Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Towards clinical translation of FLASH radiotherapy

Subjects

Abstract

The ultimate goal of radiation oncology is to eradicate tumours without toxicity to non-malignant tissues. FLASH radiotherapy, or the delivery of ultra-high dose rates of radiation (>40 Gy/s), emerged as a modality of irradiation that enables tumour control to be maintained while reducing toxicity to surrounding non-malignant tissues. In the past few years, preclinical studies have shown that FLASH radiotherapy can be delivered in very short times and substantially can widen the therapeutic window of radiotherapy. This ultra-fast radiation delivery could reduce toxicity and thus enable dose escalation to enhance antitumour efficacy, with the additional benefits of reducing treatment time and organ motion-related issues, eventually increasing the number of patients who can be treated. At present, FLASH is recognized as one of the most promising breakthroughs in radiation oncology, standing at the crossroads between technology, physics, chemistry and biology; however, several hurdles make its clinical translation difficult, including the need for a better understanding of the biological mechanisms, optimization of parameters and technological challenges. In this Perspective, we provide an overview of the principles underlying FLASH radiotherapy and discuss the challenges along the path towards its clinical application.

This is a preview of subscription content, access via your institution

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Fig. 1: FLASH radiotherapy and the therapeutic window.
Fig. 2: Radiation quality achieved with FLASH.
Fig. 3: Response of various tissues to different radiation modalities.
Fig. 4: Treatment of cutaneous lymphoma with FLASH radiotherapy.

References

  1. Thariat, J., Hannoun-Levi, J.-M., Sun Myint, A., Vuong, T. & Gérard, J.-P. Past, present, and future of radiotherapy for the benefit of patients. Nat. Rev. Clin. Oncol. 10, 52–60 (2012).

    Article  PubMed  Google Scholar 

  2. Coutard, H. Principles of X-ray therapy of malignant diseases. Lancet 224, 1–8 (1934).

    Article  Google Scholar 

  3. Lo, S. S. et al. Stereotactic body radiation therapy: a novel treatment modality. Nat. Rev. Clin. Oncol. 7, 44–54 (2010).

    Article  PubMed  Google Scholar 

  4. Dewey, D. L. & Boag, J. W. Modification of the oxygen effect when bacteria are given large pulses of radiation. Nature 183, 1450–1451 (1959).

    Article  PubMed  CAS  Google Scholar 

  5. Town, C. D. Radiobiology. Effect of high dose rates on survival of mammalian cells. Nature 215, 847–848 (1967).

    Article  PubMed  CAS  Google Scholar 

  6. Berry, R. J., Hall, E. J., Forster, D. W., Storr, T. H. & Goodman, M. J. Survival of mammalian cells exposed to x rays at ultra-high dose-rates. Br. J. Radiol. 42, 102–107 (1969).

    Article  PubMed  CAS  Google Scholar 

  7. Hornsey, S. & Bewley, D. K. Hypoxia in mouse intestine induced by electron irradiation at high dose-rates. Int. J. Radiat. Biol. Relat. Stud. Phys., Chem. Med. 19, 479–483 (1971).

    Article  CAS  Google Scholar 

  8. Field, S. B. & Bewley, D. K. Effects of dose-rate on the radiation response of rat skin. Int. J. Radiat. Biol. Relat. Stud. Phys. Chem. Med. 26, 259–267 (1974).

    Article  PubMed  CAS  Google Scholar 

  9. Hendry, J. H., Moore, J. V., Hodgson, B. W. & Keene, J. P. The constant low oxygen concentration in all the target cells for mouse tail radionecrosis. Radiat. Res. 92, 172–181 (1982).

    Article  PubMed  CAS  Google Scholar 

  10. Favaudon, V. et al. Ultrahigh dose-rate FLASH irradiation increases the differential response between normal and tumor tissue in mice. Sci. Transl. Med. 6, 245ra93 (2014).

    Article  PubMed  Google Scholar 

  11. Farr, J. B., Parodi, K. & Carlson, D. J. FLASH: current status and the transition to clinical use. Med. Phys. 49, 1972–1973 (2022).

    Article  PubMed  Google Scholar 

  12. Lin, B. et al. FLASH radiotherapy: history and future. Front. Oncol. 11, 644400 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Kacem, H., Almeida, A., Cherbuin, N. & Vozenin, M.-C. Understanding the FLASH effect to unravel the potential of ultra-high dose rate irradiation. Int. J. Radiat. Biol. 98, 506–516 (2022).

    Article  PubMed  CAS  Google Scholar 

  14. Borghini, A. et al. FLASH ultra-high dose rates in radiotherapy: preclinical and radiobiological evidence. Int. J. Radiat. Biol. 98, 127–135 (2022).

    Article  PubMed  CAS  Google Scholar 

  15. Durante, M., Brauer-Krisch, E. & Hill, M. Faster and safer? FLASH ultra-high dose rate in radiotherapy. Br. J. Radiol. 91, 20170628 (2017).

    Article  PubMed  Google Scholar 

  16. Vozenin, M. C., Hendry, J. H. & Limoli, C. L. Biological benefits of ultra-high dose rate FLASH radiotherapy: sleeping beauty awoken. Clin. Oncol. 31, 407–415 (2019).

    Article  Google Scholar 

  17. Beddok, A. et al. A comprehensive analysis of the relationship between dose rate and biological effects in preclinical and clinical studies, from brachytherapy to flattening filter free radiation therapy and FLASH irradiation. Int. J. Radiat. Oncol. 113, 985–995 (2022).

    Article  Google Scholar 

  18. Vozenin, M. C., Montay-Gruel, P., Limoli, C. & Germond, J. F. All Irradiations that are ultra-high dose rate may not be FLASH: the critical importance of beam parameter characterization and in vivo validation of the FLASH effect. Radiat. Res. 194, 571–572 (2020).

    Article  PubMed  CAS  Google Scholar 

  19. Wilson, J. D., Hammond, E. M., Higgins, G. S. & Petersson, K. Ultra-high dose rate (FLASH) radiotherapy: silver bullet or fool’s gold? Front. Oncol. 9, 1563 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Schüler, E. et al. Ultra‐high dose rate electron beams and the FLASH effect: from preclinical evidence to a new radiotherapy paradigm. Med. Phys. 49, 2082–2095 (2022).

    Article  PubMed  Google Scholar 

  21. Rothwell, B. C. et al. Determining the parameter space for effective oxygen depletion for FLASH radiation therapy. Phys. Med. Biol. 66, 055020 (2021).

    Article  PubMed Central  Google Scholar 

  22. Bourhis, J. et al. Clinical translation of FLASH radiotherapy: why and how? Radiother. Oncol. 139, 11–17 (2019).

    Article  PubMed  Google Scholar 

  23. Bourhis, J. et al. Treatment of a first patient with FLASH-radiotherapy. Radiother. Oncol. 139, 18–22 (2019).

    Article  PubMed  Google Scholar 

  24. Gaide, O. et al. Comparison of ultra-high versus conventional dose rate radiotherapy in a patient with cutaneous lymphoma. Radiother. Oncol. 174, 87–91 (2022).

    Article  PubMed  Google Scholar 

  25. Taylor, P. A., Moran, J. M., Jaffray, D. A. & Buchsbaum, J. C. A roadmap to clinical trials for FLASH. Med. Phys. 49, 4099–4108 (2022).

    Article  PubMed  Google Scholar 

  26. Montay-Gruel, P. et al. Hypofractionated FLASH-RT as an effective treatment against glioblastoma that reduces neurocognitive side effects in mice. Clin. Cancer Res. 27, 775–784 (2021).

    Article  PubMed  Google Scholar 

  27. MacKay, R. et al. FLASH radiotherapy: considerations for multibeam and hypofractionation dose delivery. Radiother. Oncol. 164, 122–127 (2021).

    Article  PubMed  Google Scholar 

  28. Jaccard, M. et al. High dose-per-pulse electron beam dosimetry: usability and dose-rate independence of EBT3 gafchromic films. Med. Phys. 44, 725–735 (2017).

    Article  PubMed  CAS  Google Scholar 

  29. Jorge, P. G. et al. Dosimetric and preparation procedures for irradiating biological models with pulsed electron beam at ultra-high dose-rate. Radiother. Oncol. 139, 34–39 (2019).

    Article  PubMed  Google Scholar 

  30. Schüler, E. et al. Experimental platform for ultra-high dose rate FLASH irradiation of small animals using a clinical linear accelerator. Int. J. Radiat. Oncol. Biol. Phys. 97, 195–203 (2017).

    Article  PubMed  Google Scholar 

  31. Lempart, M. et al. Modifying a clinical linear accelerator for delivery of ultra-high dose rate irradiation. Radiother. Oncol. 139, 40–45 (2019).

    Article  PubMed  CAS  Google Scholar 

  32. Rahman, M. et al. Electron FLASH delivery at treatment room isocenter for efficient reversible conversion of a clinical LINAC. Int. J. Radiat. Oncol. 110, 872–882 (2021).

    Article  Google Scholar 

  33. Lansonneur, P. et al. Simulation and experimental validation of a prototype electron beam linear accelerator for preclinical studies. Phys. Med. 60, 50–57 (2019).

    Article  PubMed  Google Scholar 

  34. Felici, G. et al. Transforming an IORT linac into a FLASH research machine: procedure and dosimetric characterization. Front. Phys. 8, 374 (2020).

    Article  Google Scholar 

  35. Di Martino, F. et al. FLASH radiotherapy with electrons: issues related to the production, monitoring, and dosimetric characterization of the beam. Front. Phys. 8, 570697 (2020).

    Article  Google Scholar 

  36. Moeckli, R. et al. Commissioning of an ultra‐high dose rate pulsed electron beam medical LINAC for FLASH RT preclinical animal experiments and future clinical human protocols. Med. Phys. 48, 3134–3142 (2021).

    Article  PubMed  CAS  Google Scholar 

  37. Jaccard, M. et al. High dose-per-pulse electron beam dosimetry: commissioning of the oriatron eRT6 prototype linear accelerator for preclinical use. Med. Phys. 45, 863–874 (2018).

    Article  PubMed  CAS  Google Scholar 

  38. Whitmore, L., Mackay, R. I., van Herk, M., Jones, J. K. & Jones, R. M. Focused VHEE (very high energy electron) beams and dose delivery for radiotherapy applications. Sci. Rep. 11, 14013 (2021).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Sarti, A. et al. Deep seated tumour treatments with electrons of high energy delivered at FLASH rates: the example of prostate cancer. Front. Oncol. 11, 777852 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  40. Ronga, M. G. et al. Back to the future: very high-energy electrons (VHEEs) and their potential application in radiation therapy. Cancers 13, 4942 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Hooker, S. M. Developments in laser-driven plasma accelerators. Nat. Photonics 7, 775–782 (2013).

    Article  CAS  Google Scholar 

  42. Peralta, E. A. et al. Demonstration of electron acceleration in a laser-driven dielectric microstructure. Nature 503, 91–94 (2013).

    Article  PubMed  CAS  Google Scholar 

  43. Montay-Gruel, P., Corde, S., Laissue, J. A. & Bazalova-Carter, M. FLASH radiotherapy with photon beams. Med. Phys. 49, 2055–2067 (2022).

    Article  PubMed  CAS  Google Scholar 

  44. Montay-Gruel, P. et al. X-rays can trigger the FLASH effect: ultra-high dose-rate synchrotron light source prevents normal brain injury after whole brain irradiation in mice. Radiother. Oncol. 129, 582–588 (2018).

    Article  PubMed  Google Scholar 

  45. Smyth, L. M. L. et al. Comparative toxicity of synchrotron and conventional radiation therapy based on total and partial body irradiation in a murine model. Sci. Rep. 8, 12044 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Eling, L. et al. Ultra high dose rate synchrotron microbeam radiation therapy. Preclinical evidence in view of a clinical transfer. Radiother. Oncol. 139, 56–61 (2019).

    Article  PubMed  Google Scholar 

  47. Rezaee, M., Iordachita, I. & Wong, J. W. Ultrahigh dose-rate (FLASH) X-ray irradiator for pre-clinical laboratory research. Phys. Med. Biol. 66, 095006 (2021).

    Article  CAS  Google Scholar 

  48. Gao, F. et al. First demonstration of the FLASH effect with ultrahigh dose rate high-energy X-rays. Radiother. Oncol. 166, 44–50 (2022).

    Article  PubMed  CAS  Google Scholar 

  49. Maxim, P. G., Tantawi, S. G. & Loo, B. W. PHASER: a platform for clinical translation of FLASH cancer radiotherapy. Radiother. Oncol. 139, 28–33 (2019).

    Article  PubMed  Google Scholar 

  50. Durante, M., Orecchia, R. & Loeffler, J. S. Charged-particle therapy in cancer: clinical uses and future perspectives. Nat. Rev. Clin. Oncol. 14, 483–495 (2017).

    Article  PubMed  Google Scholar 

  51. Durante, M. & Paganetti, H. Nuclear physics in particle therapy: a review. Rep. Prog. Phys. 79, 096702 (2016).

    Article  PubMed  Google Scholar 

  52. Diffenderfer, E. S., Sørensen, B. S., Mazal, A. & Carlson, D. J. The current status of preclinical proton FLASH radiation and future directions. Med. Phys. 49, 2039–2054 (2022).

    Article  PubMed  Google Scholar 

  53. Jolly, S., Owen, H., Schippers, M. & Welsch, C. Technical challenges for FLASH proton therapy. Phys. Med. 78, 71–82 (2020).

    Article  PubMed  Google Scholar 

  54. Simeonov, Y. et al. 3D range-modulator for scanned particle therapy: development, Monte Carlo simulations and experimental evaluation. Phys. Med. Biol. 62, 7075–7096 (2017).

    Article  PubMed  CAS  Google Scholar 

  55. Yokokawa, K., Furusaka, M., Matsuura, T., Hirayama, S. & Umegaki, K. A new SOBP-formation method by superposing specially shaped Bragg curves formed by a mini-ridge filter for spot scanning in proton beam therapy. Phys. Med. 67, 70–76 (2019).

    Article  PubMed  CAS  Google Scholar 

  56. Tommasino, F. et al. A new facility for proton radiobiology at the Trento proton therapy centre: design and implementation. Phys. Med. 58, 99–106 (2019).

    Article  PubMed  Google Scholar 

  57. Simeonov, Y. et al. Monte Carlo simulations and dose measurements of 2D range-modulators for scanned particle therapy. Z. Med. Phys. 31, 203–214 (2021).

    Article  PubMed  Google Scholar 

  58. van de Water, S., Safai, S., Schippers, J. M., Weber, D. C. & Lomax, A. J. Towards FLASH proton therapy: the impact of treatment planning and machine characteristics on achievable dose rates. Acta Oncol. 58, 1463–1469 (2019).

    Article  PubMed  Google Scholar 

  59. van Marlen, P. et al. Bringing FLASH to the clinic: treatment planning considerations for ultrahigh dose-rate proton beams. Int. J. Radiat. Oncol. 106, 621–629 (2020).

    Article  Google Scholar 

  60. Schwarz, M., Traneus, E., Safai, S., Kolano, A. & Water, S. Treatment planning for Flash radiotherapy: general aspects and applications to proton beams. Med. Phys. 49, 2861–2874 (2022).

    Article  PubMed  Google Scholar 

  61. Higginson, A. et al. Near-100 MeV protons via a laser-driven transparency-enhanced hybrid acceleration scheme. Nat. Commun. 9, 724 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Kroll, F. et al. Tumour irradiation in mice with a laser-accelerated proton beam. Nat. Phys. 18, 316–322 (2022).

    Article  CAS  Google Scholar 

  63. Gizzi, L. A. & Andreassi, M. G. Ready for translational research. Nat. Phys. 18, 237–238 (2022).

    Article  CAS  Google Scholar 

  64. Linz, U. & Alonso, J. Laser-driven ion accelerators for tumor therapy revisited. Phys. Rev. Accel. Beams 19, 124802 (2016).

    Article  Google Scholar 

  65. Durante, M., Debus, J. & Loeffler, J. S. Physics and biomedical challenges of cancer therapy with accelerated heavy ions. Nat. Rev. Phys. 3, 777–790 (2021).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Mairani, A. et al. Roadmap: helium ion therapy. Phys. Med. Biol. 67, 15TR02 (2022).

    Article  Google Scholar 

  67. Tessonnier, T. et al. FLASH dose rate helium ion beams: first in vitro investigations. Int. J. Radiat. Oncol. 111, 1011–1022 (2021).

    Article  Google Scholar 

  68. Tinganelli, W. et al. Ultra-high dose rate (FLASH) carbon ion irradiation: dosimetry and first cell experiments. Int. J. Radiat. Oncol. 112, 1012–1022 (2022).

    Article  Google Scholar 

  69. Tashiro, M. et al. First human cell experiments with FLASH carbon ions. Anticancer. Res. 42, 2469–2477 (2022).

    Article  PubMed  CAS  Google Scholar 

  70. Durante, M., Golubev, A., Park, W.-Y. & Trautmann, C. Applied nuclear physics at the new high-energy particle accelerator facilities. Phys. Rep. 800, 1–37 (2019).

    Article  CAS  Google Scholar 

  71. Weber, U. A., Scifoni, E. & Durante, M. FLASH radiotherapy with carbon ion beams. Med. Phys. 49, 1974–1992 (2022).

    Article  PubMed  CAS  Google Scholar 

  72. Favaudon, V., Labarbe, R. & Limoli, C. L. Model studies of the role of oxygen in the FLASH effect. Med. Phys. 49, 2068–2081 (2022).

    Article  PubMed  CAS  Google Scholar 

  73. Schüller, A. et al. The European Joint Research Project UHDpulse–Metrology for advanced radiotherapy using particle beams with ultra-high pulse dose rates. Phys. Med. 80, 134–150 (2020).

    Article  PubMed  Google Scholar 

  74. Romano, F., Bailat, C., Jorge, P. G., Lerch, M. L. F. & Darafsheh, A. Ultra‐high dose rate dosimetry: challenges and opportunities for FLASH radiation therapy. Med. Phys. 49, 4912–4932 (2022).

    Article  PubMed  CAS  Google Scholar 

  75. Ashraf, M. R. et al. Dosimetry for FLASH radiotherapy: a review of tools and the role of radioluminescence and Cherenkov emission. Front. Phys. 8, 328 (2020).

    Article  Google Scholar 

  76. Yang, Y. et al. A 2D strip ionization chamber array with high spatiotemporal resolution for proton pencil beam scanning FLASH radiotherapy. Med. Phys. 49, 5464–5475 (2022).

    Article  PubMed  CAS  Google Scholar 

  77. Montay-Gruel, P. et al. Irradiation in a flash: unique sparing of memory in mice after whole brain irradiation with dose rates above 100 Gy/s. Radiother. Oncol. 124, 365–369 (2017).

    Article  PubMed  Google Scholar 

  78. Simmons, D. A. et al. Reduced cognitive deficits after FLASH irradiation of whole mouse brain are associated with less hippocampal dendritic spine loss and neuroinflammation. Radiother. Oncol. 139, 4–10 (2019).

    Article  PubMed  Google Scholar 

  79. Montay-Gruel, P. et al. Long-term neurocognitive benefits of FLASH radiotherapy driven by reduced reactive oxygen species. Proc. Natl Acad. Sci. USA 116, 10943–10951 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Vozenin, M. C. et al. The advantage of FLASH radiotherapy confirmed in mini-pig and cat-cancer patients. Clin. Cancer Res. 25, 35–42 (2019).

    Article  PubMed  Google Scholar 

  81. Venkatesulu, B. P. et al. Ultra high dose rate (35 Gy/sec) radiation does not spare the normal tissue in cardiac and splenic models of lymphopenia and gastrointestinal syndrome. Sci. Rep. 9, 17180 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  82. Beyreuther, E. et al. Feasibility of proton FLASH effect tested by zebrafish embryo irradiation. Radiother. Oncol. 139, 46–50 (2019).

    Article  PubMed  Google Scholar 

  83. Karsch, L. et al. Beam pulse structure and dose rate as determinants for the flash effect observed in zebrafish embryo. Radiother. Oncol. 173, 49–54 (2022).

    Article  PubMed  CAS  Google Scholar 

  84. Eggold, J. T. et al. Abdominopelvic FLASH irradiation improves PD-1 immune checkpoint inhibition in preclinical models of ovarian cancer. Mol. Cancer Ther. 21, 371–381 (2022).

    Article  PubMed  CAS  Google Scholar 

  85. Levy, K. et al. Abdominal FLASH irradiation reduces radiation-induced gastrointestinal toxicity for the treatment of ovarian cancer in mice. Sci. Rep. 10, 21600 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Diffenderfer, E. S. et al. Design, implementation, and in vivo validation of a novel proton FLASH radiation therapy system. Int. J. Radiat. Oncol. 106, 440–448 (2020).

    Article  CAS  Google Scholar 

  87. Zhang, Q. et al. FLASH investigations using protons: design of delivery system, preclinical setup and confirmation of FLASH effect with protons in animal systems. Radiat. Res. 194, 656–664 (2020).

    Article  PubMed  CAS  Google Scholar 

  88. Ruan, J.-L. et al. Irradiation at ultra-high (FLASH) dose rates reduces acute normal tissue toxicity in the mouse gastrointestinal system. Int. J. Radiat. Oncol. 111, 1250–1261 (2021).

    Article  Google Scholar 

  89. Velalopoulou, A. et al. FLASH proton radiotherapy spares normal epithelial and mesenchymal tissues while preserving sarcoma response. Cancer Res. 81, 4808–4821 (2021).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Cunningham, S. et al. FLASH proton pencil beam scanning irradiation minimizes radiation-induced leg contracture and skin toxicity in mice. Cancers 13, 1012 (2021).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. Singers Sørensen, B. et al. In vivo validation and tissue sparing factor for acute damage of pencil beam scanning proton FLASH. Radiother. Oncol. 167, 109–115 (2022).

    Article  PubMed  Google Scholar 

  92. Kim, M. M. et al. Comparison of FLASH proton entrance and the spread-out Bragg peak dose regions in the sparing of mouse intestinal crypts and in a pancreatic tumor model. Cancers 13, 4244 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  93. Evans, T., Cooley, J., Wagner, M., Yu, T. & Zwart, T. Demonstration of the FLASH effect within the spread-out Bragg peak after abdominal irradiation of mice. Int. J. Part. Ther. 8, 68–75 (2022).

    Article  PubMed  Google Scholar 

  94. Tinganelli, W. et al. FLASH with carbon ions: tumor control, normal tissue sparing, and distal metastasis in a mouse osteosarcoma model. Radiother. Oncol. 75, 185–190 (2022).

    Article  Google Scholar 

  95. Liljedahl, E. et al. Long-term anti-tumor effects following both conventional radiotherapy and FLASH in fully immunocompetent animals with glioblastoma. Sci. Rep. 12, 12285 (2022).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Ngwa, W. et al. Using immunotherapy to boost the abscopal effect. Nat. Rev. Cancer 18, 313–322 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Grassberger, C., Ellsworth, S. G., Wilks, M. Q., Keane, F. K. & Loeffler, J. S. Assessing the interactions between radiotherapy and antitumour immunity. Nat. Rev. Clin. Oncol. 16, 729–745 (2019).

    Article  PubMed  Google Scholar 

  98. Durante, M., Reppingen, N. & Held, K. D. Immunologically augmented cancer treatment using modern radiotherapy. Trends Mol. Med. 19, 565–582 (2013).

    Article  PubMed  CAS  Google Scholar 

  99. Zhang, Y. et al. Can rational combination of ultra-high dose rate FLASH radiotherapy with immunotherapy provide a novel approach to cancer treatment? Clin. Oncol. 33, 713–722 (2021).

    Article  CAS  Google Scholar 

  100. Xing, S. et al. A dynamic blood flow model to compute absorbed dose to circulating blood and lymphocytes in liver external beam radiotherapy. Phys. Med. Biol. 67, 045010 (2022).

    Article  Google Scholar 

  101. Durante, M. & Formenti, S. Harnessing radiation to improve immunotherapy: better with particles? Br. J. Radiol. 93, 20190224 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  102. Yin, T., Wang, P., Yu, J. & Teng, F. Treatment-related lymphopenia impairs the treatment response of anti-PD-1 therapy in esophageal squamous cell carcinoma. Int. Immunopharmacol. 106, 108623 (2022).

    Article  PubMed  CAS  Google Scholar 

  103. Cho, Y. et al. Lymphocyte dynamics during and after chemo-radiation correlate to dose and outcome in stage III NSCLC patients undergoing maintenance immunotherapy. Radiother. Oncol. 168, 1–7 (2022).

    Article  PubMed  Google Scholar 

  104. Fouillade, C. et al. FLASH irradiation spares lung progenitor cells and limits the incidence of radio-induced senescence. Clin. Cancer Res. 26, 1497–1506 (2020).

    Article  PubMed  CAS  Google Scholar 

  105. Perstin, A., Poirier, Y., Sawant, A. & Tambasco, M. Quantifying the DNA-damaging effects of FLASH irradiation with plasmid DNA. Int. J. Radiat. Oncol. 113, 437–447 (2022).

    Article  Google Scholar 

  106. Calugaru, V. et al. Involvement of the artemis protein in the relative biological efficiency observed with the 76-MeV proton beam used at the Institut Curie Proton Therapy Center in Orsay. Int. J. Radiat. Oncol. Biol. Phys. 90, 36–43 (2014).

    Article  PubMed  CAS  Google Scholar 

  107. Buonanno, M., Grilj, V. & Brenner, D. J. Biological effects in normal cells exposed to FLASH dose rate protons. Radiother. Oncol. 139, 51–55 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  108. Moon, E. J., Petersson, K. & Olcina, M. M. The importance of hypoxia in radiotherapy for the immune response, metastatic potential and FLASH-RT. Int. J. Radiat. Biol. 98, 439–451 (2022).

    Article  PubMed  CAS  Google Scholar 

  109. Wardman, P. Radiotherapy using high-intensity pulsed radiation beams (FLASH): a radiation-chemical perspective. Radiat. Res. 194, 607–617 (2020).

    Article  PubMed  CAS  Google Scholar 

  110. Weiss, H., Epp, E. R., Heslin, J. M., Ling, C. C. & Santomasso, A. Oxygen depletion in cells irradiated at ultra-high dose-rates and at conventional dose-rates. Int. J. Radiat. Biol. 26, 17–29 (1974).

    CAS  Google Scholar 

  111. Pratx, G. & Kapp, D. S. A computational model of radiolytic oxygen depletion during FLASH irradiation and its effect on the oxygen enhancement ratio. Phys. Med. Biol. 64, 185005 (2019).

    Article  PubMed  CAS  Google Scholar 

  112. Pratx, G. & Kapp, D. S. Ultra-high-dose-rate FLASH irradiation may spare hypoxic stem cell niches in normal tissues. Int. J. Radiat. Oncol. Biol. Phys. 105, 190–192 (2019).

    Article  PubMed  Google Scholar 

  113. Petersson, K., Adrian, G., Butterworth, K. & McMahon, S. J. A quantitative analysis of the role of oxygen tension in FLASH radiation therapy. Int. J. Radiat. Oncol. 107, 539–547 (2020).

    Article  Google Scholar 

  114. Liew, H. et al. Deciphering time-dependent DNA damage complexity, repair, and oxygen tension: a mechanistic model for FLASH-dose-rate radiation therapy. Int. J. Radiat. Oncol. Biol. Phys. 110, 574–586 (2021).

    Article  PubMed  Google Scholar 

  115. Liew, H. et al. The impact of sub-millisecond damage fixation kinetics on the in vitro sparing effect at ultra-high dose rate in UNIVERSE. Int. J. Mol. Sci. 23, 2954 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  116. Boscolo, D., Scifoni, E., Durante, M., Krämer, M. & Fuss, M. C. May oxygen depletion explain the FLASH effect? A chemical track structure analysis. Radiother. Oncol. 162, 68–75 (2021).

    Article  PubMed  CAS  Google Scholar 

  117. Cao, X. et al. Quantification of oxygen depletion during FLASH irradiation in vitro and in vivo. Int. J. Radiat. Oncol. 111, 240–248 (2021).

    Article  Google Scholar 

  118. Jansen, J. et al. Does FLASH deplete oxygen? Experimental evaluation for photons, protons, and carbon ions. Med. Phys. 48, 3982–3990 (2021).

    Article  PubMed  CAS  Google Scholar 

  119. Spitz, D. R. et al. An integrated physico-chemical approach for explaining the differential impact of FLASH versus conventional dose rate irradiation on cancer and normal tissue responses. Radiother. Oncol. 139, 23–27 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  120. Labarbe, R., Hotoiu, L., Barbier, J. & Favaudon, V. A physicochemical model of reaction kinetics supports peroxyl radical recombination as the main determinant of the FLASH effect. Radiother. Oncol. 153, 303–310 (2020).

    Article  PubMed  CAS  Google Scholar 

  121. Hu, A. et al. Radical recombination and antioxidants: a hypothesis on the FLASH effect mechanism. Int. J. Radiat. Biol. https://doi.org/10.1080/09553002.2022.2110307 (2022).

    Article  PubMed  Google Scholar 

  122. McKeown, S. R. Defining normoxia, physoxia and hypoxia in tumours–implications for treatment response. Br. J. Radiol. 87, 20130676 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  123. Taylor, E., Hill, R. P. & Létourneau, D. Modeling the impact of spatial oxygen heterogeneity on radiolytic oxygen depletion during FLASH radiotherapy. Phys. Med. Biol. 67, 115017 (2022).

    Article  Google Scholar 

  124. Jin, J. Y. et al. Ultra-high dose rate effect on circulating immune cells: a potential mechanism for FLASH effect? Radiother. Oncol. 149, 55–62 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  125. Helm, A. et al. Reduction of lung metastases in a mouse osteosarcoma model treated with carbon ions and immune checkpoint inhibitors. Int. J. Radiat. Oncol. 109, 594–602 (2021).

    Article  Google Scholar 

  126. Ogata, T. et al. Particle irradiation suppresses metastatic potential of cancer cells. Cancer Res. 65, 113–120 (2005).

    Article  PubMed  CAS  Google Scholar 

  127. Chabi, S. et al. Ultra-high-dose-rate FLASH and conventional-dose-rate irradiation differentially affect human acute lymphoblastic leukemia and normal hematopoiesis. Int. J. Radiat. Oncol. 109, 819–829 (2021).

    Article  Google Scholar 

  128. Rohrer Bley, C. et al. Dose- and volume-limiting late toxicity of FLASH radiotherapy in cats with squamous cell carcinoma of the nasal planum and in mini pigs. Clin. Cancer Res. 28, 3814–3823 (2022).

    Article  PubMed  Google Scholar 

  129. Konradsson, E. et al. Establishment and initial experience of clinical FLASH radiotherapy in canine cancer patients. Front. Oncol. 11, 658004 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  130. Korreman, S. S. Motion in radiotherapy: photon therapy. Phys. Med. Biol. 57, R161–R191 (2012).

    Article  PubMed  Google Scholar 

  131. Bert, C. & Durante, M. Motion in radiotherapy: particle therapy. Phys. Med. Biol. 56, R113–R144 (2011).

    Article  PubMed  CAS  Google Scholar 

  132. El Naqa, I., Pogue, B. W., Zhang, R., Oraiqat, I. & Parodi, K. Image guidance for FLASH radiotherapy. Med. Phys. 49, 4109–4122 (2022).

    Article  PubMed  Google Scholar 

  133. Pakela, J. M., Knopf, A., Dong, L., Rucinski, A. & Zou, W. Management of motion and anatomical variations in charged particle therapy: past, present, and into the future. Front. Oncol. 12, 806153 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  134. Zelefsky, M. J. et al. Phase 3 multi-center, prospective, randomized trial comparing single-dose 24 Gy radiation therapy to a 3-fraction SBRT regimen in the treatment of oligometastatic cancer. Int. J. Radiat. Oncol. 110, 672–679 (2021).

    Article  Google Scholar 

  135. Tjong, M. C. et al. Single-fraction stereotactic ablative body radiotherapy to the lung – the knockout punch. Clin. Oncol. 34, e183–e194 (2022).

    Article  CAS  Google Scholar 

  136. Kamada, T. et al. Carbon ion radiotherapy in Japan: an assessment of 20 years of clinical experience. Lancet Oncol. 16, e93–e100 (2015).

    Article  PubMed  Google Scholar 

  137. Liang, S., Zhou, G. & Hu, W. Research progress of heavy ion radiotherapy for non-small-cell lung cancer. Int. J. Mol. Sci. 23, 2316 (2022).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  138. Durante, M. & Debus, J. Heavy charged particles: does improved precision and higher biological effectiveness translate to better outcome in patients? Semin. Radiat. Oncol. 28, 160–167 (2018).

    Article  Google Scholar 

  139. Alaghband, Y. et al. Neuroprotection of radiosensitive juvenile mice by ultra-high dose rate FLASH irradiation. Cancers 12, 1671 (2020).

    Article  PubMed Central  CAS  Google Scholar 

  140. Allen, B. D. et al. Maintenance of tight junction integrity in the absence of vascular dilation in the brain of mice exposed to ultra-high-dose-rate FLASH irradiation. Radiat. Res. 194, 625–635 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  141. Montay-Gruel, P. et al. Ultra-high-dose-rate FLASH irradiation limits reactive gliosis in the brain. Radiat. Res. 194, 636–645 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Acknowledgements

The authors thank L. Volz (GSI) and A. Quarz (GSI and TUDa) for their support in preparing figures, and F. Bochud, J. F. Germond, T. Boehlen, C. Bailat and R. Moeckli for fruitful scientific discussions.

Author information

Authors and Affiliations

Authors

Contributions

All authors contributed substantially to discussion of the content and wrote the article. M.-C.V. and M.D. researched data for the article, and reviewed and edited the manuscript before submission.

Corresponding author

Correspondence to Marco Durante.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Clinical Oncology thanks K. Kirkby, P. Maxim and A. Mazal for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Related links

Clinicaltrials.gov: https://clinicaltrials.gov/

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Vozenin, MC., Bourhis, J. & Durante, M. Towards clinical translation of FLASH radiotherapy. Nat Rev Clin Oncol 19, 791–803 (2022). https://doi.org/10.1038/s41571-022-00697-z

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41571-022-00697-z

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing