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Translational Cancer Mechanisms and Therapy

Hypofractionated FLASH-RT as an Effective Treatment against Glioblastoma that Reduces Neurocognitive Side Effects in Mice

Pierre Montay-Gruel, Munjal M. Acharya, Patrik Gonçalves Jorge, Benoît Petit, Ioannis G. Petridis, Philippe Fuchs, Ron Leavitt, Kristoffer Petersson, Maude Gondré, Jonathan Ollivier, Raphael Moeckli, François Bochud, Claude Bailat, Jean Bourhis, Jean-François Germond, Charles L. Limoli and Marie-Catherine Vozenin
Pierre Montay-Gruel
1Laboratory of Radiation Oncology/DO/Radio-Oncology/CHUV, Lausanne University Hospital and University of Lausanne, Switzerland.
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  • ORCID record for Pierre Montay-Gruel
Munjal M. Acharya
2Department of Radiation Oncology, University of California, Irvine, California.
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  • ORCID record for Munjal M. Acharya
Patrik Gonçalves Jorge
1Laboratory of Radiation Oncology/DO/Radio-Oncology/CHUV, Lausanne University Hospital and University of Lausanne, Switzerland.
3Institute of Radiation Physics/CHUV, Lausanne University Hospital, Switzerland.
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Benoît Petit
1Laboratory of Radiation Oncology/DO/Radio-Oncology/CHUV, Lausanne University Hospital and University of Lausanne, Switzerland.
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Ioannis G. Petridis
1Laboratory of Radiation Oncology/DO/Radio-Oncology/CHUV, Lausanne University Hospital and University of Lausanne, Switzerland.
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Philippe Fuchs
1Laboratory of Radiation Oncology/DO/Radio-Oncology/CHUV, Lausanne University Hospital and University of Lausanne, Switzerland.
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Ron Leavitt
1Laboratory of Radiation Oncology/DO/Radio-Oncology/CHUV, Lausanne University Hospital and University of Lausanne, Switzerland.
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Kristoffer Petersson
1Laboratory of Radiation Oncology/DO/Radio-Oncology/CHUV, Lausanne University Hospital and University of Lausanne, Switzerland.
3Institute of Radiation Physics/CHUV, Lausanne University Hospital, Switzerland.
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Maude Gondré
1Laboratory of Radiation Oncology/DO/Radio-Oncology/CHUV, Lausanne University Hospital and University of Lausanne, Switzerland.
3Institute of Radiation Physics/CHUV, Lausanne University Hospital, Switzerland.
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Jonathan Ollivier
1Laboratory of Radiation Oncology/DO/Radio-Oncology/CHUV, Lausanne University Hospital and University of Lausanne, Switzerland.
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Raphael Moeckli
3Institute of Radiation Physics/CHUV, Lausanne University Hospital, Switzerland.
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François Bochud
3Institute of Radiation Physics/CHUV, Lausanne University Hospital, Switzerland.
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Claude Bailat
3Institute of Radiation Physics/CHUV, Lausanne University Hospital, Switzerland.
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Jean Bourhis
1Laboratory of Radiation Oncology/DO/Radio-Oncology/CHUV, Lausanne University Hospital and University of Lausanne, Switzerland.
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Jean-François Germond
3Institute of Radiation Physics/CHUV, Lausanne University Hospital, Switzerland.
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Charles L. Limoli
2Department of Radiation Oncology, University of California, Irvine, California.
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Marie-Catherine Vozenin
1Laboratory of Radiation Oncology/DO/Radio-Oncology/CHUV, Lausanne University Hospital and University of Lausanne, Switzerland.
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  • For correspondence: marie-catherine.vozenin@chuv.ch
DOI: 10.1158/1078-0432.CCR-20-0894 Published February 2021
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    Figure 1.

    Summary of the temporal dosimetry characteristics of the published experimental data describing the FLASH effect in vivo (11–14, 24, 27, 28, 34–37) or in vitro (38–42) (colored dots), those that have not been able to observe the FLASH effect (43, 44) (black, gray crosses) and the dose rate deescalation studies showing the range in which the FLASH effect is lost (colored crosses). The horizontal axis denotes the dose rate per pulse for electrons (e) and protons (p) or in a single stripe (as described in ref. 27) for synchrotron radiation (Rx). The vertical axis corresponds to the total irradiation time needed for delivering 10 Gy at the average dose rate quoted by the authors of the publications. Parameters for other dose values have been changed accordingly. Adapted from Bourhis and colleagues, 2019 (15).

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    Figure 2.

    Tumor growth delay of H454 orthotopic glioblastoma implanted in the striatum of female Nude mice measured by bioluminescence (A–C) treated with 0, 10 Gy (BED = 20 Gy), 14 Gy (BED = 33.6 Gy) single dose or 2 × 7 Gy (BED = 23.8 Gy) daily fractionated WBI delivered with FLASH or CONV-RT. Mean change in relative bioluminescence ± SEM, N = 10–12 animals per group. P values were derived from the Mann–Whitney U test: **, P < 0.01; ***, P < 0.001 compared FLASH versus CONV group; ns, not significant. α/β ratio of 10 for BED calculation on the tumor. Survival curves of glioblastoma-bearing mice treated with 0, 10, or 14 Gy single dose or 2 × 7 Gy daily fractionated WBI with FLASH or CONV-RT (D–F). N = 10–12 animals per group. P values were derived from the log-rank test; compared FLASH versus CONV group. ns, not significant. Memory skills of glioblastoma-bearing mice treated with 0, 10 Gy (BED = 43.3 Gy), 14 Gy (BED = 79.3 Gy) single dose or 2 × 7 Gy (BED = 46.7 Gy) daily fractionated WBI delivered with FLASH or CONV-RT, evaluated by NOR test 4 weeks postimplantation (G–I). Mean DI ± SEM, N = 10–14 animals per group. P values were derived from the Mann–Whitney U test: *, P < 0.05; **, P < 0.01 compared Control and FLASH versus CONV group. ns, not significant. α/β ratio of 3 for BED calculation on the normal brain tissue.

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    Figure 3.

    Tumor growth delay of H454 orthotopic glioblastoma implanted in the striatum of female Nude mice treated with 0, 4 × 3.5 Gy (BED = 18.9 Gy) daily fractionated WBI; or 3 × 10 Gy (BED = 60 Gy) spaced by 48 hours WBI delivered with FLASH or CONV-RT (A and B). Mean change in relative bioluminescence ± SEM, N = 9–13 animals per group. P values were derived from the Mann–Whitney U test: **, P < 0.01; ***, P < 0.001; ****, P < 0.0001 compared FLASH versus CONV group; ns, not significant. α/β ratio of 10 for BED calculation on the tumor. Survival curves of glioblastoma-bearing mice treated with 0, 4 × 3.5 daily fractionated WBI; or 3 × 10 Gy spaced by 48 hours WBI delivered with FLASH or CONV-RT (C and D). N = 9–13 animals per group. P values were derived from the log-rank test. ***, P < 0.001; ****, P < 0.0001 versus control group; ns: not significant. Memory skills of glioblastoma-bearing mice treated with 0 Gy, 4 × 3.5 Gy (BED = 30.3 Gy) daily fractionated WBI; or 3 × 10 Gy (BED = 130 Gy) spaced by 48 hours WBI delivered with FLASH-RT or CONV-RT, evaluated by NOR test 4 weeks postimplantation (E and F). Mean DI ± SEM, N = 8–12 animals per group. P values were derived from the Mann–Whitney U test: *, P < 0.05; **, P < 0.01 compared with the CONV group. ns, not significant. α/β ratio of 3 for BED calculation on the normal brain tissue.

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    Figure 4.

    Tumor growth delay of H454 orthotopic glioblastoma implanted in the striatum of female Nude mice measured by bioluminescence (A) treated with 25 Gy (BED = 233 Gy) single-dose HBI delivered with FLASH-RT or CONV-RT. Mean change in relative bioluminescence ± SEM, N = 9–10 animals per group. P values were derived from the Mann–Whitney U test: ****, P < 0.0001; ns, not significant. α/β ratio of 10 for BED calculation on the tumor. Survival curves of H454 glioblastoma-bearing mice (B) treated with 25 Gy single-dose HBI delivered with FLASH or CONV-RT. N = 10 animals per group. P values were derived from log-rank test: ***, P < 0.01; ****, P < 0.0001 compared with the control group. ns, not significant. Memory skills of glioblastoma-bearing mice treated with 25 Gy (BED = 87.5 Gy) single-dose HBI delivered with FLASH or CONV-RT, evaluated by NOR test 4 weeks postimplantation (C). Mean ± SEM, N = 9–10 animals per group. P values were derived from the Mann–Whitney U test: ns, not significant. α/β ratio of 3 for BED calculation on the normal brain tissue.

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    Figure 5.

    Relative tumor growth delay of H454 orthotopic glioblastoma as a function of the BED delivered to the tumor with FLASH or CONV-RT, 3 weeks postirradiation (A). BED on the tumor was calculated with the following formula: Embedded Image, where Embedded Image is the number of fractions, Embedded Image is the dose per fraction, and the α/β ratio is set to 10 (B).

Tables

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  • Table 1.

    Irradiation parameters.

    BED BrainBED TumorBeam parameters
    Delivery modePrescribed dose (Gy)α/β = 3 (Gy)α/β = 10 (Gy)Graphite applicator type and size (mm)Source-to-surface distance (mm)Pulse repetition frequency (Hz)Pulse width (μs)Number of pulsesTreatment time (s)Mean dose rate (Gy/s)Instantaneous dose rate (Gy/s)
    CONV1043.320.0Circular ∅17800101.01,170–1,180116.9–117.90.18.5 × 103
    1479.333.6Circular ∅17803101.01,467146.60.19.5 × 103
    4 × 3.530.318.9Circular ∅17800101.041040.90.18.5 × 103
    2 × 746.723.8Circular ∅17800101.082282.10.18.5 × 103
    3 × 1013060.0Circular ∅17795101.01,170–1,174116.9–117.30.18.5 × 103
    25233.387.5Semicircular ∅17745101.02,620261.90.19.5 × 103
    FLASH1043.320.0Circular ∅17369–3701001.811.8 × 10–65.6 × 1065.6 × 106
    1479.333.6Circular ∅17314–3151001.811.8 × 10–67.8 × 1067.8 × 106
    4 × 3.530.318.9Circular ∅175771001.811.8 × 10–61.9 × 1061.9 × 106
    2 × 746.723.8Circular ∅17416–4181001.811.8 × 10–63.9 × 1063.9 × 106
    3 × 1013060.0Circular ∅17369–3701001.811.8 × 10–65.6 × 1065.6 × 106
    25233.387.5Semicircular ∅173251001.821.0 × 10–22.5 × 1036.9 × 106

Additional Files

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  • Supplementary Data

    • Supplementary Data - legend
    • Supplementary Data - Supplementary Figure 1: Tumor growth delay of U87 orthotopic GBM implanted in the striatum of female Nude mice measured by contrast-enhanced Cone Beam CT
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Clinical Cancer Research: 27 (3)
February 2021
Volume 27, Issue 3
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Hypofractionated FLASH-RT as an Effective Treatment against Glioblastoma that Reduces Neurocognitive Side Effects in Mice
Pierre Montay-Gruel, Munjal M. Acharya, Patrik Gonçalves Jorge, Benoît Petit, Ioannis G. Petridis, Philippe Fuchs, Ron Leavitt, Kristoffer Petersson, Maude Gondré, Jonathan Ollivier, Raphael Moeckli, François Bochud, Claude Bailat, Jean Bourhis, Jean-François Germond, Charles L. Limoli and Marie-Catherine Vozenin
Clin Cancer Res February 1 2021 (27) (3) 775-784; DOI: 10.1158/1078-0432.CCR-20-0894

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Hypofractionated FLASH-RT as an Effective Treatment against Glioblastoma that Reduces Neurocognitive Side Effects in Mice
Pierre Montay-Gruel, Munjal M. Acharya, Patrik Gonçalves Jorge, Benoît Petit, Ioannis G. Petridis, Philippe Fuchs, Ron Leavitt, Kristoffer Petersson, Maude Gondré, Jonathan Ollivier, Raphael Moeckli, François Bochud, Claude Bailat, Jean Bourhis, Jean-François Germond, Charles L. Limoli and Marie-Catherine Vozenin
Clin Cancer Res February 1 2021 (27) (3) 775-784; DOI: 10.1158/1078-0432.CCR-20-0894
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