Hypofractionated Radiotherapy Is Superior to Conventional Fractionation in an Orthotopic Model of Anaplastic Thyroid Cancer

Ayman Oweida, Andy Phan, Benjamin Vancourt, Tyler Robin, Mohammad K. Hararah, Shilpa Bhatia, Dallin Milner, Shelby Lennon, Laura Pike, David Raben, Bryan Haugen, Nikita Pozdeyev, Rebecca Schweppe, Sana D. Karam

Anaplastic thyroid cancer is an aggressive and highly lethal disease with poor outcomes and resistance to therapy. Despite multimodality treatment including radiation therapy and chemotherapy, response rates remain below 15% with a median time to progression of less than 3 months. Recent advances in radiotherapy delivery and gene-expression profiling may help guide patient selection for personalized therapy. The purpose of this study was to characterize the response to radiation in a panel of ATC cell lines and to test alternative radiotherapy fractionation schedules for overcoming radioresistance. We characterized the cellular response to radiation based on clonogenic assays and correlated radioresistance with microarray gene-expression profiling. Radioresistant cell lines had higher levels of CXCR4 compared to radiosensitive cell lines. We further tested hypofractionated RT in an orthotopic ATC tumor model and assayed tumor growth locally and distantly with in vivo and ex vivo bioluminescence imaging. Compared to conventionally fractionated RT, hypofractionated RT resulted in significantly improved tumor growth delay, decreased regional and distant metastases, and improved overall survival. Our findings demonstrate the heterogeneity of response to radiation in ATC tumors and superiority of hypofractionated RT in improving local control, metastatic spread and survival in preclinical models. These data support the design of clinical trials targeting radioresistant pathways in combination with hypofractionated RT.