Brain Tumors in Children - Congressline · – The value of extensive tumor resection has been...

Brain Tumors in Children

Michael A. Grotzer

University Children‘s Hospital of Zurich, Switzerland

Incidence of Childhood Cancer

0% 10% 20%

Others

Ewing Sarcoma

Osteosarcoma

Retinoblastoma

Rhabdomyosarcoma

Acute myeloblastic Leukemia

Hodgkin Lymphoma

Wilms Tumor

Non-Hodgkin Lymphoma

Neuroblastoma

Acute lymphoblastic Leukemia

CNS Tumors

Prognosis of Pediatric Cancer

0%

20%

40%

60%

80%

100%

1960-64 1965-69 1970-74 1975-79 1980-84 1985-89 1990-94

5-Y

ear

Sur

viva

l Pro

babi

lity

Osteosarcoma

Wilms TumorALL

CNS Tumors

Years of diagnosis

1995-99

SEER (USA)

Etiology of Childhood CNS Tumors: Hereditary Factors

� NF-1 astrocytomas (optic pathways)

� NF-2 schwannomas (vestibular, trigeminal), ependymomas, meningiomas

� Tuberous sclerosis cortical dysplasia (cortical tubers), subependymal nodules, subependymal giant cell astrocytomas

� Von Hippel-Lindau disease hemangioblastomas (cerebellar,…)

� Turcot syndrome medulloblastoma

� NBCC syndrome medulloblastoma

� Li-Fraumeni syndrome choroid plexus carcinoma, astrocytomas, medulloblastoma, ependymoma

Etiology of Childhood CNS Tumors: Ionizing Radiation

� Cranial irradiation for treatment of tinea capitis, leukemia, CNS tumors

� Radiation doses as low as 3 Gy

� Latency usually 5-25 years

� Most of these secondary CNS tumors classified as astrocytomas and meningiomas

Etiology of Childhood CNS Tumors: Other Factors

� Endogenous immunosuppression– Wiskott-Aldrich syndrome

– Ataxia teleangiektasia

� Exogenous immunosuppression– Organ-transplant recipients

– HIV infection

� Polyomaviruses ?– SV40, JC, BK

Pediatric Brain Tumors Differ From Adult Brain Tumors

� Histology:

– The types of tumors encountered in children are uncommon in adults, and vice versa

� Localization:

– infratentorial > supratentorial

� Surgery:

– The value of extensive tumor resection has been confirmed for a variaty of childhood brain tumors

� Chemotherapy:

– has been shown to be effective in improving overall outcome in several childhood brain tumors

– is increasingly used to delay or avoid using radiotherapy in children younger than 3 years of age

0

10

20

30

40

0

5

10

15

20

25

30

0

10

20

30

40

Pilocytic AstrocytomaMedulloblastomaAT/RT

0

10

20

30

40

50

-9 -19 -29 -39 -49 -59 -69 -79 -89 -99

Age (years)

0

40

80

120

160

200

0

10

20

30

Ependymoma GlioblastomaDiffuse Astrocytoma WHO II

-9 -19 -29 -39 -49 -59 -69 -79 -89 -99 -9 -19 -29 -39 -49 -59 -69 -79 -89 -99

-9 -19 -29 -39 -49 -59 -69 -79 -89 -99 -9 -19 -29 -39 -49 -59 -69 -79 -89 -99 -9 -19 -29 -39 -49 -59 -69 -79 -89 -99

malefemale

Survival by Age for Malignant Brain Tumors

Years since diagnosis

Pop

ulat

ion

Sur

viva

l Pro

babi

lity

0

0.2

0.4

0.6

0.8

1

0 1 2 3 4 5 6 7 8 9 10 11 12

Ages 0-19

Ages 20-39

Ages 40-59

Ages 60+

SEER (USA)

Technical Advances in Imaging and Neurosurgery

Irradiation Using Protons

Photons

Protons

Distance

Ene

rgy

Protons Photons

Ependymoma: Incidence and Epidemiology

� Frequency: 10-15% of all childhood CNS cancers

� Prevalence: 1 in 28,000 live birth (USA)

� Median age: 6 years

� No known predisposing exposures

Ependymoma: Localization

� Posterior fossa > supratentorial extraventricular > lateral ventricles > spinal

� The majority of tumors are localized at the time of diagnosis

� The primary tumor site remains the most likely area of disease relapse

Pathology and Grading

Ependymoma WHO II Anaplastic Ependymoma WHO III

microvascular proliferation

high mitotic activity

Ependymoma: Prognostic Factors

positive

� Total resection

� Age over 4 - 6 years

� Local XRT > 45 Gy

� Differentiated (WHO II)

negative

� Less than total resection

� Age under 4 - 6 years

� Local XRT < 45 Gy

� Anaplastic (WHO III)

6.9 years old, focal seizures

Localized Ependymoma >4 Years of Age

No residual tumor

OPConformalIrradiation

8 months

CYCVCR

CPVP16

CYCVCR

CPVP16

CYCVCR

CPVP16

CYCVCR

CPVP16

STOP

WHO III

WHO II

CYCVCR

CPVP16

Merchant TE et al. Lancet Oncol 2009n=153

median age 2.9 yearsConformal radiotherapy (59.4 Gy, 10 mm margin)

after definitive surgery

Surgery: no residual tumor

0.8 years old, head tilt (5 weeks), vomiting (2 weeks)

Localized Ependymoma <4 Years of Age

Residual Tumor<15 months

OP

10-15 months

CYCVCR

MTXVCR

CPVP16

MTXVCR

CYCVCR

MTXVCR

CPVP16

MTXVCR

CYCVCR

CPVP16

CYCVCR

CPVP16

Protonbeam Irradiationweekly VCR

CYCVCR

CYCVCR

CPVP16

CYCVCR

CPVP16

3 months

14 months later


Photons

Protons

Distance

Ene

rgy

Protons Photons

Anesthesia

Patient immobilization

Appropriate patient safety system

80%

0%local

65%

1995

Before 1930

Surgery 5-Year Survival

0%

ChemoRadio

1930-40

Since 1975

Since 1940 50%local + cs

Medulloblastoma

Medulloblastoma:Treatment for Children > 3 Years (Packer RJ, 1994)

RADIATIONPosterior fossa 54 GyCraniospinal 36 Gy

week 1 2 3 4 5 6 7 8 10 16 22 28 34 40 46 52

SURGERY Vincristin

Cisplatin

Lomustine

Longterm Effects of Current Medulloblastoma Therapy

� Growth dysfunction

� Endocrine dysfunction

� Hearing loss

� Alopecia

� Risk for second malignancies

� Social and emotional problems

� Intellectual deficits

Late Effects in Pediatric Brain Tumor Survivors: Interplay of Different Factors

Therapy Tumor Patient

RT total dose direct tissue effects development status

RT dose rate indirect mechanical effects

genetic predisposition

RT treatment volume tissue sensitivities

RT dose distribution compensating mechanisms

other therapy

experimentalChemo

craniospinalRadiation

CYC/VCRhdMTX

Carbo/VP

MTX i. ventr.

CYC/VCRhdMTX

Carbo/VP

MTX i. ventr.

CYC/VCRhdMTX

Carbo/VP

MTX i. ventr.

no CCR

<18 Months >18 Months

CCREnd of Therapy

HIT-SKK`92Medulloblastoma Age <3 years

Rutkowski S et al. N Engl J Med 2005

HIT-SKK`92

no residual tumor

residual tumor

solid metastases

n=17

n=12

n=14

0.93 ± 0.06

0.38 ± 0.15

0.56 ± 0.14

0 1 2 3 4 5 6 7 8 9 10

Years Since Diagnosis

0.0

0.2

0.4

0.6

0.8

1.0

Sur

viva

l Pro

babi

lity

14

3

7

No RT

Rutkowski S et al. N Engl J Med 2005

Intensity-Modulated Radiotherapy (IMRT)

Huang E et al. Int J Radiat Oncol Biol Phys 2002

54.2 Gy64 %

auditory apparatus radiationWHO grade 3/4 hearing loss

(n = 26 medulloblastoma)

36.7 Gy (-32%)13 %


Photons

Protons

Distance

Ene

rgy

Protons Photons

M4Extraneuraxial

metastasis

Medulloblastoma Staging: Modified Chang Classification System

M3Nodular seeding

in spinal subarachnoid

space

M1Tumor cells in CSF

M2Nodular seeding in

cerebellum, cerebral subarachnoid space, or

in 3rd or 4th ventricles

Standard Risk:Maximal Therapy

Low Risk:Minimal Therapy

High Risk: Novel Therapies

SURGERY

ClinicalFactors

+

MolecularPhenotype

Patient Stratification

Pro

gres

sion

-fre

e S

urvi

val P

roba

bilit

y

0 2 4 6 8 10

Low c-MYC (n=13)

High c-MYC (n=13)


p=0.0048

1.00

0.75

0.50

0.25

0.00

Grotzer, Clin Cancer Res 2001

c-MYC β-catenin

Ellison, J Clin Oncol 2005

Ove

rall

Sur

viva

l P

roba

bilit

y


p=0.015

Nuclear accumulation (n=27)

No accumulation (n=81)

Anaplastic medulloblastomacontains pleomorphic cells with polyhedral forms and a high growth fraction. Abundant apoptosis and examples of cell wrapping are evident

Gilbertson & Ellison Annu Rev Pathol Mech Dis 2008

Classic MB (64-83%)composed of sheets of small uniform cells with a high nuclear-to cytoplasmatic ratio

MB with extensive nodularity (3%)Desmoplastic MB (7%)combines nodules of differentiated neurocytic cells with a low growth fraction and desmoplastic internodular zones of moderately pleomorphic cells with a high growth fraction

Infants (favourable prognosis) and adults


Nodular/desmoplastic medulloblastomacombines nodules of differentiated neurocytic cells with a low growth fraction and desmoplastic internodular zones of moderately pleomorphic cells with a high growth fraction


Anaplastic MB (10-22%)contains pleomorphic cells with polyhedral forms and a high growth fraction. Abundant apoptosis and examples of cell wrapping are evident

Large-cell MB (2-4%)contains groups of large uniform cells with vesicular nuclei and a single nucleolus. Anaplasia characterizes other regions of this variant

<18 months

no CR

Localized Medulloblastoma <4 Years of Age HIT 2000

CYC / VCRhdMTX

CARBO / VP-16MTX i. ventr.

OPRadiotherapy

54 Gy conformal

Radiotherapy54 Gy conformal

CR + desmoplastic /extensive nodular

CYCVCR

CarboVP-16

CarboVP-16

CYCVCR

CISCCNUVCR

CISCCNUVCR

CISCCNUVCR

CISCCNUVCR

CYC / VCRhdMTX


CYC / VCRhdMTX


CISCCNUVCR

CISCCNUVCR

CISCCNUVCR

CISCCNUVCR

Medulloblastoma are molecularly distinct from

sPNET and AT/RT

Pomeroy SL et al. Nature 2002

Burger P, Am. J Surg Pathol 1998

Months after diagnosis

Sur

viva

l

0%

20%

40%

60%

80%

100%

0 20 40

Num

ber

of c

ases

02468

10121416

0-1 1-2 2-3 3-4 4-5 5-6 6-7

malefemale

Age (years)

WHO 2007

Atypical Teratoid/Rhabdoid CNS Tumor (AT/RT)

Mutation/deletion of the tumor suppressor SMARCB1 (INI1)

AT/RT Boston Protocol DFCI

Chi S et al. JCO 2008

V: VincristineP: CisplatinD: DoxorubicinC: CyclophosphamideE: EtoposideA: Dactinomycini.th.: MTX, Cytarabin, Hydrocortisone

2-year Overall Survival: 70 ± 10%

Unsupervised hierarchical clustering of human 1.0 exon array expression data from 103 primary medulloblastomas using 1,450 high–standard deviation genes

Northcott P A et al. JCO 2010

Nuclear β-catenin

10% 30% 25% 35%

Northcott PA et al. (2012) Nat. Rev. Neurol.

Oncogenes, Tumor Suppressors, and Key Cytogenetics

Low risk

• not large cell/anaplastic• c-MYC/MYCN not amplified• β-catenin nuclear pos. • residual tumor ≤1.5 cm2

Standard risk

• all others• all without profile

OPRadiotherapy

23.4 Gy craniospinal54 Gy local

CISCCNUVCR

CYCVCR

CISCCNUVCR

CISCCNUVCR

CYCVCR

CYCVCR

6 months

PNET5

OP

Radiotherapy23.4 Gy craniospinal

54 Gy local

± CARBOPLATIN

CISCCNUVCR

CYCVCR

CISCCNUVCR

CISCCNUVCR

CYCVCR

CYCVCR

8 months

CISCCNUVCR

CYCVCR

PNET6

SIOP PNET Study Group

Therapeutic Targets of WNT Medulloblastomas

� None of the WNT targeted therapies have shown benefits in MB

� Therapies that target mutated TP53 are not in regular use for MB therapy

� Mouse model of WNT MB developed

� Current strategy: de-escalation

� <3 years + >14 years of age

� Desmoplastic / nodular subtype

� Somatic mutations in PTCH1/2, SMO, or SUFU

� High-level amplification of the SHH effectors, GLI1/2

� Germline mutations of SUFU (young children), PTCH1 (Gorlin syndrome)

� SMO antagonists GDC-0449, IPI-926, LDE225,…

GDC-0449IPI-026LDE225

Therapeutic Targets of SHH Medulloblastomas

Rudin CM et al. N Engl J Med 2009

SMO Inhibitor Treatment in an Adult with Metastatic MB

after 2 months of therapy with GDC-0449

after 5 months of therapywith GCD-0449









TMZ naive children and adults who have relapsed after RT

(n=69)

Hh

activ

atio

nP

re S

cree

ning

LDE225 QD

TMZ, QD x 5 every 28 days

Ran

dom

izat

ion

2:1

Pos

t Tre

atm

ent F

ollo

wU

p

TMZ pretreated children and adults who have relapsed after RT

ORRT naive ± TMZ

children ≤ 6 years old(n=40)

LDE225 QD

LDE225 QD

Optional Cross-over

to LDE225 QD confirmed PD

Primary endpoints: ORRSecondary endpoints: DoR, PFS, safety, OS, QoL

LDE225 (200 mg QD): Responses in Medulloblastoma

Pre-treatment: surgery, irradiation,4 chemotherapy regimens and HDCT

Partial responsemaintained for 4 months

Therapeutic Targets of Group 3 Medulloblastomas

� Owing the pharmacological difficulty of targeting a a transcription factor, small molecule inhibitors of MYC have not yet achieved wide success or acceptance in the clinic

� Studies on other rationally chosen targets for Group 3 have not yet been described

� Mouse model available

� Current strategy: intensification

Therapeutic Targets of Group 4 Medulloblastomas

� The underlying biology of Group 4 tumors is less well understood

� Mouse model not yet available

� Current strategy: ??

XH Wu et al. Nature 2012

MB Metastases and Primary Tumors are Distinct

Conclusions

Patient subgroup status will become an integral component of prospective clinical trials

This will enable the use of treatment protocols that are rationally tailored towards each subgroup of the disease

Methods to verify patient subgroup affiliation will continue to evolve

Targeting primary tumor ≠ targeting metastasis

Brain Tumors in Children - Congressline · – The value of extensive tumor resection has been...

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