Les ultrasons focalisés pour la thérapie mini-invasive - Cyril Lafon - Présentation Radiologie Technologies ...
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Les ultrasons focalisés pour
la thérapie mini-invasive
Cyril Lafon
cyril.lafon@inserm.fr
LabTau, INSERM, Lyon, France
2 Paul Langevin et le Sonar (1917)
3
Interesting chronology
• 1920 First bioeffects report
• 1928 Medical use suggested
• 1932 Therapeutic heating
• 1942 First medical diagnosis report
1990s
1950s 1960s
Exposure conditions for diagnosis and therapy
Frequency Intensity Duration
(MHz) W/cm2 (s)
Pulse-Echo 1 - 20 1.75 < 10-6
Doppler 1 - 20 15.7 < 10-2
Physiotherapy 0.5 - 3 2.5 Cont.
Surgery 0.5 - 10 > 100 1 - 20
• Similar frequency range for diagnosis and therapy.
• ↑↑ Dose of ultrasound for a therapeutic effect
Interactions of Ultrasound with
biological tissues
Mechanical effects Thermal effects
Cavitation
Chemical effects
In most cases : Combination of the different effects
6
Ondes de chocs et lithotritie
« Spalliation » et « Squeezing »
cS>cW
cW
Ultrasons Ultrasons
Casse par l’arrière
du calcul
Direction de propagation
7 Ondes de chocs et lithotritie
8
Cavitation et lithotritie
Sokolov, Bailey
9
Cavitation et lithotritie
Bailey, Cleveland et al.
10
Ultrasonic cavitation and sonoporation
Temporal window
4T1 cells: 3 hours
Transient pores on the membrane Irreversible pores on the
of U87 MG cells (human glioma) membrane of U87 MG cells
(Zeghimi A. and al, 2014) (Zeghimi A. and al, 2014)
Effect at the cellular but also at the tissue level!11
Focalisation des ultrasons
~1000W/cm² at the focus
Tumor
Heat
Skin Bubbles of cavitation
Dimension of the focal zone:
• ≈1 cm long
• ≈1 mm in diameter12 Global development landscape of therapeutic ultrasound
13
Conformal device to targeted application
Analogy with ultrasound scanners
Different shapes of probes for different
applications e.g. Cardiac vs. Transrectal
(Therapy : extra corporeal vs. intra cavity)
Different frequencies for different applications
e.g. Ophtalmology vs. Abdominal
(Therapy : superficial vs. deap-seated)
Different acoustic sequences for different
applications e.g. Doppler vs. B-mode
Common ultrasound (Therapy : Ablation vs. cavitation)
platform14
Examples of translational research with
devices for conformal treatments
• Ablatherm® for treating prostate cancer
• Sonocloud® : An implantable ultrasound device for repeated
opening of the blood brain barrier and drug delivery into the
brain15
Examples of translational research with
devices for conformal treatments
• Ablatherm® for treating prostate cancer
• Sonocloud® : An implantable ultrasound device for repeated
opening of the blood brain barrier and drug delivery into the
brain16
Principle of Ablatherm®
• Endorectal route
• Ultrasound guidance
• Treatment volume defined by urologist
• Computer-controlled procedure
• Under rachi anesthesia
• Assessment of treatment quality with
contrast-enhanced MRI (D2)17
Intended use of Ablatherm®
As a primary therapy As a salvage therapy
Plus de 50000 patients
traitésAblatherm®: Traitement du cancer de la
prostate par HIFU
Range of published 5-year disease free Rates
Surgery EBRT Cryo Brachy HIFU
100% 97%
94% 92%
86%
83% average
80% average 82%avrg
77% average 79%
72% 70% average
61% 63%
40%
Range of Published Morbidity Rates
49% 91%
63%
Incontinence
Impotence
53%
15%
5% 7% 13%
2% 14% 5%
0%
Surgery Radiatio HIFU Surgery Radiation HIFU
n
Traitement aussi efficace et avec moins d’effets indésirables que les
techniques concurrentes19
Prostate cancer management evolution
1990 Patient lived 7 years with Prostate Cancer
§ Single treatment approach
Treatment strategy:
§ Aggressive Radical Surgery
Efficacy at all price
§ Radical Radiotherapy
1990
Patient age 60 70 80
2010
2010 Patient lives 15 years with Prostate Cancer
Treatment strategy: § Multi-treatment approach
disease control with QoL preservation § Non invasive techniques
§ Focal therapyFocal One®, last generation of HIFU device
for focal treatment in prostate
Dynamic focusing
Elastic fusion
MRI/US
&
Contrast ultrasound
2021 Contrast ultrasound after bifocal treatment guided by MRI and trans perineal biopsies Positive Positive biopsy biopsies
22
Examples of translational research with
devices for conformal treatments
• Ablatherm® for treating prostate cancer
• Sonocloud® : An implantable ultrasound device for repeated
opening of the blood brain barrier and drug delivery into the
brain23
Examples of translational research with
devices for conformal treatments
• Ablatherm® for treating prostate cancer
• Sonocloud® : An implantable ultrasound device for repeated
opening of the blood brain barrier and drug delivery into the
brain24
Primary brain tumors = A dramatic prognosis
• 56,000 patients per year US + EU
• Diffuse disease
• 100% recurrence (resistance to surgery,
chemotherapy and radiotherapy)
• Mean overall survival for Glioblastomas patients
§ 12.1 months after surgery + radiation
§ 14.6 months with concomitant TMZ (Stupp et al. 2005)
§ Poor efficacy of 2nd line chemotherapy25
US + µ-bubbles can open the BBB
Hynynen et al. (2001)
Figure from Vykhodtseva et al. (2008)
• Pre-clinical studies using pulsed ultrasound + US contrast agents
• Transient opening
• MRguided Extracorporeal US Phased Arrays (McDannold et al. 2012,
Cancer Research, …)
• Skull is the main problem for clinical application (defocusing and refraction).
• Heavy method for routine repeated BBB opening at each chemotherapy
session
Focused Array of 1000 US transducers (200kHz,
1MHz) under MRI guidance – Need of a stereotaxic
frame, shaving of the patient and cooling skin circuit26
SonoCloud® = Implantable US Device
ü Bio and MR-compatible device
ü 1 MHz, 11 mm Æ un-focused transducer
ü Power supplied by transdermal connection
ü P > 0.5 MPa, 25 ms pulse, 1 Hz (DC=2.5%), 120 s
ü SonoVue (0.1 cc/kg)
Simulated pressure field in water
Advantages:
ü No beam distortion or attenuation through the skull
ü No need for MRI, shaving and stereotaxy
ü Repeated application, concomitant with chemotherapy
ü Able to treat cortical tumorsSonocloud ® : Dispositif implantable pour
l’ouverture de la BHE
2728 Preclinical trials – Drug delivery • Carboplatin: 6-month progression free survival of 22-30% for glioblastoma patients • SonoCloud® on one hemisphere of the brain of a baboon • Mass spectrometry for quantication of platinum in ultrafiltrate plasma and brain samples Goldwirt et al. Cancer Chemother Pharmacol 2016 Loco-regional enhancement of carboplatin distribution in the brain: x 5.2 in the US field vs. controlateral
29
A 6 min Ambulatory BBB opening procedure
ü Connect device-generator with bipolar 2 min
transdermal disposable needle
ü Check quality of connection the generator 1 min
ü Deliver ultrasound for 120 s without MRI
monitoring and correction of US
2 min
ü Inject IV µ bubbles during 30 seconds
SonoVue® : 0.1cc/kg
ü Disconnect 1 min
ü MRI
• Start chemotherapy IV
• BBB opened for 6+ hrs 20 min
• Reproducible every months
291ère Mondiale: Etude clinique de
potentialisation des chimios par US
pour le traitement de GBM
Pré After US
Before US
Pas de récurrence sur cette patiente à 4 mois
30BBB opening Grading on MRI
LABORATOIRE THÉRAPIE
ET APPLICATIONS ULTRASONORES
After US
üGrade 0 = No evidence of BBB
disruption
üGrade 1 = Sub–Arachnoid
enhancement
Before US Patient 9 After US
Before US
üGrade 2 = Gray matter
enhancement
üGrade 3 = White matter
After US
enhancement
Before USBBB opening Grading on MRI
LABORATOIRE THÉRAPIE
ET APPLICATIONS ULTRASONORES
More significant opening when increasing the pressureSurvival on 19 patients
LABORATOIRE THÉRAPIE
ET APPLICATIONS ULTRASONORES
n=8 patients with no/minimal BBB opening
n=11 patients with clear BBB opening
2.6 3.9 months 8.5 12 monthsDiscussion
LABORATOIRE THÉRAPIE
ET APPLICATIONS ULTRASONORES
Feasibility
• 19 patients with 65 sonications / 52 BBB openings
• Acoustic pressure to achieve safe, repeatable BBB opening
defined
• 8 min – long procedure, compatible with ambulatory
hospitalization
Toxicity
• Transient and manageable AEs which may be due also to
chemotherapy and/or disease progression
• No safety issues including for patients with 10 sonications
Carpentier et al. Sci Transl Med 2016Discussion
LABORATOIRE THÉRAPIE
ET APPLICATIONS ULTRASONORES
Efficacy
• PFS = Secondary endpoint
• Patients with greater BBB disruption tended to have
improved PFS (3.9 vs 2.6 months) and OS (12 vs. 8.5 months)
• Preliminary results of a mono centric study on a small
population
• Including sub-optimal ultrasound dose and patients at 1st and
2nd recurrence
• Only one transducer (Sonocloud-1) and larger sonication
zone for rGBM neededClinical developments
LABORATOIRE THÉRAPIE
ET APPLICATIONS ULTRASONORES
• Feasibility study in France with SC3 began in June 2017
• Recruitment complete of 6 patients with recurrent GBM
• 24 sonications thus far; 1 patient with 11 sonications
• Clinical trial with SC9 to start in 2019ExAblate par InSightec
EXABLATE NEURO EXABLATE BODY PLATFORM
EXABLATE
PLATFORM
• 1000 element spherical phase array
transducer • Embedded phased array ultrasound
transducer (200 to 1,000 independently
• Sharp boundaries between treated and controlled transducers)
untreated areas
• Real time treatment monitoring
• Focal point controlled electronically in size
(2-5mm) and location (ExAblate par InSightec
Close loop therapy
Enables physicians to
visualize in real-time the 1. PLANNING 2. THERMOMETRY
treated tissue volume and Anatomy and beam path
superimposed in order to control
Real-time MR thermal
imaging tracked in order
its thermal response treatment and avoid non-targeted to monitor treatment
tissue
NPV
NPV
4. ADJUSTMENT 3. EVALUATION
Parameters adjusted as Thermal data integrated
necessary to ensure safe to determine cumulative
and effective response thermal impact on tissue
38
www.insightec.com39
Applications cliniques de l’ExAblate
• Système cerveau
• Système corps
• Tremblement
essentiel (FDA / CE)
entier
• Ostéome ostéoïde
• Tremblement par
Parkinson (CE) (CE)
• Dépression (Korea) • Métastases osseuses
(FDA) et tumeurs
• TOC (Korea)
osseuses bénignes
• Douleurs (CE)
neuropathiques (CE)
• Fibromes utérins
• Système prostate (FDA CE)
• Cancer (CE) • Adénomyose (CE)
• Rhizothomie
facettaire (CE)
Alternative thérapeutique non invasive40 Etudes cliniques en cours • Tumeurs cérébrales chez l’adulte (gliome) et l’enfant (bénigne) • Pallidotomie unilatérale pour Parkinson • Ouverture de la BHE (Alzeihmer et tumeurs cérébrales) • Epilepsie • www.clinicaltrials.gow • Recherche « ExAblate »
41
Take home message
• Therapeutic Ultrasound =
Mini invasive procedure and
growing field
• Conformal treatment should
be designed according a
medical need
• Different bioeffect according
to exposure conditions
Tintin et l’affaire Tournesol 195642
For additional informations !!
• Congrès ISTU 2019 • MOOC on Therapeutic
ultrasound for MDs
ISTU 2018 • FREE
Nashville, Tennessee, USA
May 14th – May 17th 2018
http://labtau.univ-lyon1.fr
www.istu.org
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