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

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

therefore should improve the therapeutic ratio.