mrgfus for bone metastases

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

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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


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


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


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


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

8

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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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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This is a team effort

Yael Inbar & interventional MR team

Radiation Oncology colleagues

Sheba Oncology clinical studies center

Insightec