# Presentation: 531385

## COG CNS Committee

**2003-2007**
**Ian Pollack**

## 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.

**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**

## CNS Committee Cross-Study Therapeutic Hypotheses

**CNS Committee Cross-Study Therapeutic Hypotheses**

## 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.

**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**

## Reduced Dose Radiotherapy Is Feasible in Standard-Risk Medulloblastomas If Combined with Adjuvant Chemotherapy

**Reduced Dose Radiotherapy Is Feasible in Standard-Risk Medulloblastomas If Combined with Adjuvant Chemotherapy**

## Amount of Residual Disease Is Associated with Outcome in Children with High-Grade Glioma

**Amount of Residual Disease Is Associated with Outcome in Children with High-Grade Glioma**

**CCG-945**
**Wisoff et al., J Neurosurg 89: 52, 1998**

## 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.

**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**

## Management of Average-Risk Medulloblastomas

**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**

## 50%

**A9961 Progression-Free Survival from Study Entry**

- 60%

- 70%

- 80%

- 90%

- 100%

- 0

- 1

- 2

- 3

- 4

- 5

- 6

- 7

**Time (Years)                                **

**Percent Progression-Free**

- RegA

- RegB

- p=0.49

- 86% +/- 2.5%

- 84% +/- 3%

## Accuracy of Staging Strongly Influences Effectiveness of Reduced Dose Therapy

**Accuracy of Staging Strongly Influences Effectiveness of Reduced Dose Therapy**

## 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).

## 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**

## RT Dose Reduction for Average-Risk Medulloblastoma (>8 yrs)

**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.**

## 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**

**(CCG-99701)**
**Phase I MTD established**
**Phase II completed 12/04**

- ACNS0332
- Protocol approved by
- CTEP/PCIRB

## 3 yr OS: 81 ± 5%

**3 yr OS:  81 **_**+ **_**5%**

- 2

## Overall Survival by Anaplasia

**3 yr OS is 64 ****±12%**

**3 yr OS: 89 ****± 5%**

**3 yr OS: 64 ****± 12%**

**Overall Survival by Anaplasia**

## Management of Low-Grade Glioma

**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)**

## Intensive Chemotherapy Followed by Irradiation Fails to Alter Prognosis in Newly Diagnosed Brainstem Glioma

**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.**

## 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)**

## 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**

## One year (GBM)

|  | 945 
(53) | 126 
(51) | p-value | Stupp (287) |
| --- | --- | --- | --- | --- |
| EFS | 32% | 33% | .47 | 27% |
| OS | 60% | 64% | .33 | 61% |

## Differences in MGMT Expression are Noted Among Childhood Malignant Gliomas and Correlate with Promoter Methylation

**Differences in MGMT Expression are Noted Among Childhood Malignant Gliomas and Correlate with Promoter Methylation**

**2**

**1**

**3**

**4**

## Slide 23

## 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)

**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)**

## 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 1o site
*(30Gy CSR/15Gy 1**o** for disseminated)*

**< CR**
- 40.5 Gy to 1o site
*(24 Gy CSR/16.5 Gy 1**o** for disseminated)*

**CR**** **
- 30 Gy to 1o site
*(21Gy CSR/9 Gy 1**o** for disseminated)*

**Chemotherapy**
- (Carbo/etoposide)

## 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**

## Ependymoma Management SchemaACNS0121 (Opened 8/25/03)

- 	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)**

## 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**

## Event-Free Survival 99703 v 9921

- 01/16/06

## BIOLOGICAL STRATIFICATION OF INFANT TUMORS:  AT/RTs are prognostically distinct from PNETs and warrant distinct therapy

**BIOLOGICAL STRATIFICATION OF INFANT TUMORS:  ****AT/RTs are prognostically distinct from PNETs and warrant distinct therapy**

## 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**

**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**

## 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**

## 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**