Estado da Arte no Tratamento do Meduloblastoma State of the Art Radiation Therapy in the Treatment of

Medulloblastoma

Thomas E. Merchant, DO, PhD Baddia J. Rashid Endowed Chair in Radiation Oncology

Chair, Radiation Oncology Discipline Children’s Oncology Group

XVII Brazilian Radiation Therapy Congress

Objectives

• Review recent US trials for medulloblastoma

• Disease control

• Functional outcomes

• Identify opportunities to advance radiation oncology and review radiation dose-volume effects

• Cognitive

• Neurologic

• Endocrine

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Medulloblastoma Therapy for Medulloblastoma 20 Years Ago

Standard of Care

• Surgery

• Craniospinal irradiation

• 36Gy

• Posterior Fossa Boost

• 54Gy

Classic Portal:

Posterior Fossa Boost

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Medulloblastoma Results from Medulloblastoma Therapy 20 Years Ago

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0 1 2 3 4 5 6

IQ

Years after Craniospinal Irradiation

Walter et al. J Clin Oncol 1999

Loss of IQ: 3.7 points per year

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Craniospinal → Combined Modality Chemotherapy is Required to Reduce CSI Dose

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36Gy→23.4Gy Reducing CSI Dose Had No Effect on IQ Loss

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90

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0 1 2 3 4 5 6

IQ

Years after Craniospinal Irradiation

Walter et al. J Clin Oncol 1999

Ris et al. J Clin Oncol 2001

Loss of IQ: 4.2 points per year

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0

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0 1000 2000 3000 4000 5000 6000

Dose (cGy)

% V

olu

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Craniospinal Dose Reductions Reducing CSI Dose Has Little Effect on Brain Dose

Total Brain DVH

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54

23.4

36.0

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0

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90

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0 1000 2000 3000 4000 5000 6000 7000

Dose (cGy)

% V

olu

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Primary Site Volume Reductions Primary Site Instead of Posterior Fossa Irradiation

Total Brain DVH

23.4

23.4

54

54

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SJMB96 Protocol St. Jude Children’s Research Hospital 1996-2003

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2cm clinical target volume margin Gajjar A, et al. Lancet Oncol 2006 Merchant TE et al. Int Radiat Oncol Biol Phys 2007

Medulloblastoma Improving Outcomes by Omitting Posterior Fossa Irradiation

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0 1 2 3 4 5 6

IQ

Years after Craniospinal Irradiation

Walter et al. J Clin Oncol 1999

Ris et al. J Clin Oncol 2001

Mulhern et al. J Clin Oncol 2005

Loss of IQ: 2.4 points per year

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Medulloblastoma (Ages 3-8 Years) Children’s Oncology Group 2004-2014

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Amendment 2: Patients with anaplastic medulloblastoma were excluded after 2008!

Medulloblastoma (Ages 8-21 Years) Children’s Oncology Group 2004-2014

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Amendment 2: Patients with anaplastic medulloblastoma were excluded after 2008!

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0 1000 2000 3000 4000 5000 6000 7000

Dose (cGy)

% V

olu

me

Brain DVH

COG Average-Risk MB Trial

18.0Gy CSI + 5.4 Gy PF +CRT

18.0Gy CSI + Conventional

23.4Gy CSI + CRT

23.4Gy CSI + Conventional

COG ACNS 0331

Medulloblastoma (Ages 3-8 Years) Children’s Oncology Group 2004-2014

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SJMB03 Protocol St. Jude Children’s Research Hospital 2003-2013

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Results unpublished

Importance of Targeting Target Volume Comparison

GTV CTV SJMB03

CTV SJMB96

GTV

CTV - SJMB03

CTV - SJMB96

CTV – Posterior Fossa

CTV P Fossa

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SJMB03 - Results

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SJMB03 - Results

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Future MB Protocol Design

Ellison DE et al. Acta Neuropathol 2010

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What about MB Age < 3 years?

• POG 8633 (Neuro-oncology 1999) • CDDP/VCR/CPM/VP16 5 year - PFS 32 + 8%

• POG 9233 (Abstract) • CDDP/VCR/CPM/VP16 4 year – PFS 25 + 6%

• PBTC-001 (J Neurooncol 2012) • CDDP/VCR/CPM/VP16 + IT + RT 5 year – PFS 57 + 15%

• IT = mafosfamide; RT = 45-54Gy

• A9934 (J Clin Oncol 2012) • CDDP/VCR/CPM/VP16 + RT 4 year – PFS 50 + 6%

• RT = 50.4-54Gy

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Medulloblastoma Age < 3 Years COG A9934 Protocol 2000-2006

5430.6/023.4CR/0> 24 mo

5430.6/023.4CR/0>24 mo

5432.4/3.618PR/SD/+<24 mo

50.432.4/018CR/0< 24 mo

Total

Dose

Primary

Site

Volume

Posterior

Fossa

Volume

Response/

ResidualAge

5430.6/023.4CR/0> 24 mo

5430.6/023.4CR/0>24 mo

5432.4/3.618PR/SD/+<24 mo

50.432.4/018CR/0< 24 mo

Total

Dose

Primary

Site

Volume

Posterior

Fossa

Volume

Response/

ResidualAge

Initial Surgery

Induction Chemotherapy

4 months

Second Surgery

Age, Risk, Response-Adapted

Conformal Radiation Therapy

Posterior Fossa + Primary Site

Maintenance Chemotherapy

8 Months

Initial Surgery

Induction Chemotherapy

4 months

Second Surgery

Age, Risk, Response-Adapted

Conformal Radiation Therapy

Posterior Fossa + Primary Site

Maintenance Chemotherapy

8 Months Period of Enrollment: 10/2000-06/2006

CTV Margin = 1.0cm

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Medulloblastoma Age < 3 Years COG A9934 Pattern of Failure

<5.4Gy

<10.8Gy

<5.1Gy

<5.6Gy

<5.4Gy

<10Gy

<11.7Gy

Lost Data

<5.4Gy

<5.4Gy

Brain Sites of recurrence

Post RT

Frontal n= 10

<5.4Gy

<10.8Gy

<5.1Gy

<5.6Gy

<5.4Gy

<10Gy

<11.7Gy

Lost Data

<5.4Gy

<5.4Gy

Brain Sites of recurrence

Post RT

Frontal n= 10

0Gy

0G

y

0Gy

0G

y

0Gy

0Gy

0G

y

0g

y

Brain Sites of recurrence Pre

RT

Primary site n = 7

=8n=887

0Gy

0G

y

0Gy

0G

y

0Gy

0Gy

0G

y

0g

y

Brain Sites of recurrence Pre

RT

Primary site n = 7

=8n=887

Progression during

Induction Chemotherapy

Progression after

Focal Irradiation

Ashley DM, Merchant TE, et al. Induction chemotherapy and conformal radiation therapy for very young children

with nonmetastatic medulloblastoma: Children's Oncology Group study P9934. J Clin Oncol. 2012 Sep 10;30(26):3181-6.

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Medulloblastoma Age < 3 Years COG A9934 Pattern of Failure

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Ashley DM, Merchant TE, et al. Induction chemotherapy and conformal radiation therapy for very young children

with nonmetastatic medulloblastoma: Children's Oncology Group study P9934. J Clin Oncol. 2012 Sep 10;30(26):3181-6.

St. Jude SJYC07 Protocol

CTV margin – 5mm

Total dose – 54Gy 23

SJYC07 – Pattern of Failure after Focal RT

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Medulloblastoma 2015 Where do we go from here?

• Reduce craniospinal dose • ACNS0331 (18Gy) • A9934 (12-15Gy)

• Reduce cumulative dose to primary site

• A9934 (50.4Gy) • PBTC-001 (45Gy)

• Smaller clinical target volume margin

• + Proton therapy • Reduce volume receiving

lowest doses • Reduce extra-CNS dose

reductions: heart, lungs, thyroid, vertebral growth plates

Primary Site CTV

• Past – Posterior Fossa

• 1996 – 20mm

• 2003 – 10mm

• 2007 – 5mm

• Future – < Tumor Bed?

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P Fossa PTV CTV GTVP Fossa PTV CTV GTV

Future MB Protocol Design

Ellison DE et al. Acta Neuropathol 2010

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SJMB12 Study Design

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SJMB12 Study RT Summary

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Low-Risk Intermediate-

Risk High-Risk

15Gy CSI 23.4Gy CSI 36Gy CSI

CTV=5mm CTV=5mm CTV=5mm

51Gy 1° Site 54Gy 1° Site 54Gy 1° Site

+ Proton Therapy + Proton Therapy + Proton Therapy

IRB Approved 5/28/2013

Medulloblastoma Cognitive Effects (IQ) in Standard Risk Patients

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Medulloblastoma 50% Risk Subnormal (<85) IQ by Age

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V25Gy V30Gy V35Gy V40Gy V45Gy V50Gy

% V

olu

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Bra

in

15yrs

12yrs

10yrs

8yrs

5yrs

3yrs

Merchant TE et al. Int J Radiat Oncol Biol Phys 2014

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3 5 8 10 12 15

Mea

n D

ose

Gy

Age at Irradiation

Math

Infratent

Hippo L

Hippo R

Temporal L

Temporal R

Brain

Supratent

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60

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Mea

n D

ose

Gy

Age at Irradiation

Reading

Infratent

Hippo L

Hippo R

Temporal L

Temporal R

Brain

Supratent0

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60

3 5 8 10 12 15

Mea

n D

ose

Gy

Age at Irradiation

Spelling

Infratent

Hippo L

Hippo R

Temporal L

Temporal R

Brain

Supratent

Medulloblastoma TD50/5 IQ, Math, Reading, Spelling

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0

10

20

30

40

50

60

3 5 8 10 12 15

Mea

n D

ose

Age at Irradiation

IQ

Hippo L

Infratent

Hippo R

Temporal L

Temporal R

Brain

Supratent

Merchant TE et al. Int J Radiat Oncol Biol Phys 2014

Medulloblastoma TD50/5 (IQ)

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0

10

20

30

40

50

60

3 5 8

Me

an D

ose

Age (years)

Hippo L

Infratent

Hippo R

Temporal L

Temporal R

Brain

Supratent

Merchant TE et al. Int J Radiat Oncol Biol Phys 2014

Medulloblastoma Comparing Dose Distributions (Photon vs. Proton)

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V25Gy+ V30Gy+ V35Gy+ V40Gy+ V45Gy+ V50Gy+ V55Gy+

Pe

rce

nt

Vo

lum

e T

ota

l B

rain

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V25Gy+ V30Gy+ V35Gy+ V40Gy+ V45Gy+ V50Gy+ V55Gy+

Pe

rce

nt

Vo

lum

e T

ota

l B

rain

Proton Dose and Volume

Photon Dose and Volume

Merchant TE et al. Cancer J 2009

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0

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1 2 3 4 5 6

IQ

Years after Radiation Therapy

Abnormal IQ

IMRT (photon)

IMPT (proton)

Medulloblastoma Estimating IQ after Radiation Therapy (IMRT vs. IMPT)

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∗𝐼𝑄 = 93.00 + 0.024 𝑥 𝐴𝑔𝑒 − 0.0091 𝑥 𝐷𝑜𝑠𝑒 𝑥 𝑡𝑖𝑚𝑒

*Merchant TE et al. Int J Radiat Oncol Biol Phys 2006

Double-Scattered Proton Beam

Double-Scattered Proton Beam

Double-Scattered Proton Beam

Double-Scattered Proton Beam

Proton Therapy - Pencil Beam Scanning

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Proton Therapy - Pencil Beam Scanning

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Proton Therapy - Pencil Beam Scanning

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Proton Therapy - Pencil Beam Scanning

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Double-Scattered Proton Beam Primary Site Boost

Double-Scattered Proton Beam CSI Composite + Primary Site Boost

Summary

• Radiation therapy for medulloblastoma continues to evolve.

• Late effects have been reduced and our knowledge about the effects of radiation dose and volume have increased.

• Current and future protocols are designed to answer questions about the role of radiation therapy in the treatment of these unique tumors.

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Thank You!