FLASH radiotherapy, which is radiotherapy delivered in a fraction of a second at ultra-high dose rates (≥ 30-40 Gy/s), has been shown in numerous preclinical studies to have the potential to be the next important improvement in cancer treatment. However, many challenges still need to be overcome before an effective clinical translation is possible. This would require a good understanding of the specific beam parameters that induces a FLASH effect, environmental conditions affecting the response, and the radiobiological mechanisms involved. To maximise the therapeutic index, we need to understand when we get 0% sparing, as seems to be the case for tumours, 10-20% sparing or 30-40% sparing of normal tissues and why that is, and if we can expand the sparing effect further, e.g. by combining FLASH radiotherapy with immunotherapy.
In addition to the biological benefit with FLASH, the short delivery time essentially removes any physiological motion during the delivery. If this can be fully exploited in the clinic, it would allow us to remove margins related to intrafractional motion, e.g. for lung or abdominal treatments, enabling gated treatments without breath-hold, e.g. for left-sided breast cancer patients, and perhaps utilise less strict immobilization equipment.
For FLASH to have a real impact in the clinic, technological advancements are needed on the motion-management side to benefit from the quick delivery and on the beam generation side to allow for conformal treatments of deep-seated tumours. Currently, only treatment of superficial tumours or intra-operative treatments are possible using high-energy (6-20 MeV) electron beams. However, FLASH proton therapy is not that far off, with the first feasibility study (FAST-01, FeAsibility Study of FLASH Radiotherapy for the Treatment of Symptomatic Bone Metastases) already carried out using transmission beams for treatment of bone metastasis. Though, conformal plans to rival state-of-the-art intensity-modulated proton therapy (IMPT) plans would require several beams, treatments using the spread-out Bragg peak (SOBP), and likely intensity modulation.
Proton/particle therapy is a niche modality only delivered to relatively few patients, e.g. the NHS capability for proton therapy in the UK is 1,500 treated patients per year once their two centres are fully utilised, which represents around 1% of all patients treated with radiotherapy in the UK. The reason for this is the very high costs associated with proton therapy centres and consequently treatments, which are far higher than for photon-based treatments, e.g. VMAT. So, even if FLASH will be the next big thing in proton/particle therapy, for FLASH to really make a difference I believe that photon FLASH is needed. However, the inefficient bremsstrahlung process requires a very intense electron beam to incident on a target which is far outside the capability of current medical linear accelerators. So, technological advancements are required on all components, and likely new concepts for intensity-modulation are required before photon FLASH becomes available clinically, e.g. the PHASER concept presented by Maxim et al.
I believe that most radiotherapy treatments will be FLASH in the not too distant future. The reason for this is the biological and practical benefits with a quick FLASH treatment. There is no real downside with FLASH, only technical challenges that we are working to find solutions for. However, due to the relative higher cost of particle therapy, even if it will become more common than now, it will likely never play more than a marginal role in the future of radiotherapy treatment. Although, most of the particle treatments delivered in the future will undoubtably be FLASH.