1

COG CNS Committee

2003-2007
Ian Pollack
2
Identify biological characteristics of
childhood CNS tumors that influence
treatment response, and initiate risk-adapted
stratification.
Develop comprehensive treatment
approaches to improve survival and quality of
life for children with primary CNS tumors.
Identify effective therapies for CNS tumors
resistant to prior treatments.
Define and validate strategies for reducing
treatment-related long-term sequelae.
Scientific Goals

3


Medullo
PNET

Infant
Tumors
Germ
Cell

Epend
ymoma
Low-
Grade
Glioma
High-
Grade
Glioma

Brainstem
Glioma
Optimize
Chemo to
Reduce
Sequelae

A
AA9
999
996
661
11
ACNS0331

C
CCC
CCG
GG-
--
9
999
997
770
003
33

A
AAC
CCN
NNS
SS-
--
0
002
223
332
22

A
AAC
CCN
NNS
SS-
--
0
004
442
221
11


A
AA9
999
995
552
22



Optimize RT
Delivery
ACNS0331

P
PP9
999
993
334
44


A
AAC
CCN
NNS
SS-
--
0
001
112
221
11
A
AAC
CCN
NNS
SS-
--
0
002
222
221
11



Chemo-RT
C
CCC
CCG
GG-
--9
999
997
770
001
11
A
AAC
CCN
NNS
SS0
003
333
332
22
P
PPO
OOG
GG-
--9
996
663
331
11


A
AAC
CCN
NNS
SS0
003
333
333
33



A
AAC
CCN
NNS
SS-
--
0
001
112
226
66

C
CCC
CCG
GG-
--9
997
771
112
22
C
CCC
CCG
GG-
--9
998
880
002
22
P
PPO
OOG
GG-
--9
998
883
336
66
A
AAC
CCN
NNS
SS0
001
112
226
66
A
AAC
CCN
NNS
SS0
002
222
222
22
A
AAC
CCN
NNS
SS0
002
222
224
44

Intensifying
Chemo
C
CCC
CCG
GG-
--9
999
997
770
002
22
C
CCC
CCG
GG-
--
9
999
997
770
003
33
A
AAC
CCN
NNS
SS0
003
333
334
44
A
AAC
CCN
NNS
SS-
--
0
001
112
222
22
A
AAC
CCN
NNS
SS-
--
0
001
112
221
11
A
AAC
CCN
NNS
SS-
--
0
002
222
223
33
A
AAD
DDV
VVL
LL0
000
001
111
11
ACNS0423
A
AAC
CCN
NNS
SS0
002
223
331
11




CNS Committee Cross-Study
Therapeutic Hypotheses
4
Observation that the use of adjuvant
chemotherapy permits CSRT dose reduction
to 2340 cGy with >75% survival for M0
medulloblastoma.
Demonstration that extent of resection is
associated with outcome for children with
medulloblastoma, ependymoma, low- and
high-grade glioma.
Initiation of the largest biological study to date
of high-grade gliomas of childhood, and
preliminary delineation of prognostic factors.
Cooperative Group Scientific
Accomplishments

5
0%
20%
40%
60%
80%
100%
0 2 4 6 8 10 12
S
u
r
v
i
v
a
l
POG-8631/CCG-923 (Reduced
Dose XRT Alone, N=46)
CCG-9892 (Reduced Dose
XRT+Chemo, N=65)
POG-8631/CCG-923 (Standard
Dose XRT Alone, N=42)
Packer et al. JCO 17: 2127, 1999; Thomas et al. JCO 18: 3004, 2000
Years Post Onstudy
Reduced Dose Radiotherapy Is Feasible in
Standard-Risk Medulloblastomas If
Combined with Adjuvant Chemotherapy
6
0%
20%
40%
60%
80%
100%
0 2 4 6 8 10 12
Years Post Onstudy
E
v
e
n
t
-
F
r
e
e

S
u
r
v
i
v
a
l
>90% Resection (N=66)
<90% Resection (N=101)
p=0.002
Amount of Residual Disease Is
Associated with Outcome in
Children with High-Grade Glioma
CCG-945
Wisoff et al., J Neurosurg 89: 52, 1998
7
Determination that moderately intensive chemo
improves survival for poor-risk medullo/PNET.
Identification of molecular factors correlated
with outcome of infant tumors.
Documentation that building upon induction
chemo in infant tumors with high-dose
consolidation or focal irradiation improves
outcome.
However, despite improvements in the
prognosis of some tumor types, others remain
resistant and late effects remain a concern.
Scientific Accomplishments

8
Management of Average-Risk
Medulloblastomas
1) Post fossa location
2) M0
3) < 1.5 cm
2
Residual
A9961
2340 cGy CSRT
5580 cGy Local RT
CCNU
CPDD
VCR
CPM
CPDD
VCR
N > 400
Has provided a platform for additional study development
Goals: 1) Further CSRT dose reduction by modifying chemo
2) Target volume reduction (boost site) using conformal RT
9
A9961 Progression-Free Survival from Study Entry
50%
60%
70%
80%
90%
100%
0 1 2 3 4 5 6 7
Time (Years)
P
e
r
c
e
n
t

P
r
o
g
r
e
s
s
i
o
n
-
F
r
e
e

RegA RegB
p=0.49
86% +/- 2.5%
84% +/- 3%
10
Accuracy of Staging Strongly Influences
Effectiveness of Reduced Dose Therapy
11
Overall Survival for A9961 by Anaplasia
0.00
0.25
0.50
0.75
1.00
0 2 4 6 8 10
Years from study entry
P
r
o
b
a
b
i
l
i
t
y
No Anaplasia (n=300)
Anaplasia (n=55)
p=0.04
Figures 5 and 6 were based on all patients on A9961 with anaplasia information (including those
ineligible by central review due to dissemination or excess residual).
12
RT Dose Reduction for Average-Risk
Medulloblastoma (<8 yrs)

2340 cGy CSRT
with VCR
Conformal tumor
bed boost (5400 cGy)
Conformal post fossa
boost (5400 cGy)
1800 cGy CSRT
with VCR
CCNU, CPDD, VCR
alt. with CPM, VCR
ACNS0331
Activation 4/04
135 pts accrued
13
ACNS0331
Activation 4/04
RT Dose Reduction for Average-Risk
Medulloblastoma (>8 yrs)
2340 cGy CSRT
w/ VCR
Conformal tumor
bed boost (5400 cGy)
Conformal post fossa
boost (5400 cGy)
CCNU, CPDD, VCR
alt. with CPM, VCR
Both strata include prospective
Trk C and erbB2/4 analysis,
expression profiling, and
histological review to identify ~
20% of tumors that are not
biologically average risk
SPECIMEN SUBMISSION
STRONGLY ENCOURAGED.
14
High-Risk PNET
Radiosensitization Study
Craniospinal (36 Gy) XRT Boost (18 Gy) XRT
Carbo Carbo Carbo (Carbo) (Carbo) (Carbo)
VCR VCR VCR VCR VCR VCR
week 1 2 3 4 5 6
CPM
VCR
CDDP
CPM
VCR
(CCG-99701)
Phase I MTD established
Phase II completed 12/04
ACNS0332
Protocol approved by
CTEP/PCIRB
15
3 yr OS: 81 5%
99701 Overall Survival for Metastatic MB

0.00
0.25
0.50
0.75
1.00
0 1 2 3 4 5 6 7
Years from study entry
P
r
o
b
a
b
i
l
i
t
y

n=58
3 yr OS: 81 + 5%
2
16
3 yr OS is 89 5%
3 yr OS is 64 12%
0.00
0.25
0.50
0.75
1.00
0 1 2 3 4 5 6 7
Years from study entry
P
r
o
b
a
b
i
l
i
t
y

Anaplasia (n=19)
No Anaplasia (n=39)
p=0.008
3 yr OS: 89 5%
3 yr OS: 64 12%
Overall Survival by Anaplasia
17
Progressive Disease
High-risk, Unresectable
< 10 years
A9952
Non-NF1
Carboplatin
VCR
6-thioguanine
Procarbazine
CCNU
VCR
NF1
Management of Low-Grade Glioma
N=250
randomized, 350 total
New Studies
Carbo/VCR/TMZ pilot
ACNS0223 (protocol
opened 7/04;
recently opened
groupwide - 32 pts)
Conformal RT pilot
ACNS0221
(recently open)
18
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
0 1 2 3 4
YEARS
E
v
e
n
t
-
F
r
e
e

S
u
r
v
i
v
a
l
Regimen A (N=32)
Regimen B (N=31)
CCG-9941
Jennings et al. JCO, 2002
A
A
Intensive Chemotherapy Followed by
Irradiation Fails to Alter Prognosis in Newly
Diagnosed Brainstem Glioma
Uniformly poor results of all
recent studies provide for reliable
natural history control data.
19
Phase I/II Studies of Radiosensitization
and Chemo-Radiotherapy for Brainstem
Gliomas
Temozolomide (ACNS0126) closed 8/05
accrued at twice rate projected (60/yr)
standardized BSG stats (SPRT), imaging,
response analysis in collaboration with PBTC
Topotecan (ACNS 0224) protocol opened
10/10/05
Gadolinium texaphyrin
Phase I completed (CCG-09712)
Phase II protocol approved by CTEP/PCIRB - in queue to
open (ACNS0222)
20
Combined Chemoradiotherapy for Non-
Brainstem High-Grade Glioma (ACNS0126)
Sequential study design
Temozolomide qd w/RT, 5d schedule p-RT - done

Natural history control (CCG-945 centrally
reviewed cohort)
100 pts each, 12-18 months accrual
EFS endpoint
Accrued at twice rate projected
Preliminary results available
Temozolomide + anti-angiogenic/signaling
inhibitor/other chemotherapeutic agent

21
One year (GBM)
945
(53)
126
(51)
p-value Stupp
(287)
EFS 32% 33% .47 27%
OS 60% 64% .33 61%
22
Differences in MGMT Expression are
Noted Among Childhood Malignant
Gliomas and Correlate with Promoter
Methylation
2
1
3
4
23
Overall Survival for HGG by MGMT
0.00
0.25
0.50
0.75
1.00
0.0 0.5 1.0 1.5 2.0 2.5 3.0
Years from study entry
P
r
o
b
a
b
i
l
i
t
y
No overexpression of MGMT (n=48)
Overexpression of MGMT (n=22)
p=0.032
24
Builds upon ADVL0011
(CCNU/temozolomide) (1CR, 1 near CR, 2 PR,
3 MR among 27 pts during induction
MTD 90 mg/m
2
CCNU and 160 mg/m
2
x 5 TMD
q6wk
ACNS0423, opened 3/21/05 has accrued 58
pts
A third study (ACNS0622) is under
development (TMZ/irinotecan)
Combined Chemoradiotherapy for Non-
Brainstem High-Grade Glioma (ACNS0423)
25
Management of Germinomas
(ACNS 0232) Approved by CTEP/CIRB
Endpoints: EFS, QOL, Neuropsych
Biopsy Confirmation
- Markers
Std RT (45Gy)
21Gy Whole ventricular
24 Gy boost to 1
o
site
(30Gy CSR/15Gy 1
o
for disseminated)
< CR
40.5 Gy to 1
o
site
(24 Gy CSR/16.5 Gy 1
o
for disseminated)
CR
30 Gy to 1
o
site
(21Gy CSR/9 Gy 1
o
for disseminated)
Chemotherapy
(Carbo/etoposide)
26
Management Paradigm for
NGGCTs (ACNS0122)
Tissue Diagnosis
(Open/Stereo Bx)
+ Markers
Induction Chemo
Carbo/VP alt with
Ifos/VP x 3
CR
(60%)
< CR
(40%)
RT
36 Gy CS Axis
54 Gy Tumor Bed
PBSC Harvest
High Dose
Chemo
Thiotepa/VP16
Second Look
Surgery
Activation 1/04
46 pts accrued
27
Ependymoma Management Schema
ACNS0121 (Opened 8/25/03)
Ependymoma
Central Pathology Review
Observation
Extent of Resection: GTR 1
Differentiated Histology
Supratentorial
Extent of Resection: STR
Any Histology
Any Location
Chemotherapy
Carboplatin/Vincristine
Cyclophosphamide/Etoposide
Duration: 7 weeks
Response Evaluation
(PD/SD/PR/CR)
Conformal Radiation Therapy
Total Dose: 59.4 Gy
Clinical Target Volume: 1.0 cm
Unresectable
Conformal Radiation Therapy
Total Dose: 59.4 Gy
Clinical Target Volume: 1.0 cm
Second Surgery
Surgery Endpoint 1: Resectability
Surgery Endpoint 2: Morbidity
Resectable
Extent of Resection: NTR/GTR 2
Any Histology
Any Location
Extent of Resection: GTR 1
Anaplastic Histology Supratentorial
Any Histology Infratentorial
Conformal Radiation Therapy
Total Dose: 59.4 Gy
Clinical Target Volume: 1.0 cm
Novel Features
1) Observation arm
2) Histo-based stratification
3) Chemo to increase rate of
GTR via 2nd-look surgery
4) Group-wide conformal RT
(270 pts accrued, twice
projected rate 5/62/76/127)
28
CCG-99703: Phase I/II Study of Intensive
Consolidation Chemo with PBSC Support
Infant Brain Tumors
Completed: Results Pending
Surgery
Induction Chemotherapy
(9921 Regimen A)
PBSC harvesting
Consolidation
CBDCA/Thio/VCR x 3 courses
29
Event-Free Survival
0.00
0.25
0.50
0.75
1.00
0 1 2 3 4 5 6 7 8
Years from study entry
P
r
o
b
a
b
i
l
i
t
y
CCG-99703 (n=92)
CCG-9921 (n=284)
Logrank p=0.025
Event-Free Survival 99703 v 9921
01/16/06
30
0%
20%
40%
60%
80%
100%
0 1 2 3 4 5 6
Years Post Onstudy
S
u
r
v
i
v
a
l
Rhabdoid (N=16)
Non-Rhabdoid PNET (N=94)
CCG-9921
p=0.02
BIOLOGICAL STRATIFICATION OF INFANT
TUMORS: AT/RTs are prognostically distinct
from PNETs and warrant distinct therapy
31
Histologic
diagnosis:
PNET
FISH:
Deletion 22
INI1 mutation analysis:
Single base pair change
Molecular Evaluation (FISH and Mutation
Analysis) Will Be Included for Stratification on
All Infant Malignant Tumor Studies
Biegel et al. Cancer Res 59: 74, 1999; Cancer Res 62: 328, 2002
32
Management of M0 Infant
Medulloblastomas (P9934)
Resection
Staging
8-36 months
Induction
Chemotherapy
4 4-wk cycles
Focal conformal RT
(Age & response-adjusted)
Maintenance
Chemotherapy
Second
Surgery
Endpoints:
Survival vs. P8633/9233
Neuropsych and endocrine outcome
Safety of 2nd-look surgery
Separate studies for M+
medullo (ACNS0334 (in queue
to open)) and AT/RT
(ACNS0333 (Protocol to
CTEP ))
SPECIMEN SUBMISSION
MANDATORY
33
Biologically based concepts for high-
risk/refractory malignant brain tumors
Examples:
Disruption of growth factor-mediated signal
transduction
R115777 (ACNS0226) - 97
Tarceva (ADVL0214) - 46
Cilengitide (ACNS0621) in development
Tarceva/Avastin (ADVL0526) in development
Induction of maturation (e.g., 13-cis-RA)
medullo (ACNS0332) in queue to open