  It has been postulated that the delivery of radiotherapy at ultra-high dose
rates ("FLASH") reduces normal tissue toxicities by depleting them of oxygen.
The fraction of normal tissue and cancer cells surviving radiotherapy depends
on dose and oxygen levels in an exponential manner and even a very small
fraction of tissue at low oxygen levels can determine radiotherapy response.
The effect of FLASH on radiation-induced normal and tumour tissue cell killing
was studied by simulating oxygen diffusion, metabolism, and radiolytic oxygen
depletion over domains with simulated capillary architectures. Two
architectural models were used: 1.) randomly distributed capillaries and 2.)
capillaries forming a regular square lattice array. The resulting oxygen
partial pressure distribution histograms were used to simulate normal and
tumour tissue cell survival using the linear quadratic model of cell survival,
modified to incorporate oxygen-enhancement ratio (OER) effects. Tumour cell
survival was found to be increased by FLASH as compared to conventional
radiotherapy, with a 0-1 order of magnitude increase for expected levels of
tumour hypoxia, depending on the relative magnitudes of radiolytic oxygen
depletion and tissue oxygen metabolism. Interestingly, for the random capillary
model, the impact of FLASH on well-oxygenated (normal) tissues was found to be
much greater, with an estimated increase in cell survival by up to 10 orders of
magnitude, even though reductions in mean tissue partial pressure were modest,
less than 7 mmHg for the parameter values studied. The presence of very small
nearly hypoxic regions in otherwise well-perfused normal tissues with high mean
oxygen levels resulted in a greater proportional sparing of normal tissue than
tumour cells during FLASH irradiation, possibly explaining empirical normal
tissue sparing and iso-tumour control results.
