FLASH Radiation Therapy Vs. Conventional Radiation Therapy: Mechanisms and Potential Improvement of Their Differential Effects on Normal and Cancer Cells
Conventional radiation therapy (CONV-RT) causes tumor regression, but it damages normal tissues. A novel radiation delivery technology called FLASH radiation therapy (FLASH-RT) which involves irradiation of tumor tissues at an ultra-high dose rate compared to the (CONV-RT) dose rate. Both forms of radiation therapy produced a similar tumor response, but only FLASH-RT reduced damage to normal tissue. FLASH-RT induces a transient hypoxia in cancer tissue and normal tissue. Since hypoxia is not present before irradiation, this cannot contribute to protection of normal tissues. The exact mechanisms of protection of normal tissue are unknown. Several hypotheses which include more efficient removal of hydroperoxides (ROOH), and repair ability of DNA, self-annihilation of long-lived organic radicals, and surviving functioning immune cells and stem cells have been proposed. Since higher dose rate produces greater damage, FLASH-RT should have caused a better tumor response than CONV-RT, but it did not. The reasons for this inconsistent observation are unknown. Since cancer cells require glucose and glutamine for their survival and proliferation, and since therapeutic doses of antioxidants block their uptake and metabolism, we suggest that supplementation with a micronutrient mixture containing therapeutic doses of multiple antioxidants may improve the tumor response of FLASH-RT by selective death of cancer cells, while protecting normal cells. Bystander effects of radiation therapy is a well-established observation. This issue has not been raised for FLASH-RT, but the risk exists. Preventive doses of the same antioxidants may reduce the risk of bystander effects of FLASH-RT.