FLASH RADIATION THERAPYWHAT IS THE FLASH EFFECT ?HOW TO CONSIDER A CLINICAL APPLICATION ? WHICH PERSPECTIVES WITH VHEE ?

Dr Pierre Montay-GruelRadiation- Oncology

CLIC WorkshopCERN, 24th November 2018

What is FLASH-RT

Conventional RT in clinics

FLASH-RT

Mean Dose Rate 0,1 Gy / sec >50 Gy / sec

Time to deliver 10Gy 100 sec 1.8 x 10-6 s

Dose Ratex 106

FLASH-RT technological basis

Electron beam~ 5 MeV energyPulsed beam

Time

Dose-rate

p pD D w

pD

1/ fw

Experimental LINAC eRT6PMB Alcen, France

Complete and precisedosimetry

C Bailat’s team at IRA

Petersson et al. 2017Jaccard et al. 2017

Montay-Gruel et al. 2017Jaccard et al. 2018

Maud Jaccard L’énergie sombre: énigme de la cosmologie moderne

FilmsThermoluminescent

Dosimeters

Ionization chamber

AlanineMethyl Viologen

All calibrated on clinical electron irradiatoror

Co-60 source

Evaluate the reliability of each dosimetry technique and theirconsistency to one another = HAVE A PRECISE DOSIMETRY

Dosimetry for ultra high dose-rate electron beamDose-rate Independent

Dose-rate dependent Use of a sorrection factor

Historical(Favaudon et al.)

Used in clinics Experimental

On-line

Petersson et al. 2017Jaccard et al. 2017

Montay-Gruel et al. 2017Jaccard et al. 2018

FLASH

Absence of radiation-induced toxicity in the Normal lung

Anti-tumor efficacy

FLASH EFFECT

HEALTHY HEALTHYFIBROSIS

Contrôlenon irradié

17 Gy CONV

17 Gy FLASH

RT Toxicityevaluation

Does FLASH irradiation spare normal brain tissuesfrom radiation-induced toxicities

8.5

9.0

9.5

10.0

10.5

11.0

11.5

Do

se

(G

y)

Lateral left

Sagittal Lateralright

Conventional dose-rate

Flash dose-rate

Delivery of a precise and homogenous dose to the brain

Precise dose delivery + good homogeneity all over the brain

Montay-Gruel et al. 2017

TLDs implanted in the brain of a mouse cadaver

Do irradiated mice develop cognitive alterations ?

4 weeks post-RT

Memory testNovel Object Recognition test

1.Habituation to the

environment

2.Learn to know an object

3.Check the knowledge

Natural animal curiostiy: Spend more time on the unknown object

Day 1 Day 2 Day 2 + 3h

UNLESS: the cognitive functions are altered

10Gy Flash-WBI preserves the spatial memory function above 100Gy/s

GOAL: Define the dose-rate limits of the functional preservation triggered by FLASH-RT

Montay-Gruel et al (2017)

Dose rate within the pulse> 105 Gy/s

Dose rate within the pulse< 105 Gy/s

Is FLASH-RT efficient to treat brain tumors

Control10Gy FLASH

10Gy CONV

FLASH and CONV-RT trigger the same antitumor effect !Montay-Gruel et al (in revision)

Controls(0 Gy)

FLASH-RT CONV

Tumor growth measurement bybioluminescence

Does FLASH-RT trigger an antitumor effect on glioblastoma ?

What are the underlying mechanisms to explainthe FLASH effect

Chronology of post-irradiation events and FLASH irradiation

10-15

10-12

10-6

1

3600

PHYSICAL Step Ionizations and excitations

PHYSICOCHEMICAL StepMolecular dissociations

Homogenous CHEMICAL StepReactions and diffusions

Heterogeneous CHEMICAL StepReactions and diffusions

BIOCHEMICAL StepDNA Repair Enzymatic

BIOLOGICAL StepCellular and tissue response

Time (s) FLASH

CONV

How to explain those striking differences ?

HYP: Back to radiobiology basics: early radio-induced events can explain those differences

Something different might happen duringthe chemical steps

O2 consumption and ROS production ???

Prev. described(Ling et al. Edward et al. Dewey et al.)

bacterian, mammalian cells, and in-vivo

1 – Make mice breathe 95% of oxygen (before and during IR)

2 – Increase oxygen tension in the brain

3 – Deliver FLASH or conventional dose-rate irradiation

4 – Evaluate memory

Montay-Gruel et al (in revision)

CONVCONV

OXYGENFLASH

FLASHOXYGEN

Memory Loss

Memory Loss

Memory Loss

MemoryOK

Increase in O2 tension reverses the FLASH effect

Less ROS produced by FLASH-RT ?

Playing with the oxygen tension = modify ROS production

CONV

FLASH

- +

Amifostine (4mM)

ROS Scavenging

RT of fish eggs Development assessment

Antioxydant partially reverses the CONV effect No effect of antioxydant on the FLASH-RT (still less armful)

Toxicity is not mediated by ROS production with FLASH-RTMontay-Gruel et al (in revision)

O2O2 O2

O2

O2

O2O2

O2

O2O2

O2

O2

O2

O2O2 O2

O2

O2

O2O2

O2

O2O2

O2

O2

O2ROS

ROS

ROS

ROS ROS

ROS

ROS

ROS

CONV-RT FLASH-RT

Brain Toxicity Less Toxicity

Transient « protective » hypoxia

HYP: FLASH-RT induces a transient radiation-induced hypoxia that protects only the normoxic tissues

Montay-Gruel et al (in revision)

And then ?

Mouse BrainFew toxicity

Treats the tumor

Mouse lungFew toxicity

Treats the tumor

MECANISMESBIOLOGIQUES

Fish eggsFew toxicity

VET CLINICAL TRIALCat patients with SCC

Few toxicityTreats the tumor

Mini pipgFew toxicity

Favaudon et al. 2014

Montay-Gruel et al. 2017Montay-Gruel et al. Sub (1)Montay-Gruel et al. Sub (2)

Montay-Gruel et al. Sub (2)

Vozenin et al. 2018

Vozenin et al. 2018

Keep investigating the mechanisms in translational research

Induce less normal tissue toxicitiesIncrease the curative doses

Be more efficient to cure the tumorsTreat quickly

Increase the patient’s QOL

Clinical translation- As soon as 2018

- 2020 for IORT

How to extend the application of FLASH-RT

in the clinical practice?

Development of a monitor chamberMandatory for a clinical application

Real-time monitoring system of FLASH irradiation accelerators:

pilot, check and verify delivered doses.

FTI program in coll. with PMB-Alcen and Aix-Marseilles University

Dosimetry is a key stone !

Courtesy of M.C. Vozenin

Which equipment?

Intra-Operative Radiation Therapy

Better in-depth access

Benefit from a rapid treatment

Under development

Courtesy of M.C. Vozenin

What are the devices able to operate at Ultra-high dose rate?

Dose rate Volume Use

FLASH dedicated devices:

Kinetron- Curie 4.4 MeV

Oriatron-CHUV 5.5 MeV

Modified linac-Stanford 20 MeV

Modified linac-Lund 20 MeV

0.1 to 300 Gy/s

Instantaneous up to 10e7Gy/s(dose rate within pulse)

Mean dose rate 0.1 to 1000 Gy/s

0.1 to 250 Gy/s0.1 to 250 Gy/s

10X10 cm

10X10 cm

10X10 cm10X10 cm

Pre-clinical studiesClinical studies for superficial

tumorsPre-clinical studies

Clinical studies for superficial tumors

Pre-clinical studiesPreclinical 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

Synchrotron light ESRF

Brookhaven national LabAustralian synchroton

Instantaneous up to 18 000 Gy/s(dose rate within slice)

Mean dose rate 40 Gy/s

mm10X10 cm

Pre-clinical studiesClinical trial

Via a technology called Microbeam/MRT

VHEE facilities250 MeV 1 Gy delivered in 10e15 s mm In development

Courtesy of M.C. Vozenin

Answer the question:

Is CLEAR VHEE (> 200Mev) technology suitable to trigger a FLASH effect?

What is the strategy currently developed in collaboration with CLEAR

Use passive physical dosimeters to record the dose Gafchromic films TLDs Alanine pellets

Use fish eggs as biological dosimeters

Radio-Onco LabDr MC Vozenin G BoivinB PetitJ OllivierDr J Romero

Service de Radio-Oncologie

Team IRADr F BochudDr R MoeckliDr C BailatDr JF Germond Dr PeterssonP Jorge-Goncalves Dr M JaccardM GondreDr D PatinDr N CherbuinDr L DesorgherDr P FroideveauDr T Buchillier

Radiation OncologyPr. J BourhisPr M OszahinEt l’ensemble du service de radio-oncologie

EPFL TeamPr D HanahanDr J Scotton

Dr V Favaudon

UC Irvine TeamPr C LimoliDr M Acharya

Animal Facility of Epalinges

A De VallièreC GodfroidP FuchsS LiuDr C Yakkala

Time spent on the unknown ubjectTime spent on the familiar object

=Memory evaluation parameter

Discrimination index

0

20

40

60

80

Dis

crim

ination Index

Tumor bearing animalsNovel Object Recognition

Control

(n=6)

10 Gy

CONV

(n=6)

10 Gy

FLASH

(n=6)

**

**No toxic effect

of FLASH-RTon the memory

Do irradiated mice develop cognitive alterations ?

Montay-Gruel et al (in revision)

BUT: Why is FLASH-RT efficient to treat tumors ?

Because most of them are hypoxic per se

Direct effects +++ = TUMOR CONTROLFew ROS production because of hypoxia

Same dose = Same direct effectsFew ROS production because of hypoxia and oxygen depletion

CONV FLASH

SAME EFFECT ON THE TUMORS

Production of ROS by water-radiolysis with FLASH-RT

4% O2 water

Less production of H2O2 with FLASH-RT

Water radiolysis Non-biological model

Montay-Gruel et al (in revision)

0 4 8 12 16 20 24 28 32 36 40 44 48 52 560

200

400

600

800

1000

1200

1400

1600

1800

Days post-irradiation

Rela

tive tum

or

volu

me

Control (n=12)

CONV (n=12)

CONV clamp (n=5)

CONV O2 (n=12)

Control clamp (n=6)

Control O2 (n=5) ***

***

SANS OXYGENE = PAS DE DIFFERENCERadicaux libres non impliqués dans

l’effet antitumoral ?

Faire varier la quantité d’oxygène = faire varier la production de radicaux libres

Montay-Gruel et al (in prep)

Irradiation air ambiant

Irradiation avec oxygène(respiration oxygène)

Irradiation sans oxygène(empêcher irrigation sanguine)

OXYGENE

SANSOXYGENE

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 600

200

400

600

800

1000

1200

1400

1600

1800

Days post-irradiation

Rela

tive tum

or

volu

me

Control (n=12)

FLASH (n=12)

FLASH clamp (n=6)

FLASH + O2 (n=12)

Control clamp (n=6)

Control O2 (n=5)

ns

***

ns

OXYGENE

SANS OXYGENE

OXYGENE = Plus de radicaux libres = plus efficace

SANS OXYGENE = moins de radicaux libres = moins efficace

Montay-Gruel et al (in revision)