ExAblate Conformal Bone System Treatment of Metastatic Bone Tumors for the Palliation of Pain

Bone is the third most common organ involved by metastatic disease behind lung and liver [6].
In breast cancer, bone is the second most common site of metastatic spread, and 90% of
patients dying of breast cancer have bone metastasis. Breast and prostate cancer metastasize
to bone most frequently, which reflects the high incidence of both these tumors, as well as
their prolonged clinical courses. Post-cancer survival has increased with improvement in
early detection and treatments. As a consequence, the number of patients developing
metastatic bone disease during their lifetime has also increased.

Current treatments for patients with bone metastases are primarily palliative and include
localized therapies (radiation and surgery), systemic therapies (chemotherapy, hormonal
therapy, radiopharmaceutical, and bisphosphonates although the primary goal of the use of
these therapies are often to address the disease itself), and analgesics (opioids and
non-steroidal anti-inflammatory drugs). Recently, radiofrequency ablation has been tested as
a treatment option for bone metastases [8]. Currently, an off label use of Cryoablation
techniques are being tested as another alternative for bone Mets palliation. The main goals
of these treatments are improvement of quality of life and functional level. These goals can
be further described:

1. Pain relief

2. Preservation and restoration of function

3. Local tumor control

4. Skeletal stabilization

Treatment with external beam radiation therapy (EBRT) is the standard of care for patients
with localized bone pain, and results in the palliation of pain for many of these patients.
Twenty to 30% of patients treated with radiation therapy do not experience pain relief
[9-13]. Re-treatment rates are generally reported in the range of 10-25%. Many patients with
relapsed pain or poor response to initial radiation may be lost to follow up or may not be
referred back to oncologists for consideration of re-radiation. In addition to relapse and
re-treatment, there is an increased risk of pathologic fracture in the peri-radiation period.
The fracture rate reported in radiation studies is generally in the range of 1% to 8%. The
hyperemic response weakens the adjacent bone and increases the risk of spontaneous fracture.
Furthermore, patients who have recurrent pain at a site previously irradiated may not be
eligible for further radiation therapy secondary to limitations in normal tissue tolerance.
Hesitation on the part of physicians to use a larger dose may be related to increased
long-term toxicity. Larger radiation dose produces a greater risk of complications such as
fibrosis of normal soft tissue, which can cause a decrement in the quality of life in cases
of life expectancy longer than 6 months. There may also be a greater incidence of acute side
effects of nausea and vomiting if the treatment field includes the stomach. The percent of
patients experiencing vomiting following EBRT ranges from about 5% to 30%.

A palliative treatment for painful bone metastases that is non-invasive, without long-term
toxicity and having minimal complications would be a useful tool for treating physicians and
also a beneficial option for patients suffering from painful bone metastases. Results of
preliminary studies indicate that ExAblate treatment of painful bone metastases may be a
beneficial treatment option [14, 15]. The ExAblate system is a non-invasive thermal ablation
device used in the coagulation of various types of soft tissue. The ExAblate system has the
potential to achieve the first three of the four previously mentioned goals in the treatment
of bone tumors; namely pain relief, preservation and restoration of functional levels and
local tumor control [11]. The ExAblate system used in the present study is a technological
advance over the ExAblate 2000 fixed transducer system in terms of flexibility of use and
reduction of positioning related pain to the patients. The ExAblate system used in this study
conforms to the patient's body shape at the location of the bone mets location.

Inclusion Criteria:

1. Men and women age 18 and older

2. Patients who are able and willing to give consent and able to attend all study visits

3. Patients who are suffering from symptoms of bone metastases

4. One to 3 painful lesions.

5. Targeted tumor(s) are ExAblate device accessible and are located in ribs, extremities
(excluding joints), pelvis, shoulders and in the posterior aspects of the following
spinal vertebra: Lumbar vertebra (L3 - L5), Sacral vertebra (S1 - S5)

6. Patients with persistent distinguishable pain associated with up to 3 tumors of which
a maximum of 2 tumors will be treated:

o If patient has pain from additional sites that are not planned for treatment, the
pain from the additional sites must be evaluated as being less intense by at least 2
points on the NRS compared to the site(s) to be treated.

7. Patient with NRS (0-10 scale) pain score ≥ 4 at the targeted tumors (i.e: both tumors
targeted for treatment must have NRS ≥ 4) irrespective of medication

8. Targeted tumors (most painful) size up to 8 cm in diameter

9. Patient whose targeted (most painful) tumors are on bone and bone-lesion interface is
deeper than 1cm from the skin.

10. Targeted (most painful) tumors clearly visible by non-contrast MRI, and ExAblate
MRgFUS device accessible

11. Able to communicate sensations during the ExAblate MRgFUS treatment

12. At least 2 weeks since chemotherapy

13. No radiation therapy to targeted (most painful) tumors in the past two weeks

Exclusion Criteria:

1. Patients who either

- Need surgical stabilization of the affected weight bearing bony structure (>7
fracture risk score, see Section 6.9) OR

- Targeted tumor is at an impending fracture site of the weigh bearing bone (>7 on
fracture risk score, see Section 6.9).

OR

o Patients with surgical stabilization of tumor site with metallic hardware

2. More than 3 painful lesions or more than 2 requiring immediate localized treatment

3. The targeted tumor(s) is (are) less than 2 points more painful compared to other
non-targeted painful lesions on the site specific NRS.

4. Targeted tumor is in the skull

5. Patients on dialysis

6. Patients with life expectancy < 6-Months

7. Patients with an acute medical condition (e.g., pneumonia, sepsis) that is expected to
hinder them from completing this study.

8. Patients with unstable cardiac status including:

- Unstable angina pectoris on medication

- Patients with documented myocardial infarction within six months of protocol
entry

- Congestive heart failure requiring medication (other than diuretic)

- Patients on anti-arrhythmic drugs

9. Severe hypertension (diastolic BP > 100 on medication)

10. Patients with standard contraindications for MR imaging such as non-MRI compatible
implanted metallic devices including cardiac pacemakers, size limitations, etc.

11. Patients with an active infection or severe hematological, neurological, or other
uncontrolled disease.

12. Known intolerance or allergies to the MRI contrast agent (e.g. Gadolinium or
Magnevist) including advanced kidney disease

13. KPS Score < 60 (See "Definitions" below)

14. Severe cerebrovascular disease (multiple CVA or CVA within 6 months)

15. Individuals who are not able or willing to tolerate the required prolonged stationary
position during treatment (can be up to 4 hrs of total table time.)

16. Target (most painful) tumor-bone interface is less then 1cm from nerve bundles, bowels
or bladder.

17. Are participating or have participated in another clinical trial for the palliation of
their targeted bone metastasis tumors in the last 30 days

18. Patients receiving chemotherapy or radiation (i.e., to the targeted lesion (s)) within
the last two weeks

19. Patients unable to communicate with the investigator and staff.

20. Patients with persistent undistinguishable pain (pain source unidentifiable)

21. Targeted (most painful) tumors size > 8 cm in diameter

22. Targeted (most painful) tumors:

- NOT visible by non-contrast MRI, OR

- NOT accessible to ExAblate device