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FLASH RADIATION THERAPY – CURRENT STATUS AND THE WAY TO
THE CLINIC
LATEST RESULTS AND ADVANCES TOWARDS
CLINICAL FLASH-RT
Joint AAPM/COMP MeetingJuly 12th, 2020
Pierre Montay-Gruel, PhDUniversity of California Irvine
Latest results and advances towards clinical FLASH-RT
Latest preclinical results on the brain
Glioblastoma and cognition
Juvenile model toforesee medulloblastoma treatment
Clinical transfer
Which beam parameters ?
Which technology with electrons ?
What are the challenges ?
FLASH-RT is efficacious against GBM and protects the brain functions
Montay-Gruel et al (in revision)Please do not circulate
D+3 W1 W2 W3 W4
1
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Time post tumor initiation (Weeks)
Rela
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T)
10 Gy
Control
10 Gy CONV
10 Gy FLASH
**
ns
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Time post tumor initiation (days)
Perc
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10 Gy
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ns.
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Dis
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10 Gy
Control 10 Gy CONV 10 Gy FLASH
***
D+3 W1 W2 W3 W41
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Time post tumor initiation (Weeks)
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14 Gy
Control
14 Gy CONV
14 Gy FLASH
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ns
0 5 10 15 20 25 30 35 40 45 50 55 60
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Time post tumor initiation (days)
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14 Gy
14 Gy CONV 14 Gy FLASHControl
**
ns
D+3 W1 W2 W3 W4
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Time post tumor initiation (Weeks)
Rela
tive lu
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escence
(norm
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ed to d
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2 x 7 Gy
Control
2 x 7 Gy CONV
2 x 7 Gy FLASH
ns
***
0 5 10 15 20 25 30 35 40 45 50 55
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Time post tumor initiation (days)
Perc
ent surv
ival
2 x 7 Gy
Control
2 x 7 Gy FLASH
2 x 7 Gy CONV
ns.
0
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Dis
crim
ination Index
2 x 7 Gy
2 x 7 Gy CONV 2 x 7 Gy FLASHControl
**
*
a. b. c.
d. e. f.
g. h. i.
Towards hypo-fractionation ?
Montay-Gruel et al (in revision)Please do not circulate
D+3 W1 W2 W3 W4
1
10
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Time post tumor initiation (Weeks)
Rela
tive lu
min
escence
(norm
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4 x 3.5 Gy
Control
4 x 3.5 Gy CONV
4 x 3.5 Gy FLASH
ns
**
0 5 10 15 20 25 30 35 40 45 50 55 60 65
0
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Time post tumor initiation (days)
Perc
ent surv
ival
4 x 3.5 Gy
Control
4 x 3.5 Gy FLASH
4 x 3.5 Gy CONV
ns.
0
10
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Dis
crim
inatio
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4 x 3.5 Gy
4 x 3.5 Gy CONV 4 x 3.5 Gy FLASHControl
ns
ns
D+3 W1 W2 W3 W4 W5 W6 W71
10
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Time post tumor initiation (Weeks)
Rela
tive lu
min
escence
(norm
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ed to d
ay o
f R
T)
3 x 10 Gy
Control
3 x 10 Gy CONV
3 x 10 Gy FLASH
****
ns
****
0 10 20 30 40 50 60 70 80 90 100
0
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Time post tumor initiation (days)
Perc
ent surv
ival
3 x 10 Gy
3 x 10 Gy CONV
3 x 10 Gy FLASH
Control
*** ****
0
10
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60
Dis
crim
inatio
n Index
3 x 10 Gy
3 x 10 Gy CONV 3 x 10 Gy FLASHControl
* *
a. b.
c. d.
e. f.
What about complete tumor control ?
Montay-Gruel et al (in revision)Please do not circulate
D+3 W1 W2 W3 W4 W5 W6 W71
10
100
1000
10000
Time post tumor initiation (Weeks)
Rela
tive lum
inescence
(norm
aliz
ed to d
ay o
f R
T)
25 Gy Hemibrain
Control
25 Gy CONV
25 Gy FLASH
****
ns
****
0 20 40 60 80 100 120 140 160 180 200 220 240
0
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Time post tumor initiation (days)
Perc
ent surv
ival
25 Gy Hemibrain
25 Gy CONV
25 Gy FLASH
Control
****
0
10
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Dis
crim
ination index
25 Gy Hemibrain
25 Gy CONV 25 Gy FLASHControl
nsns
a. b.
c.
Alaghband et al (Cancers, 2020)
Advantages of protecting the normal tissue
Medulloblastoma patients
→ Long term survival achieved >80% pediatric cases→ Surgery followed by cranio-spinal RT + chemo
→ Significant impairments cognition, mood disorders, endocrine dysfunction, cerebrovascular complications
WBRT 8 Gy FLASH / CONV-RT3 week old pups
Congnitive investigation
Memory
FearAnxiety
Social interactions
Conservation of complex congnitive functions in young animals
Alaghband et al (Cancers, 2020)
Absence of neurogenesis impairment Absence of neuroinflammation
Preservation of the endocrine system
Cellular preservation
Integrity of the adult cerebrovascular system after FLASH-RT
Preservation of tight junctions
Are electron beams suitable to transfer FLASH-RT to the clinics ?What are the challenges ?
Bourhis et al (Radiother&Oncol 2019)Montay-Gruel et al (in revision)
What do we know about the optimal parameters to obtain the FLASH effect ?
Wilson et al (Frontiers in Oncology, 2020)
What do we know about the optimal parameters to obtain the FLASH effect ?
Which technologies are currently available for a clinical transfer ?
What are the challenges ?
Wilson et al (Frontiers in Oncology, 2020)
External beam RT with 5-6 MeV LINAC is suitable for superficial skin tumor treatments
Intra Operative RT will overstep the depth penetration challenge associated with electron beams
Relatively high single dosesAccess to deeper tumorsExtremely fast beam-on time : advantage for surgeryProtection of the surrounding normal tissues
Multiple clinical applications
Conclusions
More and more preclinical data showing in different models
- Protection of the normal tissues: from cellular effect to organ function- Efficacious anti tumor effect with single doses or hypo fractionated regimen
Current studies are aiming at defining the optimal parameters to reach the FLASH effect
- Mean dose rate- Instantaneous (intra-pulse dose rate)- Pulse repetition (frequency)- Dose per pulse - Total dose- Total delivery time
Clinical tranfer is almost ready, with challenges yet to overcome (electrons)
- Penetration in the tissue (possibility of IORT or superficial tumors with EBRT)- No available VHEE technology available yet
MC Vozenin LabJ BourhisC YakkalaB PetitJ OllivierA De VallièreC GodfroidP Fuchs
F BochudC BailatJF GermondP FroideveauxN CherbuinT Buchillier
C Limoli LabJ BaulchM AcharyaV PariharY Alaghband
E GiedzinskyB AllenS Cheeks
Animal Facilities of Epalinges and Irvine
R MoeckliP Jorge-GoncalvesK PeterssonM JaccardM Gondre
