pediatric chiasmatic/ hypothalamic gliomas: … · optic nerve tumors – neurosurgeons typically,...

Pediatric Pediatric ChiasmaticChiasmatic/ / Hypothalamic Hypothalamic GliomasGliomas: :

Understanding the Understanding the Management DilemmaManagement Dilemma

Peter S. Amenta, MDPeter S. Amenta, MDDepartment of NeurosurgeryDepartment of NeurosurgeryJefferson University HospitalJefferson University Hospital

January 16, 2009January 16, 2009

The PresentationThe Presentation

Case PresentationsCase PresentationsThe DiseaseThe DiseaseThe Natural HistoryThe Natural HistoryThe LiteratureThe LiteratureTreatmentTreatment–– The Role of the NeurosurgeonThe Role of the Neurosurgeon–– Chemotherapy and RadiationChemotherapy and Radiation

Case DiscussionCase DiscussionStudy Design and GoalsStudy Design and Goals

88--yearyear--old girl from Ghana with no past medical old girl from Ghana with no past medical history presents to the CHOP emergency room via a history presents to the CHOP emergency room via a charity medical organizationcharity medical organization

Progressive blindness and Progressive blindness and proptosisproptosis of the left eyeof the left eye

Referred to ophthalmologyReferred to ophthalmology–– Minimal light perception in left eyeMinimal light perception in left eye–– Normal ophthalmologic exam in right eyeNormal ophthalmologic exam in right eye–– Normal visual fields in right eyeNormal visual fields in right eye

MRI orderedMRI ordered

Patient Presentation #1Patient Presentation #1

MRI on Presentation

What to do?Watch and repeat MRI?Begin chemotherapy?Stereotactic biopsy?Open biopsy?Limited resection?Aggressive resection?

99--monthmonth--old healthy male with no past medical old healthy male with no past medical historyhistory

Patient presents to general pediatrician after Patient presents to general pediatrician after father notices father notices ““shakingshaking”” right eye for five daysright eye for five days

Referred to ophthalmologyReferred to ophthalmology–– Horizontal Horizontal nystagmusnystagmus noted in right eyenoted in right eye–– Otherwise normal ophthalmologic examOtherwise normal ophthalmologic exam–– CT orderedCT ordered

Presents to the CHOP emergency roomPresents to the CHOP emergency room


Head CT on Presentation

MRI on MRI on PresentationPresentation

What to do?What to do?Watch and repeat MRI?Begin chemotherapy?Stereotactic biopsy?Open biopsy?Limited resection?Aggressive resection?

55--yearyear--old female with no past medical history old female with no past medical history presents to an outside ophthalmologist after parents presents to an outside ophthalmologist after parents complained that the patient was walking into walls complained that the patient was walking into walls for several months. for several months.

Patient complained that she was unable to see Patient complained that she was unable to see animals at the zoo.animals at the zoo.

Visual acuityVisual acuity–– OD 20/100OD 20/100–– OS 20/125OS 20/125

FundoscopicFundoscopic exam: Optic atrophyexam: Optic atrophy


Patient #2: 8 mo malePatient #2: 8 mo malePatient #1: 8 Patient #1: 8 yoyo femalefemale Patient #3: 5 Patient #3: 5 yoyo femalefemale

Traditionally, all three patients would be characterized as haviTraditionally, all three patients would be characterized as having ng ““optic pathway optic pathway gliomasgliomas”” ……

What I intend to show . . .What I intend to show . . .1. These tumors are different disease 1. These tumors are different disease processesprocesses2. Low2. Low--grade grade gliomasgliomas of the optic chiasm/ of the optic chiasm/ hypothalamus are a unique and distinct hypothalamus are a unique and distinct disease entitydisease entity3. What we need to do as neurosurgeons3. What we need to do as neurosurgeons–– To deconstruct the literatureTo deconstruct the literature–– Define the disease and its actual prognosisDefine the disease and its actual prognosis–– Establish a multidisciplinary treatment planEstablish a multidisciplinary treatment plan

The PatientsThe Patients

Symptoms at PresentationSymptoms at Presentation

Visual disturbances (29%)Visual disturbances (29%)Headache (23%)Headache (23%)Failure to thrive (20%)Failure to thrive (20%)–– DiencephalicDiencephalic syndromesyndrome

Nausea and vomiting (14%)Nausea and vomiting (14%)Abnormal eye movement (14%)Abnormal eye movement (14%)Symptoms of endocrine dysfunction (14%)Symptoms of endocrine dysfunction (14%)

Clinical Signs at PresentationClinical Signs at Presentation

Decreased visual acuity (33%)Decreased visual acuity (33%)Visual field deficit (33%)Visual field deficit (33%)Optic atrophy (21%)Optic atrophy (21%)Abnormal Abnormal extraocularextraocular muscle exam (21%)muscle exam (21%)Signs of endocrine abnormalities (21%)Signs of endocrine abnormalities (21%)Ataxia (12%)Ataxia (12%)PapilledemaPapilledema (9%)(9%)

Copyright ©2005 American Academy of Pediatrics

DiencephalicDiencephalic SyndromeSyndromeEmaciationEmaciation–– Multiple authors note complete Multiple authors note complete

absence of subcutaneous fatabsence of subcutaneous fat–– Multiple theories as to Multiple theories as to

underlying mechanism, but underlying mechanism, but none have been proven none have been proven

OveractivityOveractivity and pleasantnessand pleasantness–– Escalating to euphoriaEscalating to euphoria

Initial growth accelerationInitial growth acceleration

Autonomic disturbanceAutonomic disturbance–– Skin pallor, erratic temperature Skin pallor, erratic temperature

control, diaphoresis, heat control, diaphoresis, heat intoleranceintolerance

Table: Fleischman, A. et al. Pediatrics 2005;115:e742-e748.

The DiseaseThe Disease

EpidemiologyEpidemiology75% of optic pathway tumors occur in patients <12 75% of optic pathway tumors occur in patients <12 years of ageyears of age–– 60% of these tumors involve the chiasm and hypothalamus60% of these tumors involve the chiasm and hypothalamus

OCHGsOCHGs compose 2compose 2--5% of pediatric intracranial 5% of pediatric intracranial tumorstumors1 1

–– 65% occur in the first five years of life65% occur in the first five years of life

Anterior lesions (20Anterior lesions (20--40%) 40%) –– Involve the chiasm with or without the optic nervesInvolve the chiasm with or without the optic nerves

Posterior lesions (33Posterior lesions (33--60%)60%)–– Involve the chiasm and hypothalamus with or without the Involve the chiasm and hypothalamus with or without the

optic tractsoptic tracts33

Imaging CharacteristicsImaging Characteristics

General characteristicsGeneral characteristics–– Solid, cystic, or combinationSolid, cystic, or combination–– Classically described as globular/ Classically described as globular/ exophyticexophytic

suprasellarsuprasellar massmassCTCT–– LowLow--density to density to isodenseisodense–– Intense enhancement with contrastIntense enhancement with contrast

MRIMRI–– T1: LowT1: Low--intensity with marked gadolinium intensity with marked gadolinium

enhancementenhancement–– T2: T2: HyperintenseHyperintense massmass

Found to grow Found to grow posteropostero--superiorly with superiorly with invaginationinvagination of the third ventricleof the third ventricleWith lateral progression, may involve the With lateral progression, may involve the Circle of WillisCircle of Willis

Histology: LowHistology: Low--grade grade GliomasGliomasJuvenile Juvenile pilocyticpilocytic astrocytomasastrocytomas (60%)(60%)–– WHO grade I circumscribed WHO grade I circumscribed astrocytomasastrocytomas–– Biphasic patternBiphasic pattern

Rosenthal fibersRosenthal fibersLooseLoose--textured textured astrocytesastrocytes and and microcystsmicrocystsFrequently not cystic in the optic pathway and medullaFrequently not cystic in the optic pathway and medulla

FibrillaryFibrillary astrocytomasastrocytomas (40%)(40%)–– WHO grade II diffuse WHO grade II diffuse astrocytomasastrocytomas–– WellWell--differentiateddifferentiated–– HypercellularityHypercellularity and nuclear and nuclear atypiaatypia–– Expand the white matterExpand the white matter–– May undergo malignant transformationMay undergo malignant transformation

VerhoeffVerhoeff defines three defines three histologicallyhistologically distinct distinct categories of categories of pilocyticpilocytic astrocytomaastrocytoma

Coarsely ReticulatedCoarsely Reticulated

Finely ReticulatedFinely ReticulatedCan be confused with Grade II Can be confused with Grade II astrocytomasastrocytomas

Coarsely Fibrillated Coarsely Fibrillated Most common variant of adult Most common variant of adult pilocyticpilocytic astrocytomasastrocytomas

Histology: LowHistology: Low--grade grade GliomasGliomas

4421212525Tow Tow ‘‘0303

1113131414Suarez Suarez ‘’‘’0606

141419193333AhnAhn ’’0606

4412121616HorwichHorwich ‘‘8585

3311111414Wright Wright ’’8989

335588GuillamoGuillamo ‘‘0303

6 6 (2%)(2%)

45 (16%)45 (16%)3 (1%)3 (1%)54 (19%)54 (19%)178 178 (62%)(62%)

286286TotalsTotals

11

11

11

GangliogliomaGanglioglioma

331010221616WisoffWisoff ‘‘9090

77111113133322Sutton Sutton ‘‘9595

666638385050LaithierLaithier ‘‘0303

171725254343Hoffman Hoffman ‘‘9393

553388Chamberlain Chamberlain ‘‘9595

338816162727CapCappellipelli ‘‘9898

OtherOtherLow Grade Low Grade AstrocytomasAstrocytomas

(NOS)(NOS)

FibrillayFibrillayAstrocytomaAstrocytoma

PilocyticPilocyticAstrocytomaAstrocytoma

Number Number of of

PatientsPatients

Study by Study by AuthorAuthor

Histology of Tumors Found at the Hypothalamus and Histology of Tumors Found at the Hypothalamus and Optic Chiasm Arranged by StudyOptic Chiasm Arranged by Study

Path images

Coronal brain slice through the hypothalamus. A large soft tissue mass is shown expanding the hypothalamus. Histology exhibited juvenile pilocytic astrocytoma. (Images courtesy of Roy H. Rhodes, MD, PhD. Robert Wood Johnson University Hospital. Department of Pathology.)

Gross Pathology

Histology: Juvenile Pilocytic Astrocytoma

Rosenthal Fibers

Endothelial Hyperplasia and Vascular Mural Sclerosis

Microcysts Filled with Eosinophilic Material

Images courtesy of Roy H. Rhodes, MD, PhD. Robert Wood Johnson University Hospital. Department of Pathology.

OCHGsOCHGs and Disseminationand Dissemination

5% rate of CNS dissemination in 150 patients 5% rate of CNS dissemination in 150 patients with lowwith low--grade grade gliomasgliomas–– 50% of these patients had 50% of these patients had OCHGsOCHGs

When compared to lowWhen compared to low--grade grade gliomasgliomas in other in other locationslocations–– Estimated 20Estimated 20--fold increased risk of developing fold increased risk of developing

multicentricmulticentric spread with spread with OCHGsOCHGs–– Prevailing theoryPrevailing theory

InvaginationInvagination of the floor of the third ventricle eventually of the floor of the third ventricle eventually breaches the breaches the ependymalependymal liningliningCSF disseminationCSF dissemination

T1-weighted MRI with gadolinium demonstrating multiple areas of metastatic disease

Spontaneous RegressionSpontaneous Regression

PiccirilliPiccirilli et al., Childs et al., Childs NervNerv SystSyst 2006;22:1332. 2006;22:1332. ParsaParsa et al., Arch et al., Arch OphthalmolOphthalmol 2001;119:516. 2001;119:516. ParrazziniParrazzini et al., Am J et al., Am J NeuroradNeurorad 1995;16:7111995;16:711

OCHGsOCHGs and Neurofibromatosis type 1and Neurofibromatosis type 1

Associated with neurofibromatosis Associated with neurofibromatosis type 1 (NFtype 1 (NF--1)1)–– 1414--40% of NF40% of NF--1 patients will 1 patients will

develop develop OCHGsOCHGs

Vast majority of tumors arise prior Vast majority of tumors arise prior to six years of ageto six years of age

TraditionallyTraditionally–– Tumors associated with NFTumors associated with NF--1 are 1 are

considered to behave less considered to behave less aggressivelyaggressively

–– Higher incidence of spontaneous Higher incidence of spontaneous regressionregression

NFNF--1 1 notnot necessarily protectivenecessarily protective

Natural HistoryNatural History

Natural HistoryNatural HistoryNatural history of Natural history of OCHGsOCHGs is erratic and highly is erratic and highly variablevariable

Debate in the literatureDebate in the literatureCongenital, nonCongenital, non--neoplastic, selfneoplastic, self--limiting, limiting, hamartomatoushamartomatous lesions lesions Progressive, prone to recurrence, associated with Progressive, prone to recurrence, associated with significant morbidity and mortalitysignificant morbidity and mortality

Ambiguity and inconsistency in the literatureAmbiguity and inconsistency in the literature–– Failure to classify tumors with a consistent/ Failure to classify tumors with a consistent/

reproducible systemreproducible system

Problems in the Literature: SourcesProblems in the Literature: SourcesThe existing literature is derived from a wide The existing literature is derived from a wide range of sourcesrange of sources–– NFNF--1 clinics predominately see indolent tumors1 clinics predominately see indolent tumors–– NeuroNeuro--oncologists and radiation oncologists see oncologists and radiation oncologists see

mostly those children with progressive diseasemostly those children with progressive disease–– NeuroNeuro--ophthalmologists primarily see intraophthalmologists primarily see intra--orbital orbital

optic nerve tumorsoptic nerve tumors–– NeurosurgeonsNeurosurgeons

Typically, patients present to neurosurgical service Typically, patients present to neurosurgical service following the first diagnostic CT or MRIfollowing the first diagnostic CT or MRIBroad spectrum of disease prior to the evolution of the Broad spectrum of disease prior to the evolution of the natural coursenatural course

Problems in the Literature: The Problems in the Literature: The Importance of Anatomic LocationImportance of Anatomic Location

Tumors grouped together regardless of anatomic Tumors grouped together regardless of anatomic locationlocation–– Tumors of the optic apparatusTumors of the optic apparatus–– Optic pathway Optic pathway gliomasgliomas

Survival in relation to involvement of the chiasmSurvival in relation to involvement of the chiasm–– GliomasGliomas confined to the optic nerve are amenable to confined to the optic nerve are amenable to

complete resection with limited morbidity and mortalitycomplete resection with limited morbidity and mortality–– LowLow--grade grade gliomasgliomas confined to the optic nerveconfined to the optic nerve

85% long85% long--term survivalterm survival

–– LowLow--grade grade gliomasgliomas involving the optic chiasminvolving the optic chiasm44% long44% long--term survival term survival

Rush et alRush et al

Problems in the Literature: The Problems in the Literature: The Importance of Anatomic LocationImportance of Anatomic Location

0%0%22.2%22.2%Type Type IIIbIIIb ((ChiasmaticChiasmatic--hypothalamic hypothalamic lesions)lesions)

54.1%54.1%87.5%87.5%Type Type IIIaIIIa ((ChiasmaticChiasmatic lesions)lesions)

41.6%41.6%75%75%Type II (Optic tract lesions)Type II (Optic tract lesions)

88.8%88.8%100%100%Type I (Type I (RetrobulbarRetrobulbar--prechiasmaticprechiasmaticlesions)lesions)

10 years10 years5 years5 yearsTumor LocationTumor Location

SurvivalSurvival

Survival at 5 and 10 Years in Patients with Low-Grade Optic Pathway Gliomas Initially Treated With Radical Resection

The Dodge Classification Systems The Dodge Classification Systems for Optic Pathway for Optic Pathway GliomasGliomas

Taylor T, et al.,British Journal of Radiology (2008) 81, 761-766.

The Dodge ClassificationSystem (DC), 1958 The Modified Dodge

Classification (MDC)System, 2008

The DC breaks down tumors into preThe DC breaks down tumors into pre--chiasmaticchiasmatic, , chiasmaticchiasmatic, and , and postpost--chiasmaticchiasmatic

The MDC provides a more detailed anatomical description based The MDC provides a more detailed anatomical description based on the images obtained by modernon the images obtained by modern--day MRI.day MRI.–– Not currently in widespread usageNot currently in widespread usage

Problems in the Literature: The Problems in the Literature: The Importance of HistologyImportance of Histology

Tumors grouped together regardless of histologyTumors grouped together regardless of histology–– Outcomes in low and highOutcomes in low and high--grade grade astrocytomasastrocytomas compared within the compared within the

same studiessame studies

Multiple studies include tumors in which no Multiple studies include tumors in which no histologichistologicdiagnosis was confirmeddiagnosis was confirmed–– Diagnosis made by imaging characteristics aloneDiagnosis made by imaging characteristics alone

Majority of studies include sporadic and NFMajority of studies include sporadic and NF--1 tumors 1 tumors togethertogether–– Is there a difference in the natural history?Is there a difference in the natural history?–– Tumors associated with NFTumors associated with NF--1 are considered to behave less 1 are considered to behave less

aggressivelyaggressivelyBut, are we diagnosing these tumors at an earlier stage secondarBut, are we diagnosing these tumors at an earlier stage secondary to y to screening?screening?

Surgical InterventionSurgical Intervention

Hoyt and Hoyt and BaghdassarianBaghdassarian (1969): (1969): Setting the Surgical Setting the Surgical ““StandardStandard””

36 patients with presumed optic pathway 36 patients with presumed optic pathway gliomasgliomas–– HistologicHistologic verification in only 21 of the 36 verification in only 21 of the 36 –– Remainder of diagnoses based on Remainder of diagnoses based on tomographictomographic

pneumoencephalographypneumoencephalography and clinical presentationand clinical presentation–– Tumors located at multiple points along optic Tumors located at multiple points along optic

pathwaypathway–– Includes both adult and pediatric tumorsIncludes both adult and pediatric tumors

Hoyt and Hoyt and BaghdassarianBaghdassarian: : ConclusionsConclusions

Optic Optic gliomasgliomas are are ““congenital, noncongenital, non--neoplastic, neoplastic, hamartomatoushamartomatous, and self, and self--limitinglimiting””

NeuroradiologicalNeuroradiological imaging permits accurate diagnosis, imaging permits accurate diagnosis, eliminating the need for histological diagnosiseliminating the need for histological diagnosis

Neither Neither transcranialtranscranial operations or radiation prolong lifeoperations or radiation prolong life

Neurosurgical intervention limited to:Neurosurgical intervention limited to:–– Recurrent increases in intracranial pressure Recurrent increases in intracranial pressure –– The relief of severe The relief of severe proptosisproptosis in a blind eye in a blind eye

Partial resection is Partial resection is ““no sinno sin””

Why discuss this paper?Why discuss this paper?

Repeatedly referenced throughout the Repeatedly referenced throughout the literatureliterature

Describes the fundamentals of the primary Describes the fundamentals of the primary treatment algorithm over the next two to treatment algorithm over the next two to three decadesthree decades

Not until the early 1980s do we see literature Not until the early 1980s do we see literature that challenges this studythat challenges this study

Standard Treatment Protocol at Standard Treatment Protocol at CHOP 1975CHOP 1975--19911991

All patients underwent tumor biopsy via All patients underwent tumor biopsy via pterionalpterional or or transcallosaltranscallosal approachapproach–– If lowIf low--grade grade astrocytomaastrocytoma, then limited resection and , then limited resection and

decompression of the ventricular system and/or chiasmdecompression of the ventricular system and/or chiasm–– No attempt at gross total resectionNo attempt at gross total resection

Younger childrenYounger children–– ActinomycinActinomycin D and D and vincristinevincristine

Older childrenOlder children–– RadiationRadiation

At time of progressionAt time of progression–– Treated with modality not yet utilizedTreated with modality not yet utilized–– Radical resection if progression despite chemotherapy Radical resection if progression despite chemotherapy

and radiationand radiationSutton, et al

TorontoToronto’’s The Hospital for Sick s The Hospital for Sick Children 1976Children 1976--19911991

Retrospective analysis of 88 children with Retrospective analysis of 88 children with biopsybiopsy--proven lowproven low--grade grade astrocytomasastrocytomasTumor resection of 50% or more Tumor resection of 50% or more –– Recurrence rate of 24% (versus 42.9% for < 50% Recurrence rate of 24% (versus 42.9% for < 50%

resection)resection)–– All patients with greater than a 50% resection All patients with greater than a 50% resection

survivedsurvived

ConclusionConclusion–– Resection should be considered in all patients at Resection should be considered in all patients at

the time of presentation and recurrencethe time of presentation and recurrence

The Early 1990sThe Early 1990sA shift to more aggressive A shift to more aggressive attempts at resectionattempts at resection–– Improvement in modern Improvement in modern

imaging imaging –– Advancements in surgical Advancements in surgical

technologytechnology

Resection categoriesResection categories

100%Total

Resection

50-99%Subtotal

Resection

25-50%Partial

Resection

< 25%Biopsy

Percentage of Tumor Resection

Resection Category

Established Indications for SurgeryEstablished Indications for Surgery

All patients require a biopsy for All patients require a biopsy for histological diagnosis histological diagnosis

Tumor Tumor debulkingdebulking for the treatment of for the treatment of obstructive hydrocephalusobstructive hydrocephalus

Significant tumor progression associated Significant tumor progression associated with worsening symptomswith worsening symptoms

SurgerySurgeryProponents of Proponents of cytoreductivecytoreductive surgerysurgery–– Literature to support arrest of growth or regression after Literature to support arrest of growth or regression after

radical subtotal resectionradical subtotal resection

Low grade Low grade astrocytomasastrocytomas in other anatomic locationsin other anatomic locations–– Cerebellum: GTR Cerebellum: GTR PFS approaches 100% PFS approaches 100% –– SupratentorialSupratentorial: GTR : GTR PFS 50PFS 50--95%95%

Optic Pathway Optic Pathway GliomasGliomas–– Radical Resection Radical Resection prolonged PFS in ~ 2/3 of patients prolonged PFS in ~ 2/3 of patients

(Hoffman (Hoffman ‘‘93, 93, WisoffWisoff ‘‘90)90)

Radical ResectionRadical Resection

But, what about the risks?But, what about the risks?–– Further compromise in vision, endocrine dysfunction, Further compromise in vision, endocrine dysfunction,

strokestroke–– Are the surgical risks acceptable considering the true Are the surgical risks acceptable considering the true

natural history has never been defined?natural history has never been defined?

Advances in chemotherapy and radiationAdvances in chemotherapy and radiation–– Are the available adjuvant therapies effective enough Are the available adjuvant therapies effective enough

to justify limited resection and medical therapy?to justify limited resection and medical therapy?

Chemotherapy and Chemotherapy and RadiationRadiation

ChemotherapyChemotherapyAttempt to delay or eliminate need for radiationAttempt to delay or eliminate need for radiation

Trial results difficult to compare due to variability Trial results difficult to compare due to variability in:in:–– Indication to begin treatmentIndication to begin treatment–– Classification of response to treatmentClassification of response to treatment–– Evaluation of time to responseEvaluation of time to response

Multiple small studies of single agents in recurrent Multiple small studies of single agents in recurrent OCHGsOCHGs–– Show limited rates of tumor regressionShow limited rates of tumor regression–– Higher rates of disease stabilizationHigher rates of disease stabilization–– EtoposideEtoposide (VP16) as example (VP16) as example

–– 27% regression rate27% regression rate–– 54% 54% disease stabilizationdisease stabilization

FrontFront--Line: Line: VincristineVincristine and and CarboplatinCarboplatin–– Highest progression free survivalHighest progression free survival–– WellWell--toleratedtolerated

Problems with chemotherapeutic regimensProblems with chemotherapeutic regimens–– CarboplatinCarboplatin allergy allergy –– Concerns for leukemia with multiple agentsConcerns for leukemia with multiple agents

LomustineLomustine (CCNU), (CCNU), ProcarbazineProcarbazine, , CyclophosphamideCyclophosphamide, or , or EtoposideEtoposide

–– High frequency hearing loss with CPPDHigh frequency hearing loss with CPPD

LafayLafay--Cousin et al., Cancer 2008;112:892Cousin et al., Cancer 2008;112:892

ChemotherapyChemotherapy

66% (5yr)66% (5yr)130 OPG +NF1130 OPG +NF1VCR/VCR/CarboCarbo(COG, (COG, AterAter ’’06)06)

48% (5yr)48% (5yr)39% OPG39% OPG

52% (3yr)52% (3yr)34% (5yr)34% (5yr)

73% (3yr)73% (3yr)

45% (3yr)45% (3yr)

68% (3yr)68% (3yr)78% OPG78% OPG

5050% (% (33yr)yr)

PFSPFS

84%84%50%50%204 LGG204 LGG61 OPG61 OPG

VCR/VCR/CarboCarbo(SIOP(SIOP--LGG1)LGG1)

87%87%42%42%85 85 OPGOPGProc/Proc/CarboCarbo, VP/CPPD, , VP/CPPD, Vcr/CpmVcr/Cpm ((LaithierLaithier ‘‘03)03)

100%100%35%35%34 34 LGGLGG29 OPG29 OPG

CCPPDPPD/VP/VP((MassaminoMassamino ‘‘02)02)

9966%%36%36%42 42 LGGLGG33 OPG33 OPG

TPCDVTPCDV((PradosPrados ‘‘97)97)

94%94%3333.3%.3%78 78 LGGLGG58 OPG58 OPG

VCR/VCR/CarboCarbo(Packer (Packer ‘‘97)97)

9696%%112.5%2.5%224 4 OPGOPGVCR/AMDVCR/AMD(Packer (Packer ‘‘88)88)

DzDz Stable RateStable RateCR+PRCR+PRNNDrugsDrugs((Author)Author)

Larger MultiLarger Multi--Agent StudiesAgent Studies

VP = Etoposide/ Carbo = Carboplatin/ VCR = Vincristine/ TPCDV = 6-Thioguanine, Procarbazine, 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), Vincristine (TPCV)/ CPPD = Cyclophosphamide/ AMD = AMD 3100

Recent Chemotherapeutic Recent Chemotherapeutic ProtocolsProtocols

TemozolomideTemozolomide ((TemodarTemodar))–– GururanganGururangan ’’07: N=30, 54% disease stabilization, 07: N=30, 54% disease stabilization,

5yr PFS = 30%5yr PFS = 30%–– Nicholson Nicholson ’’07: N=21, 57% disease stabilization07: N=21, 57% disease stabilization

VinblastineVinblastine: N=51, 24% partial response or complete : N=51, 24% partial response or complete remission, 74% disease stabilization (34/46)remission, 74% disease stabilization (34/46)–– Some with initial minor progression, then responseSome with initial minor progression, then response

GururanganGururangan et al., et al., NeuroNeuro--OncolOncol 2007;9:161.2007;9:161.Nicholson et al., Cancer 2007;110:1542.Nicholson et al., Cancer 2007;110:1542.LafayLafay--Cousin et al., Cancer 2005;103:2636Cousin et al., Cancer 2005;103:2636

Future Potential RegimensFuture Potential RegimensTarget angiogenesisTarget angiogenesis

Vascular Vascular prolifprolif in PA, increased VEGFin PA, increased VEGFAvastin/CPT11Avastin/CPT11

Adult Phase II in Recurrent HGG: 63% Adult Phase II in Recurrent HGG: 63% respresp rate rate Open trial for HGG in PBTCOpen trial for HGG in PBTCPacker et al.: 10 Recurrent LGG. Packer et al.: 10 Recurrent LGG. 1CR, 5 PR1CR, 5 PRThalidomide, Thalidomide, CelebrexCelebrex, , FenofibrateFenofibrate, Oral VP16, Oral VP16

Target molecular abnormalitiesTarget molecular abnormalitiesActivity in HActivity in H--rasras mutants not Kmutants not K--rasras defective pathways defective pathways (more common in NF1)(more common in NF1)mTORmTOR inhibitor inhibitor -- RAD001RAD001MultiMulti--institutional trial for institutional trial for RecRec--LGG in nonLGG in non--NF1 ptsNF1 ptsNF consortium considering for NF consortium considering for RecRec--OPGOPG

CXCR4 GCXCR4 G--protein coupled receptor pathway inhibitors protein coupled receptor pathway inhibitors ––AMD3100, AMD3100, RolipramRolipram (increases (increases cAMPcAMP))

TorontoToronto’’s The Hospital for Sick s The Hospital for Sick Children 1976Children 1976--1991: Radiotherapy1991: Radiotherapy

Data is unclearData is unclearRadiation used for surgically challenging tumors, tumors inRadiation used for surgically challenging tumors, tumors in which lesser resection was achieved, and in larger tumors which lesser resection was achieved, and in larger tumors as adjuvant therapyas adjuvant therapy

Radiation did not necessarily prevent recurrenceRadiation did not necessarily prevent recurrence–– 42.4% rate of recurrence with radiation as part of 42.4% rate of recurrence with radiation as part of

initial interventioninitial intervention–– 34.5% rate of recurrence with surgery as only initial 34.5% rate of recurrence with surgery as only initial

interventionintervention

Radiation therapy is associated with a significantRadiation therapy is associated with a significantmorbiditymorbidity

RadiotherapyRadiotherapySignificant toxicitySignificant toxicity–– Vision worse in 7Vision worse in 7--14%14%–– Endocrine dysfunction: Endocrine dysfunction: PanhypopituitarismPanhypopituitarism, GH deficiency, GH deficiency–– Cerebrovascular DiseaseCerebrovascular Disease

MoyaMoya MoyaMoya in 3/5 (60%) NF+, 2/23 (9%) NFin 3/5 (60%) NF+, 2/23 (9%) NF-- ((KestleKestle ’’93 )93 )Vascular disease in 11/37 (30%) NF+, 2/32 (6%) NFVascular disease in 11/37 (30%) NF+, 2/32 (6%) NF-- (Grill (Grill ’’99 )99 )

Secondary tumorsSecondary tumorsNeurocognitiveNeurocognitive DeficitsDeficits

CappelliCappelli ’’98: 18/51 (35%), 12 with mental retardation, all had 98: 18/51 (35%), 12 with mental retardation, all had received radiationreceived radiationLacazeLacaze ’’03: Mean IQ 19 points lower in the patients receiving 03: Mean IQ 19 points lower in the patients receiving radiationradiationSutton Sutton ’’95: N=3395: N=33

–– 43% in special education (all received RT, mean age 5.7 yrs, onl43% in special education (all received RT, mean age 5.7 yrs, only y 3 > 6yo)3 > 6yo)

–– 57% in regular school (4 no RT) (12 RT, mean age 11yrs, 4 were 57% in regular school (4 no RT) (12 RT, mean age 11yrs, 4 were 55--8yo)8yo)

RadiotherapyRadiotherapy

12% (3)12% (3)52% 52% (13)(13)

36% (9)36% (9)69% (10yr)69% (10yr)24%24%4545--6060992525GrabenbauerGrabenbauer ‘‘0000

13% (7)13% (7)54% 54% (29)(29)

33% (18)33% (18)66% (10yr)66% (10yr)(all 69)(all 69)

45%45%775454CappelliCappelli ’’9898

13%13%73% (10yr)73% (10yr)50 (med)50 (med)3838JenkinJenkin ’’9393

7% (3)7% (3)36% 36% (16)(16)

57% (25)57% (25)80% (10yr)80% (10yr)4040--6060(mean 52)(mean 52)

7.57.55757BatainiBataini ’’9191

9% (2)9% (2)61% 61% (14)(14)

30% (7)30% (7)88% (6yr)88% (6yr)4545--56.656.6(mean 54)(mean 54)

662424Pierce Pierce ’’9090

14% (3)14% (3)77% 77% (17)(17)

9% (2)9% (2)87%87%(5,10,15yr)(5,10,15yr)

3838--56.956.9(mean 47)(mean 47)

10.210.22525FlickingerFlickinger ‘‘8888

9% (2)9% (2)48% 48% (11)(11)

43% (10)43% (10)90% (10yr)90% (10yr)4545--505010102929HorwichHorwich ‘‘8585

VAVAWorseWorse

VAVAStableStable

VAVAImprovedImproved

PFSPFSRespResp..(CR+PR)(CR+PR)

TD (Gy)TD (Gy)Median Median F/U (yr)F/U (yr)

NNAuthorAuthor

45 45 -- 60 60 GyGy10 yr PFS 6510 yr PFS 65--90%90%Improvement in vision in 9Improvement in vision in 9--57%57%

Radiotherapy: ConclusionsRadiotherapy: Conclusions

Radiation can be used as adjuvant therapy Radiation can be used as adjuvant therapy at the time of initial surgery if visual &/or at the time of initial surgery if visual &/or motor function are compromisedmotor function are compromised

Radiation can be used at the time of Radiation can be used at the time of recurrencerecurrence

Radiotherapy: Recent AdvancesRadiotherapy: Recent AdvancesConformalConformalStereotacticStereotacticProton beamProton beamGoalsGoals–– May limit exposure to May limit exposure to mesialmesial temporal lobestemporal lobes–– Hypothalamus and vasculature probably still at Hypothalamus and vasculature probably still at

riskrisk–– Early response rates and PFS look similarEarly response rates and PFS look similarToxicity to be determinedToxicity to be determined

Debus et al., IJROBP 1999;44:243.Debus et al., IJROBP 1999;44:243.Saran et al., IJROBP 2002;53:43.Saran et al., IJROBP 2002;53:43.Marcus et al., IJROPB 2005;61:374.Marcus et al., IJROPB 2005;61:374.

Back to our three Back to our three patients . . .patients . . .



Patient #1Patient #1

Operative/ Postoperative CourseOperative/ Postoperative Course

-- OrbitozygomaticOrbitozygomatic craniotomy craniotomy -- IntradualIntradual sectioning of optic nerve approximately 1 cm before the chiasmsectioning of optic nerve approximately 1 cm before the chiasm-- Sacrifice of ophthalmic arterySacrifice of ophthalmic artery-- IntraIntra--orbital dissection of cranial nervesorbital dissection of cranial nerves-- En bloc resection with clean marginsEn bloc resection with clean margins-- Pathology: Juvenile Pathology: Juvenile pilocyticpilocytic astrocytomaastrocytoma (WHO I)(WHO I)

-- NFNF--1 work1 work--up negativeup negative-- Right frontal craniotomyRight frontal craniotomy

-- Vessels encased in tumorVessels encased in tumor-- Multiple biopsies and tumor Multiple biopsies and tumor debulkingdebulking

-- Pathology: Grade II Pathology: Grade II fibrillaryfibrillary astrocytomaastrocytoma-- Currently receiving weekly chemotherapy with Currently receiving weekly chemotherapy with vincristinevincristineand and carboplatincarboplatin (ten week course)(ten week course)-- Repeat MRI at twelve weeksRepeat MRI at twelve weeks-- NystagmusNystagmus resolvingresolving


-- OrbitozygomaticOrbitozygomatic craniotomy craniotomy -- Infiltration of chiasm, encasement of vasculatureInfiltration of chiasm, encasement of vasculature-- Inferior, lateral, and posterior resectionInferior, lateral, and posterior resection-- Frozen Section: Grade II Frozen Section: Grade II AstrocytomaAstrocytoma-- Final Pathology: Grade III Final Pathology: Grade III AstrocytomaAstrocytoma-- Severe Severe intraoperativeintraoperative vasospamvasospam with loss of global EEG on right hemispherewith loss of global EEG on right hemisphere


Postoperative MRI Postoperative MRI Enhanced with Enhanced with

GadoliniumGadolinium

Conclusions and The Conclusions and The StudyStudy

ConclusionsConclusionsLowLow--grade grade OCHGsOCHGs represent a distinct disease represent a distinct disease entityentity–– A class of tumors defined by a specific anatomic locationA class of tumors defined by a specific anatomic location

Must be evaluated separately from other Must be evaluated separately from other gliomasgliomas of the visual of the visual pathway (Cancer, pathway (Cancer, FlickengerFlickenger))

–– A class of tumors separate from those of a higher A class of tumors separate from those of a higher histological grade histological grade

All patients require at least a biopsy for histological All patients require at least a biopsy for histological diagnosisdiagnosis

Associated with an extremely low morbidity and Associated with an extremely low morbidity and mortality ratemortality rate

The utility of radical surgical resection has The utility of radical surgical resection has yet to be proven in the literatureyet to be proven in the literature

ConclusionsConclusionsAdjuvant therapies Adjuvant therapies –– ChemotherapyChemotherapy

Effective means of treatment while delaying radiationEffective means of treatment while delaying radiationVarying efficacy in the literatureVarying efficacy in the literatureNew regimens actively being exploredNew regimens actively being explored

–– RadiotherapyRadiotherapyTrends support stabilization/ possible improvement of Trends support stabilization/ possible improvement of vision and prevention of death secondary to tumor vision and prevention of death secondary to tumor progressionprogressionContraindicated in those children presenting under the Contraindicated in those children presenting under the age of 5 age of 5 yoyo

The Proposed StudyThe Proposed StudyGoalGoal–– To define the extent of resection of To define the extent of resection of OCHGsOCHGs in children as an in children as an

independent predictor of survivalindependent predictor of survival

Patient Population: Patient Population: OCHGsOCHGs seen by neurosurgery at CHOP seen by neurosurgery at CHOP between 1985between 1985--20052005

Surgical Endpoints: Extent of Resection, ComplicationsSurgical Endpoints: Extent of Resection, Complications

Functional Endpoints (Minimum follow up of three years):Functional Endpoints (Minimum follow up of three years):–– Progression free survivalProgression free survival–– SurvivalSurvival–– Functional VisionFunctional Vision–– Endocrine StatusEndocrine Status–– Neuropsychiatric parameters: Cognitive ability, Behavior, IQNeuropsychiatric parameters: Cognitive ability, Behavior, IQ

Independent VariablesIndependent VariablesPathology/ HistologyPathology/ HistologyAge at diagnosis: <1, 1Age at diagnosis: <1, 1--5, >5 5, >5 yoyoAge at time of resection: <1, 1Age at time of resection: <1, 1--5, >5 5, >5 yoyoExtent of resectionExtent of resectionPrior chemotherapy or radiationPrior chemotherapy or radiationPresentation with/ without existing Presentation with/ without existing endocrinopathyendocrinopathyVisual status at presentationVisual status at presentation

Thank YouThank YouLeslie N. Sutton, MD Leslie N. Sutton, MD –– Department of NeurosurgeryDepartment of Neurosurgery–– The ChildrenThe Children’’s Hospital of Philadelphias Hospital of Philadelphia

Phillip B. Storm, MDPhillip B. Storm, MD–– Department of NeurosurgeryDepartment of Neurosurgery–– The ChildrenThe Children’’s Hospital of Philadelphias Hospital of Philadelphia

Jeffrey Greenfield, M.D., Ph.D.Jeffrey Greenfield, M.D., Ph.D.–– Fellow, Department of NeurosurgeryFellow, Department of Neurosurgery–– The ChildrenThe Children’’s Hospital of Philadelphias Hospital of Philadelphia

Mike Fischer, M.D. Mike Fischer, M.D. –– Department of Department of NeuroNeuro--Oncology Oncology –– The ChildrenThe Children’’s Hospital of Philadelphias Hospital of Philadelphia

pediatric chiasmatic/ hypothalamic gliomas: … · optic nerve tumors – neurosurgeons typically,...

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