Comparable Long-Term Tumor Control for Hypofractionated FLASH Versus Conventional Radiation Therapy in an Immunocompetent Rat Glioma Model

Purpose: To ensure a clinical translation of FLASH radiation therapy (FLASH-RT) for a specific tumor type, studies on tumor control and toxicity within the same biological system are needed. In this study, our objective was to evaluate tumor control and toxicity for hypofractionated FLASH-RT and conventional radiation therapy (CONV-RT) in an immunocompetent rat glioma model. Methods and Materials: Fisher 344 rats (N = 68) were inoculated subcutaneously with NS1 glioma cells and randomized into groups (n = 9-10 per group). CONV-RT (∼8 Gy/min) or FLASH-RT (70-90 Gy/s) was administered in 3 fractions of either 8 Gy, 12.5 Gy, or 15 Gy using a 10-MeV electron beam. The maximum tumor diameter was measured weekly, and overall survival was determined until day 100. Long-term tumor control was defined as no evident tumor on day 100. Animals were evaluated for acute dermal side effects at 2 to 5 weeks after completed RT and for late dermal side effects at 3 months after initiation of treatment. Results: Survival was significantly increased in all irradiated groups compared with control animals (P <.001). In general, irradiated tumors started to shrink at 1 week post–completed RT. In 40% (23 of 58) of the irradiated animals, long-term tumor control was achieved. Radiation-induced skin toxic effects were mild and consisted of hair loss, erythema, and dry desquamation. No severe toxic effect was observed. There was no significant difference between FLASH-RT and CONV-RT in overall survival, acute side effects, or late side effects for any of the dose levels. Conclusions: This study shows that hypofractionated FLASH-RT results in long-term tumor control rates similar to those of CONV-RT for the treatment of large subcutaneous glioblastomas in immunocompetent rats. Neither treatment technique induced severe skin toxic effects. Consequently, no significant difference in toxicity could be resolved, suggesting that higher doses may be required to detect a FLASH sparing of skin