1

Stanley H. Benedict, Ph.D.University of Virginia

Kamil Yenice, Ph.D.University of Chicago

AAPM 2008 50th Annual Meetin g, Hous ton, TexasTherapy Contin uing Educat ion Course: SBRT: I & IIMonday, Jul y 28, 2008: 7:30 – 9:25AM

Stereotactic Body Radiation Therapy (SBRT) II:Physics and Dosimetry Consideratio ns

Stereotactic Body Radiation Therapy (SBRT) I:Radio biology and Clinical Expe rien ce

Brian Kavanagh, M.D., MPHUniversity of Colorado

Eric Chang, M.D.UT MD Anderson

Conflict of interestdisclosure

I haveno conflict of interest to disclose.

OutlineEvolution from conventionalRT to SRSto SBRT

Epidemiology, Rationale, Indicationsusing SBRTfor spinal metastases

Radiobiologyof SBRT

MD Anderson clinical pathwayfor spinal metastases

Summaryof Results from Li terature

Casepresentations

Summaryandconclusion

•Historical ly fractionated RT required large safetymargins~2cm around tumor for treatment uncertainties

•Associated with unacceptable toxicity at singledoselevelsneededfor tumor response

•CT-treatment planning, and hi-precision targeting withstereotaxy has permitted safedelivery of single-doseRT to intracra nial lesions(SRS)with very small tono margins

IG-IMSRT Evolution

2

•SRSfor brain metastasisyields:1-, 2-yr FFP 50% for 15--18Gy

and>80% for 22-24Gy

(Vogelbaum, J Neurosurg 104:907-12,2006)

•Current SBRT technology includesIG robotic techniques,MLC,inverseplanning software to generate IMRT plansconforming to tumor with steepdosegradientsneedednear OARs suchas spinal cord

IG-IM SRT Evolution Evolution of intracranial SRSto SBRT…

IntracranialSRS Extracranial SBRTdelivery systems

3

93 pts18-24 Gy x 1Spinal cord <12-14 GyCauda max 15.6GyLC 90%F/U 15mosOS 15mos

IJROBP 71:484-90,2008

Background on Spinal MetastasesA common sequelae of cancer, present in 30 – 70% patients at

post mortem examination, of which 14% will be symptomatic (pain, neurologic sx’s) at sometime during their illness1

40% of skeletal metastases occur in the spine which is themost common osseous site of tumor spread

Conventional radiation therapy widely used but is inherently limited by spinal cord tolerance

1Perrin RG. Metastatic tumors of theaxial spine.Curr Opin Oncol 1992:4:545-532

Epidemiologyof SpinalMetastases

Klimo , P. et al. Oncol ogi st2004;9:188 -196

SBRT

SBRT?

4

RATIONALE

• Manyptsdevelop recurrentor progressivepain,tumorprogressionor neurologic deteriorationdespiteconventional externalbeamirradiation,radiopharmaceuticals,surgery,or systemic therapy

• Patientsare very interestedin noninvasivetreatmentoptionsfor spinal metastaseswhich arenot amenableto orare refractory to conventionalirradiation

GENERAL INDICATIONS

LIMITED DISEASE - Newly diagnosed solitary or oligo- spinal metastases

PRIMARY - “Radioresistant” subtypes

POST-OP – adjuvant or elective treatment

SALVAGE - surgical or RT recurrences

Spinal instability is a contraindi cation

“Therapeutic Window” for conventionalRT

Radiosensitive lymphomas, germcell tumorsetc.

5

Previously irradiatedspinalcord,melanomasRenal cell cancer, sarcomasetc.

Little or notherapeuticwindow existsforconventionalirradiation

SBRT dosimetrically widensthe therapeuticwindowbylowering doseto theOAR

OAR

Astrahan M, IJROBP 71:3:963,2008

DT is transition dose at which final porti on of curve becomelinear

L imitations in the linear-quadratic model for high doses

Astrahan M, IJROBP 71:3:963,2008

6

Park C, Timmerman RD, IJROBP 71:3:963-4,2008.

Single Fraction Equivalent Dose(SFED) vs BED

For high doseablative RT

Defined -asdosein a singlefx that would havesamebiological effect asany largedaily dose

fractionation regimen

Park C, Timmerman RD, IJROBP 71:3:963-4,2008.

Park C, Timmerman RD, IJROBP 71:3:963-4,2008

80%

10%20%

50%

90%

(a)

90%

80%

50%

20%B

C

(b)

A

Spinal Cord Radiation Exposure

Ryu S et al. Cancer109: 628-36, 2007

Henry Ford group proposes 10 Gy to 10% spinal cord astolerance

7

White Matter Necrosisof Rat spinal cord

•Major causeof paralysis•Occurs within 120 - 210 daysafter irradiation 20 Gy x 1•Pathogenesisfocusedon either primary glial or vascular

ori ginCharacterizedby demyelination, lossof axons,focal

necrosis,liquefactive necrosis after > 20 Gy x 1Vascular edema is usually associatedwith development

of white matter necrosis

Bijl HP et al. Van Der Kogel AJ, IJROBP 52:205-11,2002

20mm 8mm 4mm 2mm

Single

Bijl HP et al. Van Der Kogel AJ, IJROBP 52:205-11,2002

IsoeffectDose(ED50) according to irradiated length of rat cord

Bijl HP et al. Van Der Kogel AJ, IJROBP 52:205-11,2002

CentralBeam

GrazingLateralBeams(constantdepth doseprof ile)

High precision proton irrad iation of rat spinal cord

Bijl HP et al, IJROBP 61:543-551,2005

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White matternecrosisin left latcolumn aftergrazing irradi ation

Extensive whiteMatter necrosisinDorsal column

No lesionsin grayMatter or lateralcolumnsBijl HP et al, IJROBP 61:543-551,2005

Regional Differencesin Radiosensitivity in Rat Spinal Cord

Full widthAndLateralbeam

CentralBeam

Dose-responseCurvesfor Paralysis

Bijl HP et al, IJROBP 61:543-551, 2005

Bath/ShowerDose-responseof Paralysisof Limbs toUnmodulatedProtons in Rat Cervical Spinal Cord

Spinal cord toleranceof relatively small volumes(shower)stronglyaffectedby low doseirra diation (bath)

Bijl HP et al. IJROBP 64:1204-10,2006

Referral fromneurosurgerymedicaloncologyradiationoncologyself referral

Multi -disciplinaryTumor board• Patient selection•Discussionof complex cases•Triaging candidates

Jointconsultationpain,QOL assessment,Neurological exam,

informedconsent,video,Protocol registration

SBRTsimulation1. immobilization2. intrathecalcontrast3. CT acquisition

IMRT treatmentplanningQ/A dosimetry-film-ion chamber

Treatment setupCT acquisitionimagefusion, DRR,port film, delivery

Protocol follow-up q3 monthspain,QOL,neuroexam,MRI

SpinerecurrenceOr newdisease

Clinical Pathway for Stereotactic Body Radiotherapy program

9

013/15

Pain relief

12mo39.6Mets18M il ker-zabel

2003

3 severe

mypthy

84%

Symptomatic

improvement

9mo16-25/

1-5

Mets74Gibbs

2007

4/222cases

(1.8%)

>80%9-23mo222Total

1 (3%)3 increased

symptoms

23mo16-30

/1-5fx

Benign32Dodd

2006

0

M81%LC

11mo70/33

20/5

Primary and

metastases

35Yamada

2005

02 progression12mo59.4-70.2/33-38fxs

20 (20-55.8)/4-31fxs

Primary and

metastases

16Bilsky

2004

085%

control

9mo30/5 or

27/3

Mets63Chang

2007

cxsOutcomeF/UDosePathologyNSeries

Selectedstereotactic spineradiation therapyseries(FRACTIONATED)Selectedstereotactic spineradationseries(SINGLE SESSION)

2radiculit

1 radnecrosis

Painrelief

32/34tumors

NA25/10+6-8x1

26mets

9prim

31Benzil

2004

4/656

(0.6%)~90%2-45mos8-25656Total

03worse2316-30/1-5fxsBenign19Dodd

2006

0LTC

90%

21(3-53)20(12-25)Mets336Gerszten

2007

090%15 (2-45)18-24Mets93Yamada

2008

1 radiation

injury

85% painrelief

6.4 (0.5-49)8-18Mets177Ryu

2007

cxsOutcomeF/u

(mos)

Dose

(Gy)

PathNSeries

M.D. ANDERSON PHASEI AND II DATA Patient Positioning Accuracy and Safety Data

Int J Radiat Oncol Biol Phys 59:1288-1294, 2004

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Dates enrolled Nov 2002 – Mar 2005Patientsn 63Male 38 (60%)Female 25 (40%)

Age (yrs)Median 59Range 21-82

HistologyRenal cell 25 (39.7%)Breast 9 (14.3%)Sarcoma 8 (12.7%)Lung 7 (11.1%)Melanoma 2 (3.2%)Colon 1 (1.6%)Unk Primary 2 (3.2%)Other 9 (14.3%)

KPS score60 4 (6.3%)70 17 (27%)80 17 (27%)90 25 (39.7%)

RESULTS - Patient Characteristics RESULTS - Tumor CharacteristicsTumor volume (cc)median 37.4range 1.6 –357.9

Spinal Metastases (n)One 51Two 12

Lesion LocationSpinal 61Paraspinal 13

Levelcervical 5 (6.7%)thoracic 43 (57%)lumbar 26 (34.7%)sacral 1 (1.3%)

RESULTS - Follow-up of Tumor and Vital Status

Vital Statusalive 26 (41%)dead 37 (59%)

Tumor statusStable 57 (77%)Progressed 17 (23%)

Follow-upMedian 21.3mosRange 0.5– 49.6 mos

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PAIN AND SYMPTOM CONTROL

Narcotic use decreased from 60% (baseline), 44% (3mos), 36% (6mos)

MDASI showed reduction in pain (p<0.001), sleep disturbance(p<0.01),with no added impairment of daily function, while fatigue severityunchanged.

Pain incidence Pain severity

25%

6.7%

12

Neurotoxicity evaluation

Grade 1headache(1)

numbness(1)*

tingling (4)*

numbnessand tingling (1)*

(all reversible)

Grade 2 -4none

Grade 3-4 toxicity

Grade3

Nausea(1)

Fatigue(1)

Non-cardiacchestpain (1)

Pain,severetongueedema,trismus(1)

Grade4

None

ReportedToxicity in Literature CLINICAL CASES

FractionatedSBRT

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Case1: 46 M previouslyirradiated(40 Gy in 16 fxs)Lung cancerT12 metastasis progressed (biopsy proven)

July2004

July2005

Case2: 52 M solitary renal cell carcinoma metastasis centered on cervical vertebrae 2

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Case3: 20 F plasmacytomacausingbackpain, failedconventionalRT andsurgery

-Extradural extension causing cord compression at T10

-Needle bx revealed plasmacytoma-45 Gy in 25 fractions to T9-11

-3 mos later, recurred below: Epidural dz T11-12. RT was not an option at the time

-Laminectomy, facetectomy, resection tumor-4 mo later recurred above: Rt T7-8 neuroforamen-Received SBRT to epidural disease-Attending college and remains disease-free 4

years later

Neuroforaminal and Epidural Disease

Patternsof Failure

15

Summaryandconclusions

• LiteratureandphaseI/II datasupport thesafetyand effectivenessof stereotacticbodyradiosurgeryfor thespine

• POFdatasuggestroutinelytreatingthepediclesand posterior elementsusing a wide bonymarginposterior to thediseasedvertebrae.

• Prospectivetrials areneededto determinethetruespinal cord toleranceandto compareefficacy ofSBRS againstconventionalRT

All thefollowing are indicationsforperformingstereotacticbody

radiosurgeryfor spinal metastasesEXCEPT?:

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25%

25%

25%

25% 1. Solitaryor oligometastatic disease

2. Failure of prior XRT or surgery

3. Spinalinstability

4. Grossresidualdiseaseafter surgery

Basedon pooledpublisheddataon spinal metastases,SBRTis associatedwith a crude local control rate of:

25%

25%

25%

25%

10

1. 65-70%

2. 70-75%

3. 75-80%

4. 80%or higher

Thefollowing statements regarding spinal cordtoleranceto singlesessionsteretoactic body

radiosurgery(SBRS)are trueEXCEPT:

25%

25%

25%

25%

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1. Humanspinal cordtoleranceunknown

2. <12Gy hasbeenreported assafe

3. 10 Gy to 10%of thespinal cord volume4. Ratspinal cord tolerance canbedirectly

appliedto humans