Pediatric Medulloblastoma

PediatricMedulloblastoma

JeffBurkeen,MSIV(TexasA&M)

ShaliniMoningi,MSIV

AmandaWalker,MD

StephanieTerezakis,MD

JohnsHopkinsHospital

June10,2014

CasePresentation

• 9yopresentedtotheEDwith3monthhistory

ofintermittentheadacheassociatedwith

abdominalpainand vomiting

– HeadCTrevealeda3cmposteriorfossamass

with6mmtonsillarherniation

• PMH

– Anepisodeofileusat18months

– Otherwiseunremarkable

June10,2014

MRI

BrainMRIrevealedaheterogeneouslyenhancing2.4x2.2x3.0cm

massintheposteriorfossacenteredaroundthe4

ventricle.

T1postcontrast T2FLAIR

June10,2014

MRI

T1postcontrast

Therewasdescentof

cerebellartonsils

throughtheforamen

magnum(7mmbelow

planeoftheforamen

magnum)

Diffusionweighted

imaging(notshown)

revealedrestricted

diffusion,suggesting

highcellularity.

June10,2014

Treatment

• Surgicalresectionwasperformed

• MRIonPOD#1revealednoresidualdisease

• Pathology:medulloblastoma,gradeIV,withoutlarge

cell/anaplasticfeatures.Beta‐cateninstainingwas

negative

• CSFcytology>14dayspostopwasnegativeformalignant

cells

• Baselinelabs,audiometry,IQtestingwereallwithin

normallimits

• Diagnosis:StandardRiskMedulloblastoma

June10,2014

Epidemiology

• Mostcommonchildhoodmalignantbrain

tumor

• 20%ofpediatricCNS tumors

• ~550casesperyearintheUS

• Medianageofpresentationis5‐7yo

• 75%occurinchildren<15yo

• Morecommoninmales(~2:1)

June10,2014

Presentation

• Increasedintracranialpressure:headaches,nausea,

vomiting

• Cerebellarinvolvement:at axicgait

• Ininfants:lossofmilestones,increasedhead

circumference,headtiltduetoCNIVpalsy

• Clinicalexam:papilledema,nystagmus,CN

abnormalies(VImostcommon→"sengsun"sign

withdownwardgaze)

• 50‐75%have<3monthsofsymptoms

June10,2014

WorkUp

• Completehistory

• Completephysicalexamwithfocusonneurological

exam,fundusexam(forpapilledema)

• Labs:CBC,CMP

• Imaging:HeadCTandBrainMRI

• Ancillarytestspriortotreatment:

– Audiometry

– IQtesting

– SerumTSHandgrowthhormone

June10,2014

Workup:CSF

• 30‐40%haveCSFspreadatthetimeof

diagnosis

• CSFsamplingisrarelyobtainedprior to

surgerygiventheriskofherniationin the

settingofincreasedICP

• Ifnotobtainedpre‐operatively,mustwait10‐

14daysaftersurgerytoavoidfalse‐positive

findingsfromsurgicaldebris

June10,2014

ImagingRecommendations

• Pre‐opMRIbrainandspinalcord(post‐opspinecan

givefalsepositives)shouldbeperformed

• Timingofimagingisimportant:

– Post‐opMRIbrainwithin48hours

– IfMRIofspinenotperformedpre‐op,thenmust

wait10‐14daysaftersurgerytoavoidfalse

positives

June10,2014

TypicalImagingFindings

• CT:hyperdenseonnoncontrastCT(reflecting

highcellularity),enhanceswithcontrast

• MRI:welldefined,solid, T1hypointense,T2

hyperintensemass;oftencompresses4th

ventricle

June10,2014

DDxofposteriorfossamass inachild

• Medulloblastoma

• Astrocytoma(usuallypilocyticastrocytoma,

i.e.JPA)

• Ependymoma

• Atypicalteratoidrhabdoidtumor(ATRT)

June10,2014

Histology

• Smallroundbluecelltumor

• MostcommonembryonaltumoroftheCNS(others

includePNETs,ATRT)

• MolecularlydistinctfromPNETs

• 40%haveHomer‐Wrightrosettes

• Moststain+forneuron‐specificenolase,

synaptophysin,andnestin

June10,2014

Othersmallroundbluecelltumors

• LEARNNMR

– Lymphoma

– Ewing’s

– Acutelymphoblasticleukemia

– Rhabdomyosarcoma

– Neuroblastoma

– Neuroepithelioma

– Medulloblastoma

– Retinoblastoma

June10,2014

Histology‐ PrognosticFactors

Poorprognosis

• Largecell/anaplasticvariant

• DiploidDNA

• LOH17p

• p53mutation

• LowTrkC (tyrosinekinase

thatmediatesneuronal

differentiation)

• Her‐2Neu positive

Betterprognosis

• Desmoplasticvariant

• HighTrkCexpression

• β‐catenin

nucleopositivity

June10,2014

Histology

• Variantsofmedulloblastoma

– Classic:mostcommon

– Nodular/desmoplastic:bestprognosis,canbe

treatedwithsurgeryandchemotherapyalone

– Largecell/anaplastic:mostaggressive,always

treatunderhighriskparadigm

• Thistraditionalclassificationwilllikelybephasedout

infavorofmolecularclassification(nextslide)

June10,2014

PrognosticFactors

• Riskstratificationbasedonmolecularprofile

– Group1(~10%):Wnt/β‐cateninpathway,excellent

prognosis,5yrOS95%,usually“classic”histology

– Group2(~30%):Hedgehogpathway,goodprognosis,

peaksininfancyandyoungadults

– Group3(~25%):c‐MYCamplification,poorprognosis,5yr

OSonly50%

– Group4(~35%):neuronalsignature expression,peaksin

childhood,5yrOS50%

*Althoughbeingstudied,molecularanalysisisnotcurrentlypart ofroutine

pathologicev aluation

June10,2014

ModifiedChang’sStaging

• T1:tumor<3cmindiameter

• T2:tumor≥3cmindiameter

• T3a:tumor>3cmandwithextensionintoaqueduct

ofsylviusorforamenofluschka

• T3b:tumor>3cmandwithunequivocalextension

intobrainstem

• T4:tumor>3cmwithextensionpasttheaqueduct

ofsylviusorpastforamenmagnum

June10,2014

ModifiedChang’sStaging

• M0:noevidenceofgrosssubarachnoidor

hematogenousmetastases

• M1:microscopicCSFinvolvement

• M2:grossnodularseedingintracraniallybeyondthe

primarysite(incerebellar/cerebralsubarachnoid

space,3

ventricle,orlateralventricle(s)

• M3:grossnodularseedingofspinalsubarachnoid

space

• M4:metastasesoutsidecerebrospinalaxis

June10,2014

RiskStratification

Features StandardRisk(2/3) HighRisk(1/3)

Age ≥3yearsold <3yearsold

Extentofresection <1.5cm

residual

diseaseafter

resection

Subtotalresection,

1.5cm

2

residualtumor

M‐stage* M0bycraniospinal

MRIandCSF

M+;leptomeningial

seeding

* Note: M stage is prognostic, T stage is not

June10,2014

Surgicaldefinitions

• Neartotalresection(NTR):<1.5cm

2

residual

tumoronpost‐opMRI

• Subtotalresection(STR):51‐90%resection

• Bxonly:<50%resection

– TumorbiopsyisNOTnecessary;patientsshouldgo

straighttosurgery

• 5‐yrEFSis worseinSTRvs.GTR/NTR

June10,2014

Surgeryrisks

• Posteriorfossasyndrome

– 10‐15%ofcases

– Mayoccur12‐24hourspostopandimprovesov er

severalmonths

– SAME

– Swallowingdysfunction

– Ataxia

– Mutism

– Emotionallability

June10,2014

PrincipalsofRadiation

• Inpatients>3yopost‐opRTwithconcurrent

vincristineisdeliveredtotheentirecraniospinalaxis

followedbyaposteriorfossaortumorbedboost

• Protontherapy,IMRT,or3‐Dconformaltherapyare

acceptabletreatmentmodalities

• Pre‐opandpostopMRIsofbrainandspineare

requiredforaccuratetargetvolumedelineation

June10,2014

PrincipalsofRadiation

• DoseofRTbaseduponriskgrouping:

– Standardriskpatientstreatedwith23.4Gyin13

fractionsfollowedbyposteriorfossa/tumorbed

boostto54‐56Gy

– Highriskpatientstreatedwith36‐39.6Gyin20‐22

fractionsfollowedbyposteriorfossaboostto54‐

56Gy

• Spinemetsalsoreceiveboostandfinaldosedepends

onlocation:

– 40‐45Gyatlevelofthecord

– 50.4Gyifbelowthecord

June10,2014

Chemotherapy

• Radiationisdeliveredwithconcurrentvincristine

• Adjuvantchemotherapyisstandardofcare

• Chemotherapycanalsobegivenforyoungerpatients

inordertodelayRT,asthetoxicityprofilefor

patients<3yowhogetradiationisworsethanfor

olderchildren

June10,2014

TreatmentParadigm‐

Standard risk

• Maxsaferesection RTwithconcurrent

weeklyvincristine adjuvantchemowith8

cyclesofcisplatin/CCNU(i.e.lomustine) /

vincristine

• RTisCSI23.4Gywithposteriorfossaortumor

bedboostto54Gy

• OSat5years:86%,EFS:81%(CCG/POG

A9961)

June10,2014

TreatmentParadigm‐

Highrisk(>3yo)

• SimilartostandardriskptsexceptRTisthe

following:

– CSIdoseis36Gy‐ 39.6Gyratherthan23.4Gy

– Entireposteriorfossaboostto54Gy

– RTwithconcurrentvincristinefollowedby

adjuvantchemotherapy(similar tostandardrisk)

• POG9031demonstratedthosewithM1

diseasehad5yrEFSof65%

June10,2014

Treatmentparadigm:<3yo

• Bydefinition,alwayshighriskif<3yo

• Surgeryfollowedbyintensivechemotherapyis

primarytreatment

• RTreservedforsalvagetherapy

June10,2014

CraniospinalIrradiation

• Goals:Achieveuniformdosethroughoutthe

subarachnoidspace

• Spinefield(s)deliveredwithPAbeam

• Cranialfieldsdeliveredwithopposedlaterals

• Cranialand spinefieldsmustbematched

– Thecollimatorandcouchmustberotatedduringdeliveryof

cranialfieldsinordertoaccountforbeamdivergence

• Movingjunction(i.e.gapand feather)isoftenused

betweenfieldstominimizeareasofpotential

underdose/overdose

June10,2014

CraniospinalIrradiation

• Specificapproachvariesbyinstitution

• Setup

• ProneorSupine

• Immobilizewithareproduciblesetup

– Body immobilizationwithalphacradle,vaclockbag,etc.

– Aquaplastmaskforheadimmobilization;neckhyperextended

toavoiddivergenceofPAbeamthroughmouth

– CTsim

– Anesthesiamayberequired

June10,2014

AdvantagestoPronevs.Supine

Prone

• Directvisualizationoflightfieldsforspinefieldsetup

(therapistsoftenpreferprone)

Supine

• Oftenmorecomfortableforthepatient;potentiallyless

movementduringtreatment

• Easyairwayaccessforpatientsrequiringsedation

June10,2014

TraditionalProneTechnique

• Simandplace spinefieldsfirst:

• SSDsetup(cranialfieldswillbeSAD)

• Borders

– Superior:C4‐C7(whileavoidingexitdosethroughoralca vity)

– Inferior:establishterminationofthecalsacasdeterminedby

MRI(~S2)andcover1‐2cminferiorly.

– Lateral:covertherecessesoftheentirevertebralbodieswith

atleast1cmmarginoneitherside.Mustcoverthesacral

foramina

(“spade”shape)

June10,2014

• Spinefield:

– Numberofspinefields

• Youngchildren:entirespinecanoftenbeencompassed

inonefield

• Inolderchildren,mayneedtwoadjacentfields

– TrytoavoidextendingSSDbecausethisincreasesexitdose

– Matchingadjacentspinalfields:Therewill beagapatthe

skinwithadjacentfieldbordersmatchingattheanterior

surfaceofthespinalcanal(someinstitutionsmatchatthe

depthofmid‐spinalcord)

TraditionalProneTechnique

June10,2014

• Brain anduppercervicalspinearetreated

withlateralfields

– SADsetup

– Placeisocenterinmidlineinsamecoronalplane

asspinefieldtoavoidant/postshiftsduring

treatment

– Musthavecover ageofcribriformplate(0.5–1cm

toblockedge)

– Trytominimizedosetoeyeandlens

TraditionalProneTechnique

June10,2014

• Brain anduppercervicalspinearetreated

withopposedlateralfields

TraditionalProneTechnique

• Borders

– Supandpost:flash

– 0.5‐1cmmarginon

cribriformplate(must

contour)

– 1cmmargininferiorto

middlecranialfossa

– 1cmmarginanteriorto

vertebralbodies

June10,2014

Techniqueformatchingbrainandspinefield:

• Inorderforthecranialfieldtomatchdiverging

spinefields,thecollimatormustrotate

• Angleofcollimatorrotationcanbecalculated

withthefollowingequation:

coll

=arctan(L

/2*SSD)

=lengthofposteriorspinefield

SSD=sourcetosurfacedistanceofposteriorspinefield

TraditionalProneTechnique

June10,2014

Techniqueformatchingbrainandspinefield:

• Inorderforthespinefieldtomatchdiverging

cranialfields,couchmustrotatetowardthe

gantry

• Angleof“couchkick”canbecalculatedwiththe

followingequation:

couch

=arctan(L

/2*SAD)

=lengthoflateralcranialfield

SAD=sourcetoaxisdistanceoflateralcranialfield

TraditionalProneTechnique

June10,2014

TheCase:CSI

• OurpatientwastreatedCSIto23.4Gyinthe

supineposition

June10,2014

The“gapandfeather”technique

• Ratherthanrotatingthecouchtomatchdivergenceofcranial

beam,agapof0.5cmisplacedbetweenthebrainandspine

fieldeachday(collimatorisstillrotated).

• Feathering“spreadsout”thecoldspotatthegapbetween

thebrainandspinefields,aswellasanycoldspotsinthecord

duetoskingapwhenmorethanonespinefieldisrequired.

• Featheringisaccomplishedwiththeuseofasymmetricjaws.

– Forcranialfields:opencaudalborderofcranialfieldby

1cmeachday,cycleevery3days.

– Forspinefields:shiftisocenter(s)caudallyby1cmforeach

day;adjustblocksforeachdayaccordingly.

June10,2014

Day3

6/10/2014

Day2Day1

June10,2014

TheCase:TumorBedBoost

AfterCSIto23.4Gy,patientreceivedlimitedtargetboosttotumorbed

withIMRTphotonstoatotaldoseof54Gy

• GTV:

– tumorbed+grossresidualdisease,includingT1signal

abnormalitywithandwithoutcontrast

– Donotincludesurgicaldefectsvisibleonpost‐opMRIthatdid

not

containdiseaseonpre‐opMRI

• CTV:

– GTV+1–1.5cm

– excludingbone,tentorium,andentiretyofbrainstem(however,

brainstemimmediatelyadjacenttotumorbedshouldbe

includedasthisisanareaofpotentialmicroscropicdisease)

• PTV:

– CTV+3–5mm

June10,2014

StandardRisk:TumorBed vs.Posterior

FossaBoost

• CurrentCOGprotocol(ACNS0331)iscomparing

posteriorfossaboostvs.tumorbedboostin

standardriskpatients

• However,thereisevidenceavailabletosupport

limitingtheboostvolumetothetumorbed

– Fa ilurerateswithinposteriorfossaaftertumorbedboost

arecomparabletohistoricalexperiencewithtreating

entireposteriorfossa

• Woldenetal.,JCO,2003(PMID:12915597)

• Merchantetal.,IJROBP,2008(PMID:17892918)

June10,2014

Posteriorfossaboost

• CTV=entireposteriorfossa,includingbrainstem

• PTV=CTV+3‐5mm(excludepituitaryunless

involved)

• BonyLandmarks

– Superior:1cmabovethemidpointofalinedrawn

betweentheforamenmagnumandthevertex

– Anterior:posteriorclinoidsandanteriorC1(the

pituitaryshouldbeblockedunlessinvolved)

–

Inferior:C1‐C2junction

– Posterior:internaloccipitalprotuberance

June10,2014

RTlateeff ects

• DecreasedIQ

• Decreasedgrowth

• Ototoxicity

• Hypopituitarism

• Secondarymalignancy

June10,2014

FactorsfordeclineinIQafterCSI

• Age<7yo(mostimporant)

• Higherdose (36Gyvs.23.4Gy)

• HigherIQatbaseline

• Femalegender

June10,2014

References

June10,2014

1) Lee,N.L.,Lu,J.J.TargetVolumeandFieldSetup:APracticalGuideforConformalandIntensity‐ModulatedRadiationTherapy

(2013).

2) HansenE.K.,Roche,M.HandbookofEvidence‐BasedRadiationOncology. 2

Ed.(2010).

3) Gajjaretal.Medulloblastomainveryyoungchildren:outcomeofdefinitivecraniospinalirradiationfollowingincomplete

responsetochemotherapy(1994). JCO.12:1212‐1216.

4) Miralbell.Radiotherapyinpediatricmedulloblastoma:qualityassessmentofPediatricOncologyGroupTrial903(2006).IJROBP.

64(5):1325‐30.

5) Thomasetal.Low‐stagemedulloblastoma:finalanalysisoftrialcomparing

standard‐dosewithreduced‐doseneuraxisirradiation

(2000).JCO.18(16):3004‐11.

6) Zeltzeretal.Metastasisstage,adjuvanttreatment,andresidualtumorareprognosticfactorsformedulloblastomainchildren:

conclusionsfromtheChildren’sCancerGroup921randomizedphaseIIIstudy(1999).JCO.17(3):832‐845.

7) Packeretal.PhaseIIIstudyofcraniospinal

radiationtherapyfollowedbyadjuvantchemotherapyfornewlydiagnosedaverage‐

riskmedulloblastoma(2006).JCO.24(25):4204‐8.

8) Monjeetal.Hedgehogs,flies,wnts,andMYCs:thetimehascomeformanythingsinmedulloblastoma(2011).JCO.29(11):1395‐

9) Woldenetal.Patternsoffailureusingaconformalradiationtherapytumorbedboost

formedulloblastoma(2003).JCO.21

(16):3079‐83.

10) Merchantetal.Multi‐inst itutionalprospectivetrialofreduced‐dosecraniospinalirradiation(23.4Gy)followedbyconformal

posteriorfossa(36Gy)andprimarysiteirradiation(55.8Gy)anddose‐intensivechemotherapyforaverage‐riskmedulloblastoma

(2008).IJROBP.70(3):782‐7.

11) Risetal.Intellectualoutcome

afterreduced‐doseradiationtherapyplusadjuvantchemotherapyformedulloblastoma:a

Children’sCancerGroupstudy(2001).JCO.19(15):3470‐76.

12) Armstrongetal.Evaluationofmemoryimpairmentinagingadultsurvivorsofchildhoodacutelymphoblasticleukemiatreated

withcranialradiotherapy(2013).JNCI.105(12):899‐907.