Embed Size (px)
Citation preview
¡ Robin M .Jones M.D.¡ Assistant Professor of Neurology HMS¡ MGH CN CME October 30,2015
¡ Exposure to radiation¡ Second tumors¡ Cohort of Leukemics exposed to prophylactic
radiation¡ NF sensitivity to XRT
¡ Genetic syndromes with known somatic mutations and increased brain tumors provide molecular data on possible genetic alterations in signalling tumor growth; only associated with 1-5% of tumors; but give us important information about tumor biology
¡ Gorlin¡ NF¡ TS ¡ Li fraumeni¡ Turcot¡ Von Hippel Lindau
¡ Tumor Type¡ Medulloblastoma(std
risk 60%,high risk 20%
¡ Low grade glioma¡ High grade glioma¡ Brain stem glioma(low
grade focal,20%,diffuse 80%)
¡ Ependymoma
¡ % childhood tumors¡ 20%
¡ 30%¡ 10%¡ 15%
¡ 10%
At least 50% pediatric tumors arise in infratentorial region
Except in less than 1 yr 60% supratentorial
¡ Clinical presentation often depends on location of the tumor
¡ Always look for increased intracranial pressure
¡ Headache¡ Nausea and vomiting¡ In young infants macrocephaly
¡ Suprasellar; field deficits visual loss; new onset strabismus; endocrine disturbances; precocious puberty; central diabetes insipidus (in isolation often missed for months!!); diencephalic syndrome normal linear growth but severe FTT with increased appetite and hyperactivity
¡ Classic examples ; Craniopharygioma. Germ cell tumor; optic pathway pilocytic low grade tumors;
¡ Headache ; seizure; often non-specific non-localizing signs of increased intracranial pressure; can be associated with hemiplegia.
¡ Classic examples; supratentorial low grade glioma; pilocytic astrocytoma; supratentorial ependymoma; choroid plexus papilloma and carcinoma.
¡ Parinaud syndrome in pineal tumors; light near dissociation and impaired upgaze due to pressure on the dorsal midbrain.
¡ Increased intracranial pressure in central tumors ; poorly localizing
¡ Central neurocytoma, germ cell tumors; pineal tumors.
¡ Ataxia; gait disturbance, headache, nausea, progressive symptoms of morning nausea and nighttime awakening with vomiting with progression to hydrocephalus; papilledema, eye movement abnormalities, altered consciousness, vertigo or auditory sx;
¡ Medulloblastoma¡ Ependymoma¡ Pilocytic astrocytoma
¡ Cranial neuropathies; 6 and 7 common, 9/10 difficulty swallowing; gait disturbance, coordination difficulties,
¡ Pontine glioma¡ Infiltrating ependymoma and
medulloblastoma¡ Metastatic leptomeningeal disease often
seen in metastatic medulloblastoma
¡ Pain; back and neck¡ Torticollis¡ Bowel and bladder dysfunction¡ Radicuolpathy¡ Weakness¡ Spasticity and gait disturbance
EpendymomaMyxopapillary ependymomaLow grade gliomasPilocytic astrocytomasLow grade astrocytomas
¡ Any localizing findings¡ Non-specific headache in child associated
with nighttime vomiting, morning vomiting, neurologic regression, unexplained macrocephaly in infant; new onset endocrinopathy or visual loss, unremitting migraine or tension headache in child under age 4.
¡ Surgery¡ Chemotherapy¡ Radiation therapy
¡ 53% of childhood cancer includes leukemia and brain tumors
¡ Both require CNS therapy¡ In U.S.>, 4,500 kids >15 years dx’d with
leukemia or brain tumor per year¡ 5 year survival rates are converging;¡ Leukemia 79.3, Brain tumors 73.3%
¡ Survivors of multimodality therapy in CNS tumors can have severe neurologic sequellae
¡ Patients with leukemia often relapse in the CNS
¡ Models for ALL CNS prophylaxis have taught us about the severe poorly understood complication of leukoencephalopathy
Huse and Holland, Nature Rev. Cancer 2010
¡ MGH patients who told me their stories¡ Emmet Schmidt, Verne Caviness, Elizabeth
Dooling.¡ Howard Weinstein, David Ebb, Nancy Tarbell,
Torunn Yock, Shannon MacDonald, Annah Abrams, William Butler, Tina Duhaime, Beverly LaVally, Sue Ann Waterman, and the staff of the MGHfC
¡ Bowers DC, et al. Late-occurring stroke among long term survivors in childhood leukemia and brain tumors; a report from the childhood cancer survivor study. Journal of Clinical Oncology 2006; 24: 5277.
¡ Campen J, et al. Cranial irradiation increases risk of stroke in pediatric brain tumor survivors. Stroke 2012; 43: 3035.¡ CTBRUS Statistical Reports Primary Brain Tumors in the US 2000-04. Hinsdale Central Brain Tumor Registry of the US,
2008.¡ Gudrunardottir T, et al. Cerebellar mutism. Childs Nervous system 2011; 27: 355-363.¡ Heckl S, et al. Radiation-induced cavernous hemangiomas of the brain. Cancer 2002; 94: 3285.¡ Law N, et al. Clinical and neuroanatomical predictors of cerebellar mutism syndrome 2012; 14: 1294-1303.¡ Leary ES, et al. The molecular classification of medulloblastoma: driving the next generation clinical trials. Current Opinion
in Pediatrics, 2012; 24: 33-39.¡ Liu, C & Zong H. Developmental origins of brain tumors. Current Opinion in Neurology 2012; 22: 844-847.¡ Merchant TE, et al. Brain tumors across the age spectrum: biology, therapy, and late effects. Seminars in Radiation
Oncology 2010; 20: 58-66.¡ Mulhern RK, et al. Neuropsychological functioning of survivors of childhood medulloblastoma randomized to receive
conventional or reduced-dose craniospinal irradiation: a pediatric oncology group study. Journal of Clinical Oncology 1998; 16: 1723.
¡ Ramaswamy V, et al. FISH and chips: the recipe for improved prognostication and outcomes for children with medulloblastoma 2011; 204: 577-588.
¡ Rola R, et al. Radiation-induced impairment of hippocampal neurogenesis is associated with cognitive deficits in young mice. Experimental Neurology 2004; 188: 316.
Rapid advances in tumor biology –an evolving set of tools to improve survival and quality of life
David Ebb, MDPediatric Hematology-OncologyMassGeneral Hospital for ChildrenOctober 2015
Pediatric Brain Tumors
Epidemiology
o Second most common malignancy in children < 15 years of age
o 24.5 cases/million/year vs. 29.4/million for ALL n 2500 cases/year
n 20% of all pediatric malignancies
n 20% occur in children < 3 years of age
o most common solid tumor of childhoodn 10 cases/million for all other solid tumors combined
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 sx
o 95% of children with headache due to brain tumor have abnormal neuro exam
Relative Frequency of Pediatric Brain Tumors
20%
39%15%
8%8% 6-9% 3%
Medullo 20%Astro/low 40%Astro/high 10-15%Ependymoma 8%BSG 8%Cranio 6-9%SPNET 3%
Treatment - Overview
o The Challenge for multi-modality therapy:
Can potentially curative interventions be tempered or deferred to preserve function without compromising survival?
o Rapid pace of new scientific discoveryn How can we integrate new insights regarding genetic and
epigenetic contributors to tumorigenesis in formulating and validating new treatment paradigms?
Challenges: Age, location, and…o Age
n Developing brain far more vulnerable to injury from XRT (+/-chemo) mandating deferral or constraint on dose/field in infants and young pts
o Locationn Though extent of resection is important predictor of outcome, midline
tumors often not resectable without unacceptable risk of functional deficits
n BBB contributes to potentially less effective delivery of active drugs to CNSo HD chemo with HSCTo Regional Rx with intrathecal deliveryo Uncertain delivery of monoclonal antibodies into CNS
Challenges: …Biologyo Biology
n Historically broad categories based on histology
n Increasing understanding of distinctive molecular features o Now more sophisticated understanding of
behavior/response to standard cytotoxic therapies
o development of stratified therapy plans based on unique biology and targetable molecular perturbations
Case 1o 19 mos infant in excellent health
until 3 wks prior to dxn new probs with walking (started
walking age 11 months); irritable
n 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
High Grade Gliomas
o high grade gliomas constitute 10-15% of pediatric brain tumorsn 66% hemispheric; 20% diencephalic; 14% post-
fossa/brainstem
n include anaplastic astrocytoma (grade 3) and glioblastoma multiforme (grade 4)
n median age at dx = 10 years
n 25-50% will ultimately disseminate
High Grade Gliomas - Prognosis
o Very poor (same as adults)
n median progression free survival of 1-1.5 years
n few survivors beyond 3 years
Prognostic factors
o Extent of resection
o Histology
o Location
o Driver mutationsn TP53, PTEN, PDGFR, EGFR, IDH1
o Mutations in Histone and Chromatin Remodeling genesn The growing recognition of epigenetic modifiers
Impact of Histology
AA
GBM
Qaddoumi et, Cancer 115, 2009Review of 6212 cases from SEER database ’73-’05
Prognostic impact of extent of resection
Das, Childs NervousSystem, 2012
Across multiple studies, GTR achievable in ~25%
Impact of p53 expression levels on Survival in pediatric high grade glioma
CCG-945: Pollack, NEJM 346, 2002p53 expression seen with mutant TP53
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
PTEN expression: mutation associated with decreased survival
PTEN inhibits PI3K/AKT signalingFrequently deleted in adult HGGRarely deleted in childhood HGG
Thorarinsdottir et al,Clin Cancer Res 14, 2008
Prognostic impact of MGMT expression levels in pediatric glioma patients: same as adults
CCG-945: Pollack, JCO 24, 2006
MGMT: DNArepair enzyme
MGMT promoter:Methylated = unexpressed (blue)
Hypomethylated = transcribed (red)
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 tumors
o H3 Lys27Met mutation affects H3.3 (H3F3A) and H3.1n H3.3 K27M typically associated with midline tumors in
thalamus, brainstem and spine
n Tumors bearing this mutation have a terrible prognosis
Epigenetics: Different frequencies of driver mutations in histone H3.3 and mutations in chromatin remodeling genes
Schwartzentruber, Nature, 2012
Impact of age on prognosis
Sanders, Pediatr Blood Cancer 49, 2007
16 pts < 3 yrsTreatment: surgery, chemo
RT: scheduled = 6at progression = 6
none = 3
5 year survival by agePts <1 yr at dx: OS = 100%, EFS = 46.9%
Pts >1 and <3 at dx: OS = 37.5%, EFS = 12.5%
Why do infants do better? One possible explanation
o TP53 mutations rare in infants < 3yrsn 12% in children < 3yrs
o 14% of GBMs
o 10% of AAs
n 40% in children > 3yrso 45% of GBMs
o 32% of AAs
n Tumors with TP53 mutations may be resistant to cytotoxic effects of chemo/RT which depend on functional p53 (Pollack, Cancer Res 61, 2001)
Treatment
surgery
XRT/Chemo
Post-RT Chemotherapy
High Grade Gliomas - Treatment
o Surgeryn complete resections rarely achieved due to
infiltrative nature
n radical (>90%) resection correlates with longer survival when combined with XRTo 31 vs. 12 months for grade 3 (A.A.)
o XRT - 55-60 Gyn prolongs survival - marginal benefit for GBM
MGMT expression and EFS in Pediatric HGG Rx’d with Temodar
ACNS0126: XRT + Temodar. Cohen, Neuro-Oncol 13(3), 2011
3 yr EFS: GBM = 7%AA = 13%
MGMT overexpression:22/71 = 31%
Small survivaladvantage if MGMT
Expression low
Current COG study for newly dx’dHigh Grade Gliomao XRT phase: Randomized trial - 3 regimens
n XRT + Vorinostat (HDAC)
n XRT + TMZ
n XRT + Bevacizumab
o Post-XRT maintenance with Bevacizumab/Temodarn Adult trials now exploring combinations of Bev,
TMZ, Irinotecan +/- Cilengitide
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 palsy
o 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 biopsied
n 14% in medulla; 8% in midbrainn Dorsally exophytic
o arise from floor of 4th ventricle
Brainstem Gliomas - Presentation
o Cranial nerve palsies in 50%o Intrinsic Pontine lesions
n short duration of symptoms (median 1 month)
n bilteral CN palsies, long tract signs, ataxia
Brainstem Gliomas - Prognosis
o Generally awfuln depends on site, histology and
resectability
n Intrinsic pontine lesions o not resectable - no role for surgery
o median survival 8-12 months with XRT
o 2 year survival < 20%
DIPG
o XRT + TMZ no better (or worse) than RT alone (Jalali et al, IJROBP 77, 2010) Cohen, COG 0126 study
Cohen, COG 0126: Neuro-Oncol 2011
DIPG: newly discovered biology and a novel concept for therapyo DIPG remains one of the most dismal
diagnoses in all of oncologyn Median survival < 12 monthsn 2 yr survival < 10%n No improvements in outcome for decadesn XRT transiently improves QOL and marginally
prolongs life but not curativen Dx is radiographic – no tissue = little opportunity
to learn about biologyo 2/3 are HGG but are they the same as other HGGs?
DIPG biology: analysis by DNA microarray - Toronto o Examination of 11 samples (9 post-mortem)
o EGFR not amplifiedn Strong expression in only 3/11 (weak in 4/11)
o PDGFRA amplified in 4/11 (36%)n Strong PDGFR-a in 7/11 and weak in 4/11
o All tumors showed expression of p-mTORn PDGFR and mTOR potential Rx targets
Zarghooni et al, JCO 28, 2010
PARP
o Poly (ADP-ribose) polymerase (PARP-1)n Repairs single strand DNA breaks (chemo) and
double strand breaks (XRT)n Overexpression may mediate resistance to chemo
(e.g. TMZ) and XRT
o PARP-1 expressed in 6 DIPG tumorsn Amplified in 3/11
o PARP inhibition (+ targeting of PDGFR and mTOR) may offer novel strategy for DIPG Rx
Zarghooni et al, JCO 28, 2010
Case 3
o 6 y.o. with 6 month h/o worsening headachesn Headaches became more frequent and more severe over the month prior to dx
with 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 quadrantanopia
o Started on amitriptyline for possible migraines due to family hx
o Sched for brain MRI due to concern about poss mass lesion
n Acute worsening of vision and new unsteadinesso Referred to ER for imaging
o CT: 5 cm solid/cystic mass in R thalamus with midline shift
o Started on decadron
o OR next a.m.: resection
Pilocytic astrocytoma
Low Grade Gliomas
o 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) astros
n Presentation of low grade gliomaso 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
Supratentorial Low Grade Gliomas- treatment and outcomeo Treatment - aggressive attempt at complete resection
of hemispheric 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 resectable
o 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 variable
n often remain stable for yearso PFS at 3 and 5 yrs: 58% and 48% with obs
o 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 Temodaro Vinblastineo Irinotecan and Avastino Vinorelbineo ? BRAF V600E antagonists
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 (target for Vemurafenib) only in ~10%
Treatment of Low Grade Gliomas - Non-surgical options
o XRTn 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 yr
o 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 tumors
n 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 Outcome
o Surgeryn 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 prolactin
o Bitemporal visual field defect
o 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 symptoms
oCombination of headache, decreased growth rate, visual impairment, and polydipsia with polyuriashould raise suspicion for Cranio
oDifferential diagnosis:n Pituitary adenomas
n Hypothalamic/optic tract gliomas (usually low grade)
n Rathke’s cleft cysts
n Germ cell tumors
n 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 Gy
oControversy re: functional outcomes with radical surgery vs limited surg + RT
Long term Sequelae of XRToVision
n Optic neuropathy rare at 54 Gy
n ~ 50% of pts require cyst decompression prior to , during +/or after XRT
n Cyst epithelium may continue to secrete fluid 4 mosafter RT completed
n Follow cyst volumes q 2 wks with MRI/CT during RT to assure RT field is still appropriate
Long term Sequelae of XRT
oNeuroendocrine (Kiehna + Merchant, Neurosurg Focus 2010)
n70% require GH supplementation
n90% require thyroid supplementation
n40% require Rx of hypogonadism
n75% require cortisol replacement
nDI uncommon with XRT
Long term Sequelae of XRToCognitive outcomes
n Improved with increasingly conformal therapy
n Overall IQ stable x 5 yrs post-XRT in St Judesseries
n Younger pts < 7 yrs at higher risk for impairment
n 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 structures
o 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
Case 6o 12 month old 2 mos h/o
lethargy, loss of milestonesn Stopped cruising
n Slower crawling
n Irritable/clingy
o Neuro evaln Disprop increase in HC
n Head ultrasound – hydro
n MRI – post-fossa mass
Ependymomas
o Epidemiologyn 5-10% of childhood brain tumorsn tend to affect very young children
o 25-40% < 2 years old at diagnosis
o Sites of Diseasen 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)
Ependymoma Subgroups
Pajtler et al, Cancer Cell, 2015
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 prognosis
o 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 irradiated
n only 15-45% PFS if incompletely resected and irradiated
n 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 surgery
o 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 (20-40%) since late 70’s
o Seeding uncommon => local field
o 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 GTR
o Conformal XRTo Post-RT randomization to obs vs chemo
n Maintenance chemo: VCR/CDDP/CTX/VP-16, 4 cycles
Case 7o 20 y.o. well until 1 month prior to dx
n Worsening headaches
n Increasing clumsiness
n Diplopia
n 3 episodes of emesis in a.m. during wk prior to dx
n Taken to ER due to worsening HA’s and N/V
n CT revealed 4 cm PF mass with hydrocephalus
n Referred to MGHo Started on decadron; imaging of brain/spine with MRI
o tumor resected
Medulloblastoma
Scope of the problemo Epidemiology of CNS tumors in pediatrics
n 2000 cases per yearo > 30,000 CNS tumors dx’d annually in adults
n 40% of peds CNS tumors are low grade gliomas
n Medulloblastoma is most common malignant tumor in childreno 20% of all peds CNS tumors
o 40% of post-fossa tumors
o ~ 400 cases per year
Demography of Medulloo Most arise in first decade
o peak age at diagnosis = 5 years
o median age at dx = 7 years
o 80% diagnosed by 15 years
o 10-15% dx’d in infancy
o 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 ataxia
n 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 (1.5cm2 threshold)
n Age at diagnosiso Infants <3-5 yrs treated on separate studies
n Histologyo Classic
o Large cell/anaplastic – poor (recent)
o Desmoplastic – improved in infants
Standard risk patientso Patients with non-metastatic disease
o Less than 1.5cm2 residual disease on post-op MRI
o Classic or desmoplastic histology
o > 3 years of age
High risk patientso Disseminated disease
o Residual tumor on post-op scan > 1.5cm2
o Diffuse anaplasia
o MYC amplified
Low Risk Patientso Wnt pathway tumors
n Mutations in beta catenin
Treatment - Multimodalityo Surgery
o Radiation
o Chemotherapy
Treatment I - Surgeryo extent of resection is important predictor of survival
n used for treatment stratificationo < 1.5 cm2 residual disease => standard risk
o > 1.5 cm2 residual disease => high risk
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 dissemination 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 weeks
n as many as 20-30% of children are affected
n may result from transient impairment of afferent/efferent pathways of the dentate nuclei
n 50% may suffer long term impairments in language
Treatment II - Radiation
n Craniospinal XRT std since 1950’so Dose constrained or witheld in infants
n 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 - neurocognitive
o 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
Progressive decline in neurocognitivefunction after XRT
o Importance of longitudinal surveillance and assessment of evolving need for academic and vocational support
Palmer et al, JCO 19:2001
Efforts to reduce long-term adverse effects of XRTo Current COG study randomizing between
1800 and 2400 cGy for CSI for pts 3-7 yrsn Pts > 7 yrs receive 24 Gy CSI
n All pts receive boost to 54 Gy
o Same study randomizing 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 tumors
o 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 Gy n Post RT chemo:
VCR/CDDP/CTX
o EFS = 65-70%
Mograbi, POG 9631, Fall 2007 report
Jackaki, CCG 99701, JCO 2012
Impact of anaplasia in high risk pts
Jackaki CCG 99701, fall 2007 study progress report
CSI 36 Gy with boost to PF and mets
concurrent VCR and Carbo as RT sensitizer
Post-RT chemo:VCR, CTX, CDDP
Favorable impact of Desmoplasia
Cohen et al, CCG 99703, Spring ’08 progress report
Rutkowski et al, NEJM 2005:352
Are there subtypes that should be treated less intensively even if clinically high risk?
Gajjar et al,Lancet Oncology 7,
2006
Infants – a unique challengeo Adverse effects of XRT most profound in very
young children
o 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 matter
n COG study: Children > 3 yrs at dx drop FSIQ by 17.4 pts at 4 yrs from dx
Therapeutic Challenges - Radiation
o Craniospinal XRT in infancyn 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 systemic
o 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 3
o 3 cycles of VCR, CDDP, CTX, VP-16 followed by Thiotepa/Carbo with PBSCR x 3
o 3 yr EFS M0: 67%
o 3 yr OS M0: 76%
Cohen and GeyerCOG study report,
fall, 2007
German Infant Medullo Study – chemo alone
inclusion of systemic + intraventricular MTX
o 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%
Medullo – Toxicity of Chemo alone (no RT)
o Moderate to severe leukoencephalopathy in 15 of 23 patients in German study with IT and systemic MTXn Severity correlated with number of doses of
intraventricular MTX
n Neurocognitive deficits less than for pts Rx’d with XRT, but still significant
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 P53
o MYC/MYC-N
o 17p- (40-50%)
o MYC+/LDHB/CCNB1+ gene signature
o Anaplastic histology
o Favorablen TRK-C (NT-3 receptor)
n Wnt/Beta-catenin
n 6q-
n Low MYC expression
n Desmoplastic histology
Single gene predictors
Grotzer et al, JCO, March, 2000Gilbertson, Cancer Research 58,’98
Tabori et al, JCO 28, 2010
TP53 mut:5 yr OS = 0%
in avg risk
TP53 WT: 5 yr OS = 74%
Risk Group Stratification by Gene Expression Profile – Cluster analysis
Pomeroy et al, Nature, 1/24/02
Gene Expression profile and clinical parameters – an updated stratification scheme
Fernandez-Tijiero et al, JCO 22, 2004
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
Molecular subgroups of Medullo: the current consensus – Taylor et al, Acta Neuropathol, 2012
Prognostic Significance of clinical, histopathologicaland molecular characteristics in HIT 2000 cohort
N = 184 pts enrolled 2000-2012 Pietsch et al, Acta Neuropathol, 2014
PTCH1 and the Hedgehog pathway
Hedgehog inhibition in Medullo
Rudin et al, NEJM 361;12, 2009
The Challenge for multi-modality therapy
o 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 Ependymomao Increased conformality of XRT plan and delivery
n Germ Cell tumorso Response-based XRT dosing with inclusion of chemo
The Challenge for multi-modality therapy
o 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 survival
o 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 therapy
n Neuroendocrinen Ophthon Intensive home and school-based rehabilitative support
o OT/PT, speech, feeding team
n 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-
oncology
o Neurosurgery
o Radiation oncology
o Neuro-radiology
o Nursing
o Peds Surgery
o Endocrinology
o Ophthalmology
o Social work
o Psychiatry
o Child life
o Neuropsych
o ENT
Our patients and their families
