Patient Advocate Symposium Neuro-Oncology Paul Brown, MD

1
7th Annual NCCTGPatient Advocate
SymposiumNeuro-Oncology

• Paul Brown, MD
• Professor of Oncology
• Department of Radiation Oncology
• Mayo Clinic
• Rochester, MN

2
Brain Cancers Frequency

• Total new primary 17,500 (1.35)
• Total deaths primary 14,000 (2.35)
• Total metastatic tumors 300,000
• 30 of patients with cancer develop brain
  metastases eventually

3
Types of Primary Adult Brain Tumors

• Other
• Primary CNS lymphomas
• Germ cell tumors
• Ependymomas
• Medulloblastoma
• Pituitary adenomas
• Meningiomas
• Chordomas

• Gliomas
• Low Grade
• Pilocytic
• Oligodendroglioma
• Mixed tumors
• Astrocytomas
• High Grade
• Anaplastic
• Glioblastoma Multiforme

NCCTG Research
Worse Survival
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Glioblastoma Multiforme

• Rapid progression
• Greater extent resection beneficial
• Radiation doubles survival

T1 post-contrast
FLAIR
5
High Grade GliomaBackground

• Time period 1 Yr Surv 5 Yr Surv
• McGill Univ 1939-1958 44 7
• Mayo Clinic 1990-1994 47 10
• Jean Bouchard (McGill Univ. Montreal), Radiation
  therapy of tumors and diseases of the nervous
  system, Lea Febinger 1966.
• Buckner et al. "A phase III study of radiation
  therapy plus carmustine with or without
  recombinant interferon-alpha in the treatment of
  patients with newly diagnosed high-grade glioma."
  Cancer 92(2) 420-33, 2001.
• Values taken from curves

Very Frustrating!!!
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Phase III Study New GBM Radiation /-
Temozolomide
Focal RT daily
573 patients accrued.
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EORTC/NCIC Phase III GBM Trial Overall Survival

100
90
80
70
Plt0.0001
60

50
40
30
TMZ/RT
20
RT
10
0
0
6
12
18
24
30
36
42
months
8
OS no different than EORTC RT TMZ
9
N057K Phase I Newly Dx GBMRTTMZ RAD001 Dr.
Sarkaria
Open
RT (60 Gy) TMZ75 mg/M2/d RAD-001 q wk
TMZ 200 mg/M2 D1-5 q 28d RAD001- 1,8,15,21 q 28d
Newly Dx GBM
Sample Size Phase I 9-30 Phase II 120

• Translational correlates (Phase I)
• Pre and post RAD001 FDG-PET
• Phase I limited JAX and RST

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N0874 Phase II Newly Dx GBMRTTMZ Vorinostat
(SAHA) Dr. Galanis/Wen
NCCTG/ABTC Intergroup
Activated to Group
RT (60 Gy) TMZ75 mg/M2/d SAHA q400mg 5d/7d
SAHA500mg D1-7, 15-21 q 28d TMZ 150 mg/M2 D 1-5
q 28 D
Newly Dx GBM
Sample Size Phase I 12-24 Phase II 108

• Translational correlates
• Neurocognitive testing
• Tumor H1-4 acetylation, MGMT, pAKT, cdK
  inhibitors (p21Waf-1/Cyp1, p27Kip-1)

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N0877 Phase I-II Randomized Newly Dx GBMRTTMZ
Dasatanib vs Placebo Dr. Laack
Upcoming
TMZ 150-200 mg/M2 D1-5, q 28d Placebo D1-5 X 6
cycles
RT (60 Gy) TMZ 75mg M2/D placebo
N146
Arm A
Newly Dx GBM
12 Random
TMZ 150-200 mg/M2 D1-5, q 28d Dasatanib D1-5 or
placebo X 6 cycles
RT (60 Gy) TMZ 75mg/M2/D Dasatanib 40-100mg
bid
Arm B
Translational 1)QOL 2) Tumor Tissue
receptors, signaling and gene expression
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Randomized Phase II Recurrent GBM Comparisons
Yung WKA, et al. Br J Cancer. 200083588-593. Gol
i, et al. abstract 2003, Clinical Science
Symposium ASCO 2007. Cloughesy, et al. abstract
2010, oral presentation ASCO 2008.
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Upcoming
R0825 Phase III Randomized Newly Dx GBMRTTMZ
/- Bevacizumab Brown/Jaeckle
Sample Size 720 Primary endpoints OS and PFS
30 Gy TMZ Placebo
R A N D O M I Z E
TMZ d 1-5 of 28-d cycle Placebo 12 cycle max
30 Gy TMZ
GBM Tissue available
30 Gy TMZ Bev
TMZ d 1-5 of 28-d cycle Bev 12 cycle max
Analysis for MGMT methylation, molec profile
Stratify by (Random 10d post start
RT) Recursive partitioning analysis (RPA) class
(III vs IV vs V) MGMT methylation
status Molecular profile
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Oligodendroglioma

• Classified as low-grade or anaplastic
• Very responsive to treatment chemotherapy and
  radiation
• Prognosis and treatment response strongly
  correlated with 1p 19q LOH

100 response to chemotherapy with 1p 19q LOH
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Intergroup-9402
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Kaplan-Meier estimates of overall survival by
treatment group
Cairncross, G. et al. J Clin Oncol 242707-2714
2006
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Kaplan-Meier estimates of overall survival by 1p
and 19q deletion
Median survival 1p,19q intact equal to Gr3 astro
Cairncross, G. et al. J Clin Oncol 242707-2714
2006
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PROPOSED NEWLY DIAGNOSED ANAPLASTIC GLIOMA
INTERGROUP TRIALS
CODEL NCCTG N0577
1p/19q deletion
Newly Diagnosed AO / AOA Assess 1p/19q
No (or single) 1p/19q deletion
CATNON EORTC 26503
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NCCTG N0577 Intergroup Phase III Anaplastic
Oligo / Mixed Glioma 1p/19q Codeleted
N245
N245
N50

• Translational correlates
• 1p/19q translocation
• MGMT promotor methylation
• QOL/neurocog

RT vs. RT TMZ Primary endpoint - OS
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EORTC 26053 CATNON Gr 3 AG, 0-1 deletionsPh III
RT/-TMZ ? TMZ vs Observation
Activated in Europe, Pending in US
N680

• Primary endpoint OS
• Secondary endpoints
• PFS
• Quality of life
• Cognition
• Neurological deterioration free survival

• Pre-study 1p/19q testing
• Stratification
• - Methylation status

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Low-Grade Gliomas
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Low Grade Astrocytomas

• Types
• Pilocytic astrocytoma
• Oligodendroglioma
• Oligoastrocytoma
• Low grade astroctyoma

• Occur in younger patients (20-50 years)
• Diffuse in nature
• Slow growing
• More likely to present with seizure
• Responsive to radiation

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Mayo Clinic Experience-Long Term
OS

• 314 pts (1960-1992)
• 75 adjuvant Tx
• Median F/U 14 yrs
• GTR better OS and PFS
• Multivariate Analyses
• -Benefit for adjuvant RT
• Schomas SNO 2007

GTR
Survival
Plt0.0001
STR
PFS
P0.004
GTR
Survival
STR
Time (yrs)
CP1288306-14
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Upcoming
E0F05 Phase III Symptomatic or Progressive LGG
RT /- Temozolomide
N 540
Focal RT daily 28 x 180 cGy Total dose 50.4 Gy
Symptomatic uncontrolled headaches or
seizures, focal deficits, cognitive symptoms
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Brain Metastases
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Management of Brain MetsTherapeutic Choices

• WBRT alone
• Surgical resection /- WBRT
• Single brain metastasis
• Stereotactic radiosurgery /- WBRT
• high dose radiation to small, discrete,
  well-defined target with rapid dose fall-off

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N0574
Radiosurgery
1-3 Brain Mets on MRI
QOL, Neurocog
Radiosurgery WBRT