Harnessing Particle Ions for FLASH Radiotherapy.

FLASH radiotherapy continues to be an emerging clinical treatment that utilises ultra-high dose rate radiation (>40 Gy/s) to elicit normal tissue sparing compared to conventional (CONV) dose rate delivery. This is termed the FLASH effect, which has also been demonstrated to lead to effective tumour control. FLASH sparing has been demonstrated in many studies using electrons and now increasingly with particle ions, particularly protons. Due to unique properties such as deeper penetrance and a narrow range of energy deposition providing more precision targeting, this makes hadron radiotherapy using FLASH an exciting innovation for cancer treatment to help improve outcomes for cancer patients. Furthermore, through the use of higher linear energy transfer (LET) particles such as helium and carbon ions, FLASH offers the potential to combine sparing of normal tissues with enhanced biological effectiveness in tumour cell killing, important for tumours that are more resistant to conventional photon radiotherapy. However, the physical and biological parameters by which the FLASH sparing effect occurs is complex and has not been fully characterised. Factors including total dose, pulse structure (dose and duration), beam energy and LET have all been reported to impact tissue sparing. Additionally, the underlying biological mechanism of action of FLASH remains a point of contention within the field. In this review, we provide an up-to-date report on FLASH studies conducted with particle ion therapies, including in vitro and in vivo studies, using different experimental models. We present both the cellular and molecular outcomes of the studies performed using protons, helium and carbon ions, plus other ion sources, and the accumulating evidence that demonstrate the strong clinical potential for these modalities in cancer treatment.