Transcript Document 7476272

COG CNS Committee
2003-2007
Ian Pollack
1
Scientific Goals
• 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.
2
CNS Committee Cross-Study
Therapeutic Hypotheses
Germ
Cell
Epend
ymoma
LowGrade
Glioma
Medullo
PNET
Infant
Tumors
A
A99996611
ACNS0331
C
CC
CG
G-9999770033
A
AC
CN
NS
S-- A
AC
CN
NS
S-00223322
00442211
A
A99995522
Optimize RT
ACNS0331
Delivery
P
P99993344
A
AC
CN
NS
S-00112211
A
AC
CN
NS
S-00222211
Optimize
Chemo to
Reduce
Sequelae
HighGrade
Glioma
C
CC
CG
G--9999770011
Chemo-RT
A
AC
CN
NS
S-00112266
AC
CN
NS
S00333333
A
AC
CN
NS
S00333322 A
P
PO
OG
G--99663311
Intensifying
C
CC
CG
G--9999770022
Chemo
C
A
CC
CG
G-AC
CN
NS
S-- A
AC
CN
NS
S-9999770033
00112222
00112211
A
AC
CN
NS
S00333344
A
AC
CN
NS
S-00222233
Brainstem
Glioma
C
CC
CG
G--99771122
C
CC
CG
G--99880022
P
O
G
POG--99883366
A
AC
CN
NS
S00112266
A
AC
CN
NS
S00222222
A
AC
CN
NS
S00222244
A
AD
DV
VLL00001111
ACNS0423
A
AC
CN
NS
S00223311
3
Cooperative Group Scientific
Accomplishments
• 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.
4
Reduced Dose Radiotherapy Is Feasible in
Standard-Risk Medulloblastomas If
Combined with Adjuvant Chemotherapy
POG-8631/CCG-923 (Standard
Dose XRT Alone , N=42)
CCG-9892 (Reduced Dose
XRT+ Chemo , N=65)
100%
Survival
80%
60%
POG-8631/CCG-923 (Reduced
Dose XRT Alone , N=46)
40%
20%
0%
0
2
4
6
8
10
12
Years Post Onstudy
Packer et al. JCO 17: 2127, 1999; Thomas et al. JCO 18: 3004, 2000
5
Amount of Residual Disease Is
Associated with Outcome in
Children with High-Grade Glioma
Event-Free Survival
100%
80%
60%
>90% Resection (N=66)
40%
20%
<90% Resection (N=101)
p=0.002
0%
0
2
4
6
8
Years Post Onstudy
CCG-945
Wisoff et al., J Neurosurg 89: 52, 1998
10
12
6
Scientific Accomplishments
• 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.
7
Management of Average-Risk
Medulloblastomas
1) Post fossa location
2) M0
3) < 1.5 cm2 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
8
A9961 Progression-Free Survival from Study Entry
Percent Progression-Free
RegA
RegB
100%
86% +/- 2.5%
90%
80%
84% +/- 3%
70%
60%
p=0.49
50%
0
1
2
3
4
5
6
7
Time (Years)
9
Accuracy of Staging Strongly Influences
Effectiveness of Reduced Dose Therapy
10
Overall Survival for A9961 by Anaplasia
1.00
No Anaplasia (n=300)
Anaplasia (n=55)
Probability
0.75
0.50
0.25
p=0.04
0.00
0
2
4
6
8
10
Years from study entry
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).
11
RT Dose Reduction for Average-Risk
Medulloblastoma (<8 yrs)
1800 cGy CSRT
with VCR
2340 cGy CSRT
Conformal tumor
bed boost (5400 cGy)
Conformal post fossa
boost (5400 cGy)
with VCR
ACNS0331
Activation 4/04
135 pts accrued
CCNU, CPDD, VCR
alt. with CPM, VCR
12
RT Dose Reduction for Average-Risk
Medulloblastoma (>8 yrs)
Both strata include prospective
cGy CSRT analysis,
Trk C and2340
erbB2/4
w/ VCR
expression profiling, and
histological review to identify ~
Conformal
fossa
Conformal
tumor
20%
of tumors
that post
are
not
boost (5400 cGy)
bed boost (5400 cGy)
biologically “average risk” –
ACNS0331
SPECIMEN
SUBMISSION
CCNU, CPDD, VCR
Activation 4/04
STRONGLY
ENCOURAGED.
alt. with
CPM, VCR
13
High-Risk PNET
Radiosensitization Study
Carbo
VCR
Carbo
VCR
Carbo
VCR
Craniospinal (36 Gy) XRT
week
1
2
CPM
VCR
(CCG-99701)
Phase I MTD established
Phase II completed 12/04
3
(Carbo)
VCR
(Carbo)
VCR
(Carbo)
VCR
Boost (18 Gy) XRT
4
ACNS0332
Protocol approved by
CTEP/PCIRB
5
6
CDDP
CPM
VCR
14
99701 Overall Survival for Metastatic MB
1.00
n=58
Probability
0.75
3 yr OS: 81 + 5%
0.50
2 3 yr OS: 81 ± 5%
0.25
0.00
0
1
2
3
4
5
6
7
Years from study entry
15
Overall Survival by Anaplasia
1.00
Probability
No Anaplasia (n=39)
3 yr OS is 89 ± 5%
3 yr OS: 89 ± 5%
0.75
Anaplasia (n=19)
0.50
3 yr OS is 64 ±12%
3 yr OS:
64 ± 12%
0.25
p=0.008
0.00
0
1
2
3
4
5
6
7
Years from study entry
16
Management of Low-Grade Glioma
Progressive Disease
High-risk, Unresectable
< 10 years
New Studies
A9952
• Carbo/VCR/TMZ pilot
– ACNS0223 (protocol
NF1
opened 7/04;
recently opened
groupwide - 32 pts)
Non-NF1
• Conformal RT pilot
Carboplatin
VCR
N=250
randomized, 350 total
6-thioguanine
Procarbazine
CCNU
VCR
– ACNS0221
(recently open)
17
Intensive Chemotherapy Followed by
Irradiation Fails to Alter Prognosis in Newly
Diagnosed Brainstem Glioma
100%
90%
Uniformly poor results of all
recent studies provide for reliable
natural history control data.
Event-Free Survival
80%
70%
60%
50%
40%
Regimen A (N=32)
Regimen B (N=31)
30%
A
20%
A
10%
0%
0
1
CCG-9941
Jennings et al. JCO, 2002
2
3
4
YEARS
18
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)
19
Combined Chemoradiotherapy for NonBrainstem High-Grade Glioma (ACNS0126)
• Sequential study design
– Temozolomide qd w/RT, 5d schedule p-RT - done
– Temozolomide + anti-angiogenic/signaling
inhibitor/other chemotherapeutic agent
• 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
20
One year (GBM)
126
(51)
33%
p-value
Stupp
(287)
EFS
945
(53)
32%
.47
27%
OS
60%
64%
.33
61%
21
Differences in MGMT Expression are
Noted Among Childhood Malignant
Gliomas and Correlate with Promoter
Methylation
1
2
3
4
22
Overall Survival for HGG by MGMT
1.00
Probability
0.75
No overexpression of MGMT (n=48)
0.50
0.25
Overexpression of MGMT (n=22)
p=0.032
0.00
0.0
0.5
1.0
1.5
2.0
2.5
3.0
Years from study entry
23
Combined Chemoradiotherapy for NonBrainstem High-Grade Glioma (ACNS0423)
• Builds upon ADVL0011
(CCNU/temozolomide) (1CR, 1 near CR, 2 PR,
3 MR among 27 pts during induction
• MTD 90 mg/m2 CCNU and 160 mg/m2 x 5 TMD
q6wk
• ACNS0423, opened 3/21/05 – has accrued 58
pts
• A third study (ACNS0622) is under
development (TMZ/irinotecan)
24
Management of Germinomas
(ACNS 0232) – Approved by CTEP/CIRB
Biopsy Confirmation
- Markers
Std RT (45Gy)
Chemotherapy
21Gy Whole ventricular
24 Gy boost to 1o site
(Carbo/etoposide)
(30Gy CSR/15Gy 1o for disseminated)
CR
< CR
30 Gy to 1o site
40.5 Gy to 1o site
(21Gy CSR/9 Gy 1o for disseminated)
(24 Gy CSR/16.5 Gy 1o for disseminated)
Endpoints: EFS, QOL, Neuropsych
25
Management Paradigm for
NGGCTs (ACNS0122)
Tissue Diagnosis
Induction Chemo
(Open/Stereo Bx)
Carbo/VP alt with
Ifos/VP x 3
+ Markers
PBSC Harvest
High Dose
Chemo
Thiotepa/VP16
< CR
CR
(40%)
(60%)
Second Look
Surgery
RT
36 Gy CS Axis
54 Gy Tumor Bed
Activation 1/04
46 pts accrued
26
Ependymoma Management Schema
ACNS0121 (Opened 8/25/03)
Ependymoma
Central Pathology Review
Extent of Resection: GTR 1
Differentiated Histology
Supratentorial
Extent of Resection: STR
Any Histology
Any Location
Observation
Chemotherapy
Carboplatin/Vincristine
Cyclophosphamide/Etoposide
Duration: 7 weeks
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
Response Evaluation
(PD/SD/PR/CR)
Unresectable
Resectable
Conformal Radiation Therapy
Total Dose: 59.4 Gy
Clinical Target Volume: 1.0 cm
Second Surgery
Surgery Endpoint 1: Resectability
Surgery Endpoint 2: Morbidity
Conformal Radiation Therapy
Total Dose: 59.4 Gy
Clinical Target Volume: 1.0 cm
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) 27
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
28
Event-Free Survival 99703 v 9921
Event-Free Survival
1.00
Probability
0.75
CCG-99703 (n=92)
0.50
CCG-9921 (n=284)
0.25
Logrank p=0.025
0.00
0
1
2
3
4
5
6
7
8
Years from study entry
01/16/06
29
BIOLOGICAL STRATIFICATION OF INFANT
TUMORS: AT/RTs are prognostically distinct
from PNETs and warrant distinct therapy
100%
Survival
80%
60%
Non-Rhabdoid PNET (N=94)
40%
Rhabdoid (N=16)
20%
p=0.02
0%
0
CCG-9921
1
2
3
4
Years Post Onstudy
5
6
30
Molecular Evaluation (FISH and Mutation
Analysis) Will Be Included for Stratification on
All Infant Malignant Tumor Studies
Histologic
diagnosis:
PNET
FISH:
Deletion 22
INI1 mutation analysis:
Single base pair change
Biegel et al. Cancer Res 59: 74, 1999; Cancer Res 62: 328, 2002
31
Management of M0 Infant
Medulloblastomas (P9934)
Induction
Separate studies
forSecond
M+
Chemotherapy
Surgery
8-36
months
4
4-wk
cycles
medullo (ACNS0334 (in queue
to open)) and AT/RT
Maintenance
Focal conformal RT
(ACNS0333
(Protocol
to
(Age & response-adjusted)
Chemotherapy
CTEP ))
Endpoints:
SPECIMEN
Survival vs. P8633/9233 SUBMISSION
Neuropsych and endocrine outcome
Safety of 2nd-look
surgery
MANDATORY
Resection
Staging
32
Biologically based concepts for highrisk/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
33