Proton FLASH radiotherapy ameliorates radiation-induced salivary gland dysfunction and oral mucositis and increases survival in a mouse model of head and neck cancer.

Head and neck cancer radiotherapy often damages salivary glands and oral mucosa, severely negatively impacting patients' quality of life. The ability of FLASH- Proton Radiation therapy (F-PRT) to decrease normal tissue toxicity while maintaining tumor control compared to Standard Proton Radiation therapy (S-PRT) has been previously demonstrated for several tissues. However, its potential in ameliorating radiation-induced salivary gland dysfunction and oral mucositis and controlling orthotopic head and neck tumor growth has not been reported. The head and neck area of C57BL/6 mice was irradiated with a single dose of RT (ranging from 14-18 Gy) or a fractionated dose of 8 Gy x 3 of F-PRT (128 Gy/s) or S-PRT (0.95 Gy/s). Following irradiation, the mice were studied for radiation-induced xerostomia by measuring their salivary flow. Oral mucositis was analyzed by histopathological examination. To determine the ability of F-PRT to control orthotopic head and neck tumors, tongue tumors were generated in the mice and then irradiated with either F-PRT or S-PRT. Mice treated with either a single dose or fractionated dose of F-PRT showed significantly improved survival than those irradiated with S-PRT. F-PRT-treated mice showed improvement in their salivary flow. S-PRT-irradiated mice demonstrated increased fibrosis in their tongue epithelium. F-PRT significantly increased the overall survival of the mice with orthotopic tumors compared to the S-PRT-treated mice. The demonstration that F-PRT decreases radiation-induced normal tissue toxicity without compromising tumor control, suggests that this modality could be useful for the clinical management of head and neck cancer patients.