Abstract A22: The impact of dose reduction upon local tumor control for stereotactic radiation therapy in an orthotopic rat model of osteosarcoma
Authors: Custis James T. , Schwartz Anthony L. , Harmon Joseph F. , Powers Barbara E. , Chubb Laura S. , LaRue Susan M. , Ehrhart Nicole P. , Ryan Stewart D. 
Published: May 2015

Purpose: Primary bone tumors such as osteosarcoma (OSA) are rare but devastating tumors that most commonly affect young people. For adolescents and dogs with OSA, local tumor control can be difficult to achieve with finely fractionated radiation therapy. Stereotactic radiation therapy (SRT) is a promising treatment modality that results in the delivery of ablative radiation dose to the tumor, while preferentially minimizing dose to the surrounding normal tissues. In our clinical experience with SRT in dogs, a total dose of 36Gy delivered in three fractions has been associated with excellent local tumor control based upon clinical response and histopathology of the irradiated tumor. The risk of post radiation fracture is related to pre-existing tumor associated osteolysis and the effect of irradiation upon normal bone. A previously established orthotopic rat model was used to perform a dose reduction study in an effort to optimize the SRT protocol.

Methods & Materials: Twenty-four nude rats were injected with 1 x 10^6 canine osteosarcoma cells into the distal femoral metaphyses. Two weeks after tumor inoculation, rats were treated with SRT delivered once daily in three equal fractions. The tumor affected bone of six rats each were treated to a total dose of 36Gy (12Gy/fx), 33Gy (11Gy/fx), 30Gy (10Gy/fx), or 27Gy (9Gy/fx). Tumor viability and response to SRT were evaluated once weekly for six weeks via bioluminescence imaging, radiographs of the femur, and urine pyridinoline levels (PYD). Acute radiation effects of the skin were evaluated by Veterinary Radiation Therapy Oncology Group (VROTG) normal tissue toxicity scoring rubric. Post mortem histology provided an objective measure of tumor necrosis.

Results: In all treatment groups, PYD levels were significantly increased two weeks after tumor inoculation (p&lt;0.0001) and were significantly decreased three weeks after SRT (p &lt;0.0001) as compared to baseline. No statistical difference in PYD levels was noted between radiation groups. Mean tumor necrosis for each radiation dose group was: 87% for 36Gy, 58% for 33Gy, 63% for 30Gy, and 74% for 27Gy. The mean overall tumor necrosis was 70%. There was no statistically significant difference between treatment groups. None of the animals experienced greater than grade I skin toxicity.

Conclusions: All four protocols were well tolerated and associated with mild, transient skin toxicity. In canine and human osteosarcoma data, improved duration of local tumor control is correlated with tumor necrosis of 80% or higher. While there was no statistical significance between treatment groups, only the 36Gy group achieved that benchmark of tumor control. Consideration of SRT as a therapeutic option for adolescents with OSA requires further evaluation via orthotopic models. Future dose reduction studies evaluating the clinically relevant concurrent administration of carboplatin and SRT are warranted.

Citation Format: James T. Custis, Anthony L. Schwartz, Joseph F. Harmon, Barbara E. Powers, Laura S. Chubb, Susan M. LaRue, Nicole P. Ehrhart, Stewart D. Ryan. The impact of dose reduction upon local tumor control for stereotactic radiation therapy in an orthotopic rat model of osteosarcoma. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr A22.