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
se S
urvi
val
Wor
se S
urvi
val
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
