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Medulloblastoma

Medulloblastoma. Sidnei Epelman, M.D. Medulloblastoma. Most common malignant brain tumor of childhood - 20% Diagnosed in children less than 15 years Bimodal distribution – 3- 4 years and 8 – 9 years Male predominance Undifferentiated blue round cell tumor - WHO IV

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Medulloblastoma

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  1. Medulloblastoma Sidnei Epelman, M.D.

  2. Medulloblastoma • Mostcommonmalignantbrain tumor ofchildhood - 20% • Diagnosed in childrenlessthan 15 years • Bimodal distribution – 3- 4 yearsand 8 – 9 years • Male predominance • Undifferentiatedblue round cell tumor - WHO IV • Originatingfrompluripotentneuroectodermalstemcells • Cerebellar PNET • Rareinheritedsyndromes • Sporadicevolution

  3. MedulloblastomaPrognosticMarkers • Age • M stage • Extentofresection • Histologicvariant • Molecular markers • Beta catenin • MYCN, MYCC • ERBB2 • SHH

  4. Genes andSignalingpathways • WTN pathwayaberrant in Turcot`s syndrome– 15% - betterprognosis • Amplificationof MYCC oncogene – largecellvariant – pooreroutcome • ExpressionofTyrosinekinase receptor ERBB2 – 40% - pooreroutcome • Increasedexpression neurotrophin-3 receptor (TYKC) – bettersurvival • Amplificationof OXT2 homeobox gene – anaplasticvariant • Elevationsof beta catenin in expressioninvolved in Wntsignalingpathway – improvedsurvival

  5. Genes andSignalingpathways • Nevoid basal cell carcinoma syndrome – inheritedgermlinemutationof PTCH gene onchromosome 22 – encodessonichedgehog (SHH) receptor PATCHED1 (PTC1) thatnormallyrepresses SHH • Somaticmutation PTC1 associated – desmoplasticvariant – potentialtarget – 10-20%

  6. Metastatictumors • Platelet-derived growth factor receptor beta • Memberof RAS-MAP kinasepathway

  7. Histologicalvariants • Classicorundifferentiated – 70% • Desmoplastic / extensivenodularity – betterprognosis • Largecell / anaplastic – poorerprognosis

  8. Prognostic Markers

  9. MEDULLOBLASTOMA in children less than 3 years Medulloblastoma/PNET of young children are more aggressive than those of older children: • It grows more rapidly • Recurrence occurs usually within one year from diagnosis • Higher chance to metastasize from the primary tumor site to other parts of the brain and spine

  10. Medulloblastoma in younger than 3 years • Management is complicated • Avoiding use ofRadiotherapydue to late effects to thebrain • 40% disseminatedatdiagnosis • Betterprognosisfactor – biologyofthe tumor • Desmoplastic – 75% cure withchemotherapyalone

  11. Symptoms at presentantion Those children less than 3 years old: • Behavioral (48%) • Headache (12%) • Not reported in those less than 2 years old • Seizures (7%) • Enlarging head in less than 1 year old • Gastrointestinal symptoms like

  12. Treatment • Systemictreatment for tumorslikely to metastatize • Reduce tumor burden prior to use ofanothertreatmentmodality • Used in children < 3 years in order to sparesideeffectsofradiationtherapy • Limitations • Bloodbrainbarrier

  13. Treatment • Multi-modalitytreatment – dependentupon • Histology • Location • Age • Surgery • RadiationTherapy • Chemotherapy

  14. Surgery • Total ornear-total – bettersurvival • Cerebellarmutismsyndrome – 25% • Nystagmus • Truncalhypotonia • Dysmetria • Dysphagia • Markedemotionallability

  15. Neuroradiographic staging • Central review of international studies – inadequate spinal neuroimaging or misinterpreted in 25% of patients

  16. Effects of radiotherapy on the developing brain of the young child • Learning difficulties • Attention/concentration difficulties • Short-term memory deficits • Social adjustment problems • Hearing, speech and language problems • Impaired physical growth (hypothalamus, pituitary, spine)

  17. RadiationSideEffects Late effects Neurocognitive Endocrine Vascular Secondarymalignancies • Acuteeffects • Generallyrelated to tumor inflammation • Dependentupon tumor location • Nausea • Vomiting • Headaches • Weighloss • Mucosites • Fatigue

  18. ManagementAlternatives with increased efficacy • Intensivechemotherapywithperipheralstemcellsupport • Protocolwithhigh-dosemethotrexate • Focal radiationtherapy to primary site

  19. Survival of Young Children with Medulloblastoma and Supratentorial PNET • Event-free survival is poor with conventional chemotherapy strategies attempting to either • delay (Baby POG 1) • avoid irradiation (CCG-921; CCG-9921; BB-SFOP; St.Jude/Duke/CHOP “Baby” & UK-CCG “Baby” protocols): • Medulloblastoma =<10-34% 2 to 3 year EFS • ST PNET=0-19% 2 to 3 year EFS • Median time to relapse for pts. <3 years of age at diagnosis…6 to 9 mos

  20. Head Start treatment strategy • Delivery of highly intensive chemotherapy over a relatively short time period after diagnosis (less than 6 months) • Avoidance of brain irradiation in children achieving complete responses to initial treatment • Reduction in the doses and volume of brain irradiation for those children either with incomplete responses to initial treatment or older children (6 to 10 years old)

  21. TreatmentLocalizeddisease • Geyer – 9921 - SystemicChemotherapy – 92 pts • 5 year EFS – 32% • 83% ofEventfree - survivorshad no RT • Grill – SFOP - intensifiedsalvagestrategies - 79 pts • ProlongedchemoplusHdosisand local RT/CSA • M0R0 - 73% - 5y-OS • M0R+ – 41% • M+ - 13%

  22. TreatmentLocalizeddisease • Rutkowski – Systemicand intraventricular chemotherapywithMethotrexate • HIT-SKK 92 – 43 pts • M0R0 – 82% – 7yPFS • M0R+ - 50% • M+ - 33% • Survivalaccordinghistology • Desmoplastic - 85% • Classic - 34%

  23. Proposal COG - SIOP< 3-5years – M0 Desmoplastic • Regimen A – modified HIT without IT • Regimen B – Modified 99703 • Regimen C – HITSKK92 • No Radiotherapy Classic • Regime D – 99703 with focal conformalRt • Regime E – 99703 with focal conformal RT andlow dose CSI • No/Low dose CSI

  24. TretamentMetastaticdisease • HIT 2000 – M+ - IntensifiedChemotherapy + RT • IntenseInduction (CDDP, CFM, VCR, hdMTXandI.ventr)+ HD Chemo + Conventional RT 24 Gy + boostwhen residual tumor • Objetive response rate 82% • Chi – Head start 2 – regime A2 • Induction (CDDP, CFM, ETO, VCR, hdMTX) + HD Chemo (Carbo, ETO, TT) + or – RT local/CSA • 60% 3yOS • 49% 3yEFS

  25. Santa Marcelina Hospital/ TUCCAMedulloblastoma/ < 3 yearsof age • 9/14 patients - H Dosis MTX withcarboplatinandCyclowithout RXT • 4 alive • 4 Progressivedisease • 1 Diedof LMA , 6 yearsafterdiagnosisofMedulloblastoma in remission • 5/14 otherprocotolswithlowdosis • 4 progressivedisease • 1alive 5 years

  26. Conclusions M0 • Stratificationaccordinghistology • Desmoplastic • Chemo-only management • Classical • Evaluationofintensifiedchemoandattempt to avoid as much RT M+ • Desmoplastic • Reductionoftreatment • Classical • Intensifiedchemo + Hdosis+ RT; newagents?

  27. Future

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