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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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
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
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
You need low
concentrations of
O2 to observe
radiolytic
depletion of O2
and evidence of
hypoxia!
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
At 17 Gy FLASH irradiation produces less lung fibrosis than CONV
17 Gy of FLASH irradiation produces similar tumor growth delay as
17.5 Gy of CONV irradiation
Triple negative breast cancer Head & Neck Carcinoma
Radiotherapy and Oncology 124 (2017) 365–369
10 Gy of FLASH irradiation produces less inflammation than
10 Gy of CONV irradiation
Loss of the FLASH effect in brain
of hyper-oxygenated animalsFLASH produces less ROS than
standard dose rate irradiation in water
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.
FLASH induces less microglial activation, i.e. neuroinflammation
Fractionated FLASH iso-efficient on GBM tumor growth delay
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
• 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
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)
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
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
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