Radiation Oncology and Neurosurgery departments Vertebral Intracavitary Cement & Samarium (VICS). A Novel Approach to treat Painful Vertebral Metastases H. Ashamalla, M. Macedon,, E. Cardoso, L. Weng,, B. Mokhtar, A. Guirguis, N. Panigrahi. Radiation Oncology and Neurosurgery departments New York Methodist Hospital, Weill Medical college of Cornell University, NY.

Background Each year, more than 100,000 patients in the U.S. develop bone metastases. Bone is the third most common site of metastatic disease after liver and lung Up to 40% of patients presenting with bone mets. will have spinal/vertebral mets, 90% of whom will develop severe axial pain

Metastatic Bone Disease Epidemiology - Etiology Estimated Number of Persons Living with Cancer1 Number of New Cases in 20041 Incidence of Bone Metastases2 Breast 2,184,125 (24%) 217,440 (16%) 65-75% Prostate 1,838,653 (20%) 230,110 (17%) Bladder 521,945 (6%) 60,240 (4%) 40% Lung 388,538 (4%) 173,770 (13%) 30-40% Thyroid 273,642 (3%) 23,600 (2%) 60% Other 4,013,458 (43%) 705,160 (52%) Total 9,220,361 (100%) 1,368,030 (100%) 1. SEER Cancer Statistics Review 1975 – 2001, National Cancer Institute 2. Coleman, R.E. Cancer Treatment Reviews. 2001;27:165-176.

Metastatic Bone Disease Metastasis Sites Most common sites of metastasis Vertebra (69%) Pelvis (41%) Femur (25%) Hip (14%) Median time from cancer diagnosis to bone metastasis is 30 months

Vertebral Compression fractures (VCF)- Metastatic cancer in the bone causes skeletal complications every 3 to 4 months. 17 – 50% of patients with metastatic breast cancer will develop VCFs annually. Median time to first fracture among breast cancer patients (not on bisphosphonate) is 12.8 months.

Metastatic Bone Disease Treatment Goals Reduce pain Eradicate or reduce tumor when primary tumors are involved Prevent neurologic complications Treat pathologic fractures and prevent recurrent fracture

A) Surgical Treatment Operative Management Vertebral column reconstruction A or P decompression with internal fixation Oncology patients are generally poor candidates for open surgery due to soft bone/tumor mass and co-morbidities Minimally Invasive Procedures Kyphoplasty Vertebroplasty

Balloon Kyphoplasty Patient placed in lateral decubitus position Trochar inserted into anterior vertebral body under fluoroscopic guidence Curretting performed for tissue sample Balloon inflated to decompress the fracture and to open up space for cement injection Balloon removed and PMMA bone cement injected into cavity to stabilize the vertebra

Balloon Kyphoplasty

Balloon Kyphoplasty Shown to significantly reduce pain associated with VCF in patients with metastatic bony lesions However, this procedure does not address the neoplastic component of the problem

B) Radiation Treatment for Bony Metastasis External radiation Radionuclides – systemic administration, localize to all bony mets Strontium-90 Samarium-153

Samarium-153 Created by bombarding Samarium-152 (stable) with neutrons Comes from manufacturer complexed to EDTMP Beta particles from Sm-153 travel 3.1mm in tissue, 1.7mm in bone Typically administered at the dose of 1mCi/kg

Samarium-153 (systemic) When given IV, Sm-153-EDTMP (Quadramet) has an affinity for bone and will concentrate in areas of high bone turnover, especially bony metastasis Mechanism of relief of bone pain is unknown, but may be due to suppression of the growth of the tumor cells from radiation Major adverse effect of systemic administration is hematologic toxicity with nadir at 3-4wks: Leukopenia 60% Thrombocytopenia 69% Decr. Hemoglobin 40%

Vertebral Intracavitary Cement and Samarium {VICS} Procedure Materials Methods

Vertebral Intracavitary Cement and Samarium {VICS} A novel approach to bony metastasis Employs combination of balloon kyphoplasty and anti-tumoral activity of Sm-153 injected directly into the affected vertebra

Objectives Study feasibility of intravertebral administration of Sm-153 with kyphoplasty Assess procedure-related morbidities (specifically hematological) related to procedure Monitor pain relief and durability of response

Eligibility Inclusion criteria: Exclusion criteria Documented bone mets with intact anterior wall of vertebra Recurrent pain or progression of metastases in areas treated by prior external RT Acceptable candidate for kyphoplasty Good performance status, Karnofsky ≥ 60 Exclusion criteria Epidural soft tissue component Cord impingement or compression Inability to undergo anesthesia

IRB approval was obtained After signing consent, all patients were assessed for pre-op pain level. Pre-op MRI, CT and/or bone scan, confirming presence of bony metastasis.

VICS Procedure Insertion of trochar and balloon as with the balloon Kyphoplasty approach Under tight radiation safety measures, Sm-153 in escalating doses(1-4mCi) is co-injected and mixed with the cement as it is injected into the cavity of the vertebra using a three way valve. Equipment, drapes, and room are surveyed post-operatively. Contaminated needles etc. are taken to the radioactive lab to allow for safe decay

Procedure Serial Samarium nuclear scans were obtained post-op on days 0, 1, 2, and 4. F/U bone scans and MRI’s were obtained at least 1 month post procedure Serial blood counts were also monitored

Patients 33 procedures were performed in 26 patients (18 males and 8 females). Seven patients had procedures performed in two vertebral levels. The mean age of the cohort was 64 years (range 33 to 86). The mean pain score prior to treatment was 8.8/10.

Patients Type # % Lung 12 46 Prostate 5 19 Colon 2 7.5 Multiple Myeloma Urinary Bladder 1 4 Ovary Breast Stomach Head & neck

Distribution of Treated Vertebrae Of the 33 vertebrae treated, 20 were in the lumbar spine, 12 were in the thoracic spine and 1 was in the sacral spine.

Escalating Doses of Samarium Dose of samarium (mCi) Number of Procedures (Patients) 1 4(3) 2 7(7) 2.5 6(5) 3 8(5) 4 8(6)

A) Patients’ tolerance: There was no mortality or procedure-related complications. There was no hematological toxicity, no significant change in the WBC, Hg and platelets was seen at one month after the procedure. Estimation of dose contribution to spinal cord using diagrammatic and inverse square models was 40 ± 6 cGy.

B) Pain control: All patients tolerated procedure very well. The mean pain score (VAS) improved from 8.5 (±2) prior the procedure to 2.6 (±3.1) one day after the procedure (p<0.0001). The ECOG performance scores only improved marginally from 2.4 (±1) before to 2 (±1) after (p=0.035, one-sided test).

C) Accuracy and Feasibility: Whole body Samarium scans confirmed the local absorption injected 153Samarium-EDTMP in the intended vertebra in 32 out of the 33 injections. One patient did not demonstrate clear absorption of the 153Samarium-EDTMP in the site with no evidence of spillage nor there was systemic absorption. No appreciable radiation leakage or spillage was encountered.

Localization of Sm-153 in the injected vertebra persistently shown at 3, 24, 48, and 96 hours of post injection. 3 hrs 24 hrs 48 hrs 96 hrs

C) Accuracy and Feasibility: Prior to treatment (A B) low-signal lesion and hyperintensity (arrows) in the anterior aspect of the vertebral body. 12 months after procedure (C , D): local control of the disease is observed

C) Accuracy and Feasibility: On the left side there is evidence of targeting at the injected L2. Decrease in signal from day 1 to day 3 after treatment is observed. The decline of radioactivity was consistent with the known half life of 153Sm and followed the physical in-vitro decay. On the right side, the curve shows the mean in vivo decay of 153Sm in 11 patients (± 1SD) as compared to in vitro decay.

D) Systemic absorption Variable systemic absorption was evident in Samarium scans in all patients (9-75%). The mean ratio between the concentrations of 153Sm in the target vertebrae and normal tissues was 37±26.3 (ranging from 9.3 to 92.1). Patients with wide spread bone disease had demonstrated Samarium absorption in distant metastatic sites. Asymptomatic extravasation of cement/Samarium was encountered in 6 vertebrae (6/33).

Ant. Post Ant. Post Bone scan Samarium scan Absorbed Sm-153 targets other skeletal lesions: right clavicle, manubrium, and right posterior ilium. All these lesions were present on pre-treatment bone scan. Ant. Post Ant. Post Bone scan Samarium scan

D) Cytotoxic effect: Reduced intensity of bone tracer (99mTc-MDP) uptake was studied in 8 patients The ratio of mean counts in the intended vertebra to soft tissue after correction to background was 12.1 prior to the procedure dropped down to 6.9 at the last follow up scan (3-12 months)

D) Cytotoxic Effect Whole-body bone scans before treatment, at 8 and 22 months post-treatment. The new scan reveals reduction of uptake at the treated vertebra L1, while new area of uptake appears at L2.

Drawbacks to VICS Radiation Safety: Open liquid radiation source. Obtaining Sm-153 on a timely basis from manufacturer Unsuitable for open procedures

Conclusions Vertebral Intracavitary Cement and Samarium {VICS} Injection of Sm-153 is feasible and can be performed safely No adverse effects were seen as a result of the procedure No hematologic toxicities were seen Indirect evidence for the cytotoxicity of the procedure is observed through reduction of the intensity of uptake in bone scan.

Future Directions Need direct head-to-head comparison of VICS with balloon Kyphoplasty to determine if there is any net change in the duration of response, or in level of pain relief