77thth Annual NCCTG Annual NCCTGPatient Advocate SymposiumPatient Advocate Symposium

Neuro-OncologyNeuro-Oncology

Paul Brown, MDPaul Brown, MD

Professor of OncologyProfessor of Oncology

Department of Radiation OncologyDepartment of Radiation Oncology

Mayo Clinic Mayo Clinic

Rochester, MNRochester, MN

Brain Cancers: FrequencyBrain Cancers: Frequency

• Total new primaryTotal new primary 17,500 (1.35%)17,500 (1.35%)

• Total deaths primaryTotal deaths primary 14,000 (2.35%)14,000 (2.35%)

• Total metastatic tumors Total metastatic tumors 300,000300,000– ~30% of patients with cancer develop brain ~30% of patients with cancer develop brain

metastases eventuallymetastases eventually

Types of Primary Adult Brain TumorsTypes of Primary Adult Brain Tumors

GliomasGliomas• Low GradeLow Grade

– PilocyticPilocytic– OligodendrogliomaOligodendroglioma– Mixed tumorsMixed tumors– AstrocytomasAstrocytomas

• High GradeHigh Grade– AnaplasticAnaplastic– Glioblastoma MultiformeGlioblastoma Multiforme

OtherOther• Primary CNS Primary CNS

lymphomaslymphomas• Germ cell tumorsGerm cell tumors• EpendymomasEpendymomas• MedulloblastomaMedulloblastoma• Pituitary adenomasPituitary adenomas• MeningiomasMeningiomas• ChordomasChordomas

Wor

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Wor

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NCCTG NCCTG ResearchResearch

Glioblastoma MultiformeGlioblastoma Multiforme• Rapid progressionRapid progression

• Greater extent resection Greater extent resection beneficialbeneficial

•Radiation doubles survivalRadiation doubles survival

T1 post-contrastT1 post-contrast FLAIRFLAIR

High Grade GliomaHigh Grade GliomaBackgroundBackground

Time periodTime period 1 Yr Surv1 Yr Surv 5 Yr Surv5 Yr Surv

McGill UnivMcGill Univ 1939-19581939-1958 44% 44% 7% 7%

Mayo ClinicMayo Clinic 1990-19941990-1994 47% 47% 10%* 10%*

Jean Bouchard (McGill Univ. Montreal), Radiation therapy of tumors and diseases of the nervous system, Lea & Febinger 1966.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 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." treatment of patients with newly diagnosed high-grade glioma." CancerCancer 9292(2): 420-33, 2001.(2): 420-33, 2001.

*Values taken from curves*Values taken from curves

Very Frustrating!!!

Focal RT daily

Temozolomide

Concomitant TMZ/RT*

Adjuvant TMZ

Weeks6 10 14 18 22 26 30

RT Alone

R 0

573 patients accrued.573 patients accrued.

Phase III Study: New GBM Phase III Study: New GBM Radiation +/- TemozolomideRadiation +/- Temozolomide

EORTC/NCIC Phase III GBM Trial: EORTC/NCIC Phase III GBM Trial: Overall SurvivalOverall Survival

months

0 6 12 18 24 30 36 420

10

20

30

40

50

60

70

80

90

100

P<0.0001

TMZ/RT

RT

%

OS no different than OS no different than EORTC RT + TMZEORTC RT + TMZ

CM923704-9

N057K:N057K: Phase I Newly Dx GBM: Phase I Newly Dx GBM:RT+TMZ+ RAD001: Dr. SarkariaRT+TMZ+ RAD001: Dr. SarkariaN057K:N057K: Phase I Newly Dx GBM: Phase I Newly Dx GBM:RT+TMZ+ RAD001: Dr. SarkariaRT+TMZ+ RAD001: Dr. Sarkaria

RT (60 Gy) + TMZ

75 mg/M2/d + RAD-001 q wk

Newly Dx GBM

TMZ 200 mg/M2 D1-5 q 28d +

RAD001- 1,8,15,21 q 28d

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

Open

Sample Size: Phase I 9-30Phase II: 120

CM923704-10

N0874:N0874: Phase II Newly Dx GBM: Phase II Newly Dx GBM:RT+TMZ + Vorinostat (SAHA) Dr. Galanis/WenRT+TMZ + Vorinostat (SAHA) Dr. Galanis/Wen

N0874:N0874: Phase II Newly Dx GBM: Phase II Newly Dx GBM:RT+TMZ + Vorinostat (SAHA) Dr. Galanis/WenRT+TMZ + Vorinostat (SAHA) Dr. Galanis/Wen

RT (60 Gy) + RT (60 Gy) + TMZTMZ

75 mg/M2/d + 75 mg/M2/d + SAHA q400mg SAHA q400mg

5d/7d5d/7d

Newly Dx Newly Dx GBMGBM

SAHA500mg D1-7, SAHA500mg D1-7, 15-21 q 28d +15-21 q 28d +

TMZ 150 mg/M2 D TMZ 150 mg/M2 D 1-5 q 28 D**1-5 q 28 D**

Activated to GroupActivated to GroupNCCTG/ABTC NCCTG/ABTC IntergroupIntergroup

Sample Size:Phase I: 12-24Phase II: 108

Translational correlates• Neurocognitive testing• Tumor H1-4 acetylation, MGMT, pAKT, cdK

inhibitors (p21Waf-1/Cyp1, p27Kip-1)

CM923704-11

N0877:N0877: Phase I-II Randomized Newly Dx GBM: Phase I-II Randomized Newly Dx GBM:RT+TMZ +Dasatanib vs Placebo: Dr. LaackRT+TMZ +Dasatanib vs Placebo: Dr. Laack

N0877:N0877: Phase I-II Randomized Newly Dx GBM: Phase I-II Randomized Newly Dx GBM:RT+TMZ +Dasatanib vs Placebo: Dr. LaackRT+TMZ +Dasatanib vs Placebo: Dr. Laack

RT (60 Gy) + TMZ

75mg M2/D+ placebo

Newly Dx GBM

TMZ 150-200 mg/M2 D1-5, q 28d +

Placebo D1-5 X 6 cycles

Upcoming

RT (60 Gy) + TMZ

75mg/M2/D + Dasatanib 40-

100mg* bid

TMZ 150-200 mg/M2 D1-5, q 28d +

Dasatanib D1-5 or placebo X 6 cycles

Translational: 1)QOL; 2) Tumor Tissue: receptors, signaling and gene expression

1:2 Random

Arm A

Arm B

N=146

CM923704-12

Randomized Phase II Recurrent GBM Randomized Phase II Recurrent GBM ComparisonsComparisons

Randomized Phase II Recurrent GBM Randomized Phase II Recurrent GBM ComparisonsComparisons

Yung WKA, et al. Br J Cancer. 2000;83:588-593.

Goli, et al. abstract #2003, Clinical Science Symposium ASCO 2007.

Cloughesy, et al. abstract #2010, oral presentation ASCO 2008.

TMZTMZ BV-Phase IIRBV-Phase IIR BV-DukeBV-Duke

6 mo PFS6 mo PFS 21%21% 50%50% 43%43%

Median OSMedian OS 7.3 mos7.3 mos 8.9 mos8.9 mos 9.2 mos9.2 mos

CM923704-13

GBM GBM Tissue Tissue

availableavailable

30 Gy +30 Gy +TMZTMZ

R#R#AANNDDOOMMIIZZEE 30 Gy +30 Gy +

TMZ + TMZ + BevBev

30 Gy +30 Gy +TMZ + PlaceboTMZ + Placebo

TMZ d 1-5 of 28-d TMZ d 1-5 of 28-d cycle + Placebocycle + Placebo12 cycle max12 cycle max

# # Stratify by: (Random 10d post start RT)Stratify by: (Random 10d post start RT)Recursive partitioning analysis (RPA) class (III vs IV vs V)Recursive partitioning analysis (RPA) class (III vs IV vs V)MGMT methylation statusMGMT methylation statusMolecular profileMolecular profile

TMZ d 1-5 of 28-d TMZ d 1-5 of 28-d cycle + Bevcycle + Bev 12 cycle 12 cycle maxmax

Sample Size= 720Primary endpoints:OS and PFS

*Analysis for MGMT *Analysis for MGMT methylation, molec profilemethylation, molec profile

R0825:R0825: Phase III Randomized Newly Dx GBM: Phase III Randomized Newly Dx GBM:RT+TMZ +/- Bevacizumab: Brown/JaeckleRT+TMZ +/- Bevacizumab: Brown/Jaeckle

R0825:R0825: Phase III Randomized Newly Dx GBM: Phase III Randomized Newly Dx GBM:RT+TMZ +/- Bevacizumab: Brown/JaeckleRT+TMZ +/- Bevacizumab: Brown/Jaeckle

Upcoming

OligodendrogliomaOligodendroglioma• Classified as low-grade or Classified as low-grade or

anaplasticanaplastic• Very responsive to Very responsive to

treatment: chemotherapy treatment: chemotherapy and radiationand radiation

• Prognosis and treatment Prognosis and treatment response strongly response strongly correlated with 1p & 19q correlated with 1p & 19q LOHLOH

100% response to chemotherapy with 1p 19q LOH

Intergroup-9402Intergroup-9402

Oligo,Oligo,MixedMixedn= 289n= 289

RRAANNDDOOMMIIZZEE

PCV 4 cycles PCV 4 cycles → → RTRT

RTRT

Copyright © American Society of Clinical Oncology

Cairncross, G. et al. J Clin Oncol; 24:2707-2714 2006

Kaplan-Meier estimates of overall survival by treatment group

Copyright © American Society of Clinical Oncology

Cairncross, G. et al. J Clin Oncol; 24:2707-2714 2006

Kaplan-Meier estimates of overall survival by 1p and 19q deletion

Median survival 1p,19q intact equal to Gr3 astroMedian survival 1p,19q intact equal to Gr3 astro

CM923704-18

Newly Newly Diagnosed Diagnosed AO / AOA:AO / AOA:

Assess Assess 1p/19q1p/19q

No (or No (or single) single) 1p/19q 1p/19q

deletiondeletion

CODELCODELNCCTG NCCTG N0577N0577

1p/19q 1p/19q deletiondeletion

CATNONCATNONEORTC 26503EORTC 26503

PROPOSED NEWLY DIAGNOSED PROPOSED NEWLY DIAGNOSED ANAPLASTIC GLIOMA ANAPLASTIC GLIOMA INTERGROUP TRIALSINTERGROUP TRIALS

CM923704-19

NCCTG N0577:NCCTG N0577: Intergroup Phase III Anaplastic Intergroup Phase III Anaplastic Oligo / Mixed Glioma 1p/19q Codeleted Oligo / Mixed Glioma 1p/19q Codeleted

NCCTG N0577:NCCTG N0577: Intergroup Phase III Anaplastic Intergroup Phase III Anaplastic Oligo / Mixed Glioma 1p/19q Codeleted Oligo / Mixed Glioma 1p/19q Codeleted

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

Newly Diagnosed

AO/AO 1p/19q

co-deletion

RT (5960cGy)

TMZ x 12 cycles

RT + TMZ TMZ (Stupp)

RT vs. RT +TMZ:Primary endpoint - OS

N=245

N=245

N=50

CM923704-20

EORTC 26053 CATNON: Gr 3 AG, 0-1 deletionsEORTC 26053 CATNON: Gr 3 AG, 0-1 deletionsPh III RT+/-TMZ Ph III RT+/-TMZ TMZ vs Observation TMZ vs ObservationEORTC 26053 CATNON: Gr 3 AG, 0-1 deletionsEORTC 26053 CATNON: Gr 3 AG, 0-1 deletionsPh III RT+/-TMZ Ph III RT+/-TMZ TMZ vs Observation TMZ vs Observation

• Pre-study 1p/19q testing• Stratification:

- Methylation status

• Primary endpoint: OS• Secondary endpoints:

• PFS• Quality of life• Cognition• Neurological deterioration free survival

No adjuvant treatment

follow-up

Adjuvant TMZ 200 mg D1-5 q28D, X 12 mo

RANDOMIZATION

SURGERY

RT 59.4 Gy + concurrent

temozolomide 75mg/m2/D

RT 59.4 Gy

Activated in Europe, Pending in US

N=680

Low-Grade GliomasLow-Grade Gliomas

Low Grade AstrocytomasLow Grade Astrocytomas

TypesTypes• Pilocytic astrocytomaPilocytic astrocytoma• Oligodendroglioma Oligodendroglioma • OligoastrocytomaOligoastrocytoma• Low grade Low grade

astroctyomaastroctyoma

• Occur in younger patients Occur in younger patients (20-50 years)(20-50 years)

• Diffuse in natureDiffuse in nature• Slow growingSlow growing• More likely to present with More likely to present with

seizureseizure• Responsive to radiationResponsive to radiation

Su

rviv

al

Su

rviv

al

0.0

0.2

0.4

0.6

0.8

1.0

0 10 20 30

Su

rviv

al

Su

rviv

al

Time (yrs)Time (yrs)

GTRGTR

STRSTR

GTRGTR

STRSTR

CP1288306-14

P<0.0001P<0.0001

P=0.004P=0.004

OS

PFS

•314 pts (1960-1992)314 pts (1960-1992)•75% adjuvant Tx75% adjuvant Tx•Median F/U 14 yrsMedian F/U 14 yrs•GTR better OS and GTR better OS and PFSPFS

•Multivariate AnalysesMultivariate Analyses -Benefit for adjuvant RT-Benefit for adjuvant RT

Schomas SNO 2007Schomas SNO 2007

Mayo Clinic Experience-Long TermMayo Clinic Experience-Long Term

CM923704-24

Focal RT daily — 28 x 180 cGyTotal dose 50.4 Gy

Temozolomide 75 mg/m2 po qd for 6 weeks,then 150-200 mg/m2 po qd day 1-5 q 28 days for 12 cycles

Concomitant TMZ/RT

Adjuvant TMZ

Weeks6 10 14 18 22 26 30

RT Alone

R 0

*Symptomatic = uncontrolled headaches or seizures, focal deficits, cognitive symptoms

E0F05 Phase III Symptomatic* or Progressive LGG: RT +/- E0F05 Phase III Symptomatic* or Progressive LGG: RT +/- TemozolomideTemozolomide

N= 540

Upcoming

Brain MetastasesBrain Metastases

Management of Brain MetsManagement of Brain MetsTherapeutic ChoicesTherapeutic 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

N0574N0574

1-3 Brain 1-3 Brain Mets on MRIMets on MRI QOL, QOL,

NeurocogNeurocog

Radiosurgery Radiosurgery

Radiosurgery + Radiosurgery + WBRTWBRT