“FLASH radiotherapy is potentially a game-changing technology,” said Jian-Yue Jin, speaking at the recent ASTRO 2020 Annual Meeting. “It can significantly spare normal tissues, as demonstrated in various animal models by various research groups. However, the mechanism of FLASH is not well understood.”
Jin, from Seidman Cancer Center, University Hospitals, and Case Western Reserve University, described how he and his colleagues are using computational modelling to study potential mechanisms of FLASH radiotherapy, where radiation delivered at high dose rates (40 Gy/s and above) destroys tumours while vastly reducing damage to normal tissue. In particular, the team is investigating the hypothesis that FLASH dose rates significantly reduce the killing of circulating immune cells during radiotherapy, which contributes to the reported FLASH effect.
The team devised a computational model to determine the effect of radiation dose rate on immune cell killing. The model, which assumes that all immune cells are within the circulating blood, considers an irradiated blood volume that takes up A% of cardiac output and contains B% of the total circulating blood. The value of A% depends upon the irradiated location and is, for example, 100% for the heart, 50% for the lung and 15% for the whole brain. B% is dependent on the total irradiated volume, with a value of 5–10% for a tumour and 100% for the whole body.
The researchers used their model to calculate the irradiated blood volume and dose to this volume for various values of A% and B%, doses of 2–50 Gy and blood circulation times of 60 s (for an adult human) and 5–10 s (for a mouse). They then used the linear-quadratic model to calculate the percentage of circulating immune cells killed at conventional and FLASH dose rates, simulating dose rates from 1.7 mGy/s to 333 Gy/s.
The model revealed that the killing of circulating immune cells reduces dramatically as dose rate increases. Jin shared an example with parameters chosen to reflect 30 Gy irradiation of a human lung. “The percentage of circulating immune cells killed was reduced from 95% at very low dose rates to only 10% at the very high dose rates,” he explained.
Looking at the effects of blood circulation time and the irradiated location revealed that the threshold dose rate for the FLASH effect to occur increases as circulation time decreases and as A% increases. “This threshold dose rate depends on many factors,” said Jin. “For mice, it is about 10 Gy/s for whole brain, 40 Gy/s for lung and abdomen and 90 Gy/s for the heart. This result is similar to reported FLASH effects in experiments.”
Jin pointed out that the level of this threshold may be a factor of 10 lower in humans than in mice. “This is very important, because it suggests that X-ray-based FLASH systems can be developed and are not as challenging as we previously thought,” he explained.
The model also showed that the FLASH effect on immune cells increases at higher values of dose per fraction. The FLASH effect becomes prominent at larger than 20 Gy/fraction and vanishes at low doses of less than 2 Gy/fraction. Jin noted that the FLASH effect also vanishes when B% is 100%, representing total-body irradiation.
FLASH radiotherapy: from preclinical promise to the first human treatment
“FLASH dose rates dramatically reduce killing of circulating immune cells,” Jin concluded. “The immune system plays an important role in repairing normal tissue damage by radiation, and radiation-induced lymphopenia [a reduction in immune cells in the blood] is associated with poor tumour control and patient survival. Therefore FLASH-related sparing of immune cells may have a positive effect on both normal tissue sparing and tumour control.”
Jin added that oxygen depletion – another potential FLASH mechanism – may have a positive effect on normal tissue sparing, but a negative effect on tumour control. “Therefore, the FLASH effect may be the combined effect of the sparing of immune cells and oxygen depletion,” he told the ASTRO audience.