brain tumors & stem cell transplantation

Pediatric Brain tumorPediatric Brain tumor&&

Stem Cell TransplantationStem Cell Transplantation

A. Hedayati-AslA. Hedayati-AslMahak Cancer Children’s Hospital

Stem Cell Transplantation Department

Most common childhood Most common childhood malignanciesmalignancies

0

5

10

15

20

25

30

Leukemia

brain tumor

lymphoma

neuroblastoma

soft tissue sarcoma

Wilms tumour

bone tumors

others

Brain tumorsBrain tumors

• Second malignancy in childhood Second malignancy in childhood

• Mortality among this group Mortality among this group approaches 45%approaches 45%

EpidemiologyEpidemiology • 2,200 primary brain tumor /year2,200 primary brain tumor /year• 28cases/ million of children 28cases/ million of children • High incidence in infants and young High incidence in infants and young

children up to 7 year of age.children up to 7 year of age.

EtiologyEtiology

• Ionizing radiation (tina capitis , ALL )Ionizing radiation (tina capitis , ALL )• Other cancer (retioblastoma , rabdoid Other cancer (retioblastoma , rabdoid

tumor ,endocrin tumor)tumor ,endocrin tumor)• Immunosuppression (wiscott-Aldrich Immunosuppression (wiscott-Aldrich

syndrome , ataxia-telangectasia ,organ syndrome , ataxia-telangectasia ,organ transplantation)transplantation)

• Familial (Li-fraumeni)Familial (Li-fraumeni)• Enviromental exposure (effect of cellular Enviromental exposure (effect of cellular

plone&mobile, SV40 virus (M plone&mobile, SV40 virus (M B,epandymoma)B,epandymoma)

CytogeneticCytogenetic • Delation of 17 Delation of 17 • Tisomy 7Tisomy 7• Monosomy 22Monosomy 22• Delation 22q11mutation p53Delation 22q11mutation p53

Normal Anatomy of Brain (MRI)

• Supratentorial compartment:Supratentorial compartment:– Cerebral hemispheresCerebral hemispheres– Basal gangliaBasal ganglia– Thalamic nucleiThalamic nuclei– Lateral ventriclesLateral ventricles– HypothalamusHypothalamus– Corpus callosumCorpus callosum

• Infratentorial compartment:Infratentorial compartment:– CerebellumCerebellum– Brain stem (MB/P/MO)Brain stem (MB/P/MO)– 44thth ventricle ventricle

Sagittal

Axial

Location of tumorLocation of tumor

• Inferatentorial 43.2% (1-10 years )Inferatentorial 43.2% (1-10 years )• Meduloblastoma ,astrocytoma ,epandymoma, brain stem gliomaMeduloblastoma ,astrocytoma ,epandymoma, brain stem glioma

• Supratentoril 40.9% (1Supratentoril 40.9% (1stst year of year of life &>10 years )life &>10 years )

• Glioma (high ,low grade )epandymoma ,craniopharangioma Glioma (high ,low grade )epandymoma ,craniopharangioma chiasmatic ,germcell tumorchiasmatic ,germcell tumor

• Spinal cord 4.9%Spinal cord 4.9%

• Multiple sites 11%Multiple sites 11%

Pediatric brain tumors Pediatric brain tumors

• AstrocytomaAstrocytoma• MedulloblastomaMedulloblastoma• EpendymomaEpendymoma• GliomaGlioma

SymptomSymptom

• Headache.Headache.• SeizureSeizure• Memory Loss.Memory Loss.• Motor weakness.Motor weakness.• Visual symptomsVisual symptoms• Language deficitLanguage deficit

• Cognitive changesCognitive changes• Personality changesPersonality changes• Change in Change in

consciousnessconsciousness• Nausea and Nausea and

vomitingvomiting• Sensory deficitSensory deficit• PapilledemaPapilledema

Pediatric Brain Tumors

Posterior fossa neoplasm – MedulloblastomaPosterior fossa neoplasm – Medulloblastoma

Medulloblastoma

MedulloblastomaMedulloblastoma

Most common “malignant” brain tumor inMost common “malignant” brain tumor inchildrenchildren StagingStaging M0 – no metsM0 – no mets M1 – positive cytologyM1 – positive cytology M2 – intracranial metsM2 – intracranial mets M3 – spinal cord metsM3 – spinal cord mets M4 – extraneural diseaseM4 – extraneural disease

MedulloblastomaMedulloblastomaRadiographsRadiographs

• • well delineated masswell delineated mass• • arises from vermis arises from vermis

75%75%• • fills 4th ventriclefills 4th ventricle• • calcification 15%calcification 15%• • hydrocephalus 95%hydrocephalus 95%• • enhancesenhances• • subarrachnoid seedingsubarrachnoid seeding

Intrinsic Intrinsic pontine gliomapontine glioma

Pediatric Brain Tumors

Brain Stem GliomaBrain Stem Glioma

EpandymumaEpandymuma

Pediatric Brain TumorsPediatric Brain Tumors

Supratentorial tumors – Astrocytoma & ependymoma

Pinealoblastoma & craniopharyngiomaPinealoblastoma & craniopharyngioma

Cerebellar AstrocytomaCerebellar Astrocytoma

Cerebellar AstrocytomaCerebellar Astrocytoma

AstrocytomasAstrocytomas

Common Brain Common Brain TumorsTumors

Location Percentage

Infratentorial 45-60

Supratentorial Hemispheric

Midline – Suprasellular / Pineal region

25-4015-20

Distribution of common brain tumors in Distribution of common brain tumors in children – location and histologic children – location and histologic

appearanceappearance

Infra-tentorial % of all brain tumors

PNET (Medulloblastoma) 20-25

Low grade astrocytoma cerebellar

12-18

Ependynoma 4-8

Malignant glioma, brain stem 3-6

Other 2-5

Total 45-60INTP - PPO, PHO, IAP.P2 – 17/27

Supratentorial % of all brain tumorsLow grade astrocytoma 8-20Malignant glioma 6-12Ependymoma 2-5Mixed glioma 1-5Ganglioglioma 1-5Oligodendroglioma 1-2Chorioid plexus tumor 1-2PNET 1-2Meningioma 0.5-2Other 1-3Total 25-40

Distribution of common brain tumors in Distribution of common brain tumors in children – location and histologic children – location and histologic

appearanceappearance

INTP - PPO, PHO, IAP.P2 – 18/27

Staging Work upStaging Work up

• Dissemination extraneurally rare – staging Dissemination extraneurally rare – staging work up seldom indicatedwork up seldom indicated

• Spinal MRI/CSF cytology – mandatory Spinal MRI/CSF cytology – mandatory Medulloblastoma, Medulloblastoma,

• PF ependymoma, Germ cell tumorPF ependymoma, Germ cell tumor• Blood / CSF - Blood / CSF - FP, FP, HCG – Germ cell HCG – Germ cell

tumorstumors

ImagingImaging • MRIMRI

• CTscanCTscan

TreatmentTreatment • Surgery Surgery

• Radiothrapy Radiothrapy

• ChemotherapyChemotherapy

• HSCTHSCT

Pediatric brain tumors-Pediatric brain tumors-prognosisprognosis• Low: 5-20% survival in brain stem Low: 5-20% survival in brain stem

tumorstumors• High: 60-80% survival in High: 60-80% survival in

medulloblastomamedulloblastoma

Problem Associated tumors Peri / intraoperative Management

Postop management

Odema Large tumors small tumors in critical areas

Corticosteroids Dexona0.1mg/kg Q6h

Corticosteroids tapered

Obstructive hydrocephalus

Intra and periventricular tumors

External ventricular drain placement or VP shunt

Closure or permanent

Seizures Tumors of cerebral hemispheres

Anticonvulsant phenytoin

Stopped in follow-up

Hypothalamic Pituitary hormonal insufficiency

Tumors close to hypothalamus

Endocrine Evaluation, Steroids fluid and electrolyte balance

Hormone replacement

Perioperative Perioperative ManagementManagement

RadiotherapyRadiotherapy• High energy machinesHigh energy machines• Volume – Craniospinal irradiation, localised Volume – Craniospinal irradiation, localised

irradiationirradiation• Dose – 50-60 Gy / 24-36 Gy, 180-200 Gy / #Dose – 50-60 Gy / 24-36 Gy, 180-200 Gy / #• STRS/STRT – Interstitial brachytherapy / STRS/STRT – Interstitial brachytherapy /

conformal and intensity modulated treatmentconformal and intensity modulated treatment• Delay/defer irradiation for children younger than Delay/defer irradiation for children younger than

3 years3 years

TreatmentTreatment General principlesGeneral principles

Useful and standard

Medulloblastoma, malignant astrocytomas, optic pathway / hypothalamic gliomas, malignant tumors in children less than 3 years of age.

Upfront CT / neo-adjuvant CT, HD CT - BMT

Useful drugs: CCNU/VCR/Prednisalone, Procarbazine, Carboplatinum, Vincristine, Temozolamide

TreatmentTreatment General principlesGeneral principles

ChemotherapyChemotherapy

Infratentorial Infratentorial TumorsTumors

• High riskHigh risk• MM11

• >1.5 cms residual tumor>1.5 cms residual tumor• <3 years<3 years• RT + CTRT + CT

• Standard riskStandard risk• RTRT• ?CT?CT

Medulloblastoma Sx Adjuvant Treatment

Cerebellar Astrocytoma Ependymomas Brain stem glioma

Sx alone ?RT (adjuvant) Sx Adjuvant RT RT alone

MedulloblastomaMedulloblastoma• ‘• ‘Standard risk’ stageStandard risk’ stage<1.5<1.522 cm residual, cm residual, >3 yrs of age, >3 yrs of age, no spreadno spread• • TreatmentTreatment

surgical resectionsurgical resectioncraniospinal radiationcraniospinal radiation((2340 cGy to CSA with boost to 53402340 cGy to CSA with boost to 5340) ) chemotherapychemotherapy

EpendymomaEpendymoma• • Peak incidence between birth and 4 yrsPeak incidence between birth and 4 yrs• • male:female :: 1.4:1male:female :: 1.4:1• • Majority are histologically benignMajority are histologically benign• • Locally invasive and difficult to resectLocally invasive and difficult to resectentirelyentirely• • Controversies exist regarding role ofControversies exist regarding role ofadjunctive radiotherapy and/oradjunctive radiotherapy and/orchemotherapychemotherapy

Supratentorial TumorsSupratentorial TumorsHemispheric tumors:Gliomas: Low grade: Sx alone

High grade: Sx RT + CT (adjuvant)Ependymomas: Sx RT (adjuvant)

Optic pathway/ Sx CT RT HypothalamicGliomas

Craniopharyngioma Sx RT Pineal region tumors Individualized treatment

Midline Supratentorial Tumors

Hemispheric Hemispheric AstrocytomaAstrocytoma• • Outcome determined by:Outcome determined by:tumor histology, extent of resection, locationtumor histology, extent of resection, location• • 5 yr survival with subtotally resected low5 yr survival with subtotally resected lowgrade gliomas is 90%grade gliomas is 90%low grade tumors may remain quiescentlow grade tumors may remain quiescent• • ControversiesControversiesadjuvant therapy (chemotherapy before radiotherapy)adjuvant therapy (chemotherapy before radiotherapy)treatment of epilepsytreatment of epilepsyradiotherapy modalityradiotherapy modality

PNETPNET• • < 5% of supratentorial < 5% of supratentorial

tumors in childrentumors in children• • Radical surgical resectionRadical surgical resection– – gross total improved gross total improved

survivalsurvival• • CSF dissemination commonCSF dissemination common• • Adjuvant treatmentAdjuvant treatment– – craniospinal irradiationcraniospinal irradiation– – chemotherapychemotherapy• • survivalsurvival– – <30% at 5 yrs<30% at 5 yrs

Treatment…ChemotherapyTreatment…ChemotherapyMost commonly used agentsMost commonly used agents• CyclophosphamideCyclophosphamide• VCRVCR• CarboplatinCarboplatin• CisplatinCisplatin• EtoposideEtoposideNewer agentsNewer agents• TemozolomideTemozolomide• Molecularly targeted therapy (erlotinib, RAD001,etc.)Molecularly targeted therapy (erlotinib, RAD001,etc.)• Anti-angiogenic therapy (bevacizumab, Anti-angiogenic therapy (bevacizumab, • ImmunotherapyImmunotherapy

BT & HSCTBT & HSCT

• Historically, brain tumors have been Historically, brain tumors have been treated with neurosurgical resection treated with neurosurgical resection and radiation therapy. and radiation therapy. Demonstration of the efficacy of Demonstration of the efficacy of chemotherapy has lagged behind chemotherapy has lagged behind that for most other types of tumors, that for most other types of tumors, but currently chemotherapy is being but currently chemotherapy is being employed more frequently. employed more frequently.

BT & HSCTBT & HSCTRecognition of the chemo-sensitivity of Recognition of the chemo-sensitivity of

many types of brain tumors, in many types of brain tumors, in conjunction with the still relatively conjunction with the still relatively guarded prognoses of many of these guarded prognoses of many of these patients, has also logically led to patients, has also logically led to exploration of the use of exploration of the use of hematopoietic cell support as a hematopoietic cell support as a means of increasing dose intensity. means of increasing dose intensity.