# FLASH Radiotherapy

FLASH radiotherapy is an emerging form of radiotherapy which delivers a high dose of radiation to the patient in an ultra-short time frame which produces a tumour killing effect comparable to conventional radiotherapy but with less damage to surrounding healthy tissue. The treatment is in the early stages of development and is not yet widely available as a form of cancer therapy.

## FLASH-RT development

Research into high-dose radiotherapy yielding cells which were more resistant to radiation was first performed in the 1950s, but without any breakthrough achievements, research dwindled after the 1960s. However, in 2014 a research paper published by V. Favaudon et al. coined the term FLASH, which was defined as irradiating tissue with a dose ≥ 40 Gy/s. The research involved comparing conventional radiotherapy performed on mice to FLASH radiotherapy administered using a linear electron accelerator (LINAC) able to generate 4.5 MeV electrons with a high beam current, such that a high dose could be administered by a single beam in less than 500ms. This research showed that when compared to CONV-RT, the onset and progression of pneumonia and pulmonary fibrosis were measurably inhibited following a solitary exposure to 17 Gy FLASH-RT, yet the effect on a tumour was comparable. More recently, in 2019 first human FLASH-RT treatment was performed at Lausanne University Hospital, which concluded that FLASH-RT was both feasible and safe. Subsequently, in 2023 the first proton clinical trial of FLASH-RT was performed at the joint Cincinnati Children's Hospital Medical Center UC Health Proton Therapy Center in Cincinnati, Ohio, affiliated with University of Cincinnati Health and Cincinnati Children's Hospital Medical Center. The trial focused on bone metastases of 10 patients with an age range of 27-81 years old, and a 50/50 split in sex, it concluded that FLASH-RT was clinically feasible and that the findings supported further exploration into FLASH-RT. The results were first presented at the 2022 American Society for Radiation Oncology Annual Meeting.

### Comparison of FLASH-RT and CONV-RT

| Parameter | FLASH-RT | CONV-RT |
| Mean dose rate | ≥ 40 Gy/s (minimum threshold) | ≤ 1 Gy/min |
| Delivery time | < 200 ms | > 1 min |
| Dose delivery | High dose in a single fraction | Low dose in a single fraction |
| Tumor control | A similar antitumor effect as CONV-RT | Effective tumor killing |
| Normal tissue sparing | Damage to healthy tissues reduced | Acute and late damage to healthy tissues |
| Defects | Early stages of development/few facilities | Radiation injury, limited treatment window |

## Oxygen depletion hypothesis

The increased radiosensitivity of cells in an oxygenated environment compared to a hypoxic one is known as the oxygen effect, this is the basis of one of the first and most widely investigated hypotheses which could explain the FLASH effect. Many research papers have been published investigating whether FLASH RT creates a hypoxic environment in healthy tissue, which makes it less radiosensitive. The oxygen depletion was thought to be caused by radiolysis of water molecules, where water breaks down into hydrogen peroxide, hydrogen radicals and other oxygen compounds. However, experimental studies demonstrated that oxygen depletion does not occur. A new hypothesis is needed to explain the FLASH effect, which can also account for the differential response between healthy tissue and cancer at ultra-high dose rates.

## Blood volume as a target for FLASH radiotherapy

Since blood is constantly flowing around the human body, during CONV-RT a large volume of this blood is expected to be irradiated. A possible reason for FLASH-RT sparing normal tissues is that a lower total blood volume is irradiated when compared with CONV-RT. Blood carries more than just oxygen throughout the body, it contains immune cells which help to fight infection and disease. Multiple studies have investigated this possibility, one being Jin. et al., 2020, where it was observed that circulating blood cells experienced a significantly lower impact during FLASH-RT, resulting in the killing of only 5-10% of cells, in contrast, CONV-RT exhibited a much more substantial effect, leading to the death of 90-100% of cells. Aside from immune cells, studies have shown that the proinflammatory signalling in the form of the secretion of proinflammatory cytokines is reduced during FLASH-RT when compared to CONV-RT.

## Stem cell niche preservation

Adult stem cells are found throughout the human body in locations known as niches. These cells multiply by cell division to replenish dying cells and regenerate tissue. These cells are essential for recovery from certain forms of cancer such as leukemia, where some treatment plans can involve stem cell transplants. A more recent hypothesis which may explain the FLASH effect is that hypoxic stem cell niches are preserved more readily through FLASH RT. Pratx and Kapp, 2019, suggest that stem cells which reside in a hypoxic niche are relatively radioresistant, but whenever surrounding tissue is damaged, the stem cells become more oxygenated and therefore more radiosensitive. This theory suggests that as FLASH-RT is delivered in a single, ultra-short dose, the stem cells do not have time to react to the damage done to the surrounding tissue, therefore maintaining their radio-resistance and increasing the overall survivability of the niche.