FLASH THERAPYAn innovation in radiation therapy

Lucia Giuliano

Sapienza University of Rome- INFN

The Radiation therapy goal is to destroy cancer cells, minimizing the damage to the rest of the body

as well as any side effect. The “FLASH” Therapy, an innovative technique in radiation therapy, has

shown that short pulses of electrons at very high dose rates are less harmful to healthy tissues

but just as efficient as conventional dose rate radiation to inhibit tumor growth.

The therapy has been successfully tested with low energy electrons in small animals. It foresees

millisecond pulses of radiation (beam on time < 100-500ms) delivered at a high dose-rate (>40-100

Gy/s), over 2000 times faster and more than 1000 more intense than conventional

Radiotherapy. We will discuss the genesis of this methodology, the instrumentations used and its

evolution.

Abstract

105° Congresso Nazionale della Società Italiana di Fisica Gran Sasso Science Institute, L'Aquila, 23-27 Settembre 2019

FLASH THERAPY AN INNOVATION IN RADIATION THERAPY

Brief introduction of Radiation therapy

FLASH therapy : a new idea of Radiotherapy

Pre-clinical studies and first patient treatment

Accelerators for FLASH therapy

Conclusions

Contents

RADIATION THERAPY

The goal of Radiation therapy (RT) is :

oTo destroy the cancer cells

oTo avoid ionizing radiation in healthy

tissues

RadiationTherapy

Radiotherapy

Photons

(g-rays,X-rays)

Electrons

Particletherapy

Protons

Ions

Neutrons

Courtesy of A. Faus Golfe et al. IPAC2018, Vancouver, BC, Canada

250MeV electrons

2 MV photons

150MeV protons

250MeV/u C12

15 MeV electrons

ACCELERATORS FOR CANCER THERAPY

oAccelerators for Radiotherapy are:

5-30MeV S band electron LINACS (~ 13000 worldwide*)

Compact, reliable

oAccelerators for proton and ion-beam therapy are:

250 - 400MeV cyclotron or synchrotron based system (~95 worldwide**)

LINACs for particle therapy are coming soon … (public research institutes and private

companies)

*data from Chernyaev, A.P., and S.M.Varzar. “Particle accelerators in modern world.” Physics of Atomic Nuclei 77.10(2014): 1203-1215

** data from website of Particle Therapy Co-Operative Group, facility in operation- June 2019

0

2000

4000

6000

8000

10000

12000

14000

Radiotherapy Particle therapy

Medical accelerators in the world

Big and complex facilities

FLASH THERAPY

FLASH THERAPY is a radiation

therapy with ms pulses of radiation,

beam-on time < 100-500ms and high

dose.

FLASH EFFECT is the improvement of

the healthy tissue tolerance to the

delivered dose.

The FLASH therapy makes possible

to deliver higher dose rate (>40-

100Gy/s).

For a given dose delivered to the

patient, FLASH irradiation time is over

1000 times shorter than conventional

treatments.

Example n=100Hz

40ms

Example n=100MHz

30ms

30ms

Dose rate =0,1 Gy/s

Dose rate =125 Gy/s

Courtesy of Prof. Vincent Favaudon

𝟏𝟎−𝟗

Temporal structure of energy deposition in the flash effect

BRIEF HISTORY OF FLASH THERAPY

1966

• The reduction in normal tissue toxicity was described using mouse models• Hornsey S, Alper T. “Unexpected dose-rate effect in the killing of mice by radiation » .Nature 1966-

1971

• Hendry et al. showed that high dose rate electron beams induced hypoxia• Hendry JH, Moore JV, Hodgson BW, Keene JP. «The constant low oxygen concentration in all the target

cells for mouse tail radionecrosis”. Radiation Research 1982-

2014

• A report of Favaudon and Vozenin (Curie Institut) revealed the differential response to high dose rates between normal and tumor tissue irradiated with RT-FLASH

• V. Favaudon et al., “Ultrahigh dose-rate FLASH irradiation increases the differential response between normal and tumour tissue in mice”, Science Translational Medicine 6, 2014

2019

• Treatment of a first patient with FLASH radiotherapy -• Jean Bourhis et al., «Treatment of a first patient with FLASH-radiotherapy», Radiotherapy and

Oncology. 2019 (article in press)

FLASH THERAPY IN MICE: FIRST EXPERIMENT

g-rays electrons

Facility 𝟏𝟑𝟕Cs

irradiator

LINAC

Nominal energy (MeV) 0,66 4,5

Pulse vs continuous Continuous Pulsed

Pulse repetition

frequency (Hz)

- 150 Hz

Dose (Gy) 17 17

Mean Dose rate (Gy/s) 0,03 60

Temporal width of

pulse

- 1 ms

Healthy Fibrosis Healthy

Control 17Gy CONV 17Gy FLASH

FLASH irradiation protects lungs from

radiation-induced fibrosis and it is as efficient

as CONV irradiation in the repression of

tumor growth

V. Favaudon et al., “Ultrahigh dose-rate FLASH irradiation increases the differential response between normal and tumour tissue in mice”, Science Translational Medicine 6, 2014

FLASH THERAPY IN MICE: FIRST EXPERIMENT

g-rays electrons

Facility 𝟏𝟑𝟕Cs

irradiator

LINAC

Nominal energy (MeV) 0,66 4,5

Pulse vs continuous Continuous Pulsed

Pulse repetition

frequency (Hz)

- 150 Hz

Dose (Gy) 17 17

Mean Dose rate (Gy/s) 0,03 60

Temporal width of

pulse

- 1 ms

Healthy Fibrosis Healthy

Control 17Gy CONV 17Gy FLASH

FLASH irradiation protects lungs from

radiation-induced fibrosis and it is as efficient

as CONV irradiation in the repression of

tumor growth

V. Favaudon et al., “Ultrahigh dose-rate FLASH irradiation increases the differential response between normal and tumour tissue in mice”, Science Translational Medicine 6, 2014

FLASH EFFECTCONFIRMED IN LARGER MAMMALS

CONV FLASH

Facility LINAC LINAC

Nominal energy (MeV) 4,5 - 6 MeV 4,5 - 6 MeV

Pulse vs continuous Pulsed Pulsed

Pulse repetition

frequency (Hz)

10 200

Dose (Gy) 28-31-34 28-31-34

Mean Dose rate (Gy/s) 0,08 300

Temporal width of pulse few ms 1 ms

Vozenin, et al, The advantage of Flash RT confirmed in mini-pig and cat-cancer patients.” Clinical Cancer Research. 2018;

Thirty-six weeks post radiotherapy, macroscopic visualization showed

necrosis lesions in conventional irradiated spotsnormal skin in FLASH-irradiated spots and

TREATMENT OF A FIRST PATIENT WITH FLASH THERAPY

Type of cancer: cutaneous lymphoma on skin surface.

Day 0 5 months FLASH

Facility LINAC eRT6

Nominal energy (MeV) 5,6

Pulse repetition

frequency (Hz)

100

Time of exposure 90 ms

Dose (Gy) 15

Mean Dose rate (Gy/s) 166

Temporal width of pulse 1 ms (10pulses)

Jean Bourhis et al., «Treatment of a first patient with FLASH-radiotherapy», Radiotherapy and Oncology. 2019

It was shown no decrease of the thickness of the

epidermis and no disruption at the basal

membrane with limited increase of the

vascularization.

MEDICAL LINAC SCHEME

Jaccard M et al., «High dose-per-pulse electron beam dosimetry: Commissioning of the Oriatron eRT6 prototype linear accelerator for preclinical

use.» Medical Physics,2018

Signals used to monitor the output: the beam current (BC), the collimator current (CC), the reflected high-

frequency (RHF) power, and the electron gun current (EGC).

DEVICES USING FLASH CONCEPT

Devices Dose rate Surface Use

FLASH 𝐞−

Kinetron-Curie 4.5 MeV 0.1 to 300 Gy/s 10X10 cmPre-clinical studies

Clinical studies for superficial

tumors

Oriatron-CHUV 5.5 MeVInstantaneous up to

10e7Gy/s

Mean dose rate 0.1 to 1000

Gy/s

10x10 cm Pre-clinical studies

Clinical studies for superficial

tumors

Modified linac-Stanford 20

MeV

0.1 to 250 Gy/s 10x10 cm Pre-clinical studies

Modified linac-Lund 20 MeV 0.1 to 250 Gy/s 10x10 cm Pre-clinical studies

FLASH 𝐩+

Modified proton

cyclotron (IBA) 230

MeV- Curie

2 Gy /min

40 Gy /s

20 x20mm

12X12 cm

Used in clinical practice

In development for pre-

clinical studies

Proton-Therapy Centers

with PBS

Instantaneous >200 Gy/s

Mean dose rate 2-4 Gy/min

Few mm

20X20 cm

N.A.

Used in clinical practice

Courtesy of Dr Pierre Montay-Gruel

RESEARCH PERSPECTIVES

Understanding the FLASH RT

limits (min/max dose/time)

Clarifying bio mechanisms underlying

FLASH effect

Definingconditions for

clinical practice

Accelerator dedicated for clinical

use

SCHEME OF LINAC UNDER STUDY

LINAC: RF cavity

S band 6-7 MeV

Waveguide

Magnetron

3GHz

3 MW peak power

RF Circulator

Electron GUN

thermionic

50kV

Modulator

Sordina IORT Technologies S.p.A.

TARGET PERFORMANCEfor an accelerator for pre-clinical studies

• Variable energy: 5-7 MeV (for other pre-clinical

investigations)

• Samples surface variable: 10x10 cm – 4x4cm (high

homogeneity for in-vitro screening)

• Target dose per pulse: 5 Gy

• Pulse width: few ms

• Mean Dose rate: 1000 Gy/s

• 𝟏𝟎𝟔 < Dose-rate in pulse:< 𝟏𝟎𝟕 Gy/s

• Pulse repetition frequency: n= 300Hz

FLASH conditions

Sordina IORT Technologies S.p.A.

CHALLANGESfor an accelerator for pre-clinical studies

• Reliability and reproducibility for pre-clinical study

• Beam dynamics for high charge beam

• Novel dosimetry for high dose rate (Comparison against

conventional mode)

Sordina IORT Technologies S.p.A.

CONCLUSIONS

• Releases high Gy level dose in microsecond pulses.

• The healthy tissues can support high dose rate without harmful

effects of ionizing radiation.

• Several studies on animals and clinical treatment on one patient

performed

• A few LINAC accelerators have been used for pre-clinical studies

about FLASH therapy.

• An additional novel accelerator is under study (SIT-Sapienza

University cooperation) to be used in pre-clinical studies , tunable

and with advanced performances.

THANK YOU FOR YOUR ATTENTION