The evolution of new diagnostic algorithms and therapeutic strategies based on a decade of explosive biological discovery - A brief overview and a glimmer of hope

David Ebb, MDPediatric Hematology-OncologyMassGeneral Hospital for ChildrenSeptember 5, 2017

Pediatric Brain Tumors

Epidemiology of pediatric CNS tumors

o Second most common malignancy in children < 20 years of age

n ~20% of all pediatric malignancies (leukemias 32%)n 4600 cases ages 0-19*n 20% occur in children < 3 years of age

o most common solid tumor of childhood

*SEER 2014

Scope of the problem

Pediatric CNS tumorso 4600 new cases per

yearn 5.6/100,000/yr

o ~50% are gliomasn 10-15% of total are

high graden Majority are LGG

o Adult CNS tumorso 79,000 new cases

per yearn 28.6/100,000/yr

o Majority are gliomas and meningiomasn ~90% adult gliomas

are malignant

Location of Primary

o At least 50% of pediatric tumors arise in infratentorial site

o contrasts with adults where majority are supratentorial

o infancy is exceptionn < 12 months of age, 60% are supratentorial

Clinical Presentation - Overview

o Symptoms depend on site more than histology (enormously heterogeneous in pediatrics)

o Headaches occur in 50% as presenting sxo 95% of children with headache due to brain

tumor have abnormal neuro exam

Clinical Presentation -SupratentorialCerebral Hemispheres and Optic Tractso headache most common symptomo seizures in 25%o upper motor neuron signs

n hemiparesisn hyperreflexia

o visual changesn optic nerven chiasmatic lesions (intrinsic/extrinsic)

Clinical Presentation -InfratentorialCerebellum and Brainstemo deficits of balanceo ataxic gaito impaired upper extremity coordinationo cranial nerve deficits

n loss of conjugate gaze

o If midline - sx’s of increased ICP may predominate without localizing signs

Case 1o 19 mos infant in excellent health

until 3 wks prior to dxn new probs with walking (started

walking age 11 months); irritablen Switches to L hand after

demonstrating R hand preference 2 months earlier

n Seen by PCP who obtains x-rays of legs: neg

n 2 wks PTD, stops climbing on playground, unable to put R arm through clothing, difficulty standing, unable to bear wt on R leg

n 3 days prior to dx, taken to ER: head CT reveals 5 cm L frontoparietal mass

n Surgery: HGG, grade 4/4

Pediatric High Grade Gliomas

o high grade gliomas constitute 10-15% of pediatric brain tumorsn 66% hemispheric; 20% diencephalic; 14% post-

fossa/brainstemn include anaplastic astrocytoma (grade 3) and

glioblastoma multiforme (grade 4)n median age at dx = 10 yearsn 25-50% will ultimately disseminate

High Grade Gliomas - Prognosis

o Poor (same as adults)

n median progression free survival of 1-2 yearsn Relatively few survivors beyond 3 years

Prognostic factorso Extent of resectiono Grade/Histologyo Locationo Driver mutations

n TP53, PTEN, PDGFR, EGFR, IDH1

o Mutations in Histone and Chromatin Remodeling genesn The growing recognition of crucial role of

epigenetic modifiers

Differential Expression of PDGFR and EGFR gene signatures in pediatric and adult GBM

PDGFRA

EGFR

Red = highBlue = low

Expression heat map

Paugh et al,JCO 28, 2010

Recent discoveries identifying unique genetic drivers of pediatric HGG o Mutations in Histone genes H3.1, H3.3 found

in nearly 50% of peds GBM but infrequently seen in adult GBM

o H3.3 Gly34 Arg/Val in hemispheric tumorso H3 Lys27Met mutation affects H3.3 (H3F3A)

and H3.1n H3.3 K27M typically associated with midline tumors in

thalamus, brainstem and spinen Tumors bearing this mutation have a poor prognosis

Epigenetics: Different frequencies of driver mutations in pediatric versus adult gliomas

Schwartzentruber, Nature, 2012

Treatment

surgery

XRT/Chemo

Post-RT Chemotherapy

High Grade Gliomas - Treatment

o Surgeryn radical (>90%) resection correlates with longer

survival when combined with XRTo 31 vs. 12 months for grade 3 (A.A.)

o XRT – 54-60 Gyn prolongs survival; often improves tumor related

symptomso Chemotherapy

n TMZ is the default but minimal added benefit

Poor outcome for pHGG unchanged over past 30 years

Cohen, Neuro-Oncol 2011

HGG Rx’d with XRT/TMZ/CCNU: marginally better

RT + TMZ3 yr EFS = 11%

RT + TMZ/CCNU3 yr EFS = 22%

JakackiNeuro-Onc 2016

(ACNS 0423)

Treatment

surgery

XRT/Chemo

Post-RT Chemotherapy+/- targeted agents or

immunotherapy

Case 2o 8 y.o. child in excellent health until 2-3 wk

prior to dx when he developed slight turning in or L eyen Seen by PCP who noted L head tilt and L side

esotropiao Diagnosed L 6th nerve palsyo Scheduled MRI brain o MRI: Diffuse lesion expanding brainstem

Brainstem Glioma

Brainstem Gliomas

o Epidemiologyn 10-20% of childhood CNS tumorsn median age 5-9 years

o Classification by site and histologyn 75-80% are diffuse, intrinsic pontine lesions

o majority are high grade, though often not biopsiedn 14% in medulla; 8% in midbrainn Dorsally exophytic

o arise from floor of 4th ventricle

Diffuse Intrinsic Pontine Glioma

o Very poor prognosis, median survival typically 8-12 months; 2 yr survival <20%

o Surgically unresectable, imaging is diagnosticn Historically not biopsiedn Discovery of genetic subtypes

o Need for tissue to characterize and plan Rx

DIPGo XRT + ANY DRUG

proven no better than XRT alone

Cohen, COG 0126 study

Cohen, COG 0126: Neuro-Oncol 2011

DIPG is not a single entityo Recurrent activating mutations in ACVR1 in

20% - not seen in any other cancer (Taylor, Nature Genetics, 2014)

o PARP overexpressed in majority, amplified in ~ 25%n Repairs single and double DNA strand breaksn PARP inhibitor in trials

o PDGFRa amplified in 1/3, strong expression in most (Zarghooni, JCO 2010)

Treatment?: Need to change the paradigm

surgery

XRT/Chemo

Post-RT: Chemotherapy?

ImmunoRx?

Profiling – target identification

Why do we continue to do so badly in Rx of pHGG?

o Tumors highly infiltrative-often not resectableo Biology of peds HGG is different from adults

n Strategies that hold promise in adults may not be biologically relevant or appropriate in peds

n Need to pursue better characterization of pedsHGG and recognize biological diversity within the pediatric population – Need Tissue!o Distinct subsets based on genetic/epigenetic featureso Sub-populations within the same tumor – genetic

mosaicism

New Therapies – Beyond cytotoxic chemo

o Targeting Histonesn HDAC inhibitors

o Targeting pathwaysn BRAF and MEK inhibitors

o Targeting DNA repairn PARP inhibitors

New therapies for HGG-Immunotherapyo CNS previously viewed as immunopriveleged

sanctuaryn Now recognized that there is trafficking of

immune mediators (T cells) between systemic circulation and CNS

n HGGs suppress or evade local immune response via upregulation of immune checkpoints

n Immune checkpoints: prevent auto-immunity and protect tissues against injury from systemic immune response

New therapies - Immunotherapyo Dendritic Cell (APC’s) vaccines

o Use whole tumor cell or selected TSC lysatesn Less toxic than chemo but limited efficacy to daten Requires 6-8 wks for ex-vivo expansion of cytotoxic T-cells

o May need to be combined with immunomodulators to overcome tumor-driven immunosuppression

o Adoptive cell transfer – CAR T-cellso Genetically modified T-cells with chimeric antigen

receptorsn Requires expression of tumor-specific antigens for targetingn Proven efficacy in hematopoietic malignancies but

disappointing to date in solid tumors

Checkpoint inhibitorsAnti-PD1: Pembrolizumab, Nivolumab

Anti-CTLA-4: Ipilimumab

NCI library @ Cancer.gov

Case 2aInitial Presentationo 18 y.o. with 2 wk h/o R

sided neck pain and HAo R temporal lobe masso Resected – GTR

n Glioblastoman Sequencing – p53 mutation,

MGMT mehtylated

o Focal XRT and Temodar, then Temodar for 12 mos

Relapseo New back pain 3 mos. off

Rx (16 mos after initial dx)o Metastatic to spineo Symptomatic lesion at L4

resectedn GBMn 25 mutationsn Identification of 2 mismatch

repair genes

o XRT to whole spineo Pembrolizumab and avastin

Case 3o 6 y.o. with 6 month h/o worsening headaches

n Headaches became more frequent and more severe over the month prior to dxwith occasional emesiso Family h/o migraines

n New sx’s of LUE tremor and decline in handwriting over month prior to diagnosis

n Referred to neuro clinico Exam: L sided spasticity and L inf quadrantanopiao Started on amitriptyline for possible migraines due to family hxo Sched for brain MRI due to concern about poss mass lesion

n Acute worsening of vision and new unsteadinesso Referred to ER for imagingo CT: 5 cm solid/cystic mass in R thalamus with midline shifto Started on decadrono OR next a.m.: resection

Low Grade Gliomas

Low Grade Gliomaso Cerebral Astrocytomas (low and high grade)

constitute 35% of all childhood CNS tumorsn 75-80% are low grade gliomas

o pilocytic (grade I) and fibrillary (gradeII) astrosn Presentation of low grade gliomas

o indolent courseo increased ICP in 75%o focal motor deficits commono seizures in 25% - higher frequency than GBMo onset of seizures may precede dx by 1-2 years

Low Grade Gliomas - Biologyo Alterations in BRAF found in the majority of

PLGA’s - Pfister, JCI 2008n Genetic alterations in BRAF contribute to activation of

MAPK pathway leading to either tumor growth, differentiation or oncogene-induced senescence (p16)

n Majority of BRAF alterations involve tandem duplication of gene on 7q34 o Fusion gene: BRAF-KIAA1549o Frequency depends on location and histology

n 65% of midline PLGA’s (optic, post fossa, brainstem, cord)n 11% lobar tumorsn 62% of pilocytics; 37% of diffuse (fibrillary) astrocytomasn Not found in high grade lesions

Horbinski, J Neuropathol Exp Neurol 2012

Low Grade Gliomas - Biology

Frequency of BRAF fusions decreaseswith age in cerebellar PA’s:

80% first decade50% in 2nd decade<10% age > 40 yrs

Horbinski, J Neuropathol Exp Neurol 2012

Low Grade Gliomas - treatment and outcomeo Treatment - aggressive attempt at complete resection

of hemispheric and infratentorial lesions n Exceptions - deep thalamic/hypothalamic and optic tract

lesionso only 40% of diencephalic lesions are fully resectable

n up to 80% hemispheric lesions fully resectableo optic gliomas may remain stable for many years without

progressive loss of function

o Prognosis - correlated with extent of resectionn GTR: 10 yr OS = 85-90%n STR: 10 yr OS = 65-85%

Treatment of Low Grade Gliomas – Is post-op Rx necessary following sub-total resection?

o Observation recommended n behavior of low grade astros quite variablen often remain stable for years

o PFS at 3 and 5 yrs: 58% and 48% with obso malignant transformation uncommon

n No adverse effect on survival if RT postponed in children with incompletely resected tumorso Fisher et al, Pediatr Blood Cancer 2008

n Wait for radiographic progression or clinical evidence of functional decline

Treatment of Low Grade Gliomas - Non-surgical options

o Chemotherapyn indicated for unresectable, progressive or

symptomatic low grade gliomas in children < 10 years oldo XRT avoided if possible in this age group

n Combination of vincristine/carboplatinumo 75% progression free survival at 2 years (Packer et al,

JCO 11: 1993)

o postpones XRT – indefinitely?

Progressive Low Grade Glioma –Alternative Chemo regimenso 6-TG/PCV (“the UCSF regimen”)

n Similar response/stabilization to VCR/Carbo (Prados et al, J Neurosurg 74: 1991)

n Randomized COG study comparing VCR/Carbo to 6-TG/PCV –equivalent outcomes

o Vinblastineo Irinotecan and Avastino Vinorelbineo Temodaro Therapy targeting BRAF alterations

n BRAF alterations: 80% of grade I, 13% of grade IIn Majority of BRAF alterations are tandem duplications:

BRAF-KIAA1549 fusion gene – possible Rx with MEK inhibitorsn BRAF V600E mutations only in ~10%

o target for Vemurafenib, Dabrafenib…

Treatment of Low Grade Gliomas - Non-surgical optionso XRT

n can achieve 10 year survival of >80% in incompletely resected low grade gliomaso Tarbell - 6 yr PFS of 88% in pts with

symptomatic/progressive OPG rx’d with XRTn visual improvement or stabilization in 91%

n potential neurocognitive and neuroendocrineimpairment => avoided in children < 10 yrs.

Case 4o 18 y.o. with HA x 1 yro Increased intensity and

freq of HA over 4 wks prior to dxn HA’s typically in a.m.

o N/V with HA x 2 days prior to dx

Cerebellar Astrocytoma

Cerebellar Astrocytomaso Demography

n 10-20% of childhood CNS tumorsn most common in 1st decade (6-9 years)

o Histologyn majority are pilocytic (85%)n high grade cerebellar gliomas uncommon

o Biologyn BRAF duplication/mutation in ~50% (Pfister, JCI 5/08)

o BRAF part of Ras/MAPK pathway – potential Rx target

o Presentationn increased ICP in 90% (obstructed 4th ventricle)n lower extremity ataxia

Cerebellar Astrocytomas - Therapy and Outcomeo Surgery

n 90% survival at 10-30 years with complete resection (achievable in up to 90% of cases)

o Chemon Add if progression/recurrence in pts < 10 yrs

o XRTn Defer until radiographic/clinical progression in subtotally

resected cases which fail to respond to chemotherapy

Treatment with Chemo in CerebellarLow Grade Glioma

InitialMRI

Post-chemoMRI

chemo

Case 5o 15 y.o girl with 6 yr

h/o HAn Suspected migraines

o New 3wk h/o galactorrhean Endo eval – isolated

high prolactino Bitemporal visual field

defecto Scan ordered by endo

Craniopharyngioma

Pathology

Childhood Cranios:

Adamantinomatous with cyst formation

Solid and cystic components made of squamous epithelium. Cysts contain oily viscous material with keratin and cholesterol crystals

70% of adamantinomatous cranios harbor mutation in B-catenin

Pathology

Clinical Presentation: HeadachesoHeadache due to

hydrocephalus n caused by

compression/obstruction of 3rd ventricle and foramen of monroe

n Presenting sx in 50%n Occurs in 65% of cases

Presenting symptoms: visual deficitsoVisual field defects

n Presenting sx in 20%n 60-80% have field

deficits at dx even if not initial sx

Clinical Presentation – Neuroendocrinedeficits

oNeuroendocrine deficits –52-87% at diagnosisn Growth delay due to GH defic

is most common – 75%n Gonadotropin deficits – 40%n ACTH deficit – 25%n TSH deficiency – 25%n DI – 17% preoperatively

Clinical PresentationoTime to diagnosis often very long – up to 2 years from

onset of first symptomsoCombination of headache, decreased growth rate,

visual impairment, and polydipsia with polyuriashould raise suspicion for Cranio

oDifferential diagnosis:n Pituitary adenomasn Hypothalamic/optic tract gliomas (usually low grade)n Rathke’s cleft cystsn Germ cell tumorsn LCH

Imaging Features

Solid and Cystic

Most commonly suprasellar, often with intrasellarcomponent

> 90% have calcifications on CT – not typically present in gliomas, LCH or germinomas

calcification

Suprasellar location- Solid and cystic

RadiographicFeatures

Treatment: Hormones can be replaced but you can’t make a blind man see – the role for surgery

oSurgery with GTR if possible depending on locationn Primary goals: relieve mass effect on optic structures to

preserve vision, re-establish CSF flow, reduce field size if XRT planned (cyst decompression)

n Decompression of uninvolved neuroendocrine structures (i.e. hypothalamus)

n Shunt may be required vs decompression/fenestration of dominant cysts with placement of Rickam/Ommaya reservoir in dominant cyst to facilitate repeat decompressions

Outcome of surgical resectionn If Gross Total Resection, PFS ~80%

o GTR achievable in 60-90% of caseso Significant surgical morbidity – panhypopit in 80-90%o Risk of vascular injury (stroke in ~5%)

n If subtotal resection alone, progression in 70-90%n Subtotal resection plus XRT: PFS ~ 80%n Visual outcome after radical resection

o Acuity improved in 64%, worse in 21%o Field deficit improved in 56%, worse in 17%

n Endocrineo ~80-90% of pts develop irreversible DIo GH deficiency in 75% Elliott, J Neurosurg 2010

Treatment: XRToSurvival outcome with STR

+ conformal XRT equivalent to radical resection alonen Both ~ 80% PFS at 10 yrs

oXRT dose typically 54 GyoControversy re: functional

outcomes with radical surgery vs limited surg + RT

Long term Sequelae of XRToNeuroendocrine (Kiehna + Merchant, Neurosurg Focus

2010)

n70% require GH supplementationn90% require thyroid supplementationn40% require Rx of hypogonadismn75% require cortisol replacementnDI uncommon with XRT

Long term Sequelae of XRToCognitive outcomes

n Improved with increasingly conformal therapyn Overall IQ stable x 5 yrs post-XRT in St Judes

seriesn Younger pts < 7 yrs at higher risk for impairmentn Pts with hydrocephalus requiring shunting or

multiple aspirations do worse

Other sequelae of therapyoObesity

n Observed in 40-50%n Presumed secondary to injury to hypothalamus by

tumor and therapy (surgery +/- RT)o This is important reason why surgery is undertaken with

intent to spare hypothalamic structureso Clinical trials of stimulants to Rx hypothalamic obesity

underway

Is there a role for chemotherapy?oNo clearly defined role at present

n Vast majority have beta catenin mutationso Potential therapeutic target

oSmall case series demonstrated some benefit from systemic interferon

oTrials looking at intralesional interferonn Potentially useful in treating cystic components but

uncertain benefit for management of solid components

Germ Cell Tumors

Chemotherapy

Chemosensitivity of Germ cell tumorso Germinomas exquisitely sensitive to chemo

n High CR rate to chemo (Carbo, CDDP,VP-16)n Chemo alone not sufficient

o 50% relapse if no RTn Use whole ventricular field and boost tailored to

response o NGGCT – chemo plus CSI yielded 85% EFS

n Carbo/VP-16 alt with Ifos/VP-16 x 6 cycles

Chemotherapy and XRT: Efforts to Reduce Treatment-related toxicityo Germinomas exquisitely sensitive to both XRT and

chemo. o Excellent cure rate for both localized and

disseminated tumors with XRT alone.o Inclusion of chemo appears to permit utilization of

lower doses of XRT without compromising cureo Germinomas are so chemo-responsive that efforts

were undertaken to treat with chemo alone

Excellent prognosis for localized and metastatic germinoma

SIOP CNS GCT 96, Calaminus, Neuro-Oncol 2013

Case 6o 12 month old 2 mos h/o

lethargy, loss of milestonesn Stopped cruisingn Slower crawlingn Irritable/clingy

o Neuro evaln Disprop increase in HCn Head ultrasound – hydron MRI – post-fossa mass

Ependymomaso Epidemiology

n 5-10% of childhood brain tumorsn tend to affect very young children

o 25-40% < 2 years old at diagnosiso Sites of Disease

n arise within or adjacent to ependymal lining of ventricles or central canal of cordo symptoms of increased ICP common

n 90% are intra-cranial (60% post-fossa)n locally invasive (brainstem or cord)

Survival by Ependymoma subgroup

Korshunov et al, JCO 2010

Survival by Molecular subgroup

Subgroups definedby methylation

profiling

Pajtler et al, Cancer Cell 2015

Infratentorial

Supratentorial

RELA

RELA

YAP1

No recurrent genemutations in PF tumors

OncogenicC11orf-RELA fusion gene in

70% of ST tumors, never in PF tumors

Ependymoma Subtyping and prognosiso Post-fossa group A and Supratentorial-RELA

subgroups have very poor prognosisn 10 year OS of 50%n 10 year PFS of 20%

o Post-fossa group B and ST-YAP1 groups have good prognosisn 10 year OS ~ 100%n 10 year PFS 88-100%

Pajtler et al, Cancer Cell 2015

Ependymomas - treatment and outcome

o Surgery – the importance of extent of resectionn 5 year PFS of 51-75% if completely resected

and irradiatedn only 15-45% PFS if incompletely resected and

irradiatedn complete resection often not attainable due to

invasion of vital structureso complete resection in only 40-60%

Ependymoma - Chemotherapyo Active Agents/Combinations – response rates

n Carboplatinum – 40% (Gaynon et al, Cancer 60: 1990)

n Vincristine/Cytoxan – 48% (Duffner et al, NEJM 328: 1993)

n Oral VP-16 – 2 CR in 5 relapsed pts (Needle et al, Med. Ped. Onc. 29: 1997)

n Cisplatinum - 33% (Bouffet, Med. Ped. Onc. 29: 1998)

n Cisplatin,Cytoxan,VCR,VP-16 (Garvin ISPNO 6/04)

o 42% CR, 18% PR in 34 pts with residual after surgeryo Pts with CR to chemo had 3 yr EFS of 86%o 15% progressed on chemo

Ependymoma – Sandwich Rxo Recently completed COG study used 7 wk course of chemo

after STR to facilitate 2nd look surgery/GTRn Goal was GTR prior to XRT to improve PFSn EFS was equivalent for pts with GTR1 or GTR2 after chemo +/- 2nd

surgery ~ 71%o Classic (Gr 2) = 75%o Anaplastic (Gr 3) = 66%

n Extent of resection and outcomeo GTR = 75%o STR = 41%

n Difference in outcome (STR vs GTR prior to RT) based on histologyo Grade 2 (classsic): 44 vs 80%o Grade 3 (anaplastic): 30 vs 66%

Ependymoma - XRT

o Standard of care for post-fossa ependymomas due to survival advantage since late 70’s

o Seeding uncommon => local fieldo Historically avoided or postponed in infants

and children < 3 yrs of age

Ependymoma – early conformal RTo St. Jude study by Merchant et alo N = 88 with median age of 2.85 yr (48<3yr)o Rx’d with CRT with 1mm margin

n 59 Gy if > 18 mosn 54Gy if < 18 mos

o 3 yr EFS of 75%o Neuropsych testing revealed stable function at

24 months after CRT (Merchant et al, JCO 22: 2004)

Ependymoma – Conformal RT

Merchant et al, JCO 22: 2004

EFS

Neuro-cognitiveoutcome

Ependymoma – Current COG studyo Maximal resection

n Chemo for STR followed by 2nd look surgeryo VCR/Carbo/CTX then VCR/Carbo/VP-16o 2nd look surgery if residual after chemo

n No post-op, pre-XRT chemo if GTRo Conformal XRTo Post-RT randomization to obs vs chemo

n Maintenance chemo: VCR/CDDP/CTX/VP-16, 4 cycles

Case 7o 7 y.o. well until 1 month prior to dx

n Worsening headachesn Increasing clumsinessn Diplopian 3 episodes of emesis in a.m. during wk prior to dxn Taken to ER due to worsening HA’s and N/Vn CT revealed 4 cm PF mass with hydrocephalusn Referred to MGH

o Started on decadron; imaging of brain/spine with MRIo tumor resected

Medulloblastoma

Scope of the problemn Medulloblastoma is most common malignant

tumor in childreno 20% of all peds CNS tumorso 40% of post-fossa tumorso ~ 400 cases per year

Demography of Medulloo Most arise in first decadeo peak age at diagnosis = 5 years o median age at dx = 7 yearso 80% diagnosed by 15 yearso 10-15% dx’d in infancyo male to female ratio = 2:1

Patterns of Spreado May fill the post-fossa and invade

surrounding structures (brainstem)o seeding tumor - 20-30% disseminated at dx

n > 70% are disseminated at recurrence

Clinical Presentationo Early – sx’s of incr ICP

due to obstructionn headache, early a.m.

emesis, lethargy, declining school performance

o Late signsn worsening ataxian cranial nerve deficits

(VI, VII)

HistologyClassic:

65% of cases

Desmoplastic: 25% of casesAnaplastic: 5-10% of cases

Very heterogeneous

Prognosis – the standard predictorso Clinically based risk group stratification –

past 3 decadesn Stage – localized vs disseminated n Extent of resection (1.5 cm2 threshold)n Age at diagnosis

o Infants <3-5 yrs treated on separate studiesn Histology

o Classico Large cell/anaplastic – poor (recent)o Desmoplastic – improved in infants

Standard risk patientso Patients with non-metastatic diseaseo Less than 1.5cm2 residual disease on post-op

MRIo Classic or desmoplastic histologyo > 3 years of age

High risk patientso Disseminated diseaseo Residual tumor on post-op scan > 1.5 cm2o Diffuse anaplasiao MYC amplified

Low Risk Patientso Wnt pathway tumors

n Mutations in beta cateninn Monosomy 6n Favorable if age < 16 years

Treatment - Multimodalityo Surgeryo Radiationo Chemotherapy

Treatment I - Surgeryo extent of resection is important predictor of

survival*n used for treatment stratification

o < 1.5 cm2 residual disease => standard risko > 1.5 cm2 residual disease => high risko Recent controversy regarding prognostic value

o even with complete resection, most* will recur in post-fossa or neuraxis unless treated with craniospinal XRTn *recent infant studies prove CSI not always required in

subset with GTR, no mets and favorable histology

Treatment - Surgical Complicationso Posterior Fossa Syndrome

n consists of cerebellar mutism +/-ataxia, CN VI,VII palsies, hemiparesis and labile affect

n Mutism, affective lability resolve in 4-8 weeksn as many as 20-30% of children are affectedn may result from transient impairment of

afferent/efferent pathways of the dentate nuclei n 50% may suffer long term impairments in

language

Treatment II - Radiationn Craniospinal XRT std since 1950’s

o Dose constrained or witheld in infantsn CSI to 36 Gy + PF boost will cure 50-

60% of pts with localized disease

Treatment - Complications of RTo Neurocognitive deficits

n Memoryn Attention deficitsn Processing speedn Global loss of learning

potentialn Hearing loss

o Neuroendocrine deficitsn Growthn Thyroidn Gonadal function

Complications of RT - neurocognitiveo Impact of age at dx and CSI dose (24 vs 36 Gy)

Top panels: age > 7yrsLower panels: age < 7

Right panels: HR (CSI: 36 Gy)Left panels: AR (CSI: 24 Gy)

Mulhern et al, JCO 23: 2005

Efforts to reduce long-term adverse effects of XRTo Recent COG study randomized between 1800

and 2400 cGy for CSI for pts 3-7 yrsn Pts > 7 yrs receive 24 Gy CSIn All pts receive boost to 54 Gyn Unacceptable failure rate with 18 Gy

o Same study randomized boostn Whole post-fossa vs involved field

o Infant studies using HD chemo with PBSCT +/- HD MTX to reduce or avoid XRT

XRT for medullo: Protons vs PhotonsProtons Photons

Medullo: Protons vs PhotonsProtons

Photons

Protons

Photons

Protons - Potential Benefitso Superior dose conformity

permits inclusion of focused RT in infants n possible improved survival

with XRTo fewer local failures

o Less morbidity for older children whose lesions are in close proximity to vulnerable structures n less hearing lossn avoid dose to

hypothalamus/pituitaryn spare temporal lobes in

posterior fossa boostIllustration of dose conformity

– this is no medullo

Treatment III - Chemotherapyo Medulloblastoma is among the most

chemosensitive of all pediatric CNS tumorso Chemo first added to XRT in 1970’s in effort

to improve EFSn subsequent studies in 1980’s and 1990’s designed

to test feasibility of reducing XRT dose with addition of adjuvant chemo to reduce neurotoxicity

Treatment III - Chemotherapy

o Pediatric cooperative group studies over the past 30 years have now demonstrated that the addition of chemo to surgery and XRT can improve survival, particularly in high risk children

o For standard risk children, inclusion of chemo has permitted reduction in XRT dosing (less toxicity) without compromising survival

Standard risk patientso Patients with non-

metastatic diseaseo Less than 1.5cm2 residual

disease on post-op MRIo Classic or desmoplastic

histologyo > 3 years of ageo Therapy

n CSI 24 Gy + PF boost to 54Gy with VCR

n VCR/CCNU/CDDP or VCR/CTX/CDDP

o EFS = 80%Packer JCO 24, 2008

High Risk patientso Disseminated diseaseo Greater than 1.5cm2

residual tumoro Diffuse Anaplasiao Therapy

n CSI 36 Gy + Carbon PF and mets boost to

54 Gyn Post RT chemo:

VCR/CDDP/CTXo EFS = 65-70% Jackaki, CCG 99701, JCO 2012

Infants – a unique challengeo Adverse effects of XRT most profound in very

young childreno Potentially devastating decline in cognition in

infants/young children Rx’d with CSIn Declines in IQ thought to result from “failure to learn at

age-appropriate rate, rather than loss of previously acquired knowledge” – (Mulhern et al, Lancet Oncology 5: 2004)

n Drop in IQ associated with loss of white mattern COG study: Children > 3 yrs at dx drop FSIQ by 17.4 pts

at 4 yrs from dx

Therapeutic Challenges - Radiationo Craniospinal XRT in infancy

n contraindicated due to profound effect on cognitive functioning/development and growth

Walter et al, JCO 17: 1999

Drop in IQ of ~4 points/yr with no plateau at 5 yrs from dx

Baby studies: avoidance of XRTo Head Start protocols (Finlay et al)

n single course of high dose chemo with PBSCT, inclusion of HD MTX

o French and German studiesn Chemo without MTX vs inclusion of MTX - IT

and systemico COG: 3 courses of HD chemo/PBSCT +/- MTX

Infant Studies: Baby POGo Baby POG I, 1986

Chemo for 12-24 months (VCR/CTX alt with CDDP/VP-16) followed by RT35/54 Gy. If NED after chemo, reduced RT: 24/50Gy

Medullo: PFS: 34%OS: 46%At 2 yrs

Duffner et al,NEJM 328:

1993

CCG 99703: intensified consolidation with HDCT/PBSCR x 3o 3 cycles of VCR, CDDP, CTX, VP-16 followed by

Thiotepa/Carbo with PBSCR x 3o 3 yr EFS M0: 67%o 3 yr OS M0: 76%

Cohen and GeyerCOG study report,

fall, 2007

German Infant Medullo Study – chemo aloneinclusion of systemic + intraventricular MTXo German Study for children < 3 yrs

(Rutkowski et al, NEJM 352: 2005)

n N = 43n Chemo: VCR, Cytoxan, HD MTX, Carbo, VP-16

and intraventricular MTX…no RTn 5 yr PFS = 58%

o If GTR: PFS = 82%o If STR: PFS = 50%o If M2, M3: PFS = 33%

What have we learned over the past 3 decades?o majority of patients with localized and metastatic medullo are

cured using intensive combined modality therapy – a significant advance

o Howevern 20% of non-metastatic pts will failn 25-35% of metastatic pts will succumb to diseasen Very few pts with recurrence after chemo/RT survive with current

salvage therapies (10-20% at best)n The long-term functional costs of intensive therapy in infants and

older children can be severe and debilitatingo Perhaps our infant protocols should extend to older children

n There is great biologic diversity in this disease

Lessons from 3 decades of Cooperative group trials – beyond histologyo Must identify biologic risk factors to improve

stratification/Rx for biologically high risk pts who are currently Rx’d as std risk

o Some “standard risk” pts are being over-treatedn Unnecessary toxicity and long-term functional impairmentn Who are they?

o There is a subset of pts classified as high risk by traditional criterion who may be cured with less aggressive therapyn Can we reliably define them?

o Doses of XRT may be further reduced with intensification of chemo and identification + therapeutic exploitation of biologic targets unique to medullon Risks of XRT can be curtailed with more conformal delivery

Improving survival and function: Biologically-based risk group stratification

n Adverseo P53o MYC/MYC-No 17p- (40-50%)o MYC+/LDHB/CCNB1+

gene signatureo Anaplastic histology

o Favorablen TRK-C (NT-3 receptor)

n Wnt/Beta-cateninn 6q-n Low MYC expressionn Desmoplastic histology

Risk Group Stratification by Gene Expression Profile – Cluster analysis

Pomeroy et al, Nature, 1/24/02

Are there subtypes that should be treated less intensively even if clinically high risk?

Gajjar et al,Lancet Oncology 7,

2006

Molecular subgroups of Medullo: the current consensus – Taylor et al, Acta Neuropathol, 2012

Stratification based on molecular and clinical profile - Pfister

Pfister et al, JCO 27, 2009

Clinical high risk:Mets, LC/anaplasia

Molecular high risk:17q gain, 6q gain,

myc/mycn amp

Prognostic Significance of clinical, histopathologicaland molecular characteristics in HIT 2000 cohort

N = 184 pts enrolled 2000-2012 Pietsch et al, Acta Neuropathol, 2014

Further refinement of biological risk group stratification - 2017

Schwalbe, Lancet Oncol 2017

The Challenge for multi-modality therapyo Can potentially curative interventions be tempered or

deferred to preserve function without compromising survival?n Medullo

o steadily decreasing XRT dosing with inclusion of chemo and biologically-based risk group stratification

o Targeted therapy?n Ependymoma

o Increased conformality of XRT plan and deliveryn Germ Cell tumors

o Response-based XRT dosing with inclusion of chemo

The Challenge for multi-modality therapyo Can potentially curative interventions be tempered or

deferred to preserve function without compromising survival?n Gliomas – low grade

o Identification of new therapies targeting activated MAPK/ERK pathway (mediated by BRAF) potentially permitting further deferral/avoidance of XRT and XRT-related complications

n Gliomas – high gradeo Need to improve survivalo Better understanding of biology may translate to more effective

therapies directed at molecular targets

The Challenge for multi-modality therapy: All ages, all histologies, during Rx and long after therapy is done

o Multisystem approachn Radiographic surveillance with MRI

o For recurrence and potential complications of therapyn Neuroendocrinen Ophthon Intensive home and school-based rehabilitative support

o OT/PT, speech, feeding teamn Neuropsych/QOL assessments and collaboration between

neuro-oncology team and school/community-based programso To assure optimal opportunites for functional autonomy and

happiness

on behalf of our many essential collaborators – thank youo Pediatric hematology-

oncologyo Neurosurgeryo Radiation oncologyo Neuro-radiologyo Nursingo Peds Surgery

o Endocrinologyo Ophthalmologyo Social worko Psychiatryo Child lifeo Neuropsycho ENT

Our patients and their families