VVertebral ertebral IIntracavitary ntracavitary CCement ement & & SSamarium (amarium (VICSVICS).).

A Novel Approach to treat A Novel Approach to treat Painful Vertebral MetastasesPainful Vertebral Metastases

H. Ashamalla, M. Macedon,, E. Cardoso, L. Weng,, B. H. Ashamalla, M. Macedon,, E. Cardoso, L. Weng,, B. Mokhtar, A. Guirguis, N. Panigrahi. Mokhtar, A. Guirguis, N. Panigrahi.

Radiation Oncology and Neurosurgery departmentsRadiation Oncology and Neurosurgery departmentsNew York Methodist Hospital, Weill Medical college of New York Methodist Hospital, Weill Medical college of

Cornell University, NY.Cornell University, NY.

BackgroundBackground

Each year, more than 100,000 patients in Each year, more than 100,000 patients in the U.S. develop bone metastases. the U.S. develop bone metastases.

Bone is the third most common site of Bone is the third most common site of metastatic disease after liver and lung metastatic disease after liver and lung

Up to 40% of patients presenting with Up to 40% of patients presenting with bone mets. will have spinal/vertebral mets, bone mets. will have spinal/vertebral mets, 90% of whom will develop severe axial 90% of whom will develop severe axial pain pain

Metastatic Bone DiseaseMetastatic Bone DiseaseEpidemiology - EtiologyEpidemiology - Etiology

1. SEER Cancer Statistics Review 1975 – 2001, National Cancer Institute

2. Coleman, R.E. Cancer Treatment Reviews. 2001;27:165-176.

Estimated Number Estimated Number of Persons Living of Persons Living

with Cancerwith Cancer11

Number of New Number of New Cases in 2004Cases in 200411

Incidence of Incidence of Bone Bone

MetastasesMetastases22

BreastBreast 2,184,125 (24%)2,184,125 (24%) 217,440 (16%)217,440 (16%) 65-75%65-75%

ProstateProstate 1,838,653 (20%)1,838,653 (20%) 230,110 (17%)230,110 (17%) 65-75%65-75%

BladderBladder 521,945 (6%)521,945 (6%) 60,240 (4%)60,240 (4%) 40%40%

LungLung 388,538 (4%)388,538 (4%) 173,770 (13%)173,770 (13%) 30-40%30-40%

ThyroidThyroid 273,642 (3%)273,642 (3%) 23,600 (2%)23,600 (2%) 60%60%

OtherOther 4,013,458 (43%)4,013,458 (43%) 705,160 (52%)705,160 (52%)

TotalTotal 9,220,361 (100%)9,220,361 (100%) 1,368,030 (100%)1,368,030 (100%)

Metastatic Bone DiseaseMetastatic Bone DiseaseMetastasis SitesMetastasis Sites

Most common sites of Most common sites of metastasismetastasis

Vertebra (69%)Vertebra (69%) Pelvis (41%)Pelvis (41%)

Femur (25%)Femur (25%)

Hip (14%)Hip (14%)

Median time from cancer Median time from cancer

diagnosis to bone diagnosis to bone

metastasis is 30 monthsmetastasis is 30 months

Vertebral Compression fractures Vertebral Compression fractures (VCF)-(VCF)-

Metastatic cancer in the bone Metastatic cancer in the bone causes skeletal complications causes skeletal complications every 3 to 4 months.every 3 to 4 months.

17 – 50% of patients with 17 – 50% of patients with metastatic breast cancer will metastatic breast cancer will develop VCFs annually.develop VCFs annually.

Median time to first fracture Median time to first fracture among breast cancer patients among breast cancer patients (not on bisphosphonate) is 12.8 (not on bisphosphonate) is 12.8 months.months.

Metastatic Bone DiseaseMetastatic Bone DiseaseTreatment GoalsTreatment Goals

Reduce painReduce painEradicate or reduce tumor when primary Eradicate or reduce tumor when primary

tumors are involved tumors are involved Prevent neurologic complications Prevent neurologic complications Treat pathologic fractures and prevent Treat pathologic fractures and prevent

recurrent fracturerecurrent fracture

Operative ManagementOperative ManagementVertebral column reconstructionVertebral column reconstructionA or P decompression with internal fixationA or P decompression with internal fixationOncology patients are generally poor candidates for Oncology patients are generally poor candidates for

open surgery due to soft bone/tumor mass and co-open surgery due to soft bone/tumor mass and co-morbiditiesmorbidities

Minimally Invasive ProceduresMinimally Invasive ProceduresKyphoplastyKyphoplastyVertebroplastyVertebroplasty

A) Surgical TreatmentA) Surgical Treatment

Balloon KyphoplastyBalloon Kyphoplasty Patient placed in lateral decubitus positionPatient placed in lateral decubitus position Trochar inserted into anterior vertebral body under Trochar inserted into anterior vertebral body under

fluoroscopic guidencefluoroscopic guidence Curretting performed for tissue sampleCurretting performed for tissue sample Balloon inflated to decompress the fracture and to open up Balloon inflated to decompress the fracture and to open up

space for cement injectionspace for cement injection Balloon removed and PMMA bone cement injected into Balloon removed and PMMA bone cement injected into

cavity to stabilize the vertebracavity to stabilize the vertebra

Balloon KyphoplastyBalloon Kyphoplasty

Balloon KyphoplastyBalloon Kyphoplasty

Shown to significantly reduce pain Shown to significantly reduce pain associated with VCF in patients with associated with VCF in patients with metastatic bony lesionsmetastatic bony lesions

However, this procedure does not address However, this procedure does not address the neoplastic component of the problemthe neoplastic component of the problem

B) Radiation Treatment for Bony B) Radiation Treatment for Bony MetastasisMetastasis

External radiationExternal radiationRadionuclides – systemic administration, Radionuclides – systemic administration,

localize to all bony metslocalize to all bony metsStrontium-90Strontium-90Samarium-153Samarium-153

Samarium-153Samarium-153

Created by bombarding Samarium-152 Created by bombarding Samarium-152 (stable) with neutrons(stable) with neutrons

Comes from manufacturer complexed to Comes from manufacturer complexed to EDTMP EDTMP

Beta particles from Sm-153 travel 3.1mm Beta particles from Sm-153 travel 3.1mm in tissue, 1.7mm in bonein tissue, 1.7mm in bone

Typically administered at the dose of Typically administered at the dose of 1mCi/kg1mCi/kg

Samarium-153 (systemic)Samarium-153 (systemic) When given IV, Sm-153-EDTMP (Quadramet) When given IV, Sm-153-EDTMP (Quadramet)

has an affinity for bone and will concentrate in has an affinity for bone and will concentrate in areas of high bone turnover, especially bony areas of high bone turnover, especially bony metastasismetastasis

Mechanism of relief of bone pain is unknown, Mechanism of relief of bone pain is unknown, but may be due to suppression of the growth of but may be due to suppression of the growth of the tumor cells from radiationthe tumor cells from radiation

Major adverse effect of systemic administration Major adverse effect of systemic administration is hematologic toxicity is hematologic toxicity with nadir at 3-4wks:with nadir at 3-4wks: LeukopeniaLeukopenia 60%60% ThrombocytopeniaThrombocytopenia 69%69% Decr. HemoglobinDecr. Hemoglobin 40%40%

VVertebral ertebral IIntracavitary ntracavitary CCement ement and and SSamarium amarium {{VICS}VICS}

ProcedureProcedure

MaterialsMaterials

MethodsMethods

VVertebral ertebral IIntracavitary ntracavitary CCement ement and and SSamarium amarium {{VICS}VICS}

A novel approach to bony metastasis A novel approach to bony metastasis Employs combination of balloon Employs combination of balloon

kyphoplasty and anti-tumoral activity of kyphoplasty and anti-tumoral activity of Sm-153 injected directly into the affected Sm-153 injected directly into the affected vertebravertebra

ObjectivesObjectives

Study feasibility of intravertebral Study feasibility of intravertebral administration of Sm-153 with kyphoplastyadministration of Sm-153 with kyphoplasty

Assess procedure-related morbidities Assess procedure-related morbidities (specifically hematological) related to (specifically hematological) related to procedureprocedure

Monitor pain relief and durability of Monitor pain relief and durability of responseresponse

EligibilityEligibility

Inclusion criteria:Inclusion criteria: Documented bone mets with intact anterior wall of Documented bone mets with intact anterior wall of

vertebravertebra Recurrent pain or progression of metastases in areas Recurrent pain or progression of metastases in areas

treated by prior external RTtreated by prior external RT Acceptable candidate for kyphoplastyAcceptable candidate for kyphoplasty Good performance status, Karnofsky Good performance status, Karnofsky ≥ 60≥ 60

Exclusion criteriaExclusion criteria Epidural soft tissue componentEpidural soft tissue component Cord impingement or compressionCord impingement or compression Inability to undergo anesthesiaInability to undergo anesthesia

IRB approval was obtainedIRB approval was obtainedAfter signing consent, all patients were After signing consent, all patients were

assessed for pre-op pain level.assessed for pre-op pain level.Pre-op MRI, CT and/or bone scan, Pre-op MRI, CT and/or bone scan,

confirming presence of bony metastasis.confirming presence of bony metastasis.

VICS ProcedureVICS Procedure

Insertion of trochar and balloon as with the Insertion of trochar and balloon as with the balloon Kyphoplasty approachballoon Kyphoplasty approach

Under tight radiation safety measures, Sm-153 Under tight radiation safety measures, Sm-153 in escalating doses(1-4mCi) is co-injected and in escalating doses(1-4mCi) is co-injected and mixed with the cement as it is injected into the mixed with the cement as it is injected into the cavity of the vertebra using a three way valve.cavity of the vertebra using a three way valve.

Equipment, drapes, and room are surveyed Equipment, drapes, and room are surveyed post-operatively. Contaminated needles etc. are post-operatively. Contaminated needles etc. are taken to the radioactive lab to allow for safe taken to the radioactive lab to allow for safe decaydecay

ProcedureProcedure

Serial Samarium nuclear scans were Serial Samarium nuclear scans were obtained post-op on days 0, 1, 2, and 4.obtained post-op on days 0, 1, 2, and 4.

F/U bone scans and MRI’s were obtained F/U bone scans and MRI’s were obtained at least 1 month post procedureat least 1 month post procedure

Serial blood counts were also monitoredSerial blood counts were also monitored

PatientsPatients

33 procedures were performed in 26 33 procedures were performed in 26 patients (18 males and 8 females).patients (18 males and 8 females).

Seven patients had procedures performed Seven patients had procedures performed in two vertebral levels. in two vertebral levels.

The mean age of the cohort was 64 years The mean age of the cohort was 64 years (range 33 to 86). (range 33 to 86).

The mean pain score prior to treatment The mean pain score prior to treatment was 8.8/10. was 8.8/10.

PatientsPatients

Type # % Lung 12 46

Prostate 5 19

Colon 2 7.5

Multiple Myeloma 2 7.5

Urinary Bladder 1 4

Ovary 1 4

Breast 1 4

Stomach 1 4

Head & neck 1 4

Primary Cancer Site

12

5

2

21

1 1 1 1

Lung Prostate Colon

Multiple Myeloma Urinary Bladder Ovary

Breast Stomach Head & neck

Distribution of Treated VertebraeDistribution of Treated Vertebrae

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

Thoracic

Lubmar

Sacral

Escalating Doses of SamariumEscalating Doses of Samarium

Dose of samarium Dose of samarium (mCi) (mCi)

Number of Procedures Number of Procedures (Patients) (Patients)

11 4(3)4(3)

22 7(7)7(7)

2.52.5 6(5)6(5)

33 8(5)8(5)

44 8(6)8(6)

A) Patients’ tolerance:A) Patients’ tolerance:

There was no mortality or procedure-There was no mortality or procedure-related complications. related complications.

There was no hematological toxicity, no There was no hematological toxicity, no significant change in the WBC, Hg and significant change in the WBC, Hg and platelets was seen at one month after the platelets was seen at one month after the procedure. procedure.

Estimation of dose contribution to spinal Estimation of dose contribution to spinal cord using diagrammatic and inverse cord using diagrammatic and inverse square models was 40 ± 6 cGy.square models was 40 ± 6 cGy.

B) Pain control:B) Pain control:

All patients tolerated procedure very well. All patients tolerated procedure very well. The mean pain score (VAS) improved The mean pain score (VAS) improved

from 8.5 (±2) prior the procedure to 2.6 from 8.5 (±2) prior the procedure to 2.6 (±3.1) one day after the procedure (±3.1) one day after the procedure (p<0.0001).(p<0.0001).

The ECOG performance scores only The ECOG performance scores only improved marginally from 2.4 (±1) before improved marginally from 2.4 (±1) before to 2 (±1) after (p=0.035, one-sided test). to 2 (±1) after (p=0.035, one-sided test).

C) Accuracy and Feasibility:C) Accuracy and Feasibility:

Whole body Samarium scans confirmed the Whole body Samarium scans confirmed the local absorption injected local absorption injected 153153Samarium-EDTMP in Samarium-EDTMP in the intended vertebra in 32 out of the 33 the intended vertebra in 32 out of the 33 injections. injections.

One patient did not demonstrate clear One patient did not demonstrate clear absorption of the absorption of the 153153Samarium-EDTMP in the site Samarium-EDTMP in the site with no evidence of spillage nor there was with no evidence of spillage nor there was systemic absorption. systemic absorption.

No appreciable radiation leakage or spillage was No appreciable radiation leakage or spillage was encountered. encountered.

48 hrs 96 hrs24 hrs3 hrs

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

C) Accuracy and Feasibility: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: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 absorptionD) Systemic absorption Variable systemic absorption was evident in Variable systemic absorption was evident in

Samarium scans in all patients (9-75%). The Samarium scans in all patients (9-75%). The mean ratio between the concentrations of mean ratio between the concentrations of 153153Sm Sm in the target vertebrae and normal tissues was in the target vertebrae and normal tissues was 37±26.3 (ranging from 9.3 to 92.1). 37±26.3 (ranging from 9.3 to 92.1).

Patients with wide spread bone disease had Patients with wide spread bone disease had demonstrated Samarium absorption in distant demonstrated Samarium absorption in distant metastatic sites. metastatic sites.

Asymptomatic extravasation of Asymptomatic extravasation of cement/Samarium was encountered in 6 cement/Samarium was encountered in 6 vertebrae (6/33). vertebrae (6/33).

Absorbed Sm-153 targets other skeletal lesions: Absorbed Sm-153 targets other skeletal lesions: right clavicle, right clavicle, manubrium, and right posterior ilium. All these lesions were present on manubrium, and right posterior ilium. All these lesions were present on

pre-treatment bone scan. pre-treatment bone scan.

Ant. Post Ant. PostBone scan Samarium scan

D) Cytotoxic effectD) Cytotoxic effect::

Reduced intensity of bone tracer (Reduced intensity of bone tracer (99m99mTc-Tc-MDP) uptake was studied in 8 patientsMDP) uptake was studied in 8 patients

The ratio of mean counts in the intended The ratio of mean counts in the intended vertebra to soft tissue after correction to vertebra to soft tissue after correction to background was 12.1 prior to the background was 12.1 prior to the procedure dropped down to 6.9 at the last procedure dropped down to 6.9 at the last follow up scan (3-12 months) follow up scan (3-12 months)

D) Cytotoxic EffectD) Cytotoxic Effect

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

Drawbacks to VICSDrawbacks to VICS

Radiation Safety: Open liquid radiation Radiation Safety: Open liquid radiation source.source.

Obtaining Sm-153 on a timely basis from Obtaining Sm-153 on a timely basis from manufacturermanufacturer

Unsuitable for open proceduresUnsuitable for open procedures

ConclusionsConclusions VVertebral ertebral IIntracavitary ntracavitary CCement and ement and

SSamarium amarium {{VICS}VICS} Injection of Sm-153 is feasible and can be Injection of Sm-153 is feasible and can be

performed safelyperformed safelyNo adverse effects were seen as a result No adverse effects were seen as a result

of the procedureof the procedureNo hematologic toxicities were seenNo hematologic toxicities were seen Indirect evidence for the cytotoxicity of the Indirect evidence for the cytotoxicity of the

procedure is observed through reduction procedure is observed through reduction of the intensity of uptake in bone scan.of the intensity of uptake in bone scan.

Future DirectionsFuture Directions

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