Radiation therapy is an important component of cancer treatment, with about 50% of all cancer patients requiring it at some point through the course of their illness (Basker et al. 2012). Despite being critical in current cancer treatment schemes, it carries risks due to its tendency to damage nearby cells while destroying cancer cells. This means that the elimination of cancerous tissue is limited by the dose of radiation that the patient can receive without the risk of severe radiation-induced effects (Chow and Ruda 2023). Because of this limitation, a significant proportion of research in radiotherapy is aimed towards minimizing damage to nearby healthy tissue during the targeting of cancer cells (Majeed and Gupta 2023). 

Flash Radiotherapy (FLASH-RT) is an emerging technology that could overcome the limitations of conventional radiotherapy by delivering doses of radiation several orders of magnitude higher than that of conventional radiotherapy, at ultrafast speeds typically within a fraction of a second (Chow and Ruda 2023). The term FLASH was coined by a 2014 research paper by Fauvadon et al. that defined FLASH as irradiating dose greater than 40 Gray per second (Gy/s; a unit representing the delivery of one joule of ionizing radiation energy per kilogram of matter per second). In vitro studies suggest that ultrafast pulses of radiation elicit less genomic instability than continuous prolonged radiation with the same total dose, sparing normal tissues from radiation-related side effects like skin toxicity and damage to organs-at-risk (Fauvadon et al. 2014). 

The main advantage of FLASH-RT is therefore its ability to selectively damage cancer cells while minimizing damage to surrounding local tissue (Matuszak et al. 2022). Although the precise mechanism responsible for the FLASH effect remains under investigation, one leading explanation involves the rapid production and interaction of reactive oxygen species (ROS). When ionizing radiation passes through cells, it causes the radiolysis of water, producing highly reactive molecules that can damage DNA and other cellular components (Chow and Ruda 2023; Spitz et al. 2024). At the ultrahigh dose rates used in FLASH-RT, these reactive molecules are generated almost simultaneously and at very high concentrations, increasing the likelihood that they will react with one another before causing further damage to cellular structures. FLASH irradiation may also rapidly consume oxygen in the irradiated tissue, creating a brief period of reduced oxygen availability. Oxygen normally reacts with radiation-induced DNA radicals and converts them into more permanent, difficult-to-repair lesions, so reduced oxygen can decrease this process and limit damage to normal cells. This effect may be particularly important because normal tissues are generally more oxygenated than many regions of solid tumours. Therefore, the ultrafast delivery of radiation may reduce the amount of damage produced in healthy tissue while maintaining the direct tumour-killing effects of the radiation.

Figure 1: Proposed explanation for how FLASH radiotherapy protects healthy tissue. Conventional radiotherapy produces reactive oxygen species (ROS) and allows oxygen in the tissue to be continuously replenished (Alhaddad et al. 2024). This can lead to greater ROS production and more damage to healthy cells. In contrast, the ultrafast delivery of FLASH-RT rapidly uses up available oxygen, causing a brief period of low oxygen levels (transient hypoxia). This reduces the amount of ROS produced and may therefore decrease damage to surrounding healthy tissue. 

FLASH-RT therefore represents a potential shift in how radiation therapy can be used to treat cancer. Rather than simply increasing the amount of radiation delivered to a tumour, its ultrahigh dose rate may alter the chemical and biological response of tissues, allowing cancer cells to be damaged while reducing injury to surrounding healthy cells. This could make it possible to treat tumours that are currently difficult to irradiate because of their proximity to sensitive organs. 

Bibliography

Alhaddad, Lina, Andreyan N. Osipov, and Sergey Leonov. 2024. “FLASH Radiotherapy: Benefits, Mechanisms, and Obstacles to Its Clinical Application.” International Journal of Molecular Sciences 25 (23): 12506. https://doi.org/10.3390/ijms252312506.

Baskar, Rajamanickam, Kuo Ann Lee, Richard Yeo, and Kheng-Wei Yeoh. 2012. “Cancer and Radiation Therapy: Current Advances and Future Directions.” International Journal of Medical Sciences 9 (3): 193–99. https://doi.org/10.7150/ijms.3635.

Chow, James C. L., and Harry E. Ruda. 2023. “Flash Radiotherapy: Innovative Cancer Treatment.” Encyclopedia 3 (3): 808–23. https://doi.org/10.3390/encyclopedia3030058.

DEWEY, D. L., and J. W. BOAG. 1959. “Modification of the Oxygen Effect When Bacteria Are Given Large Pulses of Radiation.” Nature 183 (4673): 1450–51. https://doi.org/10.1038/1831450a0.

Favaudon, Vincent, Laura Caplier, Virginie Monceau, et al. 2014. “Ultrahigh Dose-Rate FLASH Irradiation Increases the Differential Response Between Normal and Tumor Tissue in Mice.” Science Translational Medicine 6 (245). https://doi.org/10.1126/scitranslmed.3008973.

Majeed, H, and V Gupta. 2023. “Adverse Effects of Radiation Therapy.” Europepmc.Org, August 14. https://europepmc.org/article/nbk/nbk563259.

Matuszak, Natalia, Wiktoria Maria Suchorska, Piotr Milecki, et al. 2022. “FLASH Radiotherapy: An Emerging Approach in Radiation Therapy.” Reports of Practical Oncology and Radiotherapy 27 (2): 343–51. https://doi.org/10.5603/rpor.a2022.0038.

Spitz, Douglas R., Garry R. Buettner, Michael S. Petronek, et al. 2019. “An Integrated Physico-Chemical Approach for Explaining the Differential Impact of FLASH Versus Conventional Dose Rate Irradiation on Cancer and Normal Tissue Responses.” Radiotherapy and Oncology 139 (October): 23–27. https://doi.org/10.1016/j.radonc.2019.03.028.