mrgfus for bone metastases
DESCRIPTION
MRgFUS for Bone MetastasesRome, September 2011U pdate and Future Trends Raphael Pfeffer Sheba Medical Center, IsraelTRANSCRIPT
1Leading the world with innovative MR guided focused ultrasound therapy
MRgFUS for Bone Metastases
Rome, September 2011
update and future trends
Raphael PfefferSheba Medical Center, Israel
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MRgFUS for Bone metastases treatment principles
• Bone heating is used to ablate the adjacent periosteum• Palliation achieved by the ablation of the bone periosteum, which is the
sensory origin of the pain• What about tumor control ???
Acoustic Beam
Transducer
BoneAblated
tissue
Transducer
Soft tissue
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ExAblate for Bone: Treatment Technique
In soft tissue:
• Narrow, point-shaped focus is required
• High energy density at focal point
In bone :
• Low energy usage
• Wide beam approach
• Short treatment time
Typical sonication energy 2500J
Absorption of FUS energy by bone is ~50 times greater than that of soft tissue, therefore:
Typical sonication energy 1500J
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Importance of MR Guidance and Control
Planning: 3D Imaging for precise tumor targeting
Beam path visualization for controlled treatment
MR thermometry for real-time temperature feedback
Post treatmentcontrast imaging forprecise treatment validation
CLOSED LOOP
THERAPY
Modify parameters based on thermal feedback
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Real time MR thermometry and tissue ablation
MR thermometry demonstrates clear correlation with tissue ablation and sharp edges of sonication
Thermal dose threshold (above 240 minutes at 43° C)
Pathology of same sonication
Temperature map of a sonication
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123
12
123
2 Temperature rise at margin
3 Temperature rise in untreated area, 7mm from center
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Temperature rise at center of sonication spot
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MRgFUS for Bone metastases treatment principles
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Pain Palliation Feasibility Study
• Treated bone mets from primary tumor type: renal, colorectal, lung, breast, prostate and other cancers
• Treated lesion locations: iliac bone, ischium, sacrum, femur, scapula, humerus, clavicle
• Treated lesion type: both osteolytic and osteoblastic
• Most were radiation failure patients
Patient population: 36 treatments in 31 patients were conducted, targeting 32 metastatic lesions
Patient tumor characteristics:
CT images of patients treated with MRgFUS. Red arrows shows the
targeted bone metastases.
Published in Annals of Surgical OncologyLiberman B, Gianfelice D, Inbar Y, Beck A, Rabin T, Shabshin N, Chander G, Hengst S, Pfeffer R, Chechick A, Hanannel A, Dogadkin O, Catane R. Pain Palliation in Patients with Bone Metastasis Using MR guided Focused Ultrasound Surgery, Preliminary Multicenter Clinical Experience,
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Bone Metastases Pain Palliation Feasibility Study Results
Criteria for treatment outcomePartial response:I. Pain reduction of 2 points or more of
Visual Analog Score (VAS) at the treated site on a 0–10 scale without analgesic increase.
II. Analgesic reduction of 25% or more from baseline without an increase in pain.
Complete response: Pain score of zero at the treated site
with no concomitant increase in analgesic intake
Published in Annals of Surgical OncologyLiberman B, Gianfelice D, Inbar Y, Beck A, Rabin T, Shabshin N, Chander G, Hengst S, Pfeffer R, Chechick A, Hanannel A, Dogadkin O, Catane R. Pain Palliation in Patients with Bone Metastasis Using MR guided Focused Ultrasound Surgery, Preliminary Multicenter Clinical Experience,
36%
36%
4%
24% Complete response totreatment
Partial response totreatment
Pain progression
No response to treatment
Average pain score
5.9 (n=28)
4.0 (n=27)
3.1 (n=28)
2.6 (n=26) 1.8 (n=24)
0.0
1.0
2.0
3.0
4.0
5.0
6.0
7.0
0 10 20 30 40 50 60 70 80 90
Days post treatment
VA
S s
core
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Average VAS by Primary Tumor Type
0.0
1.0
2.0
3.0
4.0
5.0
6.0
7.0
8.0
0.0 20.0 40.0 60.0 80.0 100.0
Days since MRgFUS
Av
era
ge
VA
S
Breast Ca. (n=12) Other (n=5)
Prostate Ca. (n=4) Renal Cell Carcinoma (n=6)
Phase I study – data analysis
10Leading the world with innovative MR guided focused ultrasound therapy
Average pain score by Radiation History
2.2 (n=20)2.1 (n=12)2.0 (n=22)
5.1(n=26)
6.4 (n=24)6.6 (n=26)
3.0 (n=26)
2.9 (n=32)3.5 (n=14)
3.5 (n=32)
6.3 (n=27)6.5 (n=34)
4.5 (n=33)
3.6 (n=33)
0.0
1.0
2.0
3.0
4.0
5.0
6.0
7.0
8.0
-14 6 26 46 66 86 106
Days post treatment
Ave
rag
e p
ain
sco
re
No RadiationPost Radiation
Summary of Three Studies
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Courtesy of Sheba Medical Center
Clinical Case
• 70 year old male patient
• Primary tumor: Prostate Cancer
• Targeted lesion is osteoblastic and located in the left iliac bone
• MRgFUS procedure was performed on Jan 19th, 2006
• 26 sonications, Energy=1000J
• 48 min treatment time
• Pain in the treated area disappeared 3 days after treatment
• Patient stopped using walking cane shortly after treatment
CT image showing targeted lesion (arrow)
BM001-606 Pain score
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0 0 0 00123456789
10
0 20 40 60 80Days post treatment
Pa
in s
co
re
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MRgFUS bone metastasis treatment overview
Left: Screening MR Axial T1w with contrast, showing enhancement of the bone metastasis in the left iliac bone (marked with orange dashed circle);
Middle: MR Axial T2w planning image with ultrasound beam overlay (blue);
Right: Post treatment MR axial T1w with contrast, showing non-enhancement in the treated area (marked with orange dashed circle).
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Clinical Trials – Three studies
Objective:
To evaluate the effectiveness and safety of ExAblate in the treatment of palliation of pain from metastatic or primary bone tumors
Study design:
1. BM 004 Prospective, randomized treatment vs. Sham
Crossover allowed for non-responders
2. BM 011 Prospective, single arm, using conformal transducer
3. BM 016 Prospective, randomized treatment vs. EBRT
Longterm tumor control, including imaging at 3 & 6 months
Recruiting patients
Exclusion / Inclusion Criteria:
1. Target lesion should have a pain score of 4 or more
2. Targeted lesion is not in vertebra bodies or skull
3. Treatment area is more than 1cm from skin, major nerve or hollow viscera
14Leading the world with innovative MR guided focused ultrasound therapy
MRgFUS for Bone metastasesBackground
•Patients with a painful metastatic bone lesions.
•Conscious sedation by anesthesist during procedure.
•Procedure requires shaving of skin overlaying targeted painful tumor and placement of an IV-line.
•Treatment duration is 1 to 2 hours on the average.
•To date, known device related complications include three patients with small second degree skin burns and several cases of transient post treatment pain.
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Access to more anatomical locations
• Improved patient comfort
• High density electronically steerable transducer
• Leaking membrane to provide acoustic coupling
• Micro-coils for tracking transducer position
• Lower frequency (550kHz)
ExAblate Conformal Bone system
Patient Table
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Conformal Bone System – Initial Results
BM011 Conformal Bone System Sheba Results - Pain Score
1.0 (n=2)
6.3 (n=3)
7.0 (n=3)
1.7 (n=3)
3.3 (n=3)
5.3 (n=3)5.5 (n=3)
2.7 (n=3)
1.3 (n=3)1.0 (n=2)
0
1
2
3
4
5
6
7
8
9
10
-20 -10 0 10 20 30 40 50 60 70 80 90
Days post treatment
Av
erag
e N
RS
pai
n s
co
re
Worst Pain
Average Pain
17Leading the world with innovative MR guided focused ultrasound therapy
A
B
Ribs:A- macro pathology showing lesionB- CT images showing new bone formation.
Note: At 3M new bone formation & thickening of the cortical layer in the area of treatment
MRgFUS and tumor control
Interaction of Focused Ultrasound with bone
18Leading the world with innovative MR guided focused ultrasound therapy
Immediately Post treatment
T1w Contrast Enhanced subtraction
Pre-Treatment
T1w Contrast enhanced
*courtesy of Sheba Medical Center
Dr Yael Inbar
Tumor Control – preliminary clinical data
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BM 016 Prospective, randomized study
MRgFUS vs External Beam RadioTherapy
Goal:Pain controllocal tumor ablation within the bone
Endpoints:1. Pain assessment2. Follow up MR Imaging
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Pain Palliation of Bone Metastases or Primary Bone Tumors
Potential benefits of MRgFUS:• No ionizing radiation
•Allows retreatment if needed
•Allows treatment of patient not eligible for radiation
• Single treatment session
• Outpatient treatment
• Speedy reduction of pain
• Durable, (3 month study data)
• High Safety profile
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Pain relief comparison: EBRT and MRgFUS
MRgFUSRadiation Therapy
Complete response27%14%
Partial response71%71-73%
No response29%30%
Speed of relief1-3 days2-3 weeks (after tx completion)
Sources: InSightec, Chow E. Palliative Radiotherapy Trails for Bone Metastases: A Systematic Review. Journal of Clinical Oncology, Vol 25, No 11, April 10, 2007
Criteria for treatment outcomePartial response:
Pain reduction of 2 points or more of Visual Analog Score (VAS) at the treated site on a 0–10 scale without analgesic increase.Analgesic reduction of 25% or more from baseline without an increase in pain.
Complete response: Pain score of zero at the treated site with no concomitant increase in analgesic
intake
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BM016 current results
Total number of patients: n=11
4 active sites: • Cartuja (n=4 Pts)• Sheba (n=3 Pts)• Rome (n=3 Pts) • Jaslok (n=1 Pts)
MRgFUS (n=6 Pts, 7 lesions): 5 patients reached 3 months FU, 1 patient crossed over to XRT arm after 2 months follow-up
XRT (n=5 Pts, 5 lesions): 1 patient left the study after 1 week and the rest of 4 died (not reaching 3M FU)
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BM 016 MRgFUS vs External Beam RadioTherapy
Patient accrual slow – 3 patients in Sheba
Analysis of poor accrual
Radiotherapy available within 24 hours in department
MRgFUS requires availability of open MRI & co-ordination with radiology (MR) and anesthesiology
Therefore referring physicians reluctant to enter patients on study
Patients with acute pain do not wish to be subject to randomisation
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BM016 – Sheba results (n=3)
BM016 Sheba data - Worst pain score
10 10 10
7.5
4.5
3.5 3.5
2.5 2.5 2.52
7.5
0
1
2
3
4
5
6
7
8
9
10
11
12
-20 -10 0 10 20 30 40 50 60 70 80 90
Days post treatment
Wo
rst
pai
n s
core
XRT worst pain
MRgFUS worst pain
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BM016 – Evidence for Tumor control
BM016-6003 (Sheba patient from MRgFUS arm)
Axial T1w FS with contrast shows non-enhancement of the posterior aspect of the treated lesion
Pain: VAS dropped from 10 at screening to 0 immediately after treatment
Pre-treatment Immediately post-treatment
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BM016-6003 Sheba
CT screening – osteolytic lesion in the left ilium
6 months follow-up CT after MRgFUS Tx shows evidence for new bone formation
BM016-6003 worst pain10
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0 0 0 0 0 00
1
2
3
4
5
6
7
8
9
10
-20 0 20 40 60 80 100 120 140 160 180
Days post treatment
Wo
rst
pai
n s
core
Worst pain score
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Worst pain score - Current Status in all Sites
4.3 (n=3)4.3 (n=3)
8.0 (n=5)
8.6 (n=5)
4.8 (n=4)
0.0 (n=1)
2.0 (n=5)
3.5 (n=6)
4.1 (n=7)3.8 (n=6)
7.4 (n=7)7.6 (n=7)
0
1
2
3
4
5
6
7
8
9
10
-20 0 20 40 60 80 100 120 140 160 180
Days post treatment
Wo
rst
pai
n s
core
XRT Arm
MRgFUS Arm
BM016 all results
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Conclusions
MRgFUS is effective for treatment of painful bone metastases
Effective for recurrent pain post-XRT
Effective for radioresistant tumors e.g. renal cell ca
Initial data indicate that it should be as effective as XRT as initial therapy for painful bone metastases
Need to assess long term outcome
Treatment flow should be improved
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MRgFUS for bone metastases - the future
• MR imaging required for target delineation in radiotherapy• CNS, spine, sarcoma, (prostate)
• Image fusion has limitations
• Wide-bore MR simulators are being introduced to radiotherapy departments
• Improved tumor targeting • No registration errors between MR and CT simulation
• MRgFUS should be an integral part of the Radiotherapy Department
• Availability of MRI• Increasing number of oncological indications for MRgFUS
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MRgFUS for bone metastases - the future
Convergence of radiotherapy and interventional radiology
21st century Radiotherapy key themes– conformality
- image guidance
Holy grail of radiotherapy
know where you treat – imaging (MRI)
know how much energy is deposited in tissue
measure immediate effect on tumor
personalize dose planning for patient specific rx planning
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Utilization of MRI in Radiation Oncology
MRI Simulator in radiotherapy suite
Why not adapt MRI Simulator for MRgFUS?
increased use of MRgFUS for oncological indications
CLOSED LOOP
Increased uptake of MRI simulators
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MRgFUS for bone metastases - the future
This is a team effort
Yael Inbar & interventional MR team
Radiation Oncology colleagues
Sheba Oncology clinical studies center
Insightec