treating cancer with radiation : a new approach with flash
TRANSCRIPT
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Treating cancer with radiation :
a new approach with FLASH Therapy
J Bourhis, JF Germond, C Bailat, P Montay-Gruel, P Jorge, R Kinj, D Clerc, M Ozsahin, K
Lambercy, O Gaide, W Jeanneret, T Boehlen, R Moeckli, F Bochud, MC Vozenin,
@ Lausanne University Hospital (CHUV) Switzerland
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Cure
65%
Failure
35%
Local
1/3
Cancer
2.7 M cases / year
in UE
Metastases
2/3
Cancer cure in 2021?
Unmetclinicalneed
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How do we fight cancer ?
1950< 1900
Surgery
Radiotherapy
Chemotherapy / homonotherapy
Molecular targeted
2000
Immunotherapy
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What is FLASH therapy ?
= a new way of deliveringradiotherapy
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= A reduction of radiation toxicity to normal healthy tissues,
while maintaining a similar effect on tumors
when comparing
ultra-high
to
conventional dose rates
« FLASH » is a biological observation
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1960 1970 1980 1990 2000 2010 2020
1st DescriptionTown et al
FLASH sparing of normal tissuesRecognized in the 1970’s …
20141st tumorsProf Vozenin
20181st patient
Bourhis et al
20201st
clinicaltrials
Historical perspective
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Dose for
inducing tail
necrosis
in mice
Flash dose rates
Jolyon H. Hendry
1982
FLASH sparing
effect on normal tissues
wasrecognized
Until 1982 :
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2014 Re-discovery …
1) Sparing normal tissues
2) No sparing of tumors
Favaudon & Vozenin
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What is the magnitude
of the sparing effect on
normal tissues ?
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FLASH is consistently associated with a relative sparing of normal tissues(compared to normal radiotherapy):
1) in several types of tissues (brain, skin, lung, GI …)
2) in several animal species (cat, mouse, pig, Z-fish)
3) with several types of beam and energy (electrons, X-rays, protons)
4) accross a few Institutions (Europe, USA)
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* Experimental Platform for Ultra-high Dose Rate FLASH Irradiation of Small Animals Using a Clinical Linear Accelerator, IJRO. Juin 2016. Bill Loo, (Stanford University
... Pre-clinical data indicate a markedreduction of normal tissues side effectswhile maintaining the destruction oftumor cells.
This could revolutionize the field ofradiation oncology …*
Pr. Billy LOO MD PhD, Thoracic radiation oncology program
Stanford Cancer Institute
Results of the CHUV were first confirmed@ Stanford University
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Conventional FLASH
Vozenin et alClin Cancer Res2018
Example N°1 : FLASH effect on the skin (Pig)
31 Gy
34 Gy
28 Gy
31 Gy
34 Gy
28 Gy
(skin of a pig, @ 9 months post-RT)
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100 Gy/s
Normal
tissue
effect20 Gy/s
Same dose
Conventional RT
Example N°2 in normal brain (mice)
Control
Montay-Gruel Radiother Oncol 2017
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FLASH versus Normal RT in mouse brain
Less inflammation
Blood vessel protection
Protection of juvenile brain
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What is the effect of FLASH
on tumors ?
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So far … no sparing effect for tumors with FLASH-RT :
1) in mouse : breast, H/N, glioma, lung, GI xenografts and orthotopic models
2) in a phase I veterinarian clinical trial in SCC of cat-patients
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*Vozenin et al Clinical Cancer Research 2019
Minimal mucosal toxicity swallowing preserved
84% tumor control rate at 1 year
High cure rate in cat cancer patients(a veterinarian clinical trial @ CHUV)
6 cats with spontaneous cancerstreated with FLASH
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How does it works ?
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Potential mechanisms ?
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Mechanisms ? Some level of O2 dependency
Montay Gruel PNAS 2019
Hyper-oxygenation
with carbogen
breathing abolishes
the FLASH effect
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FouilhadeCurie institute
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Are there
potential limitations
for clinical use ?
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Possible : 30-40 Gy/s (Favaudon et al 2014)
Likely : > 100-150 Gy/s (Montay-Gruel et al 2017)
Reproducible : Dose / pulse (> 1.5 Gy and very few pulses)
Dose rate in the pulse (>= 106 Gy /s)
Overall time (< 100 ms)
(Vozenin et al 2019, Montay Gruel 2019, Bourhis et al, 2019)
How high should be the dose rate to observe a FLASH effect ?
(for small volumes / with electrons)
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JF Germond, CHUV
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Potential limitations for the clinical translation ?
The experimental conditions to observe a FLASH effect were essentially:
- Small volumes of normal tissues (a few cc)
- Mainly (but not only) with single dose (7-10 Gy or higher)
- Overall Treatment Time < 100-200 ms
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Conventional FLASH
Vozenin et alClin Cancer Res 2019
Is the magnitude of the benefit clinically meaningful ? Example for the pig’s skin
31 Gy
34 Gy
28 Gy
31 Gy
34 Gy, no necrosis
28 Gy
(late effects @ 9 months post-RT)
25 Gy no necrosis
PotentialDMF
between1.25 and
1.36
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… Clinical translation
is ongoing …
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1) Promizing, reproducible and consistent pre-clinical observations
2) Potentially less toxic, more efficient treatments for the radio-resistant tumors
3) Numerous projects initiated world wide
Great interest in the radiation oncology community
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For clinical translation : additional safety measures are needed
…
(ex @ CHUV :) Treatment
Pre-treatmentDosimetry check
0
20
40
60
80
100
0 10 20 30 40No
rmal
ized
Do
se [
%]
Depth [mm]
PDD -patient
Pre-treatment[Gy]
Alanine A [Gy]
Alanine B [Gy]
Dose [Gy]
14.9 14.9 14.9
Independent pulses and time counter device for beam stopping
0.85
0.90
0.95
1.00
1.05
1.10
TLD 1 TLD 2 TLD 3 XD 1 XD 2 XD 3 AL 1 AL 2 AL 3
RA
TIO
R
PASSIVE DOSIMETERS
Bourhis et al 2019
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First treatment of a patient with FLASH(CHUV, Oct 2018)
MultiresistantT cell lymphoma
(Bourhis et al 2019)
150 Gy/sOverall time 90 ms
Feasible
Safe
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FLASH initiatives, worldwide
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FLASH with Protons (broad beam)
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Transfert clinique au CHUV (I)
FLASH-Mobetron2 cm
Only for superficial skin cancers
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34
First Investigational Trials Planned with Mobetron FLASH HDR
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Transfert clinique @ CHUV (II) : intra-operative FLASH-THERAPY
WithPr Simon, Pr Demartines, Pr Mathevet
For cancers not amenable to A complete resection
3 cm
Arrivée au CHUV Sept-Oct 2020
Arrival @ CHUVMarch 17th 2021
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- Unmet clinical need : this is where we have most of the tumor failures …
- So far no FLASH pre-clinical data mimicking these clinical situations
- No FLASH irradiating device is currently available : technical challenges
- FLASH characteristics may not help for its use in such large volumes ?
What about large tumor volumes and deep seated tumors ?
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Next step : CHUV-CERN project
For deep seated tumors
15-20 cm
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Proc Natl Acad Sci U S A.
2019 May 28; 116(22): 10943–10951.
Published online 2019 May 16. doi: 10.1073/pnas.1901777116
Long-term neurocognitive benefits of FLASH radiotherapy driven by
reduced reactive oxygen speciesPierre Montay-Gruel, Munjal M. Acharya, Kristoffer Petersson, et al
Which tumor type first ? : glioblastoma ? one of the most non-curable cancer
Less toxicity
More efficacy
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FLASH therapy CERN–CHUV project
15-20 cm Glioblastome =cancer
profond
…
Construction of the prototype
Installation 2023
First patient 2024-25
ISREC & BILTEMA
Foundations
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1) FLASH :
- Increases the differential effect between normal tissues & tumors
- Operates at high dose / fraction, delivered in few milliseconds
- Mechanisms ?
2) Clinical translation :
- Optimal parameters for obtaining a FLASH effect in large fields needs to be investigated
- Both FLASH & high conformal delivery are needed : technical challenges (CERN +++)
Conclusions
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Remerciements
UNIL & CHUV : Pr P Eckert, Mr O Peters, Pr JD Tissot, Pr PF Leyvraz,
DO : Pr Coukos, Pr Kandalaft & l’équipe du CTE
Sponsors : ISREC & Fondation Biltema, Fondation CePO, Fond’Action, FNS, ANR, PO1, Fondation CHUV
Partenaires : PMB, CERN, IntraOp, RaySearchRecherche de nouveaux partenaires en cours pour le projet CERN-CHUV
L’équipe FLASH therapydu CHUV
Pr Vozenin (cheffe de laboratoire)
Pr Bochud et l’IRA
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