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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Page 1: Radiation Biology - AAPM

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

Page 2: Radiation Biology - AAPM

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

Page 3: Radiation Biology - AAPM

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

Page 4: Radiation Biology - AAPM

You need low

concentrations of

O2 to observe

radiolytic

depletion of O2

and evidence of

hypoxia!

Page 5: Radiation Biology - AAPM
Page 6: Radiation Biology - AAPM

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

Page 7: Radiation Biology - AAPM

At 17 Gy FLASH irradiation produces less lung fibrosis than CONV

Page 8: Radiation Biology - AAPM

17 Gy of FLASH irradiation produces similar tumor growth delay as

17.5 Gy of CONV irradiation

Triple negative breast cancer Head & Neck Carcinoma

Page 9: Radiation Biology - AAPM

Radiotherapy and Oncology 124 (2017) 365–369

Page 10: Radiation Biology - AAPM
Page 11: Radiation Biology - AAPM

10 Gy of FLASH irradiation produces less inflammation than

10 Gy of CONV irradiation

Page 12: Radiation Biology - AAPM

Loss of the FLASH effect in brain

of hyper-oxygenated animalsFLASH produces less ROS than

standard dose rate irradiation in water

Page 13: Radiation Biology - AAPM

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.

Page 14: Radiation Biology - AAPM

FLASH induces less microglial activation, i.e. neuroinflammation

Page 15: Radiation Biology - AAPM

Fractionated FLASH iso-efficient on GBM tumor growth delay

Page 16: Radiation Biology - AAPM

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

Page 17: Radiation Biology - AAPM

• 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

Page 18: Radiation Biology - AAPM

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)

Page 19: Radiation Biology - AAPM

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

Page 20: Radiation Biology - AAPM

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

Page 21: Radiation Biology - AAPM

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.

Page 22: Radiation Biology - AAPM