Physics and Biology of FLASH Radiation

Radiotherapy is an effective tool in the treatment of cancer. However, the full potential of radiotherapy is limited by the fact that radiation also damage healthy tissues. To avoid causing severe damage and suffering for patients receiving treatment, the radiation dose delivered must be limited. Even though, for many patients, a higher treatment dose would be necessary for curing them.
In cancer treatment with FLASH radiotherapy, all the radiation dose is delivered in parts of a second, more than 1 000 times quicker than in conventional radiotherapy. This new radiotherapy technique has great potential in improving cancer treatment, as it is less toxic to healthy tissues compared to standard radiotherapy but as effective at treating tumours. However, very little is known about the biological processes behind this highly beneficial FLASH effect.
We have a powerful and flexible linear accelerator available for experiments. It is capable of delivering the intense radiation fields needed for FLASH radiotherapy. By performing different cell, tissue, and mice experiments, we aim to explain the effect and to find out how to best take advantage of this treatment technique when moving towards human trials in our cancer treatment centres.

FLASH radiotherapy involves cancer treatment with radiation delivered at ultra-high dose rates, i.e. with the radiation dose delivered more than a thousand times quicker than in conventional radiotherapy. This novel radiotherapy technique shows great potential in improving cancer treatment, as it appears to be less toxic to normal tissues compared to conventional radiotherapy but as effective at treating tumours. However, very little is known about the biological mechanisms behind this highly beneficial FLASH effect. We aim to identify these mechanisms, explain the effect, and to find the optimal way of implementing the technique in clinical practice.
One of the main hypotheses to explain why FLASH radiotherapy is less toxic to normal tissues is oxygen consumption during the intense irradiation, leading to transient hypoxia in the treated volume. By measuring the oxygen concentration with an appropriately designed oxygen probe inserted in cell media or in mice, we aim to measure the drop in oxygen concentration during the brief irradiation. Thereby proving or (disproving) the hypothesis.
We also aim to elucidate when the dose rate is high enough for the beneficial FLASH effect to occur and if it is the delivery time or the pulsed time-dose structure of the irradiation that is the important characteristic for the FLASH effect to occur. We will use whole abdominal irradiation of mice to investigate this for a variety of pulse structure profiles, evaluating toxicity sparing of normal intestinal epithelium using the Swiss-roll technique.
We also aim to look at the impact of fractionated treatment for FLASH radiotherapy when treating tumours. For this, we will use subcutaneous, orthotopic, and transgenic mice models of pancreatic and bladder tumours. Treatment efficacy will be monitored and evaluated for single and hypo-fractionated treatment schemes using calliper measurements and bioluminescence and/or MR imaging.
In collaboration with Lund University (Lund, Sweden), we will assist in the delivery of the treatment as well as analyse tissue samples from canine patients suffering from spontaneous tumours, for which they will be receiving treatment in Lund with FLASH radiotherapy. We will evaluate treatment efficacy as well as treatment toxicity. This is an important step towards clinical human trials with FLASH radiotherapy.
In all our studies, we will be using electrons for FLASH radiotherapy, primarily with our own dedicated linear accelerator. Our collaborators at Penn University (Philadelphia, USA) will be performing similar studies as described above with protons. By combining our data, we will be able to elucidate if there is any difference in the FLASH sparing effect between the two radiation modalities.