Advertisement

Biological Benefits of Ultra-high Dose Rate FLASH Radiotherapy: Sleeping Beauty Awoken

  • M.-C. Vozenin
    Correspondence
    Author for correspondence: M.-C. Vozenin, Laboratoire de Radio-Oncologie, Centre Hospitalier, Universitaire Vaudois, Bugnon 46, 1011 Lausanne, Switzerland.
    Affiliations
    Laboratory of Radiation Oncology/CHUV, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland

    Department of Radiation Oncology/Department of Oncology/CHUV, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
    Search for articles by this author
  • J.H. Hendry
    Affiliations
    Department of Medical Physics and Engineering, Christie Hospital, Manchester, UK
    Search for articles by this author
  • C.L. Limoli
    Affiliations
    Department of Radiation Oncology, University of California, Irvine, California, USA
    Search for articles by this author
Published:April 19, 2019DOI:https://doi.org/10.1016/j.clon.2019.04.001

      Highlights

      • FLASH radiotherapy (FLASH-RT) is a technology that could modify the way radiotherapy is delivered in the future.
      • Ultra-fast delivery of RT at dose rates several orders of magnitude higher than the ones currently used in clinical practice.
      • This very short time of exposure leads to the striking observation of relative protection of normal tissues after FLASH-RT.

      Abstract

      FLASH radiotherapy (FLASH-RT) is a technology that could modify the way radiotherapy is delivered in the future. This technique involves the ultra-fast delivery of radiotherapy at dose rates several orders of magnitude higher than those currently used in routine clinical practice. This very short time of exposure leads to the striking observation of relative protection of normal tissues that are exposed to FLASH-RT as compared with conventional dose rate radiotherapy. Here we summarise the current knowledge about the FLASH effect and provide a synthesis of the observations that have been reported on various experimental animal models (mice, zebrafish, pig, cats), various organs (lung, gut, brain, skin) and by various groups across 40 years of research. We also propose possible mechanisms for the FLASH effect, as well as possible paths for clinical application.

      Key words

      To read this article in full you will need to make a payment

      Subscribe:

      Subscribe to Clinical Oncology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Herrera F.G.
        • Bourhis J.
        • Coukos G.
        Radiotherapy combination opportunities leveraging immunity for the next oncology practice.
        CA Cancer J Clin. 2017; 67: 65-85https://doi.org/10.3322/caac.21358
        • Bristow R.G.
        • Alexander B.
        • Baumann M.
        • Bratman S.V.
        • Brown J.M.
        • Camphausen K.
        • et al.
        Combining precision radiotherapy with molecular targeting and immunomodulatory agents: a guideline by the American Society for Radiation Oncology.
        Lancet Oncol. 2018; 19: e240-e251https://doi.org/10.1016/S1470-2045(18)30096-2
        • 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. 1971; 19: 479-483
        • 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. 1974; 26: 259-267
        • 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. 1982; 92: 172-181
        • Berry R.J.
        • Stedeford J.B.
        Reproductive survival of mammalian cells after irradiation at ultra-high dose-rates: further observations and their importance for radiotherapy.
        Br J Radiol. 1972; 45: 171-177https://doi.org/10.1259/0007-1285-45-531-171
        • Berry R.J.
        Effects of radiation dose-rate from protracted, continuous irradiation to ultra-high dose-rates from pulsed accelerators.
        Br Med Bull. 1973; 29: 44-47
        • Hall E.J.
        • Brenner D.J.
        The dose-rate effect revisited: radiobiological considerations of importance in radiotherapy.
        Int J Radiat Oncol Biol Phys. 1991; 21: 1403-1414
        • Favaudon V.
        • Caplier L.
        • Monceau V.
        • Pouzoulet F.
        • Sayarath M.
        • Fouillade C.
        • et al.
        Ultrahigh dose-rate FLASH irradiation increases the differential response between normal and tumor tissue in mice.
        Sci Transl Med. 2014; 6: 245ra93https://doi.org/10.1126/scitranslmed.3008973
        • Montay-Gruel P.
        • Petersson K.
        • Jaccard M.
        • Boivin G.
        • Germond J.F.
        • Petit B.
        • et al.
        Irradiation in a flash: unique sparing of memory in mice after whole brain irradiation with dose rates above 100Gy/s.
        Radiother Oncol. 2017; 124: 365-369https://doi.org/10.1016/j.radonc.2017.05.003
        • Montay-Gruel P.
        • Meziani L.
        • Yakkala C.
        • Vozenin M.C.
        Expanding the therapeutic index of radiation therapy by normal tissue protection.
        Br J Radiol. 2019; (in press)
        • Montay-Gruel P.
        • Bouchet A.
        • Jaccard M.
        • Patin D.
        • Serduc R.
        • Aim W.
        • 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. 2018; 129: 582-588https://doi.org/10.1016/j.radonc.2018.08.016
        • Vozenin M.C.
        • De Fornel P.
        • Petersson K.
        • Favaudon V.
        • Jaccard M.
        • Germond J.F.
        • et al.
        The advantage of FLASH radiotherapy confirmed in mini-pig and cat-cancer patients.
        Clin Cancer Res. 2018; https://doi.org/10.1158/1078-0432.CCR-17-3375
        • Loo Jr., B.W.
        • Schuler E.
        • Lartey F.
        • Rafat M.
        • King G.J.
        • Trovatin S.
        • et al.
        Delivery of ultra-rapid flash radiation therapy and demonstration of normal tissue sparing after abdominal irradiation of mice.
        Int J Radiat Oncol Biol Phys. 2017; 98: E16
        • Jaccard M.
        • Duran M.T.
        • Petersson K.
        • Germond J.F.
        • Liger P.
        • Vozenin M.C.
        • et al.
        High dose-per-pulse electron beam dosimetry: commissioning of the Oriatron eRT6 prototype linear accelerator for preclinical use.
        Med Phys. 2018; 45: 863-874https://doi.org/10.1002/mp.12713
        • Jaccard M.
        • Petersson K.
        • Buchillier T.
        • Germond J.F.
        • Duran M.T.
        • Vozenin M.C.
        • et al.
        High dose-per-pulse electron beam dosimetry: usability and dose-rate independence of EBT3 Gafchromic films.
        Med Phys. 2017; 44: 725-735https://doi.org/10.1002/mp.12066
        • Petersson K.
        • Jaccard M.
        • Germond J.F.
        • Buchillier T.
        • Bochud F.
        • Bourhis J.
        • et al.
        High dose-per-pulse electron beam dosimetry - a model to correct for the ion recombination in the advanced Markus ionization chamber.
        Med Phys. 2017; 44: 1157-1167https://doi.org/10.1002/mp.12111
        • Vozenin M.C.
        • De Fornel P.
        • Petersson K.
        • Favaudon V.
        • Jaccard M.
        • Germond J.F.
        • et al.
        The advantage of Flash radiotherapy confirmed in mini-pig and cat-cancer patients.
        Clin Cancer Res. 2019; 25: 35-42https://doi.org/10.1158/1078-0432.CCR-17-3375
        • Harrington K.J.
        Ultrahigh dose-rate radiotherapy: next steps for FLASH-RT.
        Clin Cancer Res. 2018; https://doi.org/10.1158/1078-0432.CCR-18-1796
        • Epp E.R.
        • Weiss H.
        • Santomasso A.
        The oxygen effect in bacterial cells irradiated with high-intensity pulsed electrons.
        Radiat Res. 1968; 34: 320-325
        • Phillips T.L.
        • Worsnop B.R.
        Ultra-high dose-rate effects in radiosensitive bacteria.
        Int J Radiat Biol Relat Stud Phys Chem Med. 1969; 14: 573-575
        • Nias A.H.
        • Swallow A.J.
        • Keene J.P.
        • Hodgson B.W.
        Effects of pulses of radiation on the survival of mammalian cells.
        Br J Radiol. 1969; 42: 553https://doi.org/10.1259/0007-1285-42-499-553-b
        • Nias A.H.
        • Swallow A.J.
        • Keene J.P.
        • Hodgson B.W.
        Survival of HeLa cells from 10 nanosecond pulses of electrons.
        Int J Radiat Biol Relat Stud Phys Chem Med. 1970; 17: 595-598
        • Schulz R.J.
        • Nath R.
        • Testa J.R.
        The effects of ultra-high dose rates on survival and sublethal repair in Chinese-hamster cells.
        Int J Radiat Biol Relat Stud Phys Chem Med. 1978; 33: 81-88
        • Tillman C.
        • Grafstrom G.
        • Jonsson A.C.
        • Jonsson B.A.
        • Mercer I.
        • Mattsson S.
        • et al.
        Survival of mammalian cells exposed to ultrahigh dose rates from a laser-produced plasma x-ray source.
        Radiology. 1999; 213: 860-865https://doi.org/10.1148/radiology.213.3.r99dc13860
        • Shinohara K.
        • Nakano H.
        • Miyazaki N.
        • Tago M.
        • Kodama R.
        Effects of single-pulse (< or = 1 ps) X-rays from laser-produced plasmas on mammalian cells.
        J Radiat Res. 2004; 45: 509-514
        • Sorensen B.S.
        • Vestergaard A.
        • Overgaard J.
        • Praestegaard L.H.
        Dependence of cell survival on instantaneous dose rate of a linear accelerator.
        Radiother Oncol. 2011; 101: 223-225https://doi.org/10.1016/j.radonc.2011.06.018
        • Auer S.
        • Hable V.
        • Greubel C.
        • Drexler G.A.
        • Schmid T.E.
        • Belka C.
        • et al.
        Survival of tumor cells after proton irradiation with ultra-high dose rates.
        Radiat Oncol. 2011; 6: 139https://doi.org/10.1186/1748-717X-6-139
        • Laschinsky L.
        • Baumann M.
        • Beyreuther E.
        • Enghardt W.
        • Kaluza M.
        • Karsch L.
        • et al.
        Radiobiological effectiveness of laser accelerated electrons in comparison to electron beams from a conventional linear accelerator.
        J Radiat Res. 2012; 53: 395-403
        • Laschinsky L.
        • Karsch L.
        • Lessmann E.
        • Oppelt M.
        • Pawelke J.
        • Richter C.
        • et al.
        Radiobiological influence of megavoltage electron pulses of ultra-high pulse dose rate on normal tissue cells.
        Radiat Environ Biophys. 2016; 55: 381-391https://doi.org/10.1007/s00411-016-0652-7
        • Beyreuther E.
        • Karsch L.
        • Laschinsky L.
        • Lessmann E.
        • Naumburger D.
        • Oppelt M.
        • et al.
        Radiobiological response to ultra-short pulsed megavoltage electron beams of ultra-high pulse dose rate.
        Int J Radiat Biol. 2015; 91: 643-652https://doi.org/10.3109/09553002.2015.1043755
        • Prempree T.
        • Michelsen A.
        • Merz T.
        The repair time of chromosome breaks induced by pulsed x-rays on ultra-high dose-rate.
        Int J Radiat Biol Relat Stud Phys Chem Med. 1969; 15: 571-574
        • Purrott R.J.
        • Reeder E.J.
        Chromosome aberration yields induced in human lymphocytes by 15 MeV electrons given at a conventional dose-rate and in microsecond pulses.
        Int J Radiat Biol Relat Stud Phys Chem Med. 1977; 31: 251-256
        • Schmid T.E.
        • Dollinger G.
        • Hable V.
        • Greubel C.
        • Zlobinskaya O.
        • Michalski D.
        • et al.
        The effectiveness of 20 mev protons at nanosecond pulse lengths in producing chromosome aberrations in human-hamster hybrid cells.
        Radiat Res. 2011; 175: 719-727https://doi.org/10.1667/RR2465.1
        • Michaels H.B.
        Oxygen depletion in irradiated aqueous-solutions containing electron affinic hypoxic cell radiosensitizers.
        Int J Radiat Oncol. 1986; 12: 1055-1058https://doi.org/10.1016/0360-3016(86)90224-5
        • Cruickshank G.S.
        • Rampling R.
        Peri-tumoural hypoxia in human brain: peroperative measurement of the tissue oxygen tension around malignant brain tumours.
        Acta Neurochir Suppl (Wien). 1994; 60: 375-377
        • Collingridge D.R.
        • Piepmeier J.M.
        • Rockwell S.
        • Knisely J.P.
        Polarographic measurements of oxygen tension in human glioma and surrounding peritumoural brain tissue.
        Radiother Oncol. 1999; 53: 127-131
        • Bourhis J.
        • Montay-Gruel P.
        • Gonçalves Jorge P.
        • Bailat C.
        • Petit B.
        • Ollivier J.
        • et al.
        Clinical translation of FLASH radiotherapy: why and how?.
        Radiother Oncol. 2019; ([in press])
        • Spitz D.R.
        • Buettner G.R.
        • Petronek M.S.
        • St-Aubin J.J.
        • Flynn R.T.
        • Waldron T.J.
        • 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. 2019; ([in press])
        • Schuler E.
        • Trovati S.
        • King G.
        • Lartey F.
        • Rafat M.
        • Villegas M.
        • 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. 2017; 97: 195-203https://doi.org/10.1016/j.ijrobp.2016.09.018
        • Lempart M.
        • Blad B.
        • Adrian G.
        • Back S.
        • Knoos T.
        • Ceberg C.
        • et al.
        Modifying a clinical linear accelerator for delivery of ultra-high dose rate irradiation.
        Radiother Oncol. 2019; https://doi.org/10.1016/j.radonc.2019.01.031