Ultra-high-dose-rate pulsed irradiation and the conditional FLASH effect: dosimetry, multiscale biology, and clinical translation.
- 1Academy of Military Medical Sciences, Beijing, China.
- 2School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, China.
Abstract
Ultra-high-dose-rate (UHDR) pulsed irradiation can deliver therapeutic doses within an extremely short time window, but UHDR is a physical delivery state, whereas the FLASH effect is a conditional comparative phenotype in which normal-tissue injury is reduced relative to a spatially dose-comparable conventional-dose-rate (CDR) irradiation comparator without loss of tumor control. This Review integrates evidence across four levels: physical exposure characterization, dosimetric measurement, biological comparison, and clinical translation. We examine the temporal structure and quality-assurance requirements of electron, very-high-energy electron, photon, proton, and heavy-ion UHDR platforms; synthesize positive, negative, and conditional findings across normal-tissue and tumor models; and integrate mechanistic studies spanning multiple time scales. Current evidence does not support 40 Gy/s, or any single average dose-rate metric, as either a sufficient or a necessary threshold for the FLASH effect. Effect magnitude and reproducibility are more likely determined jointly by dose per pulse, pulse structure, total delivery time, fractionation, irradiated volume, radiation quality, tissue-specific radiobiological characteristics, and biological state. Mechanistic data likewise favor multiscale coupling across time rather than a single explanatory pathway, although several causal links from early oxygen and radical dynamics to cellular and tissue outcomes still lack direct interventional validation. Human studies have established the feasibility of clinical UHDR delivery on selected electron and proton platforms and have provided preliminary safety data, but comparative clinical benefit over CDR irradiation has not yet been demonstrated. Further translation should therefore prioritize pulse-resolved traceable dosimetry, organ-specific normal-tissue dose-response relationships, late toxicity, comparable tumor control, and concurrent comparative clinical endpoints, with expansion guided by prespecified stage-gated translational criteria.
Related
- Red and near-infrared photobiomodulation in precision medicine: mechanisms, dosimetry, and clinical translation
- Machine learning predictors of post-radiotherapy cardiotoxicity in a Latin American breast cancer cohort: Clinical risk factors outperform cardiac dosimetry.
- Computer vision, Parkinson’s disease, and the unfinished work of clinical translation
- Opportunistic computed tomography assessment of bone, muscle, and adipose tissue: evidence, limitations, and clinical translation
- From wrist to heart: clinical validation and real-world translation of wearable and portable AI-enhanced electrocardiography
BibTeX
@article{zhang2026ultrahighdoserate,
title = {{Ultra-high-dose-rate pulsed irradiation and the conditional FLASH effect: dosimetry, multiscale biology, and clinical translation.}},
author = {Jincheng Zhang and Hao Lu and Guofu Dong and Changzhen Wang},
journal = {Frontiers in oncology},
year = {2026},
month = oct,
doi = {10.3389/fonc.2026.1990706},
url = {https://europepmc.org/article/MED/42909922},
note = {CC BY},
}
RIS
TY - JOUR
TI - Ultra-high-dose-rate pulsed irradiation and the conditional FLASH effect: dosimetry, multiscale biology, and clinical translation.
AU - Jincheng Zhang
AU - Hao Lu
AU - Guofu Dong
AU - Changzhen Wang
PY - 2026
DA - 2026/10/07
JO - Frontiers in oncology
DO - 10.3389/fonc.2026.1990706
UR - https://europepmc.org/article/MED/42909922
AB - Ultra-high-dose-rate (UHDR) pulsed irradiation can deliver therapeutic doses within an extremely short time window, but UHDR is a physical delivery state, whereas the FLASH effect is a conditional comparative phenotype in which normal-tissue injury is reduced relative to a spatially dose-comparable conventional-dose-rate (CDR) irradiation comparator without loss of tumor control. This Review integrates evidence across four levels: physical exposure characterization, dosimetric measurement, biological comparison, and clinical translation. We examine the temporal structure and quality-assurance requirements of electron, very-high-energy electron, photon, proton, and heavy-ion UHDR platforms; synthesize positive, negative, and conditional findings across normal-tissue and tumor models; and integrate mechanistic studies spanning multiple time scales. Current evidence does not support 40 Gy/s, or any single average dose-rate metric, as either a sufficient or a necessary threshold for the FLASH effect. Effect magnitude and reproducibility are more likely determined jointly by dose per pulse, pulse structure, total delivery time, fractionation, irradiated volume, radiation quality, tissue-specific radiobiological characteristics, and biological state. Mechanistic data likewise favor multiscale coupling across time rather than a single explanatory pathway, although several causal links from early oxygen and radical dynamics to cellular and tissue outcomes still lack direct interventional validation. Human studies have established the feasibility of clinical UHDR delivery on selected electron and proton platforms and have provided preliminary safety data, but comparative clinical benefit over CDR irradiation has not yet been demonstrated. Further translation should therefore prioritize pulse-resolved traceable dosimetry, organ-specific normal-tissue dose-response relationships, late toxicity, comparable tumor control, and concurrent comparative clinical endpoints, with expansion guided by prespecified stage-gated translational criteria.
SN - 2234-943X
ER -