MEDULLOBLASTOMA - Necessary evil of craniospinal ... Diagnosed AverageDiagnosed Average--Risk Medulloblastoma Risk Medulloblastoma ... Limited Target Volume

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  • MEDULLOBLASTOMAMEDULLOBLASTOMA

    Roger J. Packer, MD

    Executive DirectorExecutive Director

    Neuroscience and Behavioral Medicine

    Childrens National Medical Center

    Washington, DC

  • Childhood Brain TumorsChildhood Brain TumorsHeterogeneity/AgeHeterogeneity/Age--Related Challenges (early diagnosis; therapeutic options)Related Challenges (early diagnosis; therapeutic options)

    /endpoints/endpoints

    TumorTumor--TypeType % Childhood% Childhood SurvivalSurvival Survival (PFS)Survival (PFS)

    Brain TumorsBrain Tumors 19801980 20072007

    MedulloblastomaMedulloblastoma 20%20%

    AverageAverage--RiskRisk 60%60% 60%60% 8080--85% (75%+)*85% (75%+)*

    PoorPoor--RiskRisk 40%40% 35%35% 6060--70% (55%+)70% (55%+)PoorPoor--RiskRisk 40%40% 35%35% 6060--70% (55%+)70% (55%+)

    LowLow--Grade GliomasGrade Gliomas 30%30% 70%70% 80% (?)*80% (?)*

    HighHigh--Grade GliomasGrade Gliomas 10%10% 10%10% 20% (20%)20% (20%)

    Brain Stem GliomaBrain Stem Glioma 15%15% 1010--20% 1020% 10--20%20%

    LowLow--grade; Focalgrade; Focal 20%20% 50%50% 80% (50%)*80% (50%)*

    DiffuseDiffuse 80%80% 55--10% 510% 5--10%10%

    EpendymomasEpendymomas 10%10% 40%40% 6060--70% (50%)*70% (50%)*

    *Improved Quality*Improved Quality--ofof--LifeLife

  • Medulloblastoma

    Most common childhood malignant brain tumor

    Tumor with greatest apparent improvement insurvival

    - stepwise

    - effect of re-classification- effect of re-classification- challenge of quality-of-life of survivors

    Transition in care: molecular genetics

    - understanding

    - stratification- management

  • Childhood Brain TumorsChildhood Brain Tumors

    Critical Issues:Critical Issues:

    Has there been a significant increase in understanding Has there been a significant increase in understanding

    the neurobiology, genetics or causation of childhood the neurobiology, genetics or causation of childhood

    brain tumors?brain tumors?

    Have these new understandings resulted in different or Have these new understandings resulted in different or

    better management?better management?better management?better management?

    Has there been an improvement in survival?Has there been an improvement in survival?

    Has there been an improvement in quality of life of Has there been an improvement in quality of life of

    survivors?survivors?

  • Medulloblastoma

    WHO Classification

    - Medulloepithelioma

    - Ependymoblastoma

    - * Medulloblastoma

    . Desmoplastic. Desmoplastic

    . Large cell (? anaplastic)

    . Melanotic

    - Supratentorial primitive neuroectodermal

    . Neuroblastoma

    . Ganglioneuroblastoma

    - AT/RT

    * Genetically different (cytogenetics: molecular genetics)

  • Medulloblastoma

    Cellular origin

    No longer an intellectual exercise alone

    May be key to stratification/management

    For decades known

    Histologically heterogeneous ? Role of heterogeneity in outcome

    - differentiated (Rorke)

    - large-cell / anaplastic (Burger)- light immunohistochemistry molecular genetics

  • Medulloblastoma

    ? Multipotentional precursors

    Location of progenitor in cerebellum

    - cerebellum has two germinal zones

    . ventricular (? multipotentional). ventricular (? multipotentional)

    . external granular layer (? restricted)

    ? restricted neuronal precursors (neuroblasts)

  • EGL

    VZ

    E13-E17 E18-P14

    VZ

    (multipotent stem cells)

    rhombic lip

    (GCPs)

    IGL

    WM

    EGL

    E13-E17 E18-P14

    Adult

    molecular layer

    Purkinje cell

    IGLWM

  • Medulloblastoma

    Surgery

    - Not straightforward

    - Key element

    . ? for all

    . Extent of resection associated with outcome

    - What is role in disseminated patients

    - Sequelae

    - Direct Brain Damage

    - Posterior-fossa mutism

  • Medulloblastoma

    Posterior-fossa mutism

    - Delayed onset of mutism associated with hypotonia,

    cerebellar dysfunction (truncal and appendicular), emotional

    lability, supranuclear palsies (eyes, swallowing), etc

    - Incidence- Incidence

    . Center dependent

    . 25% nationally

    - 50% ? permanent sequelae; intellectual

    - Vermian damage (?)

    - Increased incidence or increased recognition

  • Medulloblastoma

    Stratification

    - Clinically/Postoperatively since early 1990s

    A. Dissemination

    B. Resection

    (C. Age)(C. Age)

    (D. Histology)

    - Two Risk Groups

    A. Average RT alone; RT + chemo (60-70%)

    B. Poor or High RT plus chemo (30 40%)

    - Infants / Young Child

    A. Separately stratified

    B. What defines an infant

  • Medulloblastoma:Medulloblastoma:

    Basic (1980s/1990s) StratificationBasic (1980s/1990s) Stratification

    Average-Risk Poor Risk

    Disease extent Localized Disseminated

    Age Older; ? > 3 years YoungerAge Older; ? > 3 years Younger

    Extent of resection Total/?Near total Partial/Biopsy

    Location Posterior-Fossa Other

  • A9961: EligibilityA9961: Eligibility

    400 patients reviewed

    334 (79%) eligible

    32 (7.6%) ineligible

    26 disseminated + residual disease26 disseminated + residual disease

    6 other

    55 (13%) unevaluable

  • A9961 Event-Free Survival from Study Entry

    60%

    80%

    100%

    Pe

    rce

    nt

    Ev

    en

    t-F

    ree

    Elig Inelg Uneval

    n=334

    n=32

    n=55

    0%

    20%

    40%

    0 1 2 3 4 5 6 7

    Time (Years)

    Pe

    rce

    nt

    Ev

    en

    t

    Overall: p=0.006

    Eligible vs. Ineligible: p=0.002

    Eligible vs. Unevaluable: p=0.15

    n=32

  • Medulloblastoma

    Large cell/anaplastic variant

    Defined as light microscopy findings of pleomorphic nuclei,

    prominent nuclei, abundant cytoplasm, large areas of necrosis,

    high-mitotic activity, high apoptosis (apoptotic lakes), cellular

    atypia; background of anaplastic tissueatypia; background of anaplastic tissue

    Related to large cell variant (? same)

    Subjective

    Does not clearly incorporate mitotic index measures

    Modified by ? Severe; focal; diffuse, etc

  • Event-Free Survival for A9961/99701 by Anaplasia

    0.50

    0.75

    1.00

    Pro

    bab

    ilit

    y

    No Anaplasia (n=339)

    Anaplasia (n=74)

    0.00

    0.25

    0 2 4 6 8 10

    Years from study entry

    p=0.0083

  • Gilbertson RJ et al, Cancer Res 1997

    Survival: ErbB2 Protein Survival: ErbB2 Protein ExpressionExpression

    p = 0.0039

    Low ErbB2

    High ErbB2

    p = 0.0039

  • Survival: cMYC RNA Expression

    Grotzer MA et al, Clin Cancer Res 2001

  • Survival: RNA Expression Survival: RNA Expression ProfileProfile

    Pomeroy SL et al, Nature 2002

    Predictor genes: Cell cycle, ribosome regulation

  • Biologic Prognostic Markers:Biologic Prognostic Markers:

    Medulloblastoma

    Favorable prognosis Unfavorable prognosis

    Disease: Local Metastatic

    Histology: Desmoplastic Large cell/Anaplastic

    Genotype: PTCH mutation? cMYC amplification

    Expression: TRKC ErbB2, cMYC,

    RNA profile: cell cycle, ribosome

    metastasis

  • Medulloblastoma

    Stratification Issues

    - With better neuro-imaging, more

    average risk high

    - improves outcome of average-risk

    - improves outcome of high-risk- improves outcome of high-risk

    - Neuroimaging not as standardized

    - Does not account for impact of therapy

    - Does not incorporate molecular marker

    - ? replace/enhance clinical

    - Intermediary risk group

  • Medulloblastoma

    Radiotherapy

    - Backbone of effective treatment

    - Necessary evil of craniospinal

    - cognitive sequelae

    - endocrinologic sequelae

    - Can it be used alone?

    ? adults

    - Can local RT be used?

    ? subsets

    ? infant/young child

    - New techniques make it less toxic/effective

    ? conformal boost

    ? proton beam

    - CSRT dose reduction

  • MedulloblastomaMedulloblastomaX-RAYS

    100

    PROTONS

    50

    10

  • CCG-923/POG 8631: Low Stage

    Medulloblastoma Reduced-Dose RT

    Treatment SchemaTreatment Schema

    RandomizedRandomized 36003600 cGycGy CSRTCSRT RandomizedRandomized 36003600 cGycGy CSRTCSRT

    vs.vs.

    23402340 cGycGy CSRTCSRT

    No chemotherapyNo chemotherapy

    Baseline and yearly neurocognitive, endocrinologic assessmentBaseline and yearly neurocognitive, endocrinologic assessment

  • Medulloblastoma

    Radiotherapy / Chemotherapy

    Chemotherapy (during/post RT) associated

    with 20-30% improvement in EFS / S

    - No randomized comparisons

    Chemotherapy standard adjuvant in children

    Sequencing of major importance

    - best EFS/S if RT not delayed

    - ? Makes up for reduced CSRT

  • Medulloblastoma Study:

    RT plus CCNU, VCR, and CPDD

    Treatment ProtocolTreatment Protocol

    RT:RT: 3600 cGy CSRT3600 cGy CSRT

    5400 cGy Total Local5400 cGy Total Local } } 1