FLASH Radiotherapy: Benefits, Mechanisms, and Obstacles to Its Clinical Application

Abstract

Radiotherapy (RT) has been shown to be a cornerstone of both palliative and curative tumor care. RT has generally been reported to be sharply limited by ionizing radiation (IR)-induced toxicity, thereby constraining the control effect of RT on tumor growth. FLASH-RT is the delivery of ultra-high dose rate (UHDR) several orders of magnitude higher than what is presently used in conventional RT (CONV-RT). The FLASH-RT clinical trials have been designed to examine the UHDR deliverability, the effectiveness of tumor control, the dose tolerance of normal tissue, and the reproducibility of treatment effects across several institutions. Although it is still in its infancy, FLASH-RT has been shown to have potential to rival current RT in terms of safety. Several studies have suggested that the adoption of FLASH-RT is very limited, and the incorporation of this new technique into routine clinical RT will require the use of accurate dosimetry methods and reproducible equipment that enable the reliable and robust measurements of doses and dose rates. The purpose of this review is to highlight the advantages of this technology, the potential mechanisms underpinning the FLASH-RT effect, and the major challenges that need to be tackled in the clinical transfer of FLASH-RT.

Keywords: FLASH radiotherapy; conventional radiotherapy; ionizing radiation; ultra-high dose rate.

Figure 1

Schematic overview of early physical, chemical, and biological phases following IR of cells and tissues. The time scale has been proposed by Vozenin et al. [32].

Figure 2

Biological benefits of FLASH-RT.

Figure 3

The anti-tumor efficacy of FLASH-RT vs. CONV-RT.

Figure 4

The FLASH-RT oxygen-depletion hypothesis. This phenomenon is not observed follow-ing CONV-RT. During CONV-RT, there is sufficient time for oxygen to diffuse back into normal cells and restore the oxygen that had been lost.

Figure 5

FLASH-RT may cause marginal mitochondrial damage, resulting in less apoptotic death and less inflammation compared to CONV-RT. IR has been shown to cause mtDNA damage either directly by interacting with it or indirectly through ROS generated by the ETC. Mitochondrial dysfunction is usually accompanied by elevated endogenous ROS levels. Mitochondrial dysfunction has been shown to activate pro-apoptotic proteins BAK and BAX, which further elicit mitochondrial outer membrane permeabilization (MOMP), leading to the release of cyt c into the cytosol, thus initiating apoptotic signaling cascades. MOMP has been found to facilitate the release of mitochondrial-derived damage-associated molecular patterns, such as oxidized mtDNA fragments, via mPTP, triggering the inflammatory response through the activation of various pro-inflammatory signaling pathways: TLR9, cGAS–STING/TBK1, and NLRP3. Abbreviations: BAX, BCL-associated X; BAK, Bcl2 homologous antagonist/killer; cyt c, cytochrome c; APAF-1, apoptotic protease activating factor-1; cGAS–STING, GMP-AMP synthase–stimulator of interferon genes DNA-sensing system; mPTP, mitochondrial permeability transition pore; TLR9, toll-like receptor 9; NLRP3, nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3.

Figure 6

FLASH-RT experiments and limitations in clinical trials: Studies in animals (mice, pigs, cats, zebrafish, and dogs) have led to further development in FLASH-RT. However, there remain various difficulties in studying its application in humans, in terms of dosage, equipment, IR source, and economical factors.