FLASH Radiotherapy

Intro

FLASH radiotherapy delivers a therapeutic radiation dose at ultra-high dose rates — empirically ≥ 40 Gy/s, often in a single pulse of < 200 ms — and produces a measurable sparing of healthy tissue toxicity while preserving anti-tumour efficacy in pre-clinical models. The FLASH effect was reproducibly observed across multiple particle types (electrons, protons, ultimately photons) and is the central radiobiological motivation for new accelerator architectures including [[vhee]]. The mechanistic basis remains contested.

Concepts

Dose-rate regime. Conventional radiotherapy delivers ~0.03 Gy/s; FLASH demands a six-orders-of-magnitude leap. The exact threshold is empirical and varies by tissue, oxygen tension, and pulse structure. Mean dose rate is one parameter; intra-pulse peak rate, pulse duration, and total irradiation time also enter every reported study.

FAST-01 — first-in-human. The first-in-human FLASH-RT clinical trial was reported in 2023 (FAST-01, bone metastases, electron FLASH). It established acute-toxicity feasibility but did not isolate the FLASH effect from conventional dose-rate radiotherapy; subsequent trials (FAST-02 and proton FLASH protocols) are extending the evidence base.

Mechanistic hypotheses. Multiple non-exclusive hypotheses are under active investigation: transient oxygen depletion in irradiated tissue; differential redox response between tumour and normal tissue; reduced inter-track radical recombination; and the long-lived-protein hypothesis (synthesised in Nature Reviews Cancer 2025). No mechanism is yet established as load-bearing.

Modality coupling. Electron FLASH is the historical entry point (Favaudon 2014, mouse-lung sparing). Proton FLASH requires either transmission geometry or fast scanning. Photon FLASH at therapeutic depth requires very-high-flux X-ray sources and is the hardest technical case. Compact VHEE sources are positioned as the modality that combines depth penetration (light particle, multi-MeV) with native sub-second delivery — the technical reason VHEE and FLASH are discussed together.

References

1. Vozenin et al., Reviews of Modern Physics 96, 035002 (2024). DOI:10.1103/RevModPhys.96.035002. Multidisciplinary FLASH review (radiobiology, physics, clinical translation). — vozeninFlash2024
2. Mascia et al., JAMA Oncology 9, 62 (2023). DOI:10.1001/jamaoncol.2022.5843. FAST-01 first-in-human FLASH-RT trial. — masciaFast012023
3. Vozenin & Limoli, Nature Reviews Cancer 25 (2025). DOI:10.1038/s41568-025-00878-9. Long-lived-protein mechanism synthesis. — vozeninMechanisms2025

Open questions

• What is the minimal pulse structure (number of pulses, intra-pulse dose, dead-time) that still triggers the FLASH effect? The "≥ 40 Gy/s" rule of thumb collapses on closer examination.
• Does the FLASH effect generalise to fractionated regimens, or is it intrinsically single-fraction?
• Which of the four competing mechanisms (oxygen depletion, redox, recombination, long-lived proteins) is rate-limiting — or are they coupled?
• How robust is FLASH-induced sparing in tissues with low baseline oxygenation (already-hypoxic tumours, irradiated re-treatments)?
• (empty-marked) — first-in-human VHEE trial: announced or projected? No public protocol as of Tour-0.