Flash Radiotherapy: Innovative Cancer Treatment

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1		James C. L. Chow	--	1258	2023-06-26 12:46:31	\|
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3	format correction	Dean Liu	Meta information modification	1258	2023-06-27 02:31:32	\|

Peer Reviewed

This is a peer-reviewed entry published in Encyclopedia Journal, full entry can be found at 10.3390/encyclopedia3030058

Flash radiotherapy (Flash-RT) is an innovative technique used in radiotherapy for cancer treatment because it delivers an extremely high dose of radiation (>40 Gy/s) to the tumour in a very short period of time, typically within a fraction of a second. This ultra-fast delivery of radiation distinguishes Flash-RT from conventional radiotherapy, which typically involves the delivery of radiation over a longer time period, often several minutes. Studies conducted in cell and preclinical models suggested that Flash-RT may spare normal tissues from radiation-related side effects, such as skin toxicity, gastrointestinal complications, and damage to organs-at-risk. This is believed to be due to the unique normal tissue response to the ultra-high dose rate. Nevertheless, while Flash-RT shows promising results in preclinical and early clinical studies, one should note that the technique is still in the early stages of development. This entry provides a comprehensive exploration of the immense potentials of Flash-RT, covering its background, mechanisms, radiation sources, recent experimental findings based on cell and preclinical models, and future prospects. It aims to provide valuable insights into this innovative radiotherapy technology for anyone interested in the subject.

flash radiotherapy ultra-high dose rate radiation dosimetry dose delivery preclinical model radiobiology oxygen depletion radiation source

Radiotherapy is a common treatment method used for cancer. It involves the use of high-energy radiation, such as X-rays or protons, to target and destroy cancer cells in the body ^[1]^[2]. Radiotherapy works by damaging the DNA inside cancer cells, which prevents them from growing and dividing further ^[3]^[4]. Radiotherapy can be highly effective in treating various types of cancer. It can be used either as a primary treatment to eliminate tumours, or in combination with other treatments like surgery or chemotherapy to enhance the overall effectiveness ^[5]. Moreover, radiotherapy allows for precise targeting of cancer cells. It can target specific areas of the body where the tumour is located, minimizing damage to healthy surrounding tissues. This makes it particularly useful for tumours that are confined to a specific region.

Although this treatment modality is the most commonly employed and highly efficient for combating tumours, it can lead to acute and long-term damage to healthy tissues ^[6]. The dosage of radiation administered to the tumour is restricted due to the potential toxicity to neighboring healthy tissues. This limitation can result in incomplete eradication of the tumour and a reduction in the overall effectiveness of radiotherapy ^[7]. Consequently, the prevention or mitigation of radiation-induced injuries to healthy tissues has always been a significant focus in radiotherapy research. Thus far, several techniques for delivering radiation doses, such as stereotactic body radiotherapy and intensity-modulated radiotherapy, have been developed to enhance the targeted radiation to the tumour while minimizing exposure to surrounding healthy tissues ^[8]^[9]^[10]. Despite these advancements, the treatment process typically involves multiple sessions, ranging from two to over twenty fractions. Consequently, patients are required to travel to the cancer center for a period of one to a couple of weeks in order to complete the radiotherapy treatment ^[11]. This is often an additional burden to already stressed patients and families.

Flash-RT offers an attractive potential solution. It is an emerging technique in radiation therapy that delivers an ultra-high dose of radiation to a tumour in an extremely short amount of time, typically within a fraction of a second (dose rate > 40 Gy/s) ^[12]. Unlike conventional radiotherapy, which delivers radiation in multiple fractions over several weeks, Flash-RT administers the entire treatment dose in a single Flash ^[13]. This novel approach to radiotherapy has shown promising results in preclinical and early clinical studies ^[14]. The main advantage of Flash-RT is its potential to increase the therapeutic ratio by selectively damaging cancer cells while minimizing damage to surrounding normal tissues. This is achieved by exploiting the differences in cellular response to high-dose radiation between tumour cells and normal cells ^[15]. A comparison between conventional and Flash radiotherapy can be found in Table 1, focusing on several key parameters and outcomes. In terms of radiation type, conventional radiotherapy employs X-ray, gamma-ray, electron, proton, and heavy-ion radiation, while Flash radiotherapy utilizes X-ray, electron, proton, and heavy-ion radiation.

The dose rate, which refers to the amount of radiation delivered per unit of time, is significantly different between the two approaches. Conventional radiotherapy typically operates at a dose rate ranging from 0.001 to 0.4 Gy/s, while Flash radiotherapy surpasses this with a much higher dose rate of over 40 Gy/s. This disparity in dose rate has implications for the irradiation time required. Conventional radiotherapy typically demands an irradiation time exceeding 120 seconds, whereas Flash radiotherapy achieves its therapeutic effect in less than 1 second. Both conventional and Flash radiotherapy demonstrate efficient tumor control, indicating their effectiveness in targeting and treating cancerous cells. However, there is a notable difference in the potential for normal tissue complications. Conventional radiotherapy carries a higher risk of normal tissue complications, while Flash radiotherapy is associated with a lower incidence of such complications. The mechanisms underlying the two techniques also differ. Conventional radiotherapy operates through mechanisms such as repair, re-oxygenation, redistribution, repopulation, oxygen depletion, and the generation of reactive oxygen species (ROS). In contrast, Flash radiotherapy relies on mechanisms such as oxygen depletion, the generation of ROS, and immunoinflammatory responses.

At present, Flash-RT continues to be a subject of ongoing research, and its implementation in clinical practice is currently limited to select research institutions ^[16]^[17]. Further studies are ongoing to evaluate its safety, efficacy, and optimal clinical applications ^[18]^[19]. The aim is to determine the full potential of Flash-RT to improve cancer treatment outcomes while reducing treatment duration and potential side effects. This entry will present a comprehensive overview of Flash-RT, covering its background, mechanisms, radiation sources, current cell and preclinical results, as well as future prospects. The intention is to make this innovative radiotherapy technology accessible to a wide range of experts, including those with backgrounds in engineering, science, and medicine. By providing a comprehensive understanding, this entry seeks to facilitate knowledge transfer and promote further exploration and collaboration in the field of Flash-RT.

Table 1. Comparison between conventional and Flash radiotherapy. ROS: reactive oxygen species.

	Conventional Radiotherapy	Flash Radiotherapy
Radiation type	X-ray, gamma-ray, electron, proton, heavy-ion	X-ray, electron, proton, heavy-ion
Dose rate (Gy/s)	0.001–0.4	>40
Irradiation time (s)	>120	<1
Tumour control	Efficient	Efficient
Normal tissue complication	High	Low
Mechanism	Repair, re-oxygenation, redistribution, repopulation, oxygen depletion, ROS	Oxygen depletion, ROS, immunoinflammatory response

Flash-RT is a relatively new concept in the field of radiotherapy. Its history can be traced back to the early 20^th century when researchers observed certain notable effects of high-dose radiation ^[16]^[18]^[20]. One of the earliest observations related to Flash-RT occurred in the late 1950s. Dewey and Boag reported on the phenomenon known as the Flash effect, which is now referred to as Flash-RT [^[21]. They conducted an experiment using ultra-high-dose-rate megavoltage X-rays to irradiate Serratia marcescens. The study demonstrated that the bacteria, when exposed to ultra-high dose rates (UHDRs) (10–20 krads/2 μs), exhibited lower radiosensitivity in a nitrogen–oxygen mixture compared to the situation when irradiated at normal dose rates (1 krads/min) in 100% nitrogen. This lower radiosensitivity corresponded to the response typically observed under anaerobic conditions. Such findings indicated that the radiosensitivity of Serratia marcescens was influenced by both the oxygen content and the dose rate of the radiation. Town ^[22] discovered that mammalian cells irradiated at an UHDR of 3.5 × 10⁶ krad/s showed interesting results. When the cells received a dose of up to 1 krads, a single pulse had a higher survival rate compared to two pulses. The result from Town is supported by Berry et al. ^[23] who observed similar outcomes in their experiments with hamster and HeLa cells, using ultra-high-dose-rate irradiation of 1 krads for a 15 ns pulse.

References

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Do Huh, H.; Kim, S. History of radiation therapy technology. Prog. Med. Phys. 2020, 31, 124–134.
Dewey, D.L.; Boag, J.W. Modification of the oxygen effect when bacteria are given large pulses of radiation. Nature 1959, 183, 1450–1451.
Town, C.D. Effect of high dose rates on survival of mammalian cells. Nature 1967, 215, 847–848.
Berry, R.J.; Hall, E.J.; Forster, D.W.; Storr, T.H.; Goodman, M.J. Survival of mammalian cells exposed to x-rays at ultra-high dose-rates. Br. J. Radiol. 1969, 42, 102–107.
Stone, H.B.; Coleman, C.N.; Anscher, M.S.; McBride, W.H. Effects of radiation on normal tissue: Consequences and mechanisms. Lancet Oncol. 2003, 4, 529–536.
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Vozenin, M.C.; Hendry, J.H.; Limoli, C.L. Biological benefits of UHDR FLASH radiotherapy: Sleeping beauty awoken. Clin. Oncol. 2019, 31, 407–415.
Matuszak, N.; Suchorska, W.M.; Milecki, P.; Kruszyna-Mochalska, M.; Misiarz, A.; Pracz, J.; Malicki, J. FLASH Radiotherapy: An emerging approach in radiation therapy. Rep. Pract. Oncol. Radiother. 2022, 27, 343–351.
Borghini, A.; Vecoli, C.; Labate, L.; Panetta, D.; Andreassi, M.G.; Gizzi, L.A. FLASH UHDRs in radiotherapy: Preclinical and radiobiological evidence. Int. J. Radiat. Biol. 2022, 98, 127–135.
Marcu, L.G.; Bezak, E.; Peukert, D.D.; Wilson, P. Translational research in FLASH radiotherapy—From radiobiological mechanisms to in vivo results. Biomedicines 2021, 9, 181.
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Lv, Y.; Lv, Y.; Wang, Z.; Lan, T.; Feng, X.; Chen, H.; Zhu, J.; Ma, X.; Du, J.; Hou, G.; et al. FLASH radiotherapy: A promising new method for radiotherapy. Oncol. Lett. 2022, 24, 1–14.
Lin, B.; Gao, F.; Yang, Y.; Wu, D.; Zhang, Y.; Feng, G.; Dai, T.; Du, X. FLASH radiotherapy: History and future. Front. Oncol. 2021, 11, 1890.
Kamperis, E.; Kodona, C.; Giannouzakos, V. A FLASH back to radiotherapy’s past and then fast forward to the future. J. Cancer Prev. Curr. Res. 2019, 10, 142–144.

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Flash Radiotherapy

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Subjects: Oncology

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James C. L. Chow

Harry E. Ruda

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Online Date: 26 Jun 2023

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