medulloblastoma

John T. Lucas Jr. John T. Lucas Jr. Resident - Radiation Oncology

Wake Forest University

North Carolina Baptist Medical Center

OverviewOverview-Epidemiology-Pathogenesis-Classification-Pathology-Presentation-Workup-Surgical Management-Treatment

- Role of Radiotherapy- Role of Chemotherapy- Radiotherapy Techniques

Blue rubber bleb nevus - 15 mo MPhoto courtesy of Johns Hopkins University School of Medicine dermatlas 2001.

Jason T. Huse & Eric C. Holland. Targeting brain cancer: advances in the molecular pathology of malignant glioma and medulloblastoma . Nature Reviews Cancer 10, 319-331 (May 2010)

- ~15% have activating mutations in PTCH1, SUFU and/or SMO

- PTCH1 germline mutations cause Gorlin's syndrome

- ~20% of sporadic harbour mutations in APC, AXIN1, AXIN2 or CTNNB1

- Turcot's syndrome, (mut in APC), has + incidence of MB

- 30–50% of cases have del: 17p + gain of 17q (forming isochr 17q: i(17)(q10)) = most common genetic lesion in MB

- del 17p – has TP53, add 17q has MYCN (Grotzer CCR 2001) (upstream of Akt, IGF2, BCL2)



-Other poor prognostic markers: + ErbB2 – Gilbertson CCR 1997


- 1st descr 1925 Bailey & Cushing*Homer-Wright rosettes

-Staining:+ for neuron-specific enolase, + synaptophysin+ nestin

Differential?Differential?

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Surgical Bx, Resection& or Shunt

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MRI SpineCSF Cytology

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Surgical ManagementSurgical Management- Ventriculostomy–Endoscopic 3rd vntrcl vs. Ext ventr drain

- Shunt may + risk of ipsilateral hearing decrease - Suboccipital Craniotomy

- NTR: <1.5cm2 residual on postop MRI- STR: 51-90% resection

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J Clin Oncol. 1999 Mar;17(3):832-45. Metastasis stage, adjuvant treatment, and residual tumor are prognostic factors for medulloblastoma in children: conclusions from the Children's Cancer Group 921 randomized phase III study. Zeltzer PM, Boyett JM, Li H, Wisoff JH, Geyer JR, McGuire-Cullen P, Stehbens JA, Shurin SB, Packer RJ.

Surgical ManagementSurgical ManagementDoes Extent of Resection Matter?

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- 5yr EFS (-) in STR vs. GTR (54 vs 78%)

Surgical ManagementSurgical Management

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SequelaeSequelae- Asceptic Meninigitis- CSF Leak- 15-25% Posterior Fossa Syndrome

• Mutism, ataxia, dysphagia, hypotonia, mood lability

• Monitor 24-48 hrs post resection• Permanent in 50%

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StagingStaging- M stage most prognostic

- CSF should be assessed 10-14 d post-op

Risk StratificationRisk Stratification- Standard Risk – 5 yr EFS 80%

>3yoa, GTR/NTR <1.5cm2 Resid & M0

- High Risk – 5 yr EFS 60%

<3yoa, unresectable/STR

or >1.5cm2 residual, &/or M+

PrognosisPrognosis- f(x) of risk, histology, and M stage

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CSI 23.4 Gy cc/wqwk Vincristine

Cone Down toPosterior Fossato 36 Gy

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R-Cavity/Resid Dz or PF to 55.8Gy

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8C q6wk Adj Cis/CCNU/Vinc

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Surgical Bx, Resection, & or Shunt

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Cytox/Vinc/MTX/Carbo/VP-16/IT MTX

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1969 Bloom et al at Royal Marsden J Clin Oncol. 2000 Aug;18(16):3004-11. Low-stage medulloblastoma: final analysis of trial comparing standard-dose with reduced-dose neuraxis irradiation.Thomas PR, Deutsch M, Mulhern R, Stehbens JA, Langston J, Stanley P, Duffner P, Rorke L, Cherlow J, Friedman HS, Finlay JL, Vietti TJ, Kun LE.hue BR, Marymont MH, Muraszko K, Langston J, Sposto R.

Role of Radiotherapy: Historical Role of Radiotherapy: Historical PerspectivePerspective-Original series from Cushing & Baylor

showed only 1/61 survivors w/surgery alone

-Addition of Adj RT from 1969 RoyalMarsden showed 25% OS @ 10 yrs w/CSI

-Historical dose was CSI to 36 Gy w/cone down to PF to 50-54 Gy

-Single most effective tx for MB, howeversequelae have changed dosing & fields

Intellectual outcome after reduced-dose radiation therapy plus adjuvant chemotherapy for medulloblastoma: a Children's Cancer Group study.Ris MD, Packer R, Goldwein J, Jones-Wallace D, Boyett JM. J Clin Oncol. 2001 Aug 1;19(15):3470-6.Medulloblastoma in childhood: progressive intellectual deterioration. Hoppe-Hirsch E, Renier D, Lellouch-Tubiana A, Sainte-Rose C, Pierre-Kahn A, Hirsch JF.Childs Nerv Syst. 1990 Mar;6(2):60-5.

Role of Radiotherapy: SequelaeRole of Radiotherapy: Sequelae- Moya moya syndrome

- Incidence ranges widely

- Secondary Malignancies

- Cognitive impairment (Limit temporal lobe dose!)- Predictors: <7 yoa most imp, dose, high IQ, F>M- Rate: Falls for >5 yrs depending on age at dx

- If < 7 yoa @ tx then 5points/yr- If > 7yoa @ tx then 1 point/yr

- Endocrine: (-) GH->(-) growth (threshold ~10 Gy)- Thyroid

- Carotid Artery Stenosis

- Ototoxicity

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J Clin Oncol. 2000 Aug;18(16):3004-11. Low-stage medulloblastoma: final analysis of trial comparing standard-dose with reduced-dose neuraxis irradiation.Thomas PR, Deutsch M, Mulhern R, Stehbens JA, Langston J, Stanley P, Duffner P, Rorke L, Cherlow J, Friedman HS, Finlay JL, Vietti TJ, Kun LE.hue BR, Marymont MH, Muraszko K, Langston J, Sposto R.

Goal: Reduce CSI dose related neuro/endo/cognitive sequelae of RT126 Patients age 3-21 w/ M0 MB

- RT: CSI to 23.4Gy w/PF boost to 55.8Gy vs. CSI 36Gy w/ PF boost to 54Gy- No Concurrent w/1.5mg/m2 Vinc qwk x 8C- No Adj Chemo

Outcome: SS Diff in 5 yr EFS 67% (36Gy) vs. 52% (23.4Gy)- Trial stopped early

Role of Radiotherapy: DoseRole of Radiotherapy: DosePOG 8631CCG 923

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Eur J Cancer. 1990 Apr;26(4):464-9. Adjuvant chemotherapy for medulloblastoma: the first multi-centre control trial of the InternationalSociety of Paediatric Oncology (SIOP I). Tait DM, Thornton-Jones H, Bloom HJ, Lemerle J, Morris-Jones P.

Goal: Improve EFS w/Chemo?286 Patients age 3-21 w/ M0 MB

- RT: CSI to 36 Gy w/PF boost to 55.8Gy- (+/-) Concurrent: w/1.5mg/m2 Vinc qwk x 8C- (+/-) Adj Chemo: Vinc/CCNU

Outcomes: - Similar to CCG 942- 5 yr EFS ~ Equivalent ** No benefit to Adj Chemo- Subgroup benefit in STR, brainstem dz, >T3 dz

Role of Radiotherapy: RT + Adj ChemoRole of Radiotherapy: RT + Adj ChemoSIOP 1

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Eur J Cancer. 1990 Apr;26(4):464-9. Adjuvant chemotherapy for medulloblastoma: the first multi-centre control trial of the InternationalSociety of Paediatric Oncology (SIOP I). Tait DM, Thornton-Jones H, Bloom HJ, Lemerle J, Morris-Jones P.

Multiple Interval Studies: -SIOP II: tried to decrease CSI dose from 35 to 25 Gy adding adj chemo

- Worse EFS and KPS/QOL following CSI+Adj Chemo compared to CSI

-HIT 91: compared order of RT vs. Chemo- EFS SS in RT immediate post-Op group

-CCG 9892: Pilot trying 23.4Gy CSI w/CC (Vinc) +Adj.Chemo (CCNU/Cis/Vinc)

- Equivalent EFS, OS relative to historical controls w/ 36 Gy CSI

Role of Radiotherapy: RT + Adj ChemoRole of Radiotherapy: RT + Adj Chemo

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Phase III study of craniospinal radiation therapy followed by adjuvant chemotherapy for newly diagnosed average-risk medulloblastoma. J Clin Oncol. 2006 Sep 1;24(25):4202-8. Packer RJ, Gajjar A, Vezina G, Rorke-Adams L, Burger PC, Robertson PL, Bayer L, LaFond D, Donahue BR, Marymont MH, Muraszko K, Langston J, Sposto R.

Goal: Replace CCNU w/Cytox 2/2 limited activity in MB421 Patients age 3-21 w/ M0 MB

- RT: CSI to 23.4Gy w/PF boost to 55.8Gy - Concurrent w/1.5mg/m2 Vinc qwk x 8C- Adj: CCNU/Cis/Vinc vs. Cytoxan/Cis/Vinc

Outcomes: Equivalent EFS, OS - SS diff in G3/4 Tox + in Cytoxan group

Role of Radiotherapy: CC ChemoRT+Adj Role of Radiotherapy: CC ChemoRT+Adj ChemoChemoCCG A9961

Role of Radiotherapy: Cone Down to Role of Radiotherapy: Cone Down to >50 Gy>50 Gy

Goal: Assess efficacy of HD RT to the PF & LD RT to the spinal axis, - Retrospective- 60 patients w/bx-proven MB treated at JCRT from 1968-1984.

Outcome:- >50Gy ~ 79% LC vs. <50Gy ~ 33% LC (P < 0.02)

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Hughes EN, Shillito J, Sallan SE, Loeffler JS, Cassady JR, Tarbell NJ. Cancer. 1988 May 15;61(10):1992-8. Medulloblastoma at the joint center for radiation therapy between 1968 and 1984. The influence of radiation dose on the patterns of failure and survival.

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Role of Radiotherapy: High Risk DzRole of Radiotherapy: High Risk Dz- Unresectable/STR or >1.5cm2 residual, &/or M+

- Immediate Post RT 2/2 HIT 91

- If M2 or M3 then,- 50.4Gy to intracranial mets- 50.4 Gy boost to focal spinal mets below cauda equina- 45 Gy above cauda equina- 39.6 Gy to diffuse spinal disease

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Role of Radiotherapy: <3 yoa Delay RT Role of Radiotherapy: <3 yoa Delay RT w/Chemow/Chemo

Goal: Delay RT till 3 yoa in order to (-) RT sequelae in malignant brain tumors198 patients all <3yo at dx, Any M stage 31% MB 38% GTR, 62% STR

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N Engl J Med. 1993 Jun 17;328(24):1725-31. Postoperative chemotherapy and delayed radiation in children less than three years of age with

malignant brain tumors. Duffner PK, Horowitz ME, Krischer JP, Friedman HS, Burger PC, Cohen ME, Sanford RA, Mulhern RK, James HE, Freeman CR, et al.

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Role of Radiotherapy: <3 yoa Delay RT Role of Radiotherapy: <3 yoa Delay RT w/Chemow/ChemoBaby

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- 60-70% ended up requiring RT, re-resection 2/2 progression @ 1-2 yrs

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Role of Radiotherapy: <3 yoa Delay RT Role of Radiotherapy: <3 yoa Delay RT w/Chemow/ChemoBaby

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Toxicity: - G5 Tox in 4 kids- 50% w/Hemorrhagic Cystitis- >90% N/V- 26% Ototoxicity (hearing loss)- Growth stunting SS- 2 Tx Related secondary malignancies- No SS impact on NeuroCog f(x) in 34 kids assessed

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Role of Radiotherapy: <3 yoa PostOp Role of Radiotherapy: <3 yoa PostOp Chemo onlyChemo only 43 patients all <3yo at dx, Any M

stage Goal: Chemo alone for 3 yoa

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Role of Radiotherapy: <3 yoa PostOp Role of Radiotherapy: <3 yoa PostOp Chemo onlyChemo only - Patients w/<GTR had marked (-) in EFS, OS

- 44% ended up needing salvage RT (mostly classic)

- Of 31 w/M0 dz, 10 required RT for salvage

- Of 12 w/>M1 dz, 9 received RT for salvage

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Role of Radiotherapy: <3 yoa PostOp Role of Radiotherapy: <3 yoa PostOp Chemo onlyChemo only Conclusion

- At <3 yoa c/s delay RT is poss- At 3 yoa c/s CSI & Adj Chemo- If desmoplastic then may avoid RT altogether- IntraVentricular chemo not w/o neuro/cognitive sequelae

- 44% w/iVentricular chemo got w/leukencephalopathy

Radiotherapy: TechniquesRadiotherapy: TechniquesCSI:- Goal: deliver a uniform dose throughout the subarachnoid space encompassing the entire intracranial vault & spinal canal- Setup: Prone vs. Supine

Prone- Prone on a torso cushion or alpha cradle- Hyperextend neck w/head immobilized w/an aquaplast

immobilization deviceSupine

- Thermoplastic Mask- Supine on flat body cushion w/legs on combifix

Prone Supine

Comfort ++ +++

Allows Field Matching + (-)

Anesthesia Possible + +++

Radiotherapy: TechniquesRadiotherapy: TechniquesCSI:- Simulate Spine 1st

- Allows calculation of collimator angle for cranial fields - Spine borders:

Sup: C2 Inf: inf S2 (end of thecal sac) Lat: 1cm lat to pedicles

- May avoid multiple spinal fields by rotating collimator or + SSD- Field Length: If <35 cm use 100cm SSD, if >35 cm then 120 cm

SSD- OARs: optic structures, lenses, mandible, thyroid gland, lung,

heart, liver, kidneys and small bowel

Radiotherapy: TechniquesRadiotherapy: TechniquesCSI:- Multiple Spinal Fields:

- If multiple spinal fields, then match at depth of mid spinal cord- Inf spinal field should have iso @ sup border of field to ½

beam block- Match fields at L1-L2 region as depth changes most here- Skin Gap = ([0.5 x Length x d]/ SSD1) + ([0.5 x length 2 x d]/SSD2)

Radiotherapy: TechniquesRadiotherapy: TechniquesCSI:- Simulate Head 2nd

- Borders: Sup: flash skin Inf: 0.5-1cm cribiform plateAnt: 1cm ant vertbrl bodies Post: 2-2.5cm post to eye

- Collimator Angle: i.e. matching divergence of spinal fields= arctan (½ length of Sup Spine field / SSD)

- Couch Angle:i.e. match diverging cranial fields= arctan (½ length cranial field / SAD)

- OARs- pituitary, optics, lenses, mandible, thyroid gland- Tx fields: opposed lateral cranial fields

Radiotherapy: TechniquesRadiotherapy: TechniquesCSI: Gap Shifting/Feathering - Every 9 Gy:

Extend inf cranial field inf by 1 cmShift upper spinal field inf by 1 cmShorten lower spine field by 1 cm

- Cranial Iso stays in same spot, Spine Iso and inf jaw moves- Recalculate Couch Angle EACH TIME

Radiotherapy: TechniquesRadiotherapy: TechniquesCSI:

Radiotherapy: TechniquesRadiotherapy: TechniquesPosterior Fossa Boost:- Use 3D CRT and MR planning

Radiotherapy: TechniquesRadiotherapy: Techniques

Current Trials: PF vs. IFRT Boost Current Trials: PF vs. IFRT Boost Phase III Randomized Standard-Dose vs. Reduced-Dose CSI and

PF Boost vs IFRT in Comb/w/Vinc,Cis,Lomustine, & Cytoxan in kids w/Newly Dx’d Standard-Risk MB. COG-ACNS0331, ACNS0331, NCT00085735

Population: 3 to 7 yrs, Standard Risk MB

Intervention: 2 randomizations -Standard-dose vs reduced-dose CSI (18Gy) concurrent w/Vinc-PF boost vs tumor bed boost -Adjuvant Vinc/Cis/Lomustine/Cytoxan

1o Outcomes: EFS & OS

2o Outcomes: -Patterns of failure -Cognitive, auditory, & endocrinologic effects-Compare the audiologic and endocrinologic toxicity -Develop prognostic gene expression signature-Assess QOL & KPS pre&post tx

Current Trials: Protons vs. PhotonsCurrent Trials: Protons vs. PhotonsProton Beam Radiotherapy for Medulloblastoma and PineoblastomaPhase: Phase II Age: 3 to 25Protocol IDs: 09-361, P01CA021239, NCT01063114

Current Trials: Radio-immunotherapyCurrent Trials: Radio-immunotherapyPhase II Pilot Study of Post-Op Intrathecal Radioimmunotherapy, Reduced-Dose CSI w/IMRT Boost, & Chemo in Standard-Risk MB MSKCC-02088, NCT00058370

Intrathecal I 131 MAb 3F8 (anti-GD2 ganglioside MAb on d1-8.-Following above-> EBRT/IMRT concurrent w/Vinc IV qwk for 8 wks

6 wks s/p RT (4 weeks after vincristine), patients receive- Cis, Lomustine, Vincristine - Tx rpts q6 wks for up to 8C if no progression

Treatment: Current Trials- Treatment: Current Trials- HyperfractionatedHyperfractionatedPhase 3 Multi -Protocol Study of Conv Reduced-Dose or Hyperfx’d RT & Combo Chemo in kids w/IC MB, Supratentorial PNET, or Ependymoma GPOH-HIT-2000, EU-205105, NCT00303810

Protocol HIT-2000-AB4 ≥ 4 yoa @ Dx w/M0 MB- Hyperfx’d RT vs. Conv reduced-dose RTAdj Vinc, lomustine, & Cis

Protocol HIT-2000-BIS4 < 4 yoa @ Dx w/M0 MB - 5C of cytoxan, vinc, mtx, carbo, etop, & IT mtx- If Residual dz s/p 3Cundergo conv fx’d reduced-dose RT

Protocol MET-HIT-2000-AB4 ≥ 4 yoa @ Dx w/M+ MB- 2C of BIS4 Chemo Hyperfx’d RT & receive AB4 Chemo- (+) OR to chemo BIS4 HD chemo

Protocol MET-HIT-2000-BIS4 < 4 yoa @ dx w/M+ MB - 2-4C of carbo/etop IV contin over 96 hrs- (+) OR HD carbo/etop/cytoxan & thiotepa- If Residual dz Conv fx’d reduced-dose radiotherapy

Current Trials: High Risk MBCurrent Trials: High Risk MBEvaluating HD Chemo w/PBSCT support in high risk patients:High Risk Primitive Neuroectodermal (PNET) Brain Tumors in Childhood. Phase: Phase II Age: 10 and underProtocol IDs: PNET HR, NCT00180791

Total Marrow Irradiation Added to an Alkylator-Intense Conditioning Regimen for Patients With High Risk or Relapsed Solid TumorsPhase: Phase I Age: 70 and underProtocol IDs: 2005LS023, UMN-MT2004-30, 0504M69306, UMN-2005LS023, NCT00623077

Phase III Randomized Study of Standard CRT w/or w/out Carbo Followed by Standard Maint Tx w/or w/out Isotretinoin & Continuation Tx w/ Isotretinoin vs No Continuation Tx in Pediatric Patients With Newly Diagnosed, Previously Untreated, High-Risk MB or Supratentorial PNET. COG-ACNS0332, ACNS0332, NCT00392327

Treatment: Current TrialsTreatment: Current TrialsRisk-Adapted Therapy for Young Children With Embryonal Brain Tumors, Choroid Plexus Carcinoma or EpendymomaPhase: No phase specified Age: Under 3 at diagnosisProtocol IDs: SJYC07, SJCRH-SJYC07, NCT00602667

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J Clin Oncol. 1999 Jul;17(7):2127-36. Treatment of children with medulloblastomas with reduced-dose craniospinal radiation therapy and adjuvant chemotherapy: A Children's Cancer Group Study. Packer RJ, Goldwein J, Nicholson HS, Vezina LG, Allen JC, Ris MD, Muraszko K, Rorke LB, Wara WM, Cohen BH, Boyett JM.

Goal: Reduce CSI dose related neuro/endo/cog sequelae of RT w/Adj Chemo

65 Patients age 3-10 w/M0 MB - RT: CSI to 23.4Gy w/PF boost to 55.8Gy - Concurrent w/1.5mg/m2 Vinc qwk x 8C- Adj: CCNU/Cis/Vinc

Outcomes: Equivalent EFS, OS relative to historical controls w/ 36 Gy CSI

Role of Radiotherapy: CC ChemoRT+Adj Role of Radiotherapy: CC ChemoRT+Adj ChemoChemoCCG 9892

CCSG 942 (Evans et al., J Neurosurg 1990;72:572-582)

CCSG 942 cont.

311 pts from 6/1975-7/1981• 233 medulloblastoma, 88 ependymoma

Surgery(RT + V) CCNU/V/Prednisone

RT: 35-40Gy CSI with 50-55Gy to Posterior fossa

CCSG 942 cont.5yr PFS: 59% (RT+Chemo) to 50% (RT) [not sig.]

5yr OS: 65% for both groups

CCSG 942 cont.5yr PFS

Low Risk:• Addition of

chemo did not help (65% vs. 60%)

CCSG 942 cont.High Risk:

• Addition of chemo with significant reduction of 5yr PFS (46% vs. 0%) [p=0.006]

SIOP I cont.71% vs. 53% (p=0.007) 53% vs. 48% (p ns)

SIOP II (Bailey et al., Med Pediatr Oncol 1995;25:166-

178)

Sandwich therapy• High Risk: Surgery

CCNU/Procarbazine/MTX RT (35Gy CSI and 55Gy to post fossa) CCNU/V

• Low Risk: Surgery CCNU/Procarb/MTx randomized to 35Gy vs. 25 Gy CSI

No stastistical differences in any group

SIOP II cont. CSI Chemo 5yr PFS 35Gy neg 60% pos 75%

25Gy neg 69% pos 41%

(p=0.07)

SIOP I cont.

Benefit of chemo for high risk group58% vs 25% (P<0.005) 52.1% vs. 33.3% (P<0.01)

SIOP I cont.

48% vs. 25% (P=0.002)

Packer et al. (Packer et al., J Neurosurg 81:690-

698,1994)

RT + cisplatin/CCNU/vincristine

Packer et al. cont.63 pts from 1983-1991: 85% 5yr PFS

Packer et al.Reduced dose as good for reduced dose for low risk group: 83% for both groups for 5yr actuarial survival rate

medulloblastoma

Health & Medicine

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gy trial

gy csi role of radiotherapy

gy thyroid

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targeting brain cancer

gy ccw qwk vincristine

eur j cancer