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
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
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)
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 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 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 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
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
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
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 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 – 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
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 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
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
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
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