Combined ultra-high and conventional dose rate irradiation spares murine normal skin and intestine from radiation induced acute toxicity.

PURPOSE: Translating FLASH radiotherapy into clinical practice is limited by technological challenges in achieving highly conformal dose delivery. A hybrid approach, combining ultra-high dose rate (UHDR) and conventional dose rate (CDR) irradiation, could potentially improve dose conformity, but biological validation is required. This study presents the first investigation into the biological response to hybrid UHDR/CDR regimens, evaluating normal tissue sparing in murine models and assessing its dependence on the UHDR dose. METHODS AND MATERIALS: Two murine models were utilized: BALB/c mice evaluated for radiation dermatitis following localized hindlimb irradiation, and C57BL/6 mice evaluated for gastrointestinal (GI) toxicity following whole-abdomen irradiation. The hybrid irradiation protocol consisted of an initial UHDR boost (10 or 20 Gy for skin; 10 or 14 Gy for abdomen), a one-minute beam-off interval, and escalating CDR doses. Irradiation was delivered using prototype electron FLASH irradiators. Normal tissue complication probability (NTCP) curves were generated to determine the median toxic dose (TD50) and dose modifying factors (DMF), comparing hybrid treatments against reference split-dose regimens delivered entirely at CDR. RESULTS: Hybrid irradiation effectively preserved the normal tissue sparing characteristic of the FLASH effect, though the magnitude of protection was highly dependent on the proportion of the UHDR boost. In the skin model, the 20 Gy UHDR boost yielded a DMF of 1.26, which decreased to 1.14 when the boost was reduced to 10 Gy. For GI toxicity, the 14 Gy UHDR boost demonstrated a tissue-sparing effect with a DMF of 1.09. However, reducing the UHDR boost to 10 Gy in the abdominal model resulted in complete overlap with the CDR reference curve, eliminating the sparing effect (DMF = 1.00). CONCLUSIONS: The FLASH normal tissue sparing effect is partially maintained when UHDR radiation is combined with CDR radiation in a hybrid protocol, with the degree of sparing relying heavily on the overall UHDR dose contribution. While these biological findings support hybrid UHDR/CDR regimens as a promising approach for the clinical implementation of FLASH-RT, the achievable dose conformity has yet to be practically validated.