Combining Intraoperative Radiotherapy With Kyphoplasty for Treatment of Spinal Metastases

Disease Background:

Bone metastases are the third most common site of metastatic spread, affecting 10% - 30% of
all cancer patients. The spine remains the most common site of bone metastases, with
incidence ranging from 30-70% depending on the primary tumour.

Spinal metastases can be a significant cause of morbidity for cancer patients: severe pain,
bone fracture, nerve root or spinal cord compression, hypercalcemia, and limited mobility.
Symptomatic spinal metastases are most frequently located in the thoracic spine (70%),
followed by lumbar spine (20%) and cervical spine (10%). Up to 15% of all cancer patients
with bone metastasis will suffer compression fracture leading to loss of function and the
impairment of mobility, while more than 70% of the patients will experience severe
cancer-related pain affecting quality of life. Newer systemic agents targeting specific
pathway or molecule within the tumor milieu has led to a dramatic improvement in life
expectancy for metastatic patients. Hence, effective palliative treatment options for spinal
metastases is an important clinical issue in today's oncologic practice.

Current Practice:

The majority of patients with spinal metastases are initially managed medically with
combination of analgesic medication, bisphosphonates, or biologic/chemotherapy agents.

When these patients develop severe pain refractory to medical options or there is a concern
for neurologic dysfunction (i.e. vertebrate fracture, nerve root compression), they will be
referred for palliative radiotherapy or surgical treatment options.

In the past decade, minimally invasive interventional therapies have become more popular to
treat severe pain from spinal metastases, especially in patients with evidence of compression
fracture. Vertebroplasty involves the percutaneous injection of cement into the vertebral
body with the goals of pain alleviation and preventing further loss of vertebral body height.
Similarly, in kyphoplasty (KYPHO), an inflatable balloon is used to create a cavity for the
cement deposition, which restores height as well as provides pain relief. However, the
immediate goal for both procedures is to achieve stabilization of the vertebral body and
prevent further compression.

Investigators assessed the safety and efficacy of vertebroplasty and kyphoplasty for pain
palliation in cancer patients. They performed ninety-seven procedures in fifty-six patients.
The median age was 62 years. The procedure was well-tolerated and no post-operative
complications or death were noted. There was a significant reduction in visual analog pain
score (VAS): median pre-and postoperative VAS score was 7 and 2, respectively (P=0.001,
student paired t-test). However, there concern for use of kyphoplasty alone in treatment of
spinal metastases: the rate of re-treatment and variable duration of pain palliation. The
rate of new compression fracture after balloon kyphoplasty in patients with malignant spinal
fracture can be as high as 10%.

Non-surgical option to treat spinal metastases usually involves the use of external beam
radiotherapy. The goals of radiation therapy are to alleviate pain, stabilize affected bone,
and decrease tumor cells within the treated site. Radiotherapy is very effective in pain
reduction, as 50-80% of all patients receiving palliative radiation will experience pain
reduction. Pain reduction from ionizing radiation, in theory, is due to the direct analgesic
effect on the nociceptors in the periosteum and electrolyte shift, which can convert
pain-inducing tissue acidosis to tissue alkalosis. Furthermore, stabilization of the
vertebral bodies can be achieved by decreasing number of tumor cells and hence, thereby
changing the imbalance of osteoclast and osteoblast activity. The latter effect can increase
re-mineralization. These effects will occur in 40-50% of patients after radiation therapy,
but can take 4-6 weeks after external beam radiation therapy course.

Several issues arise with use of external beam radiation therapy. First, an optimal dose
fraction schedule has not been well- established. The most common prescribed dose is 30 grays
(Gy) in ten fractions. However, in Radiation Therapy Oncology Group (RTOG) 9714,
investigators found no difference between 8Gy in single fraction versus extended 30Gy in 10
fraction schedule in terms of pain relief and narcotic medication usage at three months.
Furthermore, an extended radiotherapy course can lead to patient inconvenience, longer
hospitalization, and increased toxicity. In the RTOG 9714 trial, patients in the 30-Gy arm
had more grade 2-4 toxicities than 8-Gy arm. Furthermore, there is a risk of vertebral
fracture for patients treated with radiation therapy for spinal metastases. Researchers
reported 31% of their patients with spinal cord compression treated with radiotherapy alone
had vertebral collapse.

Hence, to achieve an optimal treatment option for symptomatic cancer patients with spinal
metastases, the next logical step would be to combine stabilization (kyphoplasty) technique
with direct tumor cell destruction in order to achieve maximum and durable pain palliation,
prevent potential neurological dysfunction, and improve quality of life. By combining
kyphoplasty with intraoperative radiation, one can achieve the above mentioned goals in a
single outpatient procedure.

Combination of Kyphoplasty and Intraoperative Radiation:

During a surgical procedure, the tumor bed and/or the tumor itself can be irradiated with a
single dose of radiation. Intraoperative radiation therapy [IORT] is the delivery of
radiation during a surgical intervention. The advantages of the IORT consist of the high
precision combined with optimal protection of the surrounding organs at risk. Hence, a higher
dose of radiation can be applied to the target (as compared to external beam), while
minimizing the adverse side effects to normal tissue. Furthermore, the single dose
corresponds to at least two to three time times higher biological effective dose than
conventional fractionated external beam radiotherapy. Another potential advantage is the
prevention of tumor cell proliferation during the post-operative period prior to start of
adjuvant radiotherapy.

In this study, the investigators will use low energy x-rays (photons) to treat spine lesions
during kyphoplasty. The IORT device used will be the Intrabeam®, which is a miniature X-ray
generator that produces low-energy X-rays: electrons are accelerated with a voltage of 30-50
kilovolts (kV) and hit a gold target at the tip of the drift tube. At this point the
low-energy radiation is generated and emitted isotropically, similar to a point source. Due
to its sharp dose fall off, minimal radiation protection is required in the operating room.
The ultimate goal is to treat tumor cells with optimal sparing of spinal cord. (Please refer
to Section 2.4 for more information on Intrabeam®).

Researchers at the University Medical Center in Mannheim, Germany completed a phase I trial
assessing the tolerability of the Kypho-IORT procedure. Investigators reported their
experience on performing the Kypho-IORT procedure in 18 patients (twenty-one vertebral
lesions) with unstable or painful spinal metastases. The researchers used Intrabeam® to
deliver 8Gy at 5mm distance from the spinal applicator surface using 50kV x-rays. The median
age was 63 years and median follow up was 4.5 months (range, 1-10 months).

The procedure was well-tolerated. The median surgical time was 70 minutes (range, 53-173
minutes), which included radiation delivery time of approximately two minutes. Of the 21
vertebral lesions, 18 were treated successfully (86%). During the procedure, 78% of patients
were noted to have asymptomatic paravertebral para-methoxymethamphetamine (PMMA) cement
leakage. None of the treated patients had delayed wound healing, spinal or nerve root
compression, paresthesia, new neurological deficit, or skin toxicity.

In terms of pain relief, the median visual analog pain score (VAS) was 5 prior to procedure.
The VAS decreased to 2.5 on the first post-procedure day. At six weeks, 12 of the 18 patients
were available to be evaluated and reported a median VAS score of 0/10. 67% of the patients
required analgesic medication for pain relief prior to procedure, but decreased to just 30%
at six weeks. Furthermore, imaging studies were available for 15 of the 18 patients,
revealing 93% (14/15) patients had stable disease. Only one patient had progressive disease
based on radiographic evidence, but this patient did not require any additional intervention.

INTRABEAM:

The Intrabeam® machine delivers low energy 50-kV photons directly to a target volume. The
device generates electrons and then, accelerates them in a sealed vacuum probe (drift tube,
measures 10 cm long and 3.2 mm in outer diameter). This drift tube, located within the x-ray
spectrometer (XRS) unit, incorporates a gold target on the inside surface of its tip. When
the accelerated electrons collide with the gold target at the end of the drift tube, photons
are generated and dispersed in an isotropic dose distribution. The X-ray source itself is
mounted on a balanced floor stand with six degrees of freedom to provide various treatment
positions. The Intrabeam® system is calibrated for quality assurance prior to each treatment.

For the Kypho-IORT procedure, specially designed spinal applicator tip is used. This sterile
applicator tip consists of a plastic head, which attaches to the drift tube and is then,
placed inside a stainless steel tube (metallic sleeve). The applicator tip protects the drift
tube from bending. The applicator is made of plastic in order to minimize the absorption and
attenuation of the photons. Under fluoroscopic guidance, the applicator tip is guided though
the metallic sleeves to the placed in mid-point/mid-plane of the vertebral lesion.

Due to the steep dose fall-off, a high dose to the vertebral lesion can be delivered, with
maximum sparing of spinal cord. A radiation dose of 8 Gy at a distance of 5 mm from the
applicator surface will be prescribed. This correlates to an approximate dose of 91 Gy at the
applicator surface, 45 Gy at a distance of 1mm (from the applicator surface), 27Gy at 2mm,
and 8Gy at 5mm. Further dose fall off is approximated: 2.4Gy at 10mm, 0.8Gy at 15mm, and
0.4Gy at 20mm. Assuming minimal distance of 15mm to the spinal cord, then, the spinal cord
would receive less than 1Gy.

Study Design:

The combination of intraoperative radiotherapy with kyphoplasty will provide immediate
vertebra stabilization, durable pain relief, and sterilization of tumor cells in a single
outpatient procedure. To this date, this procedure has not been performed in the United
States. The investigators plan to conduct a phase I trial of Kypho-IORT at the Loyola
University Medical Center.

Inclusion Criteria:

- Metastatic patients from solid tumor

- Estimated life expectancy of at least 3 months

- Age >= 50 years.

- Karnofsky Performance Status >= 70%

- Numeric Pain Intensity Score >= 3

- 10% or more loss of vertebrae height

- Adequate organ and marrow function as defined below:

- International normalized ratio (INR)/ prothrombin time (PT) within normal
institutional limits

- leukocytes >= 3,000 microliter (mcL)

- Absolute neutrophil count >= 1,500 mcL

- Platelets >= 100,000 mcl

- Total bilirubin within normal institutional limits

- Abnormal aspartate transaminase (AST or SGOT) or alanine transaminase (ALT or SPGT)

- Abnormal creatinine

- Ability to understand and the willingness to sign a written informed consent

Exclusion Criteria:

- Patients who have had prior external beam radiotherapy or surgery in the area of
planned intervention

- Previous radiopharmaceuticals (i.e, Ra-222, Sr-90, etc) within 30 days of procedure

- Patients who are receiving systemic therapy (chemotherapy, hormonal, immunotherapy,
bisphosphonates, etc) or other investigational agents are eligible if the systemic
therapy can be safely held two weeks prior to procedure. These therapies may be
resumed two weeks after the procedure

- Primary hematologic malignancies

- Patients with clinical or radiographic evidence of spinal cord or cauda equine
compression or effacement

- Chronic vertebrae fracture of greater than 6 months or coexisting bilateral pedicle
fracture

- Previous kyphoplasty in the same area

- Patients with severe spinal deformity requiring open reconstruction or extreme
adiposity, in which determining placement of metal sleeve would be difficult by
fluoroscopy (limited bone margin)

- History of allergic reactions attributed to compounds of similar composition to agents
used for kyphoplasty

- Uncontrolled medical illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- Pre-menopausal female