FLASH Radiotherapy: Biochemical Mechanisms, Current Evidence, and Remaining Challenges
DOI:
https://doi.org/10.22399/ijbimes.20Keywords:
Radiation therapy, conventional dose-rate, ultra-high dose rates (UHDR), underlying mechanisms, sparing of normal tissue toxicityAbstract
FLASH radiotherapy (FLASH-RT) delivers radiation in milliseconds and has consistently reduced normal-tissue toxicity without compromising tumor control. Among proposed biochemical mechanisms, radiolytic oxygen depletion (ROD) remains the most extensively examined, with enhanced radical–radical recombination and tissue antioxidant capacity considered as complementary modifiers. In ROD, ultrafast dose delivery consumes molecular oxygen faster than it can diffuse back, transiently lowering local pO₂ and suppressing oxygen-dependent peroxyl radical chemistry. While modeling predicts only small oxygen reductions at clinically realistic doses, ROD may still exert biologically meaningful effects in hypoxic stem-cell niches—microregions within normal tissues that are critical for regeneration and more susceptible to local oxygen shifts. The magnitude of ROD depends on baseline oxygenation, total dose, dose-per-pulse, and oxygen-replenishment kinetics. Key limitations include: (i) small predicted depletion in most tissues, (ii) incomplete reporting of beam and oxygenation parameters, and (iii) absence of direct, time-resolved in vivo measurements at microsecond–millisecond scales. Future progress will require standardized pO₂ and beam-structure reporting, systematic testing at physiologic oxygen levels, and development of ultrafast, spatially resolved oximetry to directly probe niche-level oxygen dynamics. Determining the relative contributions of ROD, radical recombination, and antioxidant buffering under clinically relevant conditions is essential for rational FLASH-RT optimization.
References
Baikalov, A. A. (2023). Intertrack interaction at ultra high dose rates and its role in the FLASH effect. . Frontiers in Physics, 11, Article 1215422.
Boodaghi Malidarre, R. K. (2020). A feasibility study to reduce the contamination of photoneutrons and photons in organs/tissues during radiotherapy. . Iranian Journal of Medical Physics, 17(6), 366–373.
Boscolo, D. S. (2021). May oxygen depletion explain the FLASH effect? A chemical track structure analysis. Radiotherapy and Oncology.
Boudaghi Malidarreh, R. &. (2024). FLASH radiation therapy — Key physical irradiation parameters and beam characteristics. . Journal of Instrumentation, , 19(02), P02035.
Bourhis J, e. a. (2019). Clinical translation of FLASH radiotherapy: Why and how? . Radiother Oncol, 139:11–17.
Cao, X. Z. (2021). Quantification of Oxygen Depletion During FLASH Irradiation In Vitro and In Vivo. International Journal of Radiation Oncology, Biology, Physics, 110(3), 872–882.
CD, T. (1967). Effect of high dose rates on survival of mammalian cells. Radiat Res, 32:258–279.
Delaney GP, e. a. (2005). The role of radiotherapy in cancer treatment: estimating optimal utilization from a review of evidence-based clinical guidelines. The role of radiotherapy in cancer treatment: estimating optimal utilization from a review of evidence-based clinical guidelines, 104(6):1129–1137.
Dewey DL, B. J. (1959). Modification of the oxygen effect when bacteria are given large doses of X-rays. Radiat Res, 11:587–594.
DT, G. (1994). Initial events in the cellular effects of ionizing radiations: clustered damage in DNA. Int J Radiat Biol, 65:7 17.
Favaudon V, e. a. (2014). Ultrahigh dose-rate FLASH irradiation increases the differential response between normal and tumor tissue in mice. Sci Transl Med, 6(245):245ra93.
Gray LH, C. A. (1953). The concentration of oxygen dissolved in tissues at the time of irradiation as a factor in radiotherapy. . Br J Radiol, 26:638 648.
Greene-Schloesser D, R. M. (2012). Radiation-induced cognitive impairment—from bench to bedside. . . Neuro Oncol, 14(Suppl 4):iv37–iv44.
Guillem Pratx, D. S. (2019). A computational model of radiolytic oxygen depletion during FLASH irradiation and its effect on the oxygen enhancement ratio . Phys Med Biol, 64(18):185005.
Hall EJ, G. A. (2018). Radiobiology for the Radiologist.
Hongyu Zhu, J. S. (2022). Modeling the impact of tissue oxygen profiles and oxygen depletion parameter uncertainties on biological response and therapeutic benefit of FLASH. arXiv.
Howard-Flanders, A. a. (1956). Role of oxygen in modifying the radiosensitivity of E. coli B. Nature, 3;178(4540):978-9.
Hu, A. Q. (2023). Radical recombination and antioxidants: A hypothesis on the FLASH effect mechanism. International Journal of Radiation Biology, 99(4), 620–628.
Ibáñez, B. M. (2024). Molecular insights into radiation effects and protective mechanisms: a focus on cellular damage and radioprotectors. Curr. Issues Mol. Biol, 46 (11), 12718–12732.
Jaffray DA, G. M. (2015). Radiation Therapy for cancer. Cancer: Disease Control Priorities, Third Edition (Volume 3).
Khabaz, R. B. (2018). Estimation of photoneutron dosimetric characteristics in tissues/organs using an improved simple model of linac head. . Applied Radiation and Isotopes, 133, 88–94.
Labarbe, R. H. (2020). A physicochemical model of reaction kinetics supports peroxyl radical recombination as the main determinant of the FLASH effect. . Radiotherapy and Oncology, 153, 303–310.
Montay-Gruel P, P. K. (2017). Irradiation in a flash: Unique sparing of memory in mice after whole brain irradiation with ultrahigh dose rate. . Radiother Oncol, 124(3):365-369.
Montay-Gruel, P. A.-F. (2019). Long-term neurocognitive benefits of FLASH radiotherapy driven by reduced reactive oxygen species. Proc Natl Acad Sci U S A, 116(22):10943-10951.
Nakamura, H. a. (2021). Reactive oxygen species in cancer: current findings and future directions. . Cancer Sci. , 112 (10), 3945–3952.
Nikjoo H, O. P. (1999). Quantitative modeling of DNA damage using Monte Carlo track structure. . Radiat Environ Biophys, 38:31 38.
Petersson K, A. G. (2020). A quantitative analysis of the role of oxygen tension in FLASH radiation therapy. Int J Radiat Oncol Biol Phys.
R A Rosiello, W. W. (1990 Mar). Radiation-induced lung injury. Clin Chest Med, 11(1):65-71.
Roots R, O. S. (1975). Estimation of lifetimes and diffusion distances of radicals involved in X-ray-induced DNA strand breaks or killing of mammalian cells. . Radiat Res, 64(2):306-320.
Scarmelotto, A. D.-C. (2022). The oxygen puzzle in FLASH radiotherapy: A comprehensive review and experimental outlook. Cancer Letters., 546, 215857.
Vaupel P, M. A. (2016). Hypoxia in cancer: Significance and impact on clinical outcome. Cancer Metastasis Rev, 35:225–239.
Vozenin MC, e. a. (2019). The advantage of FLASH radiotherapy confirmed in mini-pig and cat-cancer patients. Clin Cancer Res, 25(1):35–42.
Wilson JD, H. E. (2020). Ultra-high dose rate (FLASH) radiotherapy: Silver bullet or fool’s gold? . Front Oncol, 9:1563.
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