quite challenging and are often unsuccessful. Delayed fracture healing in these cases is related to the damage of blood supply and/or the impairment in the proliferation of bone cellular constituents. We have previously demonstrated the cyto-protective effect of the antioxidative drug Amifostine (AMF) on bone osteoprogenitor cells. Utilizing micro-computed tomography (µCT) after vessel perfusion, the purpose of our study is to ascertain whether AMF can also preserve the vascularity of the highly cortical murine mandible after exposure to human equivalent dose of radiation (HEDR) in a mandibular model of pathologic fracture repair.

Methods: Twenty-four male Sprague Dawley rats were randomized into 3 groups. Group 1, Fx (n=9), Group 2, XRT/Fx (n=5) and Group 3 AMF/XRT/Fx (n=7). Group 2 and 3 underwent a 5-day fractionated HEDR over the left hemimandibles. Group 3 received AMF prior to XRT. After 14 days of recovery, all groups underwent a unilateral left mandibular osteotomy with bilateral external fixation. Four to eight hours post-operatively, all animals were distracted to a maximal 2.1mm fracture gap. Consolidation and healing were allowed for 40 days prior to left ventricular catheterization and perfusion with Microfil, a silicone rubber radiopaque contrast. Vascular radiomorphometrics were quantified with µCT imaging and analyzed via One-way Anova and post Hoc Tukey with statistical significance at p<0.05.

Results: All radiated animals demonstrated a range of clinical signs of radiation-induced mucositis and alopecia, but were less apparent in the AMF pre-treated group. Upon gross inspection of the hemimandibles at the time of harvest, we observed a 84% rate of bony union in the control Fx group compared to 67% in the AMF pre-treated group and 25% in the setting of radiotherapy without AMF pre-treatment. Stereological analysis of the vascular tree revealed a substantial increase in Vessel Number (123%, p<0.05) and a corresponding decrease in Vessel Separation (55.5%, p<0.05) between AMF- treated irradiated fractured mandibles and the irradiated fractured mandibles. AMF, in fact, restored normal vascularity as we found there was no difference between the AMF-treated specimens and the non radiated control fractured mandibles.

Conclusion: For the first time to our knowledge, we have established and quantified the effect of AMF prophylactic therapy on angiogenesis in the setting of radiotherapy. This important finding may further be optimized for an effective translation into the clinical arena of pathologic fracture treatment in HNC reconstruction. Our result set the stage for exploration of this targeted therapy alone and in combination with other therapies to mitigate radiation effects in the clinical setting.