Download - Radiation Biology - AAPM
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Overview of Ultra-High Dose Rate In Vitro and FLASH-RT In Vivo
Radiation Biology
Peter Maxim, Stanford & Indiana University
Billy Loo, Stanford University
Charlie Limoli, University of California, Irvine
Marie-Catherine Vozenin, CHUV, Lausanne Univ.
Douglas Spitz, University of Iowa
Karl Bush, Stanford University
Pierre Montay-Gruel, University of California, Irvine
Eric Diffenderfer, University of Pennsylvania
Jan Schuemann, MGH, Harvard University
Marc S. Mendonca, Ph.D.
Indiana University School of Medicine
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Radiation-induced cell killing has large dose rate effects in resistant cells
HDR ~ 1 to 7 Gy/minute LDR ~ 10 to 0.01 cGy/minute
Hall and Giaccia, 2019
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Ultra-High Dose Rate - The Early Years
In the 1950’s and 1960’s ultra-high dose rates experiments were
being performed to try to answer fundamental questions in
radiation-biology including:
• The nature of lethal versus nonlethal DNA damage
• Direct versus indirect free radical diffusion induced DNA
damage
• The role of oxygen
• DNA damage induction and repair/recovery post-irradiation
Accelerators could deliver dose in
single nanosecond electron pulses
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You need low
concentrations of
O2 to observe
radiolytic
depletion of O2
and evidence of
hypoxia!
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Lung Fibrosis Studies in Mice
15 or 17 Gy 137Cs g-rays or 4.5 MeV electrons
CONV dose rate = 0.03 Gy/s
FLASH dose rate = 40 Gy/s
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At 17 Gy FLASH irradiation produces less lung fibrosis than CONV
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17 Gy of FLASH irradiation produces similar tumor growth delay as
17.5 Gy of CONV irradiation
Triple negative breast cancer Head & Neck Carcinoma
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Radiotherapy and Oncology 124 (2017) 365–369
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10 Gy of FLASH irradiation produces less inflammation than
10 Gy of CONV irradiation
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Loss of the FLASH effect in brain
of hyper-oxygenated animalsFLASH produces less ROS than
standard dose rate irradiation in water
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Reduced inflammation after FLASH
maintained 6 months post-RT
versus conventional dose rate.
FLASH protects neural complexity 6 months
post-RT versus conventional dose rate.
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FLASH induces less microglial activation, i.e. neuroinflammation
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Fractionated FLASH iso-efficient on GBM tumor growth delay
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Vozenin et al Clin Cancer Res 2018
FLASH-RT normal tissue
sparing in pig skin Veterinary FLASH Study with Cats
(SCC of the nasal planum ; n = 6 )
▪ Minimal mucosal / skin toxicity : 3/6
cats without significant side effects ;
3 with mild / moderate side effects
▪ Preservation of alimentation and
sense of smell in all cats
▪ Tumor control : 84% at 18 months
(high compared to the literature)
Before RT7 Months
Post-FLASH
14 Months
Post-FLASH
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• A 75-year-old patient had a CD30+ T-
cell cutaneous lymphoma diagnosed in
1999 classified T3 N0 M0 B0.
• Localized skin RT has been previously
used over 110 times for various
ulcerative and/or painful cutaneous
lesions progressing despite systemic
treatments.
• A tumor of 3.5 cm (Fig. 1a) was
treated with a FLASH dose of 15 Gy
in 90 ms using the prototype Oriatron
eRT6 5.6-MeV electron linac located
at Lausanne University Hospital
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Proton FLASH- Gut Studies 8- to 10-week-old C57BL/6J mice
Whole abdomen
proton irradiation
Crypt Cell Assay
Upper abdomen
proton irradiation
Pancreatic Cancer
FLASH Dose Rate: 78 ± 9 Gy/s
Standard Dose Rate: 0.9 ± 0.08 Gy/s
Diffenderfer, E.S. et al. IJROBP 106: 440-448 (2020)
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Proton FLASH- Gut Studies- 15 Gy
Flash
protons
spare
intestinal
crypt cells !
FLASH
78 ± 9 Gy/s
Standard
0.9 ± Gy/s
Diffenderfer, E.S. et al. IJROBP 106: 440-448 (2020)
FLASH protons induce less
intestinal muscle thickening
(an indicator of fibrosis)
post-irradiation
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FLASH irradiation of subcutaneous pancreatic
cancer tumors was as effective in inducing tumor
growth delay as standard dose rate delivery.
Diffenderfer, E.S. et al. IJROBP 106: 440-448 (2020)
Proton FLASH- Pancreatic Cancer Studies KPC autochthonous PanCa model
injected subcutaneously in 8- to 10-week-old C57BL/6J C57BL/6J mice
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FLASH irradiation with electrons, X-rays, and protons
spares normal tissue but is equitoxic to tumors and
therefore enhances differential responses between normal
and tumor tissues.
FLASH has the potential to minimize radiation-induced
normal tissue effects in lung, brain, gut, and skin without
any apparent decrease of the antitumor effectiveness and
therefore should improve the therapeutic ratio.
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