Brain Tumor Res Treat.  2023 Oct;11(4):223-231. 10.14791/btrt.2023.0026.

FLASH Radiotherapy: A FLASHing Idea to Preserve Neurocognitive Function

• Jo HJ
• Oh T
• Lee YR
• Kang GS
• Park HJ
• Ahn GO

• KMID: 2547410
• DOI: http://doi.org/10.14791/btrt.2023.0026

Abstract

FLASH radiotherapy (FLASH RT) is a technique to deliver ultra-high dose rate in a fraction of a second. Evidence from experimental animal models suggest that FLASH RT spares various normal tissues including the lung, gastrointestinal track, and brain from radiation-induced toxicity (a phenomenon known as FLASH effect), which is otherwise commonly observed with conventional dose rate RT. However, it is not simply the ultra-high dose rate alone that brings the FLASH effect. Multiple parameters such as instantaneous dose rate, pulse size, pulse repetition frequency, and the total duration of exposure all need to be carefully optimized simultaneously. Furthermore it is critical to validate FLASH effects in an in vivo experimental model system. The exact molecular mechanism responsible for this FLASH effect is not yet understood although a number of hypotheses have been proposed including oxygen depletion and less reactive oxygen species (ROS) production by FLASH RT, and enhanced ability of normal tissues to handle ROS and labile iron pool compared to tumors. In this review, we briefly overview the process of ionization event and history of radiotherapy and fractionation of ionizing radiation. We also highlight some of the latest FLASH RT reviews and results with a special interest to neurocognitive protection in rodent model with whole brain irradiation. Lastly we discuss some of the issues remain to be answered with FLASH RT including undefined molecular mechanism, lack of standardized parameters, low penetration depth for electron beam, and tumor hypoxia still being a major hurdle for local control. Nevertheless, researchers are close to having all answers to the issues that we have raised, hence we believe that advancement of FLASH RT will be made more quickly than one can anticipate.

Keyword

Radiotherapy; Ultra-high dose rate radiation; Neurocognitive protection

Figure

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  Fig. 1 A schematic diagram of ionization event by ionizing radiation and radiation-induced DNA damage. N stands for nucleus.

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  Fig. 2 Energy deposition of X-ray (green), proton (red), or carbon ion (blue), indicating Bragg Peak for protons and carbon ions. Note that the peak width for proton or carbon ion RT can differ depending on their energy.

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  Fig. 3 History of Radiation Oncology technology with example of prostate cancer. RT, radiotherapy; IMRT, intensity-modulated radiotherapy; 3D-CRT, three-dimensional conformal radiotherapy. Reproduced from Thariat et al. Nat Rev Clin Oncol 2013;10:52-60, with permission of Springer Nature [9].

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  Fig. 4 Images showing initial experimental set up (A) and the latest clinical set up (B) of FLASH RT by Dr. Loo Jr group. Reproduced from (A) Schüler et al. Int J Radiat Oncol Biol Phys 2017;97:195-203, under the permission of Elsevier [20]; and (B) No et al. Int J Radiat Oncol Biol Phys 2023;117:482-92, under the permission of Elsevier [23].

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  Fig. 5 Image demonstrating that FLASH effects are not observed in some studies (red dotted circles). Reproduced from Montay-Gruel et al. Clin Cancer Res 2021;27:775-84, with permission of American Association for Cancer Research [25].

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  Fig. 6 Image demonstrating the next generation of FLASH RT, known as pluridirectional high-energy agile scanning electronic radiotherapy (PHASER). Left upper corner shows distributed RF-coupling architecture with genetically optimized cell design (DRAGON) linear accelerator. Reproduced from Maxim et al. Radiother Oncol 2019;139:28-33, with permission of Elsevier [59].

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