Phase III Randomized Trial of Post-Radiation Chemotherapy in Patients With Newly Diagnosed Ependymoma Ages 1 to 21 Years
Phase: PHASE3
Conditions: Anaplastic Ependymoma, Brain Ependymoma, Cellular Ependymoma, Clear Cell Ependymoma, Ependymoma, Papillary Ependymoma
Sponsor: Children's Oncology Group

 
 
ACNS0831 
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Page 1 
 
Activated: 
March 29, 2010 
Version Date: 
2/27/2020 
Closed: 
May 29, 2019 
Amendment #: 
3 
 
 
 
 
 
 
CHILDREN’S ONCOLOGY GROUP 
 
ACNS0831 
 
Phase III Randomized Trial of Post-Radiation Chemotherapy in Patients with 
Newly Diagnosed Ependymoma Ages 1 to 21 years 
 
 
 
A Groupwide Phase III Study 
 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, AND SHOULD NOT BE COPIED, REDISTRIBUTED OR USED 
FOR ANY OTHER PURPOSE. MEDICAL AND SCIENTIFIC INFORMATION CONTAINED WITHIN THIS PROTOCOL IS 
NOT INCLUDED TO AUTHORIZE OR FACILITATE THE PRACTICE OF MEDICINE BY ANY PERSON OR ENTITY. 
RESEARCH MEANS A SYSTEMATIC INVESTIGATION, INCLUDING RESEARCH DEVELOPMENT, TESTING AND 
EVALUATION, DESIGNED TO DEVELOP OR CONTRIBUTE TO GENERALIZABLE KNOWLEDGE. THIS PROTOCOL IS 
THE RESEARCH PLAN DEVELOPED BY THE CHILDREN’S ONCOLOGY GROUP TO INVESTIGATE A PARTICULAR 
STUDY QUESTION OR SET OF STUDY QUESTIONS AND SHOULD NOT BE USED TO DIRECT THE PRACTICE OF 
MEDICINE BY ANY PERSON OR TO PROVIDE INDIVIDUALIZED MEDICAL CARE, TREATMENT, OR ADVICE TO ANY 
PATIENT OR STUDY SUBJECT. THE PROCEDURES IN THIS PROTOCOL ARE INTENDED ONLY FOR USE BY CLINICAL 
ONCOLOGISTS IN CAREFULLY STRUCTURED SETTINGS, AND MAY NOT PROVE TO BE MORE EFFECTIVE THAN 
STANDARD TREATMENT. ANY PERSON WHO REQUIRES MEDICAL CARE IS URGED TO CONSULT WITH HIS OR HER 
PERSONAL PHYSICIAN OR TREATING PHYSICIAN OR VISIT THE NEAREST LOCAL HOSPITAL OR HEALTHCARE 
INSTITUTION. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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CONTACT INFORMATION 
 
To submit site registration 
documents: 
For patient enrollments: 
Submit study data 
Regulatory documentation must 
be submitted to the CTSU via 
the Regulatory Submission 
Portal. 
Regulatory Submission Portal: 
(Sign in at www.ctsu.org,            
and select the Regulatory 
Submission sub-tab under the 
Regulatory tab.)  
 
Institutions with patients waiting 
that are unable to use the Portal 
should alert the CTSU 
Regulatory Office immediately 
at 1-866-651-2878 to receive 
further instruction and support. 
 
Contact the CTSU Regulatory 
Help Desk at 1-866-651-2878 
for regulatory assistance. 
Please refer to the patient 
enrollment section of the 
protocol for instructions on 
using the Enrollment 
application in the eRDE 
system. If you have problems 
with enrollment, refer to online 
help in the Applications area of 
the COG website. 
 
Data collection for this study 
will be done exclusively through 
the eRDE system. Please see the 
Data Submission Schedule in the 
CRF packet for further 
instructions.  
 
 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org. 
Access to the CTSU members’ website is managed through the Cancer Therapy and Evaluation 
Program - Identity and Access Management (CTEP-IAM) registration system and requires user log on 
with CTEP-IAM username and password. Permission to view and download this protocol and its 
supporting documents is restricted and is based on person and site roster assignment housed in the 
CTSU RSS.  
For clinical questions (i.e., patient eligibility or treatment-related) contact the Study PI of the Lead 
Protocol Organization. 
For non-clinical questions (i.e., unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
The CTSU Website is located at https://www.ctsu.org. 

 
 
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TABLE OF CONTENTS 
 
SECTION 
PAGE 
TABLE OF CONTENTS 
3 
STUDY COMMITTEE 
6 
ABSTRACT 
9 
ACNS0831 EXPERIMENTAL DESIGN SCHEMA 
10 
SCHEMA FOR INDUCTION (FOR PATIENTS WITH STR) 
11 
SCHEMA FOR RANDOMIZATION (FOR PATIENTS WITH GTR 1, 2 OR NTR) 
12 
SCHEMA FOR OBSERVATION (FOR PATIENTS WITH GTR1 CLASSIC HISTOLOGY ST 
LOCATION) 
13 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
14 
1.1 
Primary Objectives 
14 
2.0 
BACKGROUND 
15 
2.1 
Rationale for selected approach and trial design 
15 
2.2 
Rationale for Correlative Biological Studies 
18 
2.3 
Rationale for Neuropsychologic Studies 
20 
2.4 
Gender and Race Differences 
21 
3.0 
STUDY ENROLLMENT AND PATIENT ELIGIBILITY 
21 
3.1 
Study Enrollment 
21 
3.2 
Patient Eligibility Criteria 
25 
4.0 
TREATMENT PLAN 
27 
4.1 
Surgery and Extent of Resection Guidelines 
28 
4.2 
Treatment Plan by Extent of Resection, Histology, and Tumor Location at Time of 
Enrollment 
28 
4.3  
Randomization or Assignment for STR Patients Receiving Induction Chemotherapy 
29 
4.4 
Concomitant Therapy Restrictions during Treatment 
30 
4.5 
Induction Chemotherapy 
30 
4.6 
Maintenance Chemotherapy 
37 
5.0 
DOSE MODIFICATIONS FOR TOXICITIES 
44 
5.1 
Dose Modifications during Induction Chemotherapy 
44 
5.2 
Dose Modifications during Maintenance Chemotherapy 
46 
6.0 
DRUG INFORMATION 
49 
7.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
49 
7.1 
Required Clinical, Laboratory and Disease Evaluations for STR (Incomplete Resection) 
Patients 
50 
7.2 
Required Clinical, Laboratory and Disease Evaluations for Patients Randomized to 
Radiation Therapy followed by Maintenance Chemotherapy 
52 
7.3  
Required Clinical, Laboratory and Disease Evaluations for Patients Randomized to 
Receive Radiation Therapy followed by Observation 
53 
7.4 
Required Observations For Supratentorial Classic Ependymoma GTR1 Patients 
(Observation) 
54 
7.5 
Optional Studies 
55 
7.6 
Follow-up 
56 

 
 
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8.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA 
57 
8.1 
Criteria for Removal from Protocol Therapy 
57 
8.2 
Off Study Criteria 
57 
9.0 
STATISTICAL CONSIDERATIONS 
57 
9.1 
Study Design 
57 
9.2 
Patient Accrual and Expected Duration of Trial 
58 
9.3 
Statistical Analysis Methods 
59 
9.4 
Correlative Biology Studies 
64 
9.5 
Gender and Minority Accrual Estimates 
65 
10.0 
EVALUATION CRITERIA 
66 
10.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
66 
10.2 
Methodology to Determine Tumor Measurement 
66 
10.3 
Selection of Target and Non-Target Lesions 
68 
10.4 
Response Criteria for Target Lesions 
68 
10.5 
Response Criteria for Non-target Lesions 
69 
11.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
69 
11.1 
Purpose 
69 
11.2 
Determination of Reporting Requirements 
69 
11.3 
Reporting of Adverse Events for Commercial Agents – via CTEP AERS abbreviated 
pathway 
70 
11.4 
Routine Adverse Event Reporting 
71 
12.0 
RECORDS AND REPORTING 
71 
12.1 
CDUS 
71 
13.0 
NEUROSURGICAL GUIDELINES 
72 
13.1 
General 
72 
13.2 
Imaging Confirmation of Extent of Resection 
72 
13.3 
Peri-operative Corticosteroids 
72 
13.4 
Initial Surgery 
72 
13.5 
Second Operation 
73 
13.6 
Extent of Resection Definition and Treatment 
74 
14.0 
NEUROPATHOLOGY GUIDELINES AND CENTRAL PATHOLOGY REVIEW 
SPECIMEN REQUIREMENTS 
74 
14.1 
Histological Grading 
74 
14.2 
Central Pathology Review Required for All Patients 
74 
15.0 
OPTIONAL BIOLOGY STUDIES 
76 
15.1 
Biology Specimen Requirements 
76 
15.2 
Special Studies Performed on Samples 
78 
15.3 
Priority List of Special Biology Studies 
78 
15.4 
Sample Processing at the BPC 
78 
15.5 
Methodology 
79 
15.6 
Future Studies with Remaining Banked Biospecimens 
80 
16.0 
NEUROPSYCHOLOGICAL FUNCTION STUDY 
80 
17.0 
NEUROIMAGING STUDIES REQUIRED AND GUIDELINES FOR OBTAINING 
81 
17.1 
Rapid Central Review 
81 
17.2 
Neuroimaging 
81 

 
 
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17.3 
MR Brain With and Without Contrast 
81 
17.4 
Tumor Measurements 
82 
17.5 
MR Spine Imaging 
82 
17.6 
Central Review 
83 
17.7 
Address Information 
84 
18.0 
RADIATION THERAPY GUIDELINES 
84 
18.0.1 General Guidelines 
85 
18.0.2 Treatment Planning Specifics 
85 
18.0.3 Credentialing Requirements 
85 
18.0.4 Guidelines and Requirements for the Use of IMRT 
86 
18.0.5 Guidelines and Requirements for the Use of Proton Beam Therapy 
86 
18.0.6 Rationale for Limiting Radiation Dose and Volume to the Brainstem Using Proton 
Therapy 
86 
18.1 
Indications for Radiation Therapy 
90 
18.2 
Timing 
90 
18.3 
Emergency Irradiation 
90 
18.4 
Equipment and Methods of Delivery and Verification 
91 
18.5 
Target Volumes 
91 
18.6 
Target Dose 
95 
18.7 
Treatment Technique 
97 
18.8 
Organs at Risk 
98 
18.9 
Dose Calculations and Reporting 
100 
18.10 
Quality Assurance Documentation 
101 
18.11 
Definitions of Deviations in Protocol Performance 
103 
18.12 
Patterns of Failure Evaluation 
103 
APPENDIX I: YOUTH INFORMATION SHEETS 
105 
APPENDIX II: TANNER STAGING CRITERIA 
113 
APPENDIX III:  CTEP AND CTSU REGISTRATION PROCEDURES 
114 
APPENDIX IV:  POSSIBLE DRUG INTERACTIONS 
117 
REFERENCES 
121 

 
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AGENT 
NSC# 
IND # 
Carboplatin 
241240 
Exempt 
Cisplatin 
119875 
Exempt 
Cyclophosphamide 
026271 
Exempt 
Etoposide 
141540 
Exempt 
Filgrastim (G-
CSF) 
614629 
Exempt 
Mesna 
113891 
Exempt 
Vincristine 
067574 
Exempt 
 
 
 
 
 
 
SEE SECTION 14.0 AND SECTION 15.0 FOR SPECIMEN SHIPPING ADDRESSES 
 
 

 
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The Children's Oncology Group has received a Certificate of Confidentiality from the federal government, 
which will help us protect the privacy of our research subjects. The Certificate protects against the 
involuntary release of information about your subjects collected during the course of our covered studies. 
The researchers involved in the studies cannot be forced to disclose the identity or any information collected 
in the study in any legal proceedings at the federal, state, or local level, regardless of whether they are 
criminal, administrative, or legislative proceedings. However, the subject or the researcher may choose to 
voluntarily disclose the protected information under certain circumstances. For example, if the subject or 
his/her guardian requests the release of information in writing, the Certificate does not protect against that 
voluntary disclosure. Furthermore, federal agencies may review our records under limited circumstances, 
such as a DHHS request for information for an audit or program evaluation or an FDA request under the 
Food, Drug and Cosmetics Act. The Certificate of Confidentiality will not protect against mandatory 
disclosure by the researchers of information on suspected child abuse, reportable communicable diseases, 
and/or possible threat of harm to self or others. 
 
ABSTRACT 
 
Ependymoma accounts for 8-10% of all childhood CNS tumors with fewer than 170 new cases diagnosed 
in the United States each year in children and adults less than age 25 years.1 The mean age at diagnosis 
ranges from 51-71 months,2-5 and 25 to 40% are diagnosed in children less than 3 years of age.6 Survival 
statistics for ependymoma are generally disappointing with 5-year survival and progression-free survival 
estimates of 50-64% and 23-45%, respectively2,4,7-9 Recurrences are typically local with a median time to 
recurrence of 13-25 months 2-4,7,8,10, however, 20% of failures have isolated distant recurrence.11 Late 
recurrences are not uncommon. The standard of care for ependymoma is maximal surgical resection 
compatible with an acceptable neurologic outcome followed by post-operative radiation therapy directed at 
the primary site. The application of immediate post-operative irradiation for children younger than 3 years 
of age remains controversial, however, the feasibility and efficacy of this approach is currently being 
examined prospectively in ACNS0121 for children as young as 12 months of age.  Although multi-agent 
chemotherapy has been given in previous studies in an effort to delay or avoid irradiation, the small size of 
such studies and their non-randomized design has precluded definitive conclusions regarding the role for 
chemotherapy in ependymoma.12-14 Data from the last CCG ependymoma study, CCG-9942, presented at 
ISPNO in June 2004 (manuscript published in September 2012)15 argues that chemotherapy may play an 
important role in ependymoma. This study showed that patients with incomplete resections who received 
pre-radiation chemotherapy had a very similar outcome (55% 5-year event free survival [EFS]) compared 
to those who underwent a complete resection initially followed by immediate post-operative local radiation 
(58% 5-year EFS). A significant concern regarding pre-radiation chemotherapy is the risk of progression 
prior to radiation, which occurred in 15% of patients on CCG-9942. Other “baby brain” studies have also 
shown that a delay in radiation results in unacceptable progression rates. However, several studies have 
also shown good response rates to chemotherapy. Since surgical resection remains a critical prognostic 
factor, ACNS0121 addressed the question of whether a short course of chemotherapy given to those with 
incompletely resected tumors would increase the number of patients who can achieve a complete resection 
at second surgery prior to receiving conformal radiation (cRT). This should theoretically translate to an 
improved outcome in that subset, but those data have not yet been released. The current study proposes to 
answer the question of whether the administration of maintenance chemotherapy following radiation will 
improve event free and overall survival or whether it will only result in additional toxicity. Neurologic, 
neuropsychological and endocrine long-term sequelae of surgery, cRT, and maintenance chemotherapy will 
be assessed. This study will use a comprehensive genetic approach in order to create a molecular 
classification for ependymoma and to identify the genetic alterations underlying the biological and clinical 
behavior of various subsets of this tumor. 
 

 
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ACNS0831 EXPERIMENTAL DESIGN SCHEMA  
 
IMPORTANT NOTES: 
 
* Rapid Central Pathology Review will be performed on all Supratentorial patients. See Section 14.2.1 for details.  
 
Guidelines for extent of resection can be found in Section 4.1. 
- 
All patients with a sub total resection (STR), regardless of tumor location and histology, will receive Induction.  
- 
All patients with an infratentorial tumor GTR 1, GTR 2, or NTR will be Randomized. 
- 
All other GTR 1, GTR 2, and near total resection (NTR) supratentorial patients will be Randomized.  
- 
Only Supratentorial patients who have classic histology confirmed by Rapid Central Pathology Review and gross total 
resection 1 (GTR 1) will be assigned to Observation.  
 
≠ Under the condition that the extent of resection is indeterminate because the surgeon cannot unequivocally report that 
microscopic disease is not present OR the information necessary to determine extent of resection at the time of the operation is 
not available, the patient will be randomized to either (a) conformal radiation therapy (cRT) and maintenance chemotherapy 
OR (b) cRT and observation. 
Surgery 
Study Entry 
Central Pathology Review 
Rapid Central Pathology Review for Supratentorial Primary Tumor Location* 
Extent of Resection: STR 
 
Any histologic grade, 
Any location 
Induction Chemotherapy (7 weeks) 
Cycle A: VCR, CARBO, CPM 
Cycle B: VCR, CARBO, ETOP 
Response Evaluation 
by Rapid Central Imaging 
Review 
Off Protocol 
Therapy 
Observation 
Second Surgery 
& Rapid Central 
Imaging Review 
Conformal RT 
CTV: 0.5 cm
Maintenance 
Chemotherapy  
(4 cycles) 
Extent of Resection:  
GTR1, GTR2, or NTR 
 
Anaplastic histology ST, 
Classic histology ST GTR 2/NTR, 
Any histologic grade Infratentorial 
Randomization 
Conformal RT≠ 
CTV: 0.5 cm 
Maintenance 
Chemotherapy  
(4 cycles) 
GTR1 
(ST/Classic) 
Extent of Resection: GTR1 
 
Classic histology ST 
Observation 
DPD 
CR 
(ST/Classic) 
SD/PR, 
LPD 
CR 
GTR/NTR 
STR 
Abbreviations: 
STR = Sub Total Resection 
GTR = Gross Total Resection 
NTR = Near Total Resection 
 
ST = Supratentorial 
 
VCR = Vincristine 
CARBO = Carboplatin 
CPM = Cyclophosphamide 
ETOP = Etoposide 
RT = Radiation Therapy 
CTV = Clinical Target Volume 
 
SD = Stable Disease 
DPD = Distant Progressive Disease 
LPD = Local Progressive Disease 
PR = Partial Response 
CR = Complete Response 

 
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SCHEMA FOR INDUCTION (For patients with STR)  
 
See abbreviations on Experimental Design Schema. 
 
 
 
 
 
 
 
 
SD, PR, or LPD 
Surgery 
Study Entry 
Central Pathology Review 
- Supratentorial Patients: Rapid Central Pathology Review (submit within 5 days of study entry) 
- Infratentorial Patients: Standard Central Review (submit within 10 days of study entry) 
Extent of Resection: STR 
Any histologic grade, 
Any location 
Induction Chemotherapy (7 weeks): 
Cycle A: VCR, CARBO, CPM 
Cycle B: VCR, CARBO, ETOP 
Response Evaluation by 
Rapid Central Imaging 
Review 
DPD 
Off Protocol 
Therapy 
CR 
CR (Supratentorial/Classic) ONLY 
Observation 
Second Surgery and 
Rapid Central Imaging 
Review 
Randomization 
Call Back 
GTR or NTR 
STR 
GTR1 (Supratentorial/Classic)  
ONLY  
Conformal Radiation Therapy 
Clinical Target Volume: 0.5 cm 
Maintenance Chemotherapy (4 cycles): 
Cycles 1-3: VCR, ETOP, CDDP, CPM 
Cycle 4: ETOP, CDDP, CPM 
Observation 
Conformal Radiation Therapy 
Clinical Target Volume: 0.5 cm 
Maintenance Chemotherapy (4 cycles): 
Cycles 1-3: VCR, ETOP, CDDP, CPM 
Cycle 4: ETOP, CDDP, CPM 

 
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SCHEMA FOR RANDOMIZATION (For patients with GTR 1, 2 or NTR) 
 
See Abbreviations on Experimental Design Schema. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
Surgery 
Study Entry 
Central Pathology Review 
- Supratentorial Patients: Rapid Central Pathology Review (submit within 5 days of study entry) 
- Infratentorial Patients: Standard Central Review (submit within 10 days of study entry) 
Extent of Resection: GTR1, GTR2, or NTR 
Supratentorial Anaplastic histology, 
Infratentorial any histology, 
Supratentorial Classic histology GTR2 and NTR 
Randomization 
Call Back 
Radiation Therapy 
Clinical Target Volume 0.5 cm 
Maintenance Chemotherapy (4 cycles): 
Cycles 1-3: VCR, ETOP, CDDP, CPM 
Cycle 4: ETOP, CDDP, CPM 
Observation 

 
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SCHEMA FOR OBSERVATION (For patients with GTR1 CLASSIC HISTOLOGY ST 
LOCATION) 
 
See Abbreviations on Experimental Design Schema. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
Surgery 
Study Entry 
Central Pathology Review 
Rapid Central Pathology Review for Supratentorial Patients 
Submit within 5 days of study entry 
Extent of Resection GTR1 
Classic histology 
Supratentorial location 
 
Observation 
 

 
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1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
 
1.1 
Primary Objectives 
 
To determine the event free survival (EFS) and overall survival (OS) of children with 
completely resected ependymoma treated with post-operative conformal radiation therapy 
(cRT) and then randomized to receive or not receive four cycles of post-radiation 
maintenance chemotherapy (vincristine, cisplatin, etoposide, and cyclophosphamide 
[VCEC]). 
 
1.2 
Exploratory Objectives 
 
1.2.1 
To estimate the EFS and OS of children with incompletely resected ependymoma 
who are unable to achieve a complete response (CR) by a) post-operative induction 
chemotherapy or by b) second surgery who will then be non-randomly assigned to 
cRT followed by four cycles of maintenance chemotherapy (VCEC). 
 
1.2.2 
To further evaluate the EFS and OS of children with supratentorial classic 
ependymoma who achieve a complete resection at first or second resection OR 
children who achieve a CR to short course induction chemotherapy following first 
surgery. 
 
1.2.3 
To evaluate whether the addition of maintenance chemotherapy post-radiation 
therapy contributes to neurobehavioral morbidity and reduced functional outcomes 
over time, compared to patients treated with radiation therapy followed by 
observation alone. 
 
1.2.4 
To examine differences in neurobehavioral outcomes and quality of life of children 
treated with proton beam radiation therapy compared to children treated with 
conventional radiation delivery techniques. 
 
1.2.5 
To evaluate biologic prognostic factors in childhood ependymoma by studying 
molecular 
groups 
as 
defined 
by 
DNA 
methylation 
profiling 
and 
immunohistochemistry, copy number variants to identify 1q gain in posterior fossa 
ependymomas, CDKN2A loss (homozygous deletion) in supratentorial 
ependymomas and specific genetic alterations such as RELA fusions, 
YAP1 fusions and the H3 K27M mutation on initial tumor samples and correlating 
these data with clinical outcome. 
 
1.2.5.1 To explore prognostic molecular signatures and genomic alterations in 
ependymomas by building upon the data derived from ACNS0121 to 
correlate biomarkers listed above with WHO grade, location, extent of 
resection, treatment, EFS and OS. 
 
 

 
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2.0 
BACKGROUND 
 
2.1 
Rationale for selected approach and trial design  
 
2.1.1 
Rationale for Surgery 
Surgical resection appears to be the most important prognostic factor for children 
with ependymomas.2-5,7-10,16,17 Patients with complete resection and radiation 
therapy have a 5-year survival estimate of 67-80% and a 5-year progression-free 
survival estimate of 51-75%, compared to a 5-year survival estimate of 22-47% 
and progression-free survival estimate of 0-26% for patients with incompletely 
resected tumors treated with radiation therapy. Even though complete resection is 
considered instrumental for long-term event-free and overall survival, historically, 
complete resection is achieved only for 42 to 62% of patients.4,5,7,9 Complete 
resection is more easily achieved for tumors in supratentorial locations and from 
the roof of the fourth ventricle; tumors in other locations, including those 
intimately associated with the lower cranial nerves, have more morbidity 
associated with aggressive attempts at resection. Despite the high rate of 
incomplete resection after an initial surgery, a few studies have reported the use of 
second look surgery for patients with residual disease.18,19 ACNS0121 addressed 
this issue, and was primarily concerned with whether second surgery would 
increase the surgical morbidity to an unacceptable level. Overall, surgical 
complications in patients on ACNS0121 were noted in 110 out of the 378 patients 
enrolled with 4 patients who experienced a complication at the time of second look 
surgery. On ACNS0121 there were 25 patients who had second look surgery after 
chemotherapy and 4 patients had a surgical complication. The complications 
included vocal cord weakness in one patient, right vocal cord paresis, and right 
facial paresis which was delayed in the second patient. The third patient had 
deficits noted in cranial nerves.6-8 The fourth patient experienced a 
pseudomenigocele post-operatively with vomiting. The ACNS0121 Study 
Committee does not think that this is an unreasonably high surgical complication 
rate and they would expect a similar surgical complication rate on ACNS0831. 
Additionally, there has been a more recent publication reporting the complete 
resection rate at initial surgery is approximately 70%, which is much higher than 
previously reported.20 
 
2.1.2 
Rationale for Conformal Radiation Therapy (cRT) 
Conformal radiation therapy (cRT) may be used to increase the dose to the primary 
site and at the same time decrease the side effects of treatment. Reducing the dose 
of radiation administered to normal tissue is a logical approach for treating 
childhood ependymoma, but requires systematic evaluation and planning, 
treatment-failure monitoring, and assessment of CNS effects. Merchant et al.21 
reported the preliminary results of a St. Jude Children’s Research Hospital study 
(RT-1) that treated 64 pediatric patients with localized ependymoma after July 
1997. This study used cRT with an anatomically defined clinical target volume 
margin of 1.0 cm surrounding the postoperative residual tumor and tumor bed. 
Only six failures occurred after a median follow-up period of 17 months (range: 3 
to 43 months). This group included very young children with a median age of 3.0 
years (range: 1.1 to 22.9 years). The majority of patients received a total dose of 
59.4 Gy. Longer follow-up of this study reveals that at a median follow-up of 38.2 
months, 20 out 88 patients have failed with a median time to progression of 14 

 
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months. The 3-year progression-free survival (PFS) was 74.7% (+/- 5.7%) for 
patients with gross total resection and cRT versus 42.9% (+/- 16.2%) for patients 
who underwent near total/subtotal resection and cRT18, which are nominally 
comparable to results reported in prior studies that used substantially larger 
treatment fields. These results are promising and suggest that the volume of 
irradiation may be substantially reduced without compromising disease control in 
pediatric patients with ependymoma. ACNS0121 administered radiation in this 
fashion and we plan to continue the same dose with additional volume reduction 
in the current study.  
 
2.1.3 
Rationale for Chemotherapy 
The role of chemotherapy for intracranial ependymoma remains uncertain. 
However, recent data from CCG-9942 presented at the International Society of 
Pediatric Neuro-Oncology in June 2004 by Dr. James Garvin22 demonstrates 
compelling information in support of a potentially important role for 
chemotherapy. This study was fully published in September 2012 in Pediatric 
Blood and Cancer.15 In this study, patients without postoperative residual disease 
were treated with radiation alone. Between 1995 and 1999, there were 84 children 
ages 3-21 years enrolled on the CCG 9942 Phase II trial. Forty one patients with 
residual disease received four cycles of pre-irradiation chemotherapy with 
cisplatin, vincristine, cyclophosphamide, and etoposide. Of 35 evaluable patients, 
40% had a complete response, 17% partial response giving a 57% objective 
response rate. The 5 year OS and EFS for the whole group was 71 ± 6% and 
57 ± 6%, respectively. Interestingly, there was no difference in OS or EFS between 
patients assigned to pre-irradiation chemotherapy (5 yr EFS 55% ± 8%) because 
of post-operative residual tumor compared to the patients assigned to radiation 
alone because of no post-operative residual (5 yr EFS 58% ± 9%). This is a striking 
result since children with incomplete resections previously had fared much worse 
than those with complete resections. This strongly suggests a real benefit for 
chemotherapy in the incompletely resected patients. 5-year EFS was 65+/- 12% 
for complete response/partial response (CR/PR) compared to 50% +/- 16% for 
SD/MR. The 5-year OS after the end of induction chemotherapy for patients with 
CR/PR was 87+/- 9%, compared to 62+/- 18% for patients with MR/SD (P = 0.25). 
Although the patient numbers are small, these figures suggest that patients with a 
CR/PR to chemotherapy had an OS at 5 years better than the children who had 
complete resection plus radiation alone. However, because 15% of children 
progressed on chemotherapy, a delay in radiation seems an unwarranted risk in 
patients who have already achieved a CR with surgery. Delay in the delivery of 
radiation for ependymoma has previously been cited as a cause of increased 
recurrence rates in some “baby brain” studies of ependymoma.13,14,23 On the other 
hand, these studies also demonstrated a significant response rate, which again 
supports a role for chemotherapy.  
 
Ependymoma has been shown to be responsive to certain chemotherapeutic 
regimens. Cisplatin has response rates of approximately 33% (18% complete 
responses).24 Phase 2 data on the use of carboplatin by Gaynon et al.25 report 14 
evaluable patients with ependymoma with 2/7 patients having received prior 
cisplatin with stable disease and no objective responses. Of the 5 patients without 
prior cisplatin exposure there were 2 PRs, no CRs, and 3 progressive diseases 
(PDs). In addition to the results from CCG-9942, there are data from several 

 
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studies using adjuvant combination chemotherapy in children with newly 
diagnosed ependymoma which have shown encouraging responses. White et al. 
found an 86% response rate to four cycles of vincristine, etoposide and cytoxan in 
seven children younger than 4 years of age with newly diagnosed ependymoma.26 
Mason et al. found a 16% response rate in 10 children younger than 6 years of age 
with newly-diagnosed ependymoma treated with 4-5 cycles of cisplatin, 
vincristine, etoposide, and cytoxan.27 Duffner et al.12 reported a 48% CR/PR 
response rate to two cycles of cyclophosphamide/vincristine. Geyer et al. reported 
a 36% CR/PR response rate to chemotherapy: 44% to a regimen of vincristine, 
cisplatin, etoposide, cyclophosphamide and 30% to a regimen of vincristine, 
carboplatin, ifosfamide, etoposide, and cyclophosphamide.14 Selection of the 
chemotherapy agents, delivery schedule, and duration of treatment necessary to 
achieve these aims is difficult given the range of responses, differences in toxicity 
profiles, and lack of data from which to model such a study. However, given the 
favorable response rate to the combination of VCEC in a group-wide setting, there 
is a strong rationale to build upon the results of CCG-9942 by incorporating the 
VCEC regimen in the proposed study.  
 
2.1.4 
Rationale for Observation Only for Supratentorial GTR1 Differentiated Patients 
There are isolated reports in the literature of some supratentorial ependymoma 
patients treated with surgical resection alone who have done well.28 Therefore, this 
was the approach taken in ACNS0121 to test this prospectively. The preliminary 
results for patients who were observed only are available from ACNS0121. The 
group was defined to be only classic histology supratentorial ependymoma patients 
who had achieved a microscopic gross total resection (GTR1). Thirteen patients 
were enrolled. Two were declared ineligible based on central pathology and 
radiology review as not having ependymoma. Two of the remaining eleven 
patients experienced local relapses within 12 months of enrollment. Both patients 
were salvaged with additional surgery and radiation therapy and remain without 
evidence of disease at 18 and 30 months after salvage therapy. The investigators 
have recommended continuing this approach (observation only) for children with 
supratentorial classic ependymoma following microscopic gross total resection 
using central pathology and radiology review. 
 
 

 
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Study 
# pts 
Age) 
Histology 
Overall Schema 
Response to CT 
EFS 
OS 
BBSFOP  
73 pts  
< 5 years  
65 Grade III 
8 Grade II  
Surgery then chemo  
None  responded 
> 50%  
2 yr PFS 33% 
4 yr 22%  
2 yr 79% 
4 yr 59%  
Baby POG 
’93 
Duffner  
46 pts  
< 3 years   
Surgery then chemo 
VCR/CTX (eval after 
2 cycles)  
48% CR/PR  
2 yr 42% 
4 yr 20%  
2 yr 74% 
4 yr 35%  
CCG 9921 
‘2005 
Geyer  
 
< 3 years  
Grade II & III, 
unclear 
breakdown  
Surgery then chemo 
A: Vcr/CisEtop/CTX 
B: Vcr/Carbo/ICTX/E  
A:44% 
B:30%  
3 yr 26%  
 
SFOP  
73 pts  
< 5 yrs  
60 (88%) 
Grade III 
8 (12%) 
Grade II  
Surgery + Chemo only 
(RT @ 
recurrence/prog) 
A: Carbo, 
procarbazine, 
B: Etop/cis 
C: Vcr/CTX  
Eval after A,B,C 
Response not 
reported  
2 yr 33% 
4 yr 22%  
2 yr 79% 
4 yr 59%  
UKCCSG  
89 pts 
80 
local  
< 3yrs  
59 (66%) 
Grade II  
Surgery + Chemo only 
(RT@ 
recurrence/prog) 
1: Vcr/Carbo 
2: Vcr/MTX 
3: Vcr CTX 
4: Cis  
Not reported  
2 yr 60 % 
4 yr 45%  
2 yr 85% 
4 yr 65%  
CCG 9942 
J. Garvin 
2006  
84 pts 
39 CT  
3-21 
years  
28 Grade I 
33 Grade III 
14 Mixed 
5 Unknown  
Surgery  + chemo + 
RT Vcr/CTX/Etop/Cis  
42% CR 
18%PR  
3 yr 59.5%  
3 yr 80%  
 
2.2 
Rationale for Correlative Biological Studies 
Since ACNS0831 opened, there have been significant advances in our understanding of the 
biology of ependymoma that prompt reconsideration of the correlative biologic studies 
proposed in the original protocol. In particular, there are published findings that are 
relevant to the trial’s primary aims, because they indicate that ependymomas with specific 
molecular characteristics could be expected to have different biologic behaviors and to be 
associated with distinct patient outcomes. A complete understanding of the trial aims will 
therefore require assessment of these molecular genetic characteristics, which fall into 
three categories: (i) molecular groups as defined by DNA methylation profiling, (ii) copy 
number variants, and (iii) specific genetic alterations. 
 
These new biologic studies directly relating to trial aims test a central hypothesis: 
ependymoma biomarkers among molecular groups, copy number variants, and 
specific mutations are associated with clinical and pathologic variables, including 
patient outcome. 
 
The discovery of molecular groups with distinct clinical, pathologic, and genetic 
characteristics among medulloblastomas has been critical to our understanding of this 
disease and has suggested novel therapeutic approaches based around patient stratification 
with conventional therapies, including irradiation dose reduction for WNT-activated 

 
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medulloblastomas and targeted chemotherapy for SHH-activated medulloblastomas with 
PTCH1 or SMO mutations.29 
 
Medulloblastoma molecular groups were defined first by gene expression profiling and 
subsequently by DNA methylation profiling. Both methods have been used to define 
molecular groups of ependymoma. In the most comprehensive study to date, DNA 
methylation profiling was used to discover nine molecular groups of ependymomas drawn 
from a patient population chosen to represent the entire disease.30 Three molecular groups 
were identified in each of the three major CNS anatomic compartments: supratentorial, 
infratentorial (posterior fossa), and spinal. One molecular group from each anatomic 
compartment was enriched with tumors showing the histopathologic features of 
subependymomas, which generally occur in adults. One spinal molecular group was 
enriched with adult myxopapillary tumors. Four molecular groups were shown to be 
particularly relevant to childhood disease and thus to the ACNS0831 cohort: supratentorial 
RELA (ST-RELA), supratentorial YAP1 (ST-YAP1), posterior fossa group A (PFA), and 
posterior fossa group B (PFB). A tumor from each of these four groups can present in 
childhood; childhood ependymomas rarely occur in the other five groups, and 
ependymomas in the PFA and supratentorial ST-YAP1 groups almost always occur in 
children. 
 
Each of the four pediatric molecular groups is associated with a characteristic genetic or 
epigenetic alteration, although not all supratentorial tumors in one molecular group might 
have the specific alteration. ST-RELA and ST-YAP1 group tumors have RELA and YAP1 
fusion genes, respectively,30,31 but YAP1 fusion genes occur in only a minority of 
ST-YAP1 group tumors (Ellison, unpublished observation). PFA ependymomas are 
characterized by high expression of CXorf67 and reduced H3 K27-trimethylation 
(H3K27--me3),32 while PFB ependymomas show the reverse, i.e., high levels of 
H3K27-me3.33 
 
Several studies have demonstrated associations between ependymoma molecular groups 
and clinical variables, aside from anatomic site. Age has been mentioned above and focuses 
attention on four ‘pediatric’ molecular groups. Several studies have highlighted a 
difference in outcome between PFA and PFB ependymomas; PFA tumors, which mainly 
present in infants, have a relatively poor outcome.30,34,35 Fewer data are available for 
supratentorial ependymomas, but ST-RELA ependymomas have been reported to have a 
worse outcome than ST-YAP1 tumors.30 However, anecdotal evidence is emerging to 
suggest that the supratentorial groups might not have a significantly distinct outcome and, 
importantly, the prognostic value of ependymoma molecular groups has not yet been 
reported in a clinical trial cohort. 
 
Multiple studies have shown that copy number status of chromosome 1, specifically 
1q gain, is associated with poor outcome in pediatric PF ependymoma.36,37 1q gain is 
detected in approximately 15% of PF ependymomas, but at much lower frequencies in 
supratentorial or spinal ependymomas. The association with poor outcome is frequently 
independent of other variables. 
 
Homozygous deletion of CDKN2A, which is detected in a small proportion (<10%) of 
mainly supratentorial ependymomas, has been shown to be an adverse prognostic indicator 
in some gliomas, e.g., pleomorphic xanthoastrocytoma and anaplastic astrocytoma with 
piloid features. While less is known about this copy number alteration in ependymoma, in 

 
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one study CDKN2A loss was shown to be an important prerequisite for modeling human 
ependymoma in the mouse,38 and in another it was associated with a poor prognosis.39 
 
As indicated above, ependymomas at different anatomic sites and in different molecular 
groups are characterized by specific genetic alterations. The first genomic studies of the 
tumor suggested that recurrent mutations were not a feature of PF ependymomas. However, 
subsequent studies have demonstrated that H3 K27M mutations do occur in a small 
proportion (4%) of PFA ependymomas.32,40 An H3 K27M mutation has been associated 
with a particularly poor survival in several tumor types. It occurs in a large proportion of 
diffuse midline gliomas, which have a particularly poor prognosis. In addition, when an 
H3 K27M mutation occurs (rarely) in a WHO grade I/II glioma, patient outcome is poorer 
than expected. 
 
2.2.1 
Molecular 
groups 
as 
defined 
by 
DNA 
methylation 
profiling 
and 
immunohistochemistry 
The molecular groups will be determined by DNA methylation profiling using 
DNA extracted from FFPE tissue and Illumina EPIC (850K) arrays. 
Immunohistochemistry for H3K27-me3 will also be used to identify PFA and PFB 
tumors.33 The groups that will be defined are listed below. 
 
 
RELA (ST-RELA) 
 
YAP1 (ST-YAP1) 
 
PFA 
 
PFB 
 
2.2.2 
Copy Number Variants 
The copy number variants 1q gain and CDKN2A loss can be assessed as part of 
the analysis of data from DNA methylation profiling arrays and will also be 
evaluated by interphase fluorescence in situ hybridization (iFISH).36 
 
 
1q gain in posterior fossa ependymomas 
 
CDKN2A loss (homozygous deletion) in supratentorial ependymomas 
 
2.2.3 
Specific Genetic Alterations 
iFISH with break-apart probes to RELA and YAP1 loci on 11q13 and 11q22, 
respectively, can be used to detect gene rearrangements and is a surrogate marker 
of RELA and YAP1 gene fusions in supratentorial ependymomas.31 H3 K27M 
mutation can be detected by immunohistochemistry with a mutation-specific 
antibody that has found significant utility in diagnostic laboratories for identifying 
diffuse midline gliomas.32 
 
 
RELA fusions, specifically C11orf95-RELA fusions 
 
YAP1 fusions 
 
H3 K27M mutation 
 
2.3 
Rationale for Neuropsychologic Studies 
As survival rates among children treated for pediatric ependymoma continue to improve 
with advances in treatment regimens, increased attention must be paid to the late effects of 
treatments and the functional outcomes of these children. Neurocognitive late effects are 
an important outcome to examine, as poor neurologic functioning may contribute to 

 
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limitations in age-appropriate activities of daily living such as school performance, 
employment, independent living, and quality of life. 
 
It is well established that total radiation dose and volume of irradiated brain contribute to 
neurocognitive outcome in pediatric brain tumor survivors, with studies asserting that 
radiation dosimetry is the most clinically significant determinant of intellectual outcomes.11 
Several studies have found that lower doses of cranial radiation are associated with less 
intellectual impairment, providing evidence for the merits of reducing radiation dose and 
volume for localized pediatric brain tumor cases, when tumor control can be 
maintained.41,42 One study of cRT found stable intellectual functioning (IQ) in children up 
to three years post therapy,11 with another study showing no significant longitudinal decline 
in the intellectual ability of patients with infratentorial tumors who received local radiation 
therapy as compared to conventional craniospinal irradiation.43 
 
Recent studies have begun to extend evaluation of neurocognitive outcome beyond global 
measures of IQ to capture specific neurocognitive domains and academic performance. 
Conklin and colleagues found that children with ependymoma who were treated with cRT 
generally performed well academically many years post-treatment.44 However, reading 
skills appeared to be more vulnerable than math and spelling performance, which remained 
stable over time. Younger age at start of cRT was predictive of a significant decline in 
reading over time. While some studies have found subtle difficulties in attention and 
memory following radiation treatment of ependymoma,45 others have found intact verbal 
and visual learning.46 Across studies, a number of potential risk factors for poor 
neurocognitive outcome have been proposed, including gender, hydrocephalus at 
diagnosis, 
endocrine 
deficiencies, 
surgical 
complications, 
receiving 
pre-cRT 
chemotherapy, and younger age at cRT. 
 
Although it is well documented that childhood brain tumor survivors are at increased risk 
for poor quality of life,47 few studies have examined quality of life outcomes in 
ependymoma survivors specifically, and predictors of poor quality of life in this population 
have not been well described. In general, studies investigating both neurocognitive 
outcomes and quality of life in children with ependymoma have been plagued by 
methodological limitations, including retrospective study design and small, heterogeneous 
samples.48 ACNS0831 provides a unique opportunity to characterize the neurobehavioral 
functioning and quality of life of children post-diagnosis of ependymoma as a function of 
tumor and treatment factors and patient characteristics in prospective longitudinal design. 
 
2.4 
Gender and Race Differences 
There is no reported evidence to suggest that there are differences in outcome by gender or 
race when otherwise identical patients receive the same treatment. 
 
 
3.0 
STUDY ENROLLMENT AND PATIENT ELIGIBILITY 
 
3.1 
Study Enrollment 
 
3.1.1 
Patient Registration 
Prior to enrollment on this study, patients must be assigned a COG patient ID 
number. This number is obtained via Patient Registry module in OPEN once 
authorization for the release of protected health information (PHI) has been 

 
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obtained. The COG patient ID number is used to identify the patient in all future 
interactions with COG. If you have problems with the registration, please refer to 
the online help. For additional help or information, please contact the CTSU Help 
Desk at 1-888-823-5923 or ctsucontact@westat.com. 
 
In order for an institution to maintain COG membership requirements, every patient 
with a known or suspected neoplasm needs to be offered participation in  APEC14B1, 
Project:EveryChild A Registry, Eligibility Screening, Biology and Outcome Study. 
 
A Biopathology Center (BPC) number will be assigned as part of the registration 
process. Each patient will be assigned only one BPC number per COG Patient ID. 
For additional information about the labeling of specimens please refer to the 
Pathology and/or Biology Guidelines in this protocol.  
 
Please see Appendix III for detailed CTEP Registration Procedures for Investigators 
and Associates, and Cancer Trials Support Unit (CTSU) Registration Procedures 
including: how to download site registration documents; requirements for site 
registration, submission of regulatory documents and how to check your site’s 
registration status. 
 
3.1.2 
IRB Approval 
Each investigator or group of investigators at a clinical site must obtain IRB 
approval for this protocol and submit IRB approval and supporting documentation 
to the CTSU Regulatory Office before they can be approved to enroll patients.  
Assignment of site registration status in the CTSU Regulatory Support System 
(RSS) uses extensive data to make a determination of whether a site has fulfilled 
all regulatory criteria including but not limited to the following: 
 
An active Federal Wide Assurance (FWA) number 
 
An active roster affiliation with the Lead Network or a participating 
organization 
 
A valid IRB approval 
 
Compliance with all protocol specific requirements. 
 
In addition, the site-protocol Principal Investigator (PI) must meet the following 
criteria: 
 
Active registration status 
 
The IRB number of the site IRB of record listed on their Form FDA 1572 
 
An active status on a participating roster at the registering site. 
 
For information about the submission of IRB/REB approval documents and other 
regulatory documents as well as checking the status of study center registration 
packets, please see Appendix III.  
 
Institutions with patients waiting that are unable to use the Portal should alert the 
CTSU Regulatory Office immediately at 1-866-651-2878 in order to receive 
further instruction and support. For general (non-regulatory) questions call the 
CTSU General Helpdesk at: 1-888-823-5923. 
 
Note: Sites participating on the NCI CIRB initiative and accepting CIRB 
approval for the study are not required to submit separate IRB approval 

 
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documentation to the CTSU Regulatory Office for initial, continuing or 
amendment review. For sites using the CIRB, IRB approval information is 
received from the CIRB and applied to the RSS in an automated process. Signatory 
Institutions must submit a Study Specific Worksheet for Local Context (SSW) to 
the CIRB via IRBManager to indicate their intent to open the study locally.  The 
CIRB’s approval of the SSW is then communicated to the CTSU Regulatory 
Office.  In order for the SSW approval to be processed, the Signatory Institution 
must inform the CTSU which CIRB-approved institutions aligned with the 
Signatory Institution are participating in the study. Other site registration 
requirements 
(i.e., 
laboratory 
certifications, 
protocol-specific 
training 
certifications, or modality credentialing) must be submitted to the CTSU 
Regulatory Office or compliance communicated per protocol instructions. 
 
3.1.3 
Study Enrollment 
Patients may be enrolled on the study once all eligibility requirements for the study 
have been met. Study enrollment is accomplished by going to the Enrollment 
application in the eRDE system. If you have problems with enrollment, refer to 
online help in the Applications area of the COG website.  
 
3.1.4 
Timing 
Patients must be enrolled on study within 56 days of initial surgical resection. 
Surgical resection is defined as any attempt to resect tumor that results in the tissue 
diagnosis of ependymoma (including biopsy). Patients must be enrolled before 
treatment begins.  
 
The date protocol therapy is projected to start must be no later than 21 calendar 
days after the date of study enrollment.  
 
Enrollment onto ALTE07C1 is strongly encouraged. 
 
3.1.5 
Bilingual Services 
To allow non-English speaking patients to participate in the study, bilingual health 
care services will be provided in the appropriate language. 
 
3.1.6 
Mandatory Submission of Imaging Studies for Central Review (see Section 17.0) 
Pre-and post-operative brain and total spine MR with and without gadolinium must 
be submitted to the Quality Assurance Review Center (IROC RI (QARC)) to 
confirm eligibility.  
 
Please note that there are other required Rapid Central Imaging Review time 
points for patients with a sub-total resection. For all imaging requirements with 
timing, please see Section 17.1 and Section 17.6.  
 
3.1.7 
Mandatory Submission of Tissue for Central Pathology Review (see Section 14.0) 
All patients must have tissue submitted for central pathology review after 
study enrollment.  
 
Patients with an infratentorial primary site must have pathology slides from the time 
of diagnosis submitted to the COG Biopathology Center within 10 days of study 
enrollment.  

 
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Patients with a supratentorial primary site must have RAPID CENTRAL 
PATHOLOGY REVIEW, in order to avoid discordant diagnoses and to verify 
diagnosis criterion for treatment stratification. Pathology slides must be marked 
RAPID REVIEW and submitted by Federal Express Priority Overnight to 
the Biopathology Center within 5 days of study enrollment (see Section 14.0 
for information regarding specimen submission). Results of rapid central 
review will be available within 1 week of the submission of pathology review 
materials. 
 
3.1.8 
Assignment to Treatment Arms and Randomization 
Patients will be randomized or non-randomly assigned to treatment arms based 
upon 1) the extent of resection, 2) tumor histology, and 3) tumor location.   
 
NOTE: Treatment or randomization for supratentorial patients cannot be started 
until the central pathology review results are available. 
 
Randomization   
For patients eligible for randomization after initial surgery, randomization should 
occur as soon as possible after enrollment using the Callback function of the 
Member Site. Patients must be randomized prior to radiation. Patients who will 
receive proton therapy are eligible for this study. Definitions for extent of surgical 
resection can be found in Section 4.1.  
 
Supratentorial Patients 
Patients with classic histology supratentorial disease who have GTR1 after 
initial surgery will be non-randomly assigned to Observation only. Rapid central 
pathology review will be performed on all supratentorial tumors to confirm 
eligibility for observation only after enrollment. See Section 14.2.1 for discordant 
diagnosis. 
 
Supratentorial patients with 1) GTR2 or 2) NTR, and with 3) anaplastic histology 
or 4) indeterminate grade histology will be Randomized. 
 
Infratentorial Patients 
Patients with an infratentorial primary tumor that have a total or near total resection 
([GTR1 or GTR2 or NTR] definitions in Section 4.1) regardless of histology will 
be Randomized. 
 
STR (Incomplete Resection) Patients 
Patients with a sub-total resection (STR) (definition in Section 4.1) after initial 
surgery will be non-randomly assigned to Induction chemotherapy. Induction 
chemotherapy consists of 7 weeks (2 cycles) of chemotherapy. At the end of 
induction, patients must have rapid central imaging review to confirm response to 
therapy and determine the next steps. 
 
Patients with a Complete Response following Induction:  
Supratentorial Classic Histology: patients with a classic histology supratentorial 
tumor that have a CR following Induction chemotherapy will be non-randomly 
assigned to Observation.  

 
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Infratentorial with Any Histology and Supratentorial Anaplastic Histology: those 
who have a CR (see definition in Section 10.0) following Induction chemotherapy 
and have either an infratentorial primary or a supratentorial anaplastic primary 
tumor will be Randomized.  
 
Patients with Stable Disease, Partial Responses, Progressive Disease following 
Induction: 
Patients with stable disease (SD), partial response (PR), or locally progressive 
disease (LPD) (see definitions in Section 10.4) after Induction chemotherapy will 
undergo second surgery when possible. There is no limit to the number of surgical 
procedures performed after Induction chemotherapy and prior to cRT.   
 
Following Second Surgery 
Patients with an infratentorial primary or supratentorial anaplastic primary tumor 
who have a GTR1, GTR2, or NTR after second surgery will then be Randomized. 
 
Patients with residual disease after second surgery will be non-randomly assigned 
to receive cRT followed by maintenance chemotherapy.  
 
Patients with supratentorial classic primary tumor who have a GTR1 after second 
surgery will be assigned to Observation only. 
 
Detailed information about the Treatment Plan including randomization at 
diagnosis and following induction chemotherapy and/or second surgery can be 
found in Section 4.0.  
 
3.2 
Patient Eligibility Criteria 
Important note: The eligibility criteria listed below are interpreted literally and cannot 
be waived (per COG policy posted 5/11/01). All clinical and laboratory data required for 
determining eligibility of a patient enrolled on this trial must be available in the patient's 
medical/research record which will serve as the source document for verification at the 
time of audit.  
 
INCLUSION CRITERIA 
 
3.2.1 
Age 
Patients must be greater than 12 months of age and less than 21 years of age at the 
time of study enrollment. 
 
 
3.2.2 
Diagnosis 
 
3.2.2.1  Patients must be newly diagnosed with histologically confirmed 
intracranial ependymoma. Patients with classic ependymoma (WHO II) 
or anaplastic ependymoma (WHO III) are eligible, as are various 
subtypes described as clear cell, papillary, cellular, or a combination of 
the above.  
 
Note: Please see imaging and pathology requirements in Section 3.1.6 
and Section 3.1.7. 

 
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3.2.4 
Performance Level 
There is no minimum performance level. Children with ependymoma may suffer 
neurologic sequelae as a result of their tumor or surgical measures taken to 
establish a diagnosis and resect the tumor. In the majority of cases there is 
neurologic recovery. Neurologic recovery is not likely to be impeded by protocol 
therapy. 
 
EXCLUSION CRITERIA 
 
3.2.5 
Metastatic Disease 
Patients with evidence of metastatic disease will be excluded. Any evidence of non-
contiguous spread beyond the primary site as determined by pre- or post-operative 
MR imaging of brain, pre- or post-operative MR imaging of the spine, and post-
operative CSF cytology obtained from the lumbar CSF space (the requirement for 
lumbar CSF examination may be waived if deemed to be medically 
contraindicated). CSF cytology from a ventriculostomy or permanent VP shunt 
that reveals the presence of tumor cells is indicative of metastatic disease. 
 
3.2.6 
Ineligible Diagnoses 
Patients with a diagnosis of spinal cord ependymoma, myxopapillary ependymoma, 
subependymoma, ependymoblastoma, or mixed glioma are NOT eligible. 
 
3.2.7 
Prior Therapy 
No prior treatment other than surgical intervention and corticosteroids. Patients are 
allowed to have had more than one attempt at resection prior to enrollment.  
 
3.2.8 
Pregnant female patients are not eligible for this study.  
 
3.2.9 
Post-menarchal females may not participate unless a pregnancy test with a negative 
result has been obtained.  
 
 
3.2.10 Males and females of reproductive potential may not participate unless they have 
agreed to use an effective contraceptive method.  
 
3.2.11 Lactating females may not participate unless they have agreed not to breastfeed a 
child while on this study. 
 
REGULATORY 
 
3.2.12 All patients and/or their parents or legal guardians must sign a written informed 
consent. 
 
3.2.13 All institutional, FDA, and NCI requirements for human studies must be met. 
 
 
 

 
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4.0 
TREATMENT PLAN 
 
 
 
 
 
 
 
 
 
 
Once a patient has been determined to be eligible for protocol treatment, patients will be 
randomized or non-randomly assigned to treatment arms based upon the extent of resection, tumor 
histology, and tumor location.   
 
Patients with Gross Total Resection Supratentorial Classic Ependymoma (GTR1) will be observed 
provided that rapid central pathology review (see Section 14.2.1) confirms the diagnosis of classic 
ependymoma and post-operative neuroimaging confirms that there is no evidence of disease. If the 
patient is found not to have classic ependymoma, they will be randomized and reconsented to the 
Randomized Treatment Arm and randomized. 
 
The three treatment arms include:  
1. Induction chemotherapy followed by surgery, cRT, maintenance chemotherapy, 
observation, or a combination depending on the response;   
2. cRT followed by maintenance chemotherapy or observation;  
3. Observation only 
 
In cases when the extent of resection or histologic grade is indeterminate, patients will be 
randomized between radiation followed by maintenance chemotherapy or radiation followed by 
observation. These instances may include:  
1. Surgeon cannot unequivocally report absence of microscopic disease;  
2. Histologic grade is indeterminate;  
3. Info necessary to determine extent of resection at time of operation is unavailable. 
 
Induction chemotherapy consists of 2 cycles given over 7 weeks, and is outlined in Section 4.5. 
Guidelines for second surgery are discussed in Section 13.0. Radiation therapy will last 6-7 weeks 
depending on the dose. Radiation therapy will be directed at the primary site using an anatomically 
defined clinical target volume margin of 5 mm beyond the gross tumor volume (see Section 18.0 
for cRT details), followed by maintenance chemotherapy or observation only. Patients receiving 
proton beam therapy are eligible. Post-radiation maintenance chemotherapy consists of four 21-
day cycles (see Section 4.6 for details). 
 
MR imaging is required for radiation treatment planning. Although the immediate post-operative 
MR evaluation may be used, it is preferable to obtain an MR within 3 weeks (or coincident with 
radiation therapy planning) and no greater than 4 weeks prior to the initiation of radiation therapy. 
 
Rapid central review of imaging for response evaluation will be conducted following induction 
chemotherapy and second surgery (see Section 17.0 for details). MRIs should be obtained between 
Day 21 and 29 of Cycle B induction chemotherapy, and within 72 hours post-operatively. MRIs 
must be submitted to IROC RI (QARC) within 3 days for Rapid Central Review.  
Timing of protocol therapy administration, response assessment studies, and surgical interventions 
are based on schedules derived from the experimental design or on established standards of care.  
Minor unavoidable departures (up to 72 hours) from protocol directed therapy and/or disease 
evaluations (and up to 1 week for surgery) for valid clinical, patient and family logistical, or facility, 
procedure and/or anesthesia scheduling issues are acceptable per COG Administrative Policy 5.14 
(except where explicitly prohibited within the protocol).  

 
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4.1 
Surgery and Extent of Resection Guidelines 
Guidelines to define the extent of resection at the time of initial and second surgery (if 
applicable) are critical to the performance of this trial. Patients are allowed to have had 
more than one attempt at resection prior to enrollment. Extent of resection may be classified 
for purposes of therapy and analysis as follows: 
 
4.1.1 
GTR1 (Gross Total Resection 1) 
No residual tumor identified with the operating microscope and no evidence of 
disease on post-operative neuroimaging. 
 
4.1.2 
GTR2 (Gross Total Resection 2) 
Microscopically visible residual tumor identified with the operating microscope 
and no evidence of disease on post-operative neuroimaging. 
 
4.1.3 
NTR (Near Total Resection) 
Residual tumor evident on post-operative neuroimaging with thickness or 
nodularity measuring less than or equal to 5 mm in greatest dimension. Linear 
“streak” enhancement or signal intensity changes are not included in the 
measurement of residual tumor to determine near-total versus sub-total resection. 
 
4.1.4 
STR (Sub-Total Resection) 
Residual tumor on post-operative imaging measuring greater than 5mm in 
nodularity or thickness. The definition of STR includes any surgical intervention 
that removes tissue that may be documented by pathology as tumor. A biopsy is 
an STR. More information is available in Section 4.2.3.  
 
4.2 
Treatment Plan by Extent of Resection, Histology, and Tumor Location at Time of 
Enrollment  
 
4.2.1 
Supratentorial Anaplastic Ependymoma (GTR1, GTR2, NTR), Anaplastic or 
Classic Infratentorial Ependymoma (GTR1, GTR2, NTR), and Supratentorial 
Classic Ependymoma (GTR2, NTR) 
 
Patients will be randomized to receive either a) cRT and maintenance 
chemotherapy OR b) to receive cRT and observation.  
 
4.2.2 
Gross Total Resection Supratentorial Classic Ependymoma (GTR1) 
Patients will be observed provided that rapid central pathology review (see Section 
14.2.1) confirms the diagnosis of classic ependymoma and post-operative 
neuroimaging confirms that there is no evidence of disease. The operating 
neurosurgeon should explicitly state in the written operative report that no visible 
microscopic disease was apparent through the operating microscope.  
 
Patients who are enrolled on this treatment arm and experience local recurrence 
will be taken off protocol therapy and receive therapy at the discretion of the 
treating physician. 
 

 
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4.2.3 
Sub-Total Resection Any Histology or Location (STR) 
All patients with a sub-total resection will receive two cycles of induction 
chemotherapy. At the completion of induction, the patient will undergo evaluation 
for chemotherapy response via rapid central imaging review (see Section 17.0). 
The evaluation will be used to determine the response to chemotherapy and the 
possibility of second surgery. There is no limit to the number of surgical 
procedures performed after induction chemotherapy and prior to radiation therapy. 
For patients who undergo second resection(s), the extent of resection and 
morbidity of surgery will be assessed, including confirmation of extent of resection 
by rapid central imaging review of post-operative MRIs (see Section 17.0).  
 
Patients who develop metastatic disease (see definition in Section 10.4) at any 
time during protocol treatment will be taken off protocol therapy.  
 
4.3  
Randomization or Assignment for STR Patients Receiving Induction Chemotherapy  
 
Induction Chemotherapy Response 
Patients with supratentorial classic tumors who achieve a CR to induction chemotherapy 
will not undergo a second surgery and will be assigned to Observation. 
 
Patients with other than supratentorial classic tumors who have a CR to induction 
chemotherapy will not undergo second surgery and will be randomized. Radiation should 
begin within 30 days after completion of induction chemotherapy (Day 28 of Cycle B) and 
maintenance chemotherapy should begin within 30 days of completion of radiation 
therapy. 
 
Patients with SD/PR or local progression (see definition in Section 10.4) after induction 
chemotherapy should undergo second resection if deemed safely feasible by the 
institutional neurosurgeon. Second surgery should occur within 15 days after the 
completion of induction chemotherapy, (defined as Day 28 of Cycle B) and patients must 
have achieved count recovery post nadir. If a patient is unable to safely undergo second 
surgery or begin radiation due to inadequate count recovery, please notify the Study Chair.  
 
Second Surgery 
There might be situations in which a patient assessed after their initial surgery would not 
appear to be a candidate for second surgery due to tumor location or complications. 
However, the final decision about re-resection should be reserved until after chemotherapy 
has been completed. After the initial surgery and during the time period for which the 
chemotherapy has been planned, normal brain has a tendency to shift and reposition itself 
into a more natural configuration. Also, the appearance and extent of the residual tumor 
might become clearer, which could influence decisions about second surgery.  
 
When, after thorough consideration, it has been determined by the primary oncology team 
that second surgery would not be in the best interest of the patient, the patient should 
proceed directly to cRT and maintenance chemotherapy after notifying the Study Chair. 
Conformal radiation therapy should begin within 30 days after the completion of induction 
(defined as Cycle B Day 28). Maintenance chemotherapy should begin within 30 days of 
completion of cRT. 
 

 
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Patients with supratentorial classic tumor who achieve GTR1 after second resection will 
be non-randomly assigned to Observation. Patients with an infratentorial primary tumor or 
a supratentorial anaplastic tumor who achieve a GTR/NTR after second resection will be 
randomized.  
 
Patients with residual disease (STR) after second resection will be non-randomly assigned 
to receive radiation therapy followed by maintenance chemotherapy. Radiation should 
begin within 30 days of second surgery. If radiation therapy is delayed beyond 30 days, 
please notify the Study Chair. Maintenance chemotherapy should begin within 30 days of 
completion of radiation therapy. 
. 
4.4 
Concomitant Therapy Restrictions during Treatment 
 
4.4.1 
No other cancer chemotherapy or immunomodulating agents will be used. 
 
4.4.2 
Clinically significant drug interactions have been reported when using vincristine with 
strong cytochrome P450 isoform CYP3A4 inhibitors and inducers. Strong inhibitors of 
cytochrome CYP3A4 are known to alter vincristine metabolism, leading to increased 
vincristine neurotoxicity. Selected strong inhibitors or stimulators of cytochrome 
P450 3A4, include azole antifungals (such as fluconazole, voriconazole, itraconazole, 
ketoconazole) rifampin, phenytoin, phenobarbital, carbamazepine, and St. John’s wort. 
These drugs should be avoided with vincristine. 
 
 
The clinical outcome and significance of CYP450 interactions with cyclophosphamide and 
etoposide are less clear. CYP450 3A4 stimulators or inhibitors should be avoided or used 
with great caution. Aprepitant also interacts with CYP3A4 and should be used with caution 
with etoposide or vincristine chemotherapy. Additional inducers or inhibitors of CYP450 
enzymes can be found at http://medicine.iupui.edu/clinpharm/ddis. 
 
4.4.3 
Appropriate antibiotics, blood products, antiemetics, fluids, electrolytes, and general 
supportive care are to be used as necessary. Corticosteroids should not be used during 
chemotherapy administration as an antiemetic because of their effect on the blood-brain 
barrier. 
 
See Section 7.0 for baseline studies to be obtained prior to starting Induction therapy or 
cRT. See Section 17.0 for imaging studies to be obtained following induction therapy and 
prior to cRT. Note the imaging studies should be performed within 21 days of beginning 
radiation and MUST be performed within 28 days of beginning RT (post-op imaging can 
be used). 
 
4.5 
Induction Chemotherapy 
Patients with sub-total resection any histology or location (STR) will receive induction 
chemotherapy. Induction chemotherapy should begin within 21 days following study 
enrollment. Induction chemotherapy consists of one cycle of Cycle A (vincristine, 
carboplatin, cyclophosphamide) and one cycle of Cycle B (vincristine, carboplatin, 
etoposide). The entire length of the induction chemotherapy phase is 7 weeks unless delay 
occurs due to myelosuppression or unanticipated toxicity.  

 
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See the Parenteral Chemotherapy Administration Guidelines (CAG) on the COG website 
at: https://www.cogmembers.org/_files/disc/Pharmacy/ChemoAdminGuidelines.pdf for 
special precautions and suggestions for patient monitoring during the infusion. As 
applicable, also see the CAGs for suggestions on hydration, or hydrate according to 
institutional guidelines. 
 
 
4.5.1 
Induction Cycle A (Weeks 13) 
Dose calculations should be based on actual BSA. There is no maximum 
dosing, except for vincristine which is capped at a maximum dose of 2 mg. 
 
To begin Induction Cycle A, patients must have ANC > 1000/L and platelets 
> 100,000/L. 
 
VinCRIStine: IV push over 1 minute or infusion via minibag as per 
institutional policy. 
Days: 1 and 8 
Dose: 1.5 mg/m2/dose. For patients with BSA < 0.45 m2 the dose is 
0.05 mg/kg/dose (max. dose is 2 mg). 
 
Special precautions: FOR INTRAVENOUS USE ONLY.   
The container or the syringe containing vinCRIStine must be enclosed in an 
overwrap bearing the statement “Do not remove covering until moment of 
injection. For intravenous use only - Fatal if given by other routes.” 
 
Medication errors have occurred due to confusion between vinCRIStine and 
vinBLAStine.   
 
CARBOplatin: IV over 15–60 minutes 
Day: 1 
Dose: 375 mg/m2/dose. For patients with BSA < 0.45 m2, the dose is 
12.5 mg/kg/dose. 
Note: Infuse the diluted solution (to a concentration as low as 0.5 mg/mL). Avoid 
use of aluminum containing needles or administration sets. 
 
Medication errors have occurred due to confusion between CISplatin (Platinol®) 
and CARBOplatin (PARAplatin®). 
 
Cyclophosphamide: IV over 3060 minutes 
Days: 1 and 2 
Dose: 1000 mg/m2/dose. For patients with BSA < 0.45 m2, the dose is 
33 mg/kg/dose. 
Note: Administer cyclophosphamide after carboplatin administration. May be 
administered as undiluted drug (20 mg/mL, reconstitute with 0.9% NaCl only to 
avoid hypotonic solution) or further diluted.  
 
Mesna: IV (Short or Continuous Infusion*) 
Days: 1 and 2 
Total IV Dose: 600 mg/m2/day. For patients with BSA < 0.45 m2, the dose is 
20 mg/kg/day. 

 
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*IV short infusion:  For prophylaxis of hemorrhagic cystitis, the total daily mesna 
dose is equal to 60% of the daily cyclophosphamide dose and is administered in 3 
divided doses (200 mg/m2/dose or 6.7 mg/kg/dose if BSA < 0.45 m2) by short 
infusion over 15 to 30 minutes. The initial bolus dose of mesna may be 
administered 15 minutes before or at the same time as the cyclophosphamide dose; 
subsequent doses are given 4 and 8 hours after the start of cyclophosphamide). 
 
Hour 4 and 8 mesna can be given orally if the patient is able to tolerate oral intake 
(without vomiting). The oral dose of mesna is twice the IV dose. Patients may 
receive the last TWO bolus doses (originally at Hours 4 and 8) orally at 40% of 
the cyclophosphamide dose. The oral doses will be administered at Hours 2 and 6. 
For example: if the cyclophosphamide dose is 1,000 mg, then 200 mg of mesna 
will be given IV 15 minutes before or with the cyclophosphamide dose (Hour 0) 
and the TWO oral doses of 400 mg each will be given at Hours 2 and 6. 
 
This total daily dose can also be administered as IV continuous infusion. The 
continuous infusion should be started 15-30 minutes before or at the same time as 
cyclophosphamide and finished no sooner than 8 hours after the end of the 
cyclophosphamide infusion.   
 
Myeloid Growth Factor: Subcutaneous (preferred) or IV 
Start myeloid growth factor support (for example, G-CSF 5 mcg/kg/dose SubQ 
[preferred] or IV) 24 hours after myelosuppressive chemotherapy, until the ANC 
is > 1,500/µL after the expected nadir. Myeloid growth factor support need not be 
limited to filgrastim or biosimilar; pegfilgrastim is also permitted according to the 
institution‘s standard guidelines. May be continued without regard to vinCRIStine. 
Discontinue at least 24 hours before the start of the next chemotherapy cycle. 
 
The therapy delivery map (TDM) for Induction Cycle A is on the next page. 
 
Begin Cycle B of Induction chemotherapy on Day 22 or when blood count 
parameters are met (whichever occurs later). Patient must be off myeloid growth 
factor for at least 24 hours before starting Induction Cycle B. 

 
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4.5.2 
Induction Cycle A - Patients with STR after first surgery 
Induction Cycle A - Patients with STR after first surgery  
Induction consists of two cycles (Cycle A and Cycle B). 
Cycle A is given Weeks 1-3.  
This cycle lasts 3 weeks (21 days). 
 ____________________________ 
       Patient name or initials 
____________________________ 
DOB  
Criteria to start Cycle A: ANC > 1000/L and platelets > 100,000/L. Extensive details are in Section 4.0 (Treatment 
Overview) and Section 4.5.1. This cycle lasts 3 weeks (21 days) and this TDM is on 1 page. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
 VinCRIStine 
(VCR) 
IV push over 1 
minute% 
1.5 mg/m2/dose 
or 
0.05 mg/kg/dose 
for pts with BSA < 0.45 m2  
1 and 8 
%Or infusion via minibag as per 
institutional policy. 
 
Maximum dose is 2 mg. 
a. History, Physical Exam, 
Weight, Height 
b. Neurologic Assessment 
c. MR Brain with 
gadolinium 
d. MR Spine with 
gadolinium 
e. Electrolytes (Ca++, PO4, 
Mg++, BUN) 
f. 
Serum Creatinine or GFR 
or Creatinine Clearance 
g. Liver function (ALT, 
AST, Bili) 
h. Urinalysis 
i. CBC (diff, platelets) 
j. 
Audiogram or BAER 
 
OBTAIN OTHER STUDIES 
AS REQUIRED FOR GOOD 
PATIENT CARE 
CARBOplatin 
(CARBO ) 
IV over 15-60 
minutes 
375 mg/m2/dose 
or 
12.5 mg/kg/dose 
for pts with BSA < 0.45 m2 
1 
Administer prior to cyclophosphamide. 
 
 
Cyclophosphamide 
(CPM ) 
IV over 30-60 
minutes 
1000 mg/m2/dose 
or 
33 mg/kg/dose 
for pts with BSA < 0.45 m2  
1 and 2 
Administer after CARBOplatin 
administration. 
 
 
Mesna 
(MESNA) 
IV (short or 
continuous 
infusion [CI]) 
 
See Section 4.5.1.  
1 and 2 
Total IV dose: 600 mg/m2/day or  
20 mg/kg/day if BSA < 0.45 m2  
 
Administer concurrently with 
cyclophosphamide. 
Myeloid Growth 
Factor 
SubQ (preferred) 
or IV 
See Important Note 
Daily*, 
beginning 
on Day 3  
* Start myeloid growth factor support (for 
example, G-CSF 5 mcg/kg/dose SubQ 
[preferred] or IV) on Day 3, until the ANC 
is > 1,500/µL after the expected nadir. 
May be continued without regard to 
vinCRIStine. Discontinue at least 24 
hours before the start of the next 
chemotherapy cycle. 
Ht_____cm 
    Wt____kg 
 
     BSA____m2 
Date 
Due 
Date 
Given 
Day 
VCR 
 
____mg 
CARBO 
 
____mg 
CPM 
 
____mg 
MESNA 
 
___mg __mg __mg 
 
Myeloid Growth 
Factor@ 
Growth Factor 
Used: ______ 
___mcg 
Studies 
Comments 
(Include any held 
doses, or dose 
modifications) 
 
 
 
Enter calculated dose above and actual dose administered below. 
 
 
 
 
1 
____mg 
____mg 
____mg 
___mg __mg __mg 
 
a, b, c&, e, f, 
g, h, i, j 
 
 
 
2 
 
 
____mg 
___mg __mg __mg 
 
 
 
 
 
3 
 
 
 
 
___mcg 
 
 
 
 
8 
____mg 
 
 
 
 
e$, f$, g$, i 
 
 
 
15 
 
 
 
 
 
e$, f$, g$, i 
 
 
 
21 
 
 
 
 
 
e$, f$, g$, i 
Indicate date of 
last myeloid 
growth factor dose 
______ 
 
 
22 
Start next cycle (Cycle B, Section 4.5.3) on Day 22 or when blood count 
parameters are met (whichever occurs later). Patient must be off myeloid growth 
factor for at least 24 hrs before starting Cycle B. 
 
 
 
 
 
 
 
 
 
OBSERVATION NOTES: 
@ Stop myeloid growth factor at least 24 hours prior to next chemotherapy cycle. 
$   Repeat weekly if abnormal. 
& If post-op cranial MRI was performed > 21 days before the first day of chemo, repeat cranial MRI with gadolinium to provide an 
appropriate baseline. 
See Section 5.0 for Dose Modifications for Toxicities. For general Supportive Care Guidelines see 
https://childrensoncologygroup.org/index.php/cog-supportive-care-guidelines.  
 
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4.5.3 
Induction Cycle B (Weeks 47 of Induction) 
 
Dose calculations should be based on actual BSA. There is no maximum 
dosing, except for vincristine, which is capped at a maximum dose of 2 mg. 
 
To begin Induction Cycle B, patients must have ANC > 1000/L and platelets  
> 100,000/L and not have had myeloid growth factor administered for at least 
one day (24 hours).  
 
VinCRIStine: IV push over 1 minute or infusion via minibag as per 
institutional policy 
Days: 1 and 8 
Dose: 1.5 mg/m2/dose.  For patients with BSA < 0.45 m2, the dose is  
0.05 mg/kg/dose. (max. dose is 2 mg). 
 
Special precautions: FOR INTRAVENOUS USE ONLY.   
The container or the syringe containing vinCRIStine must be enclosed in an 
overwrap bearing the statement “Do not remove covering until moment of 
injection. For intravenous use only - Fatal if given by other routes.” 
 
Medication errors have occurred due to confusion between vinCRIStine and 
vinBLAStine.   
 
Etoposide: IV over 60120 minutes* 
Days: 1, 2, and 3 
Dose: 100 mg/m2/dose. Give immediately prior to carboplatin on Day 1. For 
patients with BSA < 0.45m2, the dose is 3.3mg/kg. 
 
Note: Infuse as diluted solution (concentration ≤ 0.4 mg/mL); *slow rate of 
administration if hypotension occurs. Rate should not exceed 300 mg/m2/hour (10 
mg/kg/hour) (hypotension risk). The use of an in-line filter during the infusion is 
suggested. 
 
Special precautions: Etoposide can be mixed in 0.9% NaCl or D5W. Avoid use of 
large volumes of D5W due to potential development of hyponatremia. 
 
CARBOplatin: IV over 15 – 60 minutes 
Day: 1 
Dose: 375 mg/m2/dose. For patients with BSA < 0.45 m2, the dose is  
12.5 mg/kg/dose. 
Note: Infuse the diluted solution (to a concentration as low as 0.5 mg/mL). Avoid 
use of aluminum containing needles or administration sets. 
 
Patients who have compromised renal function should undergo a GFR. If the 
GFR is < 100 mL/min/1.73m2 the carboplatin dose should be modified according 
to Section 5.0.   
 
 

 
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Myeloid Growth Factor: Subcutaneous (preferred) or IV 
Start myeloid growth factor support (for example, G-CSF 5 mcg/kg/dose SubQ 
[preferred] or IV) 24 hours after myelosuppressive chemotherapy, until the ANC 
is > 1,500/µL after the expected nadir. Myeloid growth factor support need not be 
limited to filgrastim or biosimilar; pegfilgrastim is also permitted according to the 
institution‘s standard guidelines. May be continued without regard to vinCRIStine. 
Discontinue at least 24 hours before the start of the next chemotherapy cycle. 
 
See Section 5.0 for Dose Modifications based on Toxicities.  
 
After patients have completed the induction chemotherapy phase, MR of the brain 
should be performed between Day 21 and 29 of Cycle B to evaluate the feasibility 
of second surgery. MRIs must be submitted for Rapid Central Review of 
response (see Section 17.0 for details). 
 
Patients with supratentorial/classic tumors who achieve a CR by induction 
chemotherapy or achieve a GTR1 at second surgery will be assigned to 
observation alone. 
 
Patients who achieve SD/PR or have locally progressive disease (see definition in 
Section 10.4) after induction chemotherapy who are deemed potentially resectable 
will go on to second surgery.  
 
Anaplastic supratentorial patients and infratentorial patients (any histology) who 
achieve a CR by induction chemotherapy or who achieve a complete resection 
(GTR/NTR) at second surgery will go on to be randomized between either: (a) cRT 
followed by maintenance chemotherapy OR (b) cRT followed by Observation.  
 
Second surgery should be performed within 15 days after completing induction 
chemotherapy, which is defined as Day 28 of Cycle B. Conformal radiation 
therapy should begin within 30 days after completing induction chemotherapy or 
second surgery. The timelines for performance of second surgery and conformal 
radiation therapy are not rigid. There is no limit to the number of surgery 
procedures performed following induction chemotherapy. See Section 13.5 for 
more details. 
 
Evidence of metastatic disease at any time during protocol therapy will remove the 
patient from protocol therapy. 
 
For cRT details, see Section 18.0. For surgical guidelines, see Section 13.0. For 
assessments to be obtained during Observation only, see Section 7.4. 
 
The therapy delivery map (TDM) for Induction Cycle B is on the next page.  
 
 

 
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4.5.4 
Induction Cycle B - Patients with STR after first surgery 
Induction Cycle B - Patients with STR after first surgery 
Induction consists of two cycles (Cycle A and Cycle B).  
Cycle B is given Weeks 4-7. 
This Cycle lasts 4 weeks (28 days). 
____________________________ 
Patient name or initials 
____________________________ 
DOB  
Criteria to start Cycle B: ANC > 1000/L and platelets > 100,000/L and no myeloid growth factor administered for at least the 
preceding day (24 hours), and adequate renal function. Extensive details are in Section 4.0 (Treatment Overview) and Section 4.5.3. 
This course lasts 4 weeks (28 days) and this TDM is on 1 page. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine 
(VCR) 
IV push over 1 
minute& 
1.5 mg/m2/dose 
or   
0.05 mg/kg for pts with 
BSA < 0.45 m2  
1 and 8 
&Or infusion via minibag as per 
institutional policy 
 
Maximum dose is 2 mg. 
a. History, Physical Exam, 
Weight, Height 
b. Neurologic Assessment 
c. MR Brain with 
gadolinium 
d. MR Spine with 
gadolinium 
e. Electrolytes (Ca++, PO4, 
Mg++, BUN) 
f. 
Serum Creatinine or 
GFR or Creatinine 
Clearance 
g. Liver function (ALT, 
AST, Bili) 
h. Urinalysis 
i. CBC (diff, platelets) 
j. 
Audiogram or BAER 
 
OBTAIN OTHER 
STUDIES AS 
REQUIRED FOR 
GOOD PATIENT 
CARE 
Etoposide 
(ETOP ) 
IV over 60-120 
minutes+ 
100 mg/m2/dose or 3.3 
mg/kg for patients with 
BSA < 0.45m2 
 
1, 2, and 3 
+Slow rate of administration if 
hypotension occurs. Give 
Immediately prior to carboplatin on 
Day 1. 
CARBOplatin 
(CARBO ) 
IV over 
15-60 minutes 
375 mg/m2/dose 
or  
12.5 mg/kg/dose for pts 
with BSA < 0.45 m2   
1 
See dose modifications for renal 
function in Section 5.1. 
Myeloid 
Growth 
Factor 
SubQ 
(preferred) or IV 
See Important Note 
Daily*, 
beginning 
on Day 4  
* Start myeloid growth factor support 
(for example, G-CSF 5 mcg/kg/dose 
SubQ [preferred] or IV) on Day 3, 
until the ANC is > 1,500/L after the 
expected nadir. May be continued 
without regard to vinCRIStine. 
Discontinue at least 24 hours before 
the start of the next chemotherapy 
cycle. 
 
Ht_____cm     Wt____kg 
 
     BSA____m2 
Date 
Due 
Date 
Given 
Day 
VCR 
 
____mg 
CARBO 
 
____mg 
ETOP 
 
____mg 
Myeloid Growth Factor# 
Growth Factor  
Used: ______ 
___ mcg 
Studies 
Comments (Include any 
held doses, or dose 
modifications) 
 
 
 
Enter calculated dose above and actual dose administered below. 
 
  
 
 
1 
____mg 
____mg 
____mg 
 
a, b, e, f, g, 
h, i, j 
 
 
 
2 
 
 
____mg 
 
 
 
 
 
3 
 
 
____mg 
 
 
 
 
 
4 
 
 
 
___ mcg 
 
 
 
 
8 
____mg 
 
 
 
e$, f$, g$, i 
 
 
 
15 
 
 
 
 
e$, f$, g$, i 
 
 
 
21 
 
 
 
 
c%, d%, 
e$, f$, g$, i  
 
 
 
28 
 
 
 
 
 
Indicate date of last 
myeloid growth factor 
dose ______ 
 
 
29 
Upon completion of Induction Cycle B, patients will undergo response evaluation, and 
receive further protocol therapy as outlined in Section 4.5.3. Patients with metastatic 
disease following Cycle B are off protocol therapy.   
 
OBSERVATION NOTES: 
$ Repeat weekly if abnormal. 
 
% Neuroimaging should be obtained between Days 21-29. 
# Stop myeloid growth factor at least 24 hours prior to next chemotherapy cycle. 
See Section 5.0 for Dose Modifications for Toxicities. For general Supportive Care Guidelines see 
https://childrensoncologygroup.org/index.php/cog-supportive-care-guidelines. 
 
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4.6 
Maintenance Chemotherapy 
Maintenance chemotherapy is for patients randomized to receive maintenance 
chemotherapy and for STR patients with residual disease after second surgery (see Section 
4.2). 
 
Maintenance chemotherapy consists of four repeated 21-day cycles. The first three cycles 
will comprise vincristine, cisplatin, etoposide, and cyclophosphamide (see Section 4.6.1). 
The fourth cycle will comprise cisplatin, etoposide, and cyclophosphamide, without 
vincristine (see Section 4.6.3).  
 
Criteria to start each Maintenance cycle: ANC > 1000/L and platelets > 100,000/L, and 
no myeloid growth factor administered for at least the preceding day (24 hours). An 
additional criterion to start Cycles 1 and 3 is adequate renal function Maintenance 
chemotherapy should begin within 30 days of completion of cRT.  
 
See the Parenteral Chemotherapy Administration Guidelines (CAGs) on the COG website 
at: 
https://www.cogmembers.org/_files/disc/Pharmacy/ChemoAdminGuidelines.pdf 
for 
special precautions and suggestions for patient monitoring during the infusion. As 
applicable, also see the CAGs for suggestions on hydration, or hydrate according to 
institutional guidelines. 
 
4.6.1 
Maintenance Chemotherapy Cycles 1 through 3  
Dose calculations should be based on actual BSA. There is no maximum 
dosing, except for vincristine which is capped at a maximum dose of 2 mg. 
 
 
 
VinCRIStine: Administer IV push over 1 minute or infusion via minibag as 
per institutional policy. 
Days: 1, 8, and 15 
Dose: 1.5 mg/m2/dose. For patients with BSA < 0.45 m2 the dose is 0.05 mg/kg 
(max. dose is 2 mg). 
 
Special precautions: FOR INTRAVENOUS USE ONLY.   
The container or the syringe containing vinCRIStine must be enclosed in an 
overwrap bearing the statement “Do not remove covering until moment of 
injection. For intravenous use only - Fatal if given by other routes.” 
 
Medication errors have occurred due to confusion between vinCRIStine and 
vinBLAStine. 
 
Etoposide: IV over 60120 minutes 
Days: 1, 2, and 3 
Dose: 100 mg/m2/dose. For patients with BSA < 0.45 m2 the dose is 3.3 mg/kg. 
Note: Administer immediately prior to CISplatin or cyclophosphamide. Infuse as 
diluted solution (concentration ≤ 0.4 mg/mL); slow rate of administration if 
hypotension occurs. Rate should not exceed 300 mg/m2/hour (10 mg/kg/hour) 
(hypotension risk). The use of an in-line filter during the infusion is suggested. 
 
Special precautions: Etoposide can be mixed in 0.9% NaCl or D5W. Avoid use of 
large volumes of D5W due to potential development of hyponatremia. 
 

 
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CISplatin: IV over 18 hours  
Day: 1 
Dose: 100 mg/m2/dose. For patients with BSA < 0.45 m2 the dose is 
3.3 mg/kg/dose. 
Note: Hydrate patients before and after CISplatin administration. See the 
Parenteral Chemotherapy Administration Guidelines (CAG) on the COG website 
at: https://www.cogmembers.org/_files/disc/Pharmacy/ChemoAdminGuidelines.
pdf  for suggestions.  
 
Special precautions: Avoid use of aluminum containing needles or administration 
sets, since aluminum interacts with CISplatin causing black precipitate formation 
and loss of potency. The infusion solution should include at least 0.2% sodium 
chloride. CISplatin solutions should not be refrigerated to avoid precipitation. 
Protect from light. CISplatin is incompatible with sodium bicarbonate and alkaline 
solutions. Accidental extravasation with solutions that are > 0.5 mg/mL may result 
in significant tissue toxicity.   
 
Medication errors have occurred due to confusion between CISplatin (Platinol®) 
and CARBOplatin (PARAplatin®). 
 
Cyclophosphamide: IV over 30-60 minutes 
Days: 2 and 3 
Dose: 1000 mg/m2/dose. For patients with BSA < 0.45 m2 the dose is 
33 mg/kg/dose. 
Note: Administer cyclophosphamide after CISplatin administration. May be 
administered as undiluted drug (20 mg/mL, reconstitute with 0.9% NaCl only to 
avoid hypotonic solution) or further diluted.  
 
Mesna: IV (short or continuous infusion*) 
Days: 2 and 3 
Total IV Dose: 600 mg/m2/day. For patients with BSA < 0.45 m2 the dose is 
20 mg/kg/day. 
*IV short infusion:  For prophylaxis of hemorrhagic cystitis, the total daily mesna 
dose is equal to 60% of the daily cyclophosphamide dose and is administered in 3 
divided doses (200 mg/m2/dose or 6.7 mg/kg/dose if BSA < 0.45 m2) by short 
infusion over 15 to 30 minutes.  The initial bolus dose of mesna may be 
administered 15 minutes before or at the same time as the cyclophosphamide dose; 
subsequent doses are given 4 and 8 hours after the start of cyclophosphamide. Hour 
4 and 8 mesna can be given orally if the patient is able to tolerate oral intake 
(without vomiting).  
 
The oral dose of mesna is twice the IV dose. Patients may receive the last 
TWO bolus doses (originally at Hours 4 and 8) orally at 40% of the 
cyclophosphamide dose. The oral doses will be administered at Hours 2 and 6. For 
example: if the cyclophosphamide dose is 1,000 mg, then 200 mg of mesna will 
be given IV 15 minutes before or with the cyclophosphamide dose (Hour 0) and 
the TWO oral doses of 400 mg each will be given at Hours 2 and 6. 
  
This total daily dose can also be administered as IV continuous infusion. The 
continuous infusion should be started 1530 minutes before or at the same time as 

 
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cyclophosphamide and finished no sooner than 8 hours after the end of the 
cyclophosphamide infusion. 
 
Myeloid Growth Factor: Subcutaneous (preferred) or IV  
Start myeloid growth factor support (for example, G-CSF 5 mcg/kg/dose SubQ 
[preferred] or IV) 24 hours after myelosuppressive chemotherapy, until the ANC 
is > 1,500/µL after the expected nadir. Myeloid growth factor support need not be 
limited to filgrastim or biosimilar; pegfilgrastim is also permitted according to the 
institution‘s standard guidelines. May be continued without regard to vinCRIStine. 
Discontinue at least 24 hours before the start of the next chemotherapy cycle. 
 
See Section 5.0 for Dose Modifications based on Toxicities.  
 
Upon completion of one cycle, do not start the next cycle of Maintenance 
chemotherapy until 24 hours after the last dose of myeloid growth factor, and ANC 
> 1000/L and platelets > 100,000/L.  
 
Following completion of the first 3 cycles of Maintenance Therapy (with 
vincristine) proceed with cycle 4 of Maintenance Therapy (without vincristine). 
Cycle 4 of Maintenance Therapy is detailed in Section 4.6.3. See Section 4.6.4 for 
the Therapy Delivery Map for Maintenance Cycle 4.  
 
The therapy delivery map (TDM) for Maintenance Chemotherapy Cycles 1 
through 3 is on the next page. 

 
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4.6.2 
Maintenance Cycles 13  
Maintenance Cycles 13 
Maintenance should begin within 30 days after completion of radiation therapy. This course is for 
patients randomized to receive maintenance chemotherapy and for STR patients with residual 
disease after second surgery (see Section 4.2). This course consists of one 21-day cycle repeated 
three times. This Course lasts 9 weeks (63 days). This therapy delivery map relates to Cycles 1, 2, 
and 3 of Maintenance. See Section 4.6.4 for the Therapy Delivery Map for Maintenance Cycle 4. 
Use a copy of this page once for each cycle. (Please note cycle number below.) 
__________________________ 
Patient name or initials 
__________________________ 
DOB  
Criteria to start each cycle: ANC > 1000/L and platelets > 100,000/L, and no G-CSF administered for at least the preceding day (24 hours). 
Additional criteria to start Cycles 1 and 3: Adequate renal function. Details are in Section 4.0 (Treatment Overview). This course lasts 9 weeks (63 
days) and this TDM is on 1 page. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine  
(VCR) 
 
IV push over 1 
minute** 
1.5 mg/m2/dose 
or 
0.05 mg/kg/dose for pts with  
BSA < 0.45 m2 
1, 8 and 15 of 
Cycles 1-3 
only 
**Or infusion via minibag as per institutional 
policy. 
 
Maximum dose is 2 mg. 
 
 
a. 
History, Physical Exam, 
Weight, Height 
b. 
Neurologic Assessment 
c. 
MR Brain with gadolinium 
d. 
MR Spine with gadolinium 
e. 
Electrolytes (Ca++, PO4, 
Mg++, BUN) 
f. 
Serum Creatinine or GFR or 
Creatinine Clearance 
g. 
Liver function (ALT, AST, 
Bili) 
h. 
Urinalysis 
i. 
CBC (diff, platelets) 
j. 
Audiogram or BAER 
k. 
Echocardiogram or Ejection 
Fraction 
 
OBTAIN OTHER STUDIES AS 
REQUIRED FOR GOOD PATIENT 
CARE 
Etoposide 
(ETOP) 
IV over 60 -120 
minutes+ 
100 mg/m2/dose 
or  
3.3 mg/kg/dose for pts with 
BSA < 0.45 m2 
 
1, 2 and 3 
+Slow rate of administration if hypotension 
occurs. 
 
Administer immediately prior to CISplatin or 
cyclophosphamide administration. 
 
 
CISplatin 
(CDDP) 
IV over 1-8 hours 
(use institutional 
standards) 
100 mg/m2/dose 
or 
3.3 mg/kg/dose for pts with 
BSA < 0.45 m2  
1 
Hydrate patients before and after CISplatin 
administration.  See CAGs for suggestions. 
Cyclophosphamide 
(CPM) 
IV over 1 hour 
1000 mg/m2/dose 
or 
33 mg/kg/dose for pts with 
BSA < 0.45 m2  
2 and 3 
Administer after CISplatin administration. 
Mesna 
(MESNA) 
IV (Short or 
continuous [CI]) 
See Section 4.6. 
2 and 3 
Total IV dose: 600 mg/m2/day or  
20 mg/kg/day if BSA < 0.45 m2  
 
Administer concurrently with CPM.    
Myeloid Growth 
Factor 
SubQ (preferred) 
or IV 
See  Important Notes 
Daily,  
starting on Day 
4 
 Start myeloid growth factor support (for 
example, G-CSF 5 mcg/kg/dose SubQ 
[preferred] or IV) on Day 3, until the ANC is > 
1,500/µL after the expected nadir. May be 
continued without regard to vinCRIStine. 
Discontinue at least 24 hours before the start of 
the next chemotherapy cycle. 
Please enter Cycle # ________  
Ht_____cm 
    Wt____kg 
    BSA____m2 
Date 
Due 
Date 
Given 
Day 
VCR 
 
____mg 
ETOP 
 
____mg 
CDDP 
 
____mg 
CPM 
 
_____mg 
MESNA 
 
__mg  __mg  __mg 
Myeloid 
Growth 
Factor* 
Growth Factor  
Used: ______ 
___mcg 
Studies 
Comments (Include any 
held doses, or dose 
modifications) 
 
 
 
Enter calculated dose above and actual dose administered below. 
 
 
 
 
1 
____mg 
____mg 
____mg 
 
 
 
a, b,  c#, d#, e, 
f%, g, h, j, j, 
k# 
 
 
 
2 
 
____mg 
 
____mg 
__mg  __mg  __mg 
 
 
 
 
 
3 
 
____mg 
 
____mg 
__mg  __mg  __mg 
 
 
 
 
 
4 
 
 
 
 
 
____mcg  
 
 
 
 
8 
____mg 
 
 
 
 
 
a, e$, f$, g$, i  
 
 
 
15 
____mg 
 
 
 
 
 
a, e$, f$, g$, i 
 
 
 
21 
 
 
 
 
 
 
a, e$, f$, g$, i 
Indicate date of last  
myeloid growth factor dose 
_____ 
 
 
22 
Start next cycle of Maintenance on Day 22 or when cycle starting criteria are met (whichever 
occurs later). Patient must be off myeloid growth factor for at least 24 hrs before starting 
Cycles 2-4. 
 
 
OBSERVATION NOTES: 
* Stop myeloid growth factor at least 24 hours prior to next chemotherapy cycle. 
#  Obtain within 1 week prior to Cycle 1 only. 
$ Repeat weekly if abnormal. 
 
 
 
 
 
% Obtain prior to Cycle 1 and 3 only 
See Section 5.0 for Dose Modifications for Toxicities. For general Supportive Care Guidelines see  
https://childrensoncologygroup.org/index.php/cog-supportive-care-guidelines.
Page 1 of 1 

 
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4.6.3 
Maintenance Chemotherapy Cycle 4 
Note: Cycle 4 of Maintenance Therapy does NOT include vinCRIStine.  
 
Dose calculations should be based on actual BSA. There is no maximum 
dosing. 
 
 
 
Etoposide: IV over 60120 minutes  
Days: 1, 2, and 3 
Dose: 100 mg/m2/dose. For patients with BSA < 0.45 m2 the dose is 3.3 mg/kg. 
Note: Administer immediately prior to CISplatin or cyclophosphamide. Infuse as 
diluted solution (concentration ≤ 0.4 mg/mL); slow rate of administration if 
hypotension occurs. Rate should not exceed 300 mg/m2/hour (10 mg/kg/hour) 
(hypotension risk). The use of an in-line filter during the infusion is suggested. 
 
Special precautions: Etoposide can be mixed in 0.9% NaCl or D5W. Avoid use of 
large volumes of D5W due to potential development of hyponatremia. 
 
CISplatin: IV over 18 hours  
Day: 1 
Dose: 100 mg/m2/dose. For patients with BSA < 0.45 m2 the dose is 3.3 mg/kg. 
Note: Hydrate patients before and after CDDP administration. See the Parenteral 
Chemotherapy Administration Guidelines (CAG) on the COG website at: 
https://www.cogmembers.org/_files/disc/Pharmacy/ChemoAdminGuidelines.pdf  
for suggestions.  
 
Special precautions: Avoid use of aluminum containing needles or administration 
sets, since aluminum interacts with cisplatin causing black precipitate formation 
and loss of potency. The infusion solution should include at least 0.2% sodium 
chloride. CISplatin solutions should not be refrigerated to avoid precipitation. 
Protect from light. CISplatin is incompatible with sodium bicarbonate and alkaline 
solutions. Accidental extravasation with solutions that are > 0.5 mg/mL may result 
in significant tissue toxicity.   
 
Medication errors have occurred due to confusion between CISplatin (Platinol®) 
and CARBOplatin (PARAplatin®).   
 
Cyclophosphamide: IV over 3060 minutes 
Days: 2 and 3 
Dose: 1000 mg/m2/dose. For patients with BSA < 0.45 m2 the dose is 
33 mg/kg/dose. 
Note: Administer cyclophosphamide after CISplatin administration. May be 
administered as undiluted drug (20 mg/mL, reconstitute with 0.9% NaCl only to 
avoid hypotonic solution) or further diluted.  
 
Mesna: IV (short or continuous infusion*) 
Days: 2 and 3 
Total IV Dose: 600 mg/m2/day. For patients with BSA < 0.45 m2 the dose is 
20 mg/kg/day. 
*IV short or continuous infusion:  For prophylaxis of hemorrhagic cystitis, the 
total daily mesna dose is equal to 60% of the daily cyclophosphamide dose and is 
administered in 3 divided doses (200 mg/m2/dose or 6.7 mg/kg/dose if BSA < 0.45 
m2) by short infusion over 15 to 30 minutes.  The initial bolus dose of mesna may 

 
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Page 42 
be administered 15 minutes before or at the same time as the cyclophosphamide 
dose; subsequent doses are given 4 and 8 hours after the start of cyclophosphamide.  
 
Hour 4 and 8 mesna can be given orally if the patient is able to tolerate oral intake 
(without vomiting). The oral dose of mesna is twice the IV dose. Patients may 
receive the last TWO bolus doses (originally at Hours 4 and 8) orally at 40% of 
the cyclophosphamide dose. The oral doses will be administered at Hours 2 and 6. 
For example: if the cyclophosphamide dose is 1,000 mg, then 200 mg of mesna 
will be given IV 15 minutes before or with the cyclophosphamide dose (Hour 0) 
and the TWO oral doses of 400 mg each will be given at Hours 2 and 6. 
 
This total daily dose can also be administered as IV continuous infusion. The 
continuous infusion should be started 15-30 minutes before or at the same time as 
cyclophosphamide and finished no sooner than 8 hours after the end of the 
cyclophosphamide infusion. 
 
Myeloid Growth Factor: Subcutaneous (preferred) or IV  
Start myeloid growth factor support (for example, G-CSF 5 mcg/kg/dose SubQ 
[preferred] or IV) 24 hours after myelosuppressive chemotherapy, until the ANC 
is > 1,500/µL after the expected nadir. Myeloid growth factor support need not be 
limited to filgrastim or biosimilar; pegfilgrastim is also permitted according to the 
institution‘s standard guidelines. May be continued without regard to vinCRIStine. 
Discontinue at least 24 hours before the start of the next chemotherapy cycle. 
 
See Section 5.0 for Dose Modifications based on Toxicities.  
 
Following completion of the Cycle 4 of Maintenance Therapy, protocol therapy is 
complete. See Section 7.0 for required observations following end of therapy.   
 
The therapy delivery map (TDM) for Maintenance Chemotherapy Cycle 4 is on 
the next page.

 
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4.6.4 
Maintenance Cycle 4 
  
Maintenance Cycle 4 
This course is for patients randomized to receive maintenance chemotherapy and for 
STR patients with residual disease after second surgery (see Section 4.2). Cycle 4 of 
Maintenance Chemotherapy consists of one 21-day cycle.  
This therapy delivery map relates to Cycle 4 of Maintenance.  
           
 ____________________________ 
       Patient name or initials 
____________________________ 
DOB  
Criteria to start this cycle: ANC > 1000/L and platelets > 100,000/L with no G-CSF administered for at least the preceding day 
 (24 hours). Details are in Section 4.0 (Treatment Overview) and Section 4.6.3. This cycle lasts 21 days and this TDM is on 1 page. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Etoposide 
(ETOP) 
IV over 
60120 
minutes+ 
100 mg/m2/dose 
or  
3.3 mg/kg/dose for pts 
with BSA < 0.45 m2 
 
1, 2 and 3 
+Slow rate of administration if 
hypotension occurs. 
 
Administer immediately prior to 
cisplatin or cyclophosphamide 
administration. 
a. 
History, Physical Exam, Weight, 
Height 
b. 
Neurologic Assessment 
c. 
MR Brain with gadolinium 
d. 
MR Spine with gadolinium 
e. 
Electrolytes (Ca++, PO4, Mg++, 
BUN) 
f. 
Liver function (ALT, AST, Bili) 
g. 
Urinalysis 
h. 
CBC (diff, platelets) 
i. 
Audiogram or BAER 
j. 
Serum Creatinine or GFR or 
Creatinine Clearance 
 
 
OBTAIN OTHER STUDIES AS 
REQUIRED FOR GOOD PATIENT 
CARE 
CISplatin 
(CDDP) 
IV over 18 
hours (use 
institutional 
standards) 
100 mg/m2/dose 
or 
3.3 mg/kg/dose for pts 
with BSA < 0.45 m2  
1 
Hydrate patients before and after 
CISPlatin administration.  See CAGs 
for suggestions. 
Cyclophosphamide 
(CPM) 
IV over 1 
hour 
1000 mg/m2/dose 
or 33 mg/kg/dose for pts 
with BSA < 0.45 m2  
2 and 3 
Administer after CISplatin 
administration. 
Mesna 
(MESNA) 
IV (Short or 
continuous 
[CI]) 
See Section 4.6. 
2 and 3 
Total IV dose: 600 mg/m2/day or  
20 mg/kg/day if BSA < 0.45 m2  
Administer concurrently with 
cyclophosphamide.    
Myeloid Growth 
Factor 
SubQ 
(preferred) 
or IV 
See Important Notes 
Daily,  
starting on Day 4 
 Start myeloid growth factor support 
(for example, G-CSF 5 mcg/kg/dose 
SubQ [preferred] or IV) on Day 3, 
until the ANC is > 1,500/µL after the 
expected nadir. Discontinue at least 
24 hours before the start of the next 
chemotherapy cycle.  
 
 
Ht_____cm 
    Wt____kg 
 
     BSA____m2 
Date 
Due 
Date 
Given 
Day 
ETOP 
 
____mg 
CDDP 
 
____mg 
CPM 
 
_____mg 
MESNA 
 
__mg  __mg  __mg 
Myeloid 
Growth Factor 
Growth Factor  
Used: _______ 
_________mcg 
Studies 
Comments (Include 
any held doses, or dose 
modifications) 
 
 
 
Enter calculated dose above and actual dose administered below. 
 
 
 
 
1 
____mg 
____mg 
 
 
 
a, b, e, f, g, h, i, 
j$ 
 
 
 
2 
____mg 
 
____mg 
__mg  __mg  __mg 
 
 
 
 
 
3 
____mg 
 
____mg 
__mg  __mg  __mg 
 
 
 
 
 
4 
 
 
 
 
____mcg 
 
 
 
 
8 
 
 
 
 
 
a, e$, f$, h, j$ 
 
 
 
15 
 
 
 
 
 
a, e$. f$, h, j$  
 
 
 
21 
 
 
 
 
 
 
Indicate date of last 
myeloid growth factor 
dose _____ 
 
 
22 
After Cycle 4 of Maintenance Chemotherapy, protocol therapy is complete. 
Refer to Section 7.0 for end of therapy required observations.  
 
OBSERVATION NOTES: 
$ Repeat weekly if abnormal. 
See Section 5.0 for Dose Modifications for Toxicities. For general Supportive Care Guidelines see  
https://childrensoncologygroup.org/index.php/cog-supportive-care-guidelines. 
  
 
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5.0 
DOSE MODIFICATIONS FOR TOXICITIES 
 
5.1 
Dose Modifications during Induction Chemotherapy 
 
5.1.1 
Carboplatin  
 
5.1.1.1 Nephrotoxicity 
If estimated creatinine clearance using the Schwartz formula drops below 
the normal range, 24-hour creatinine clearance or radionuclide GFR 
should be performed.  
 
Carboplatin should be dose-modified as below for renal insufficiency: 
GFR 
(mL/min/1.73 m2) 
Carboplatin Dose 
> 70 
50- 69 
25-49 
< 24 
375 mg/m2 (12.5 mg/kg for < 0.45 m2) 
280 mg/m2 (9.3 mg/kg for < 0.45 m2) 
187 mg/m2 (6.2 mg/kg for < 0.45 m2) 
none 
 
5.1.1.2 Ototoxicity 
Careful monitoring of children by expert audiologist and by serial 
audiometry throughout the treatment with carboplatin is recommended. 
Otoacoustic emissions (OAE) are the clinical methodology of choice for 
initial testing. If these are normal, patients do not need further evaluation, 
and should be coded as having no hearing loss. If they are abnormal, then 
brainstem evoked auditory responses (BAER) or pure tone audiometry 
should be used to more specifically describe the hearing loss. A decrease 
in auditory acuity at frequencies above 4000 Hz is expected and does not 
constitute a contraindication to further therapy. For Grades 0, 1, and 
2 ototoxicity (CTCAE) no dose modification is recommended. For Grade 
3 toxicity, a 50% reduction should be made in the carboplatin dosage. For 
Grade 4 ototoxicity, carboplatin can be continued at 50% dose reduction 
or at the discretion of treating physician and family. 
 
 
5.1.1.3 Allergic Reactions 
Carboplatin allergic reactions may be managed with pre-medications such 
as diphenhydramine 1 mg/kg IV (maximum dose 50 mg), ranitidine 
1 mg/kg IV (maximum dose 50 mg), and hydrocortisone 4 mg/kg IV 
(maximum dose 100 mg).   
 
5.1.2 
Etoposide 
 
5.1.2.1 Nephrotoxicity 
In patients with impaired renal function, the following initial dose 
modification should be considered based on measured creatinine 
clearance: 

 
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Measured CrCL 
 
> 50 mL/min/1.73m2 
 
15-50 mL/min/1.73m2 
 
Etoposide Dose 
 
100% of Dose 
 
75% of Dose 
 
Subsequent dosing should be based on patient tolerance and clinical effect. 
Data are not available in patients with creatinine clearances of < 15 
mL/min and further dose reduction should be considered in these patients. 
 
5.1.2.2  Hepatotoxicity 
If the direct bilirubin is between 2 and 3 mg/dL, give 50% of the calculated 
dose of etoposide. If the direct bilirubin is > 3 mg/dL, hold the etoposide. 
Full dose may resume when the direct bilirubin has fallen to  
< 1.2 mg/dL. 
 
5.1.2.3  Allergic Reactions 
Etoposide allergic reactions may be managed with pre-medications such 
as diphenhydramine 1 mg/kg IV (maximum dose 50 mg), ranitidine 
1 mg/kg IV (maximum dose 50 mg), and hydrocortisone 4 mg/kg IV 
(maximum dose 100 mg), and by slowing the rate of the infusion. For those 
reactions which are unable to be controlled with pre-medication and 
slowing of the rate of etoposide infusion, etoposide phosphate may be 
substituted in the same dose and at the same rate. Pre-medication for 
etoposide phosphate is recommended. 
 
5.1.3 
Vincristine 
 
5.1.3.1 Vincristine Neurotoxicity 
Seizures: Hold one (1) dose of vincristine, then reinstitute at 1 mg/m2 or 0.03 
mg/kg (for patients < 0.45 m2) (1.5 mg maximum dose) while 
anticonvulsants are continued. If seizures do not recur, then escalate to full 
dosage. Rule out syndrome of inappropriate secretion of antidiuretic 
hormone (SIADH) as a cause of seizures. In patients with supratentorial 
tumors or with leptomeningeal disease, it may be impossible to distinguish 
tumor-related seizures from vincristine-related seizures. In such cases, 
careful evaluation of anticonvulsant levels and clinical status should be made 
prior to attributing seizures to vincristine and decreasing or holding 
vincristine doses. 
 
Severe neuropathic pain (Grade 3 or greater): Hold dose(s). When 
symptoms subside, resume at 50% previous calculated dose (maximum dose: 
1 mg), then escalate to full dose as tolerated. However, since vincristine is 
an important component of curative therapy, and the majority of 
neuropathies are ultimately reversible, treating physicians may choose to 
deliver full dose therapy. Severe peripheral neuropathies, with or without a 
positive family history might suggest the need for a molecular diagnostic 
evaluation to rule out Charcot Marie Tooth Disease (CMT), Type 1A or 
Hereditary neuropathy with liability to pressure palsies. 
 
Foot Drop, paresis: Should be Grade 4 to consider holding or decreasing 
dose. These toxicities are largely reversible, though possibly over months to 

 
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years. Accordingly, holding doses of vincristine and/or lowering the dose 
may not result in rapid resolution of symptoms and may compromise cure. 
See above for comment on CMT. Physical therapy may be beneficial to 
maintain range of motion and provide ankle-foot orthoses (AFOs) and other 
forms of support. Drugs such as gabapentin may be of value. 
 
Vocal Cord Paralysis:  Hold dose(s). When symptoms subside, resume at 
50% of previous calculated dose, then escalate to full dose as tolerated. See 
above for comment on CMT. 
 
5.1.3.2 Jaw Pain 
Treat with analgesics; do not modify vincristine dose unless determined to 
be in the best interest of the patient by the treating physician. 
 
5.1.3.3 Hepatotoxicity 
If direct bilirubin is greater than 6 mg/dL hold vincristine dose. If direct 
bilirubin is 3.16 mg/dL then follow guidelines below. For direct bilirubin 
less than 3.1 mg/dL administer vincristine at full dose. 
 
Direct Bilirubin Level (mg/dL) 
Vincristine Dose Reduction 
 
< 3.1 
 
Administer Full Dose (maximum dose 2 mg) 
3.1-5 
 
Administer at 50% of calculated dose 
(maximum dose 1 mg) 
 
5.1- 6 
 
Administer at 75% of calculated dose 
(maximum dose 0.5 mg) 
 
> 6 
 
Withhold dose and administer next scheduled 
dose if toxicity has resolved. Do not make up 
missed doses. 
 
5.1.3.4 Constipation or Ileus  
Constipation or ileus (≥ Grade 3) or typhlitis: Hold dose(s); institute 
aggressive regimen to treat constipation if present. When symptoms abate 
resume at 50% of calculated dose (maximum dose: 1 mg) and escalate to 
full dose as tolerated. 
 
5.2 
Dose Modifications during Maintenance Chemotherapy 
 
 
5.2.1 
Cisplatin 
 
5.2.1.1 Hypomagnesemia 
As a consequence of renal tubular wastage of magnesium caused by cisplatin, 
hypomagnesaemia can develop. It may become symptomatic manifested by 
paresthesias, muscle cramps, weakness and occasionally disorientation or 
seizures. If this occurs, magnesium should be given orally or intravenously. 

 
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Prophylactic administration of magnesium (12 gm/L) in cisplatin hydration 
can be used to prevent low levels of magnesium. 
 
5.2.1.2 Sensorineural Ototoxicity 
Careful monitoring of children by expert audiologist and by serial 
audiometry throughout the treatment with Cisplatin is recommended. 
Audiometry prior to each maintenance cycle is recommended. Otoacoustic 
emissions (OAE) are the clinical methodology of choice for initial testing. 
If these are normal, patients do not need further evaluation, and should be 
coded as having no hearing loss. If they are abnormal, then brainstem 
evoked auditory responses (BAER) or pure tone audiometry should be 
used to more specifically describe the hearing loss. Adjust dose as below 
for unilateral or bilateral hearing loss. Use CTC 4.0 to grade ototoxicity. 
For Grade 1 ototoxicity (defined as threshold shift >20 dB at 8 kHz in at 
least one ear) reduce cisplatin by 25% of the total dose. For Grade 2 
ototoxicity, defined as Threshold shift >20 dB at 4 kHz and above in at 
least one ear); reduce the dose by 50% of the total dose. For Grade 3 
(threshold shift > 20 dB at 3 kHz or above in one ear; hearing loss 
sufficient to indicate therapeutic intervention) or Grade 4 ototoxicity 
(audiologic indication for cochlear implant and additional speech-
language related services indicated) cisplatin should be deleted and not 
restarted. 
 
5.2.1.3 Nephrotoxicity 
If Cr Clearance/GFR is greater than 60 mL/min/1.73m2 and has not 
dropped by more than 50% from original pre-chemotherapy baseline then 
give full dose Cisplatin. If Cr Clearance/GFR is 5060 mL/min/1.73m2 or 
has decreased by more than 50% of original pre-chemotherapy baseline, 
but is still  50 mL/min/1.73m2, then give 75% dose of Cisplatin.  If Cr 
Clearance/GFR is less than 50 mL/min/1.73m2 then omit cisplatin. 
 
 
5.2.2 
Cyclophosphamide  
 
5.2.2.1 Hematologic 
If chemotherapy is due and the absolute neutrophil count is below 1000/L 
or the platelet count is less than 100,000/L, the next cycle of 
chemotherapy should be delayed. Repeat CBC and platelet count twice-
weekly. The next cycle of therapy should be administered when the ANC 
> 1000 and the platelet count > 100,000, but the dose of cyclophosphamide 
should be reduced by 25% (i.e., each daily dose should be reduced by 
25%). 
 
If there is a delay more than 2 weeks and the patient has received a dose 
reduction in a previous cycle and if the ANC is above 750/L but below 
1,000/L or the platelet count is > 75,000/L but below 100,000/L, the 
next cycle of therapy should be administered, but the dose of 
cyclophosphamide should be reduced by an additional 25% (i.e., each 
daily dose should be reduced by 50%). Subsequent cycles should be given 
at full dose as long as counts recover on time. 
 

 
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5.2.2.2 Hemorrhagic Cystitis 
 
Microscopic Hematuria 
For transient microscopic hematuria (no more than 2 abnormal urinalyses 
on 2 separate days during a cycle of therapy), do not modify the 
cyclophosphamide dose. Add hydration and deliver mesna as a continuous 
infusion at 60% of the daily cyclophosphamide dose. 
 
Hydration: administer 3000 mL/m²/day (125 mL/m²/hour) using fluid 
containing at least 0.45% NaCl. Achieve urine specific gravity ≤ 1.010 
prior to start of cyclophosphamide. May use diuretics (like furosemide) to 
increase urine output. 
 
Mesna:  Start with a total daily mesna dose that is equal to 60% of the daily 
cyclophosphamide dose administer in 3 divided doses by short infusion 
over 15 to 30 minutes. The initial bolus dose of mesna may be 
administered 15 minutes before or at the same time as the 
cyclophosphamide dose; subsequent doses are given 4 and 8 hours after 
the start of cyclophosphamide. This total daily dose can also be 
administered as IV continuous infusion. The continuous infusion should 
be started 15-30 minutes before or at the same time as cyclophosphamide 
and finished no sooner than 8 hours after the end of the cyclophosphamide 
infusion. The oral dose of mesna is twice the IV dose.  Patients able to 
tolerate oral mesna may receive the last TWO bolus doses (originally at 
Hours 4 and 8) orally at 40% of the cyclophosphamide dose. The oral 
doses will be administered at Hours 2 and 6. Examples are available in the 
Chemotherapy Administration Guidelines. 
 
For persistent microscopic hematuria ( > 2 abnormal urinalyses during a 
cycle of therapy), increase hydration to 35004000 mL/m2/day and daily 
mesna dose to 100% of the cyclophosphamide dose at the schedule 
described above at the next cycle. 
 
Gross Hematuria 
All episodes of gross hematuria should be evaluated in conjunction with a 
pediatric surgical consult. Further testing, such as cystoscopy, urine 
culture, excretory urogram, and voiding cystogram should be considered 
based on good clinical judgement. 
  
For transient gross hematuria (only 1 episode, which clears to less than 
gross hematuria) during or following a cycle of therapy, do not modify 
cyclophosphamide dose. Use hydration and continuous infusion mesna at 
100% of the cyclophosphamide dose. 
 
 
For persistent gross hematuria after completion of a cycle of therapy, hold 
subsequent cyclophosphamide until the urine clears to less than gross 
hematuria. Reinstitute cyclophosphamide at full dose, with hydration and 
the mesna at 100% of the cyclophosphamide dose given as continuous 
infusion. For occurrence of a second episode of gross hematuria or 
persistence of microscopic hematuria on the continuous infusion regimen, 
continue the cyclophosphamide when the urine clears to less than gross 

 
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hematuria. For persistent gross hematuria on the mesna continuous 
infusion regimen, discontinue cyclophosphamide. 
 
5.2.2.3 Nephrotoxicity 
In patients with a measured creatinine clearance < 10 mL/min/1.73 m2, 
decrease dose by 25% (give 75% of initial dose). 
 
5.2.2.4 Hepatotoxicity 
The overall pharmacokinetics of cyclophosphamide are not significantly 
altered in the presence of hepatic insufficiency. Although there is evidence 
to suggest that toxicity may be greater in hepatic insufficiency, 
recommendations for dosage adjustment in the presence of hepatic failure 
have not been established. Consider dose adjustments according to 
institutional guidelines. 
 
5.2.3 
Etoposide 
See dose modifications during induction chemotherapy above (Section 5.1). 
 
5.2.4 
Vincristine 
See dose modifications during induction chemotherapy above (Section 5.1). 
 
 
 
6.0 
DRUG INFORMATION 
 
See the consent document for toxicities. All other information is available on the COG website in 
the Commercial Agents Monographs (https://www.cogmembers.org/_files/disc/pharmacy/ 
CommercialAgentsMonographs.pdf) and is provided under Standard Sections for Protocols at:  
https://cogmembers.org/site/pages/default.aspx?page=Prot_reference_materials.  
 
 
7.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
All baseline studies must be performed prior to starting protocol therapy unless otherwise indicated 
below.  
 
 
 
 
 
 
 
 
 
Timing of protocol therapy administration, response assessment studies, and surgical 
interventions are based on schedules derived from the experimental design or on established 
standards of care.  Minor unavoidable departures (up to 72 hours) from protocol directed therapy 
and/or disease evaluations (and up to 1 week for surgery) for valid clinical, patient and family 
logistical, or facility, procedure and/or anesthesia scheduling issues are acceptable per COG 
Administrative Policy 5.14 (except where explicitly prohibited within the protocol).  

 
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7.1 
Required Clinical, Laboratory and Disease Evaluations for STR (Incomplete Resection) Patients  
Supratentorial patients with classic histology who achieve a CR following Induction or a GTR1 following Second Surgery will 
move to the Observation Arm of the study. (See Section 7.4 for required observations).  
 
Supratentorial patients with anaplastic histology and all Infratentorial patients who achieve a CR following Induction or a 
GTR/NTR following Second Surgery will be randomized. (See Section 7.2 and Section 7.3 for required observations).  
 
STUDIES TO BE OBTAINED 
Study 
Entry 
Prior to 
Induction 
During 
Induction 
Prior to 
Second 
Surgery 
Following 
Second 
Surgery 
Prior to 
cRT 
During 
cRT 
Within 1 
Week Prior to 
Maintenance 
During 
Maintenance 
Completion of 
Therapy 12 
History, Physical Exam, Weight and Height  
X 
X 
Prior to each 
Cycle 
X 
 
X 
Every other 
week 
X 
Weekly  
X 
Neurologic Assessment 
 
X 
Prior to each 
Cycle 
X 
X 
X 
Every other 
week 
X 
Prior to each 
Cycle 
X 
MR Brain with gadolinium 
 X 3 
 X 5 
X10 
 
 X 3 
X 7 
 
X 
 
 X 
MR Spine with gadolinium 
 X 4 
 
X10 
 
 
 
 
X 
 
 X 
Lumbar CSF Cytology 1 
        X 
 
 
 
 
 
 
 
 
 
Electrolytes  
(including Ca++, PO4, Mg++, BUN) 
 
X 
Prior to each 
Cycle 6 
 
 
 
 
X 
Prior to each 
Cycle 6 
X 
Serum Creatinine or GFR or Creatinine 
Clearance 
 
X 
Prior to each 
Cycle 6 
 
 
 
 
X 
 X 11 
 
Liver Function (ALT, AST, Total Bili) 
 
X 
Prior to each 
Cycle 6 
 
 
 
 
X 
Prior to each 
Cycle 6 
X 
Urinalysis 
 
X 
Prior to each 
Cycle 
 
 
 
 
X 
Prior to each 
Cycle 
X 
CBC (w/Differential and Platelets)  
 
X 
Weekly 
 
 
X 
 
X 
Weekly 
X 
Audiogram or BAER 
 
X 
Prior to each 
Cycle 
 
 
X 
 
X 
Prior to each 
Cycle 
X 
Echocardiogram or  Ejection Fraction 
 
 
 
 
 
 
 
X 
 
 
Required Pathology Specimens  
(see Section 14.0) 
X 
 
 
  
X 
 
 
 
 
 
Ophthalmology Evaluation 9 
X 
 
 
 
 
X 
 
 
 
X 
Endocrine Evaluation 2 
 
 
 
 
 
X 
 
 
 
X 
Pregnancy Test 8 
X 
 
 
 
 
 
 
 
 
 
Studies obtained for the end of one time point can be used for the beginning of the next timepoint if timing requirements are met.  
 
1. 
Obtain unless lumbar puncture is contraindicated and deemed medically unsafe. 

 
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2.     Endocrine evaluation to include: TSH/free T4 or alternative and growth hormone. Tanner Stage (See Appendix II) and LH/FSH and Estradiol/testosterone if child has delay 
puberty or precocious puberty before age 8 in girls or 9 in boys beginning at age 11 or with signs of precocious puberty.  Cortisol (8 am) - begin screening at age 11 or with 
signs of precocious puberty.  
3. 
Obtain both pre and post-surgery.  Post-op should be done within 72 hours.  When the post-operative scan obtained within 72 hours is difficult to interpret, the scan should be 
repeated 10 or more days after surgery. 
4. 
Obtain within 10 days prior to surgery or attempt to wait 10 days after surgery; should be performed with gadolinium.  
5. 
If post-op cranial MRI was performed > 21 days before the first day of chemo, repeat cranial MRI with gadolinium to provide an appropriate baseline. 
6. 
Repeat weekly if abnormal. 
7. 
Preferably the scan should be performed within 21 days of beginning radiation and MUST be performed within 28 days of beginning RT. (Post-op imaging can be used). 
8. 
Obtain for females of childbearing potential. 
9. 
Prior to study enrollment is preferred although within 4 months of beginning RT is acceptable. 
10. 
Obtain neuroimaging between Days 21-29 of Induction Cycle B. 
11. 
Obtain prior to cycles 1 and 3 of Maintenance. Repeat weekly if abnormal. 
12. 
For patients who complete therapy following RT, obtain 4 weeks after completion of therapy. 
 
 
 
This table only includes evaluations necessary to answer the primary and secondary aims. Obtain other studies as indicated for good clinical 
care.  
 

 
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7.2 
Required Clinical, Laboratory and Disease Evaluations for Patients Randomized to Radiation 
Therapy followed by Maintenance Chemotherapy 
 
STUDIES TO BE OBTAINED 
Study 
Entry 
Prior to 
cRT 
During 
cRT 
Within 1 
Week Prior to 
Maintenance 
During 
Maintenance 
 
Four Weeks 
After 
Completion of 
Therapy10 
History, Physical Exam, Weight and Height 
X 
X 
Every other 
week 
X 
Weekly 
X 
Neurologic Assessment 
 
X 
Every other 
week 
X 
Prior to each 
Cycle 
X 
MR Brain with gadolinium 
X3 
X6 
 
X 
 
X 
MR Spine with gadolinium 
X4 
 
 
X 
 
X 
Lumbar CSF Cytology 1 
X 
 
 
 
 
 
Electrolytes 
(including Ca++, PO4, Mg++, BUN) 
 
 
 
X 
Prior to each 
Cycle 5 
X 
Serum Creatinine or GFR or Creatinine 
Clearance 
 
 
 
X 
X9 
 
Liver Functions (ALT, AST, Total Bili) 
 
 
 
X 
Prior to each 
Cycle 5 
X 
Urinalysis 
 
 
 
X 
Prior to each 
cycle 
X 
CBC (w/Differential and Platelets) 
 
X 
 
X 
Weekly 
X 
Audiogram or BAER 
 
X 
 
X 
Prior to each 
cycle 
X 
Echocardiogram or  Ejection Fraction 
 
 
 
X 
 
 
Required Pathology Specimens 
(see Section 14.0) 
X 
 
 
 
 
 
Ophthalmology Evaluation8 
X 
X 
 
 
 
X 
Endocrine Evaluation2 
 
X 
 
 
 
X 
Pregnancy Test 7 
X 
 
 
 
 
 
Studies obtained for the end of one time point can be used for the beginning of the next timepoint if 
timing requirements are met.  
 
1. 
Obtain unless lumbar puncture is contraindicated and deemed medically unsafe. 
2. 
 Endocrine evaluation to include: TSH/free T4 or alternative and growth hormone. Tanner Stage (See Appendix II) and LH/FSH 
and Estradiol/testosterone if child has delay puberty or precocious puberty before age 8 in girls or 9 in boys beginning at age 11 
or with signs of precocious puberty.  Cortisol (8 am) - begin screening at age 11 or with signs of precocious puberty.  
3. 
Obtain both pre and post-surgery.  Post-op should be done within 72 hours.  When the post-operative scan obtained within 72 hours 
is difficult to interpret, the scan should be repeated 10 or more days after surgery. 
4. 
Obtain within 10 days prior to surgery or attempt to wait 10 days after surgery; should be performed with contrast.  
5. 
Obtain prior to each cycle; repeat weekly if abnormal. 
6. 
Preferably the scan should be performed within 21 days of beginning radiation and MUST be performed within 28 days of 
beginning RT. (Post-op imaging can be used). 
7. 
Obtain for females of childbearing potential. 
8. 
Prior to study enrollment is preferred although within 4 months of beginning RT is acceptable. 
9. 
Obtain prior to cycles 1 and 3 of Maintenance. Repeat weekly if abnormal. 
10. 
Obtain all requirements 4 weeks after completion of therapy. 
 
 
 

 
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7.3  
Required Clinical, Laboratory and Disease Evaluations for Patients Randomized to Receive 
Radiation Therapy followed by Observation  
 
STUDIES TO BE OBTAINED 
Study 
Entry 
Prior to 
cRT 
During 
cRT 
 
4 Weeks 
After 
Completion 
of Therapy 
History, Physical Exam , Weight  and 
Height 
         X 
X 
Every other 
week 
X 
Neurologic Assessment 
          
X 
Every other 
week 
X 
MR Brain with gadolinium 
X3 
X5 
 
X 
MR Spine with gadolinium 
X4 
 
 
X 
Lumbar CSF Cytology 1 
        X 
 
 
 
CBC (w/Differential and Platelets) 
 
X 
 
X 
Audiogram or BAER 
 
X 
 
X 
Required Pathology Specimens  
(see Section 14.0) 
X 
 
 
 
Ophthalmology Evaluation7 
X 
X 
 
X 
Endocrine Evaluation2 
 
X 
 
X 
Pregnancy Test 6 
X 
 
 
 
Studies obtained for the end of one time point can be used for the beginning of the 
next timepoint if timing requirements are met.  
 
1. 
Obtain unless lumbar puncture is contraindicated and deemed medically unsafe. 
2. 
 Endocrine evaluation to include: TSH/free T4 or alternative and growth hormone. Tanner Stage (See 
Appendix II) and LH/FSH and Estradiol/testosterone if child has delay puberty or precocious puberty 
before age 8 in girls or 9 in boys beginning at age 11 or with signs of precocious puberty.  Cortisol (8 
am) - begin screening at age 11 or with signs of precocious puberty.  
3. 
Obtain both pre and post-surgery.  Post-op should be done within 72 hours.  When the post-operative 
scan obtained within 72 hours is difficult to interpret, the scan should be repeated 10 or more days after 
surgery. 
4. 
Obtain within 10 days prior to surgery or attempt to wait 10 days after surgery; should be performed 
with contrast.  
5. 
Preferably the scan should be performed within 21 days of beginning radiation and MUST be 
performed within 28 days of beginning RT. (Post-op imaging can be used). 
6. 
Obtain for females of childbearing potential. 
7. 
Prior to study enrollment is preferred although within 4 months of beginning RT is acceptable. 
 

 
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7.4 
Required Observations For Supratentorial Classic Ependymoma GTR1 Patients (Observation) 
 
 
 
Observation 
(Time measured from 
date of enrollment) 
 
Study 
Entry 
 
4 
Months 
 
8 
Months 
 
12 
Months 
 
 
16 
Months 
 
20 
Months 
 
24 
Months 
 
28 
Months 
 
32  
Months 
 
36 
Months 
 
42 
Months 
 
48 
Months 
 
54 
Months 
 
60 
Months  
Then 
Annually 
History and Physical  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height, Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Neurologic Assessment 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
MR Brain with 
gadolinium 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MR Spine1 (with 
gadolinium) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
CSF Cytology 2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Audiogram or BAER 
X 
 
 
X4 
 
 
X4 
 
 
X4 
 
X4 
 
X4 
Ophthalmology 
Evaluation 
X 
 
 
X4 
 
 
X4 
 
 
X4 
 
X4 
 
X4 
Endocrine Evaluation 3 
X 
 
 
X4 
 
 
X4 
 
 
X4 
 
X4 
 
X4 
Required Pathology 
Specimens (see 
Section 14.0) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1. 
Repeat if new symptoms develop or if patient has local recurrence. 
2. 
Obtain unless lumber puncture is contraindicated and deemed medically unsafe. Must be negative at baseline, otherwise patients is excluded.  
3. 
Endocrine evaluation to include: TSH/free T4 or alternative and growth hormone. Tanner Stage (see Appendix II) and LH/FSH and Estradiol/testosterone if child has 
delayed puberty or precocious puberty before age 8 in girls or 9 in boys beginning at age 11 or with signs of precocious puberty.  Cortisol (8 am) - begin screening at age 
11 or with signs of precocious puberty.  
4. 
Repeat only if clinically indicated or abnormal at baseline. 
  
 

 
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7.5 
Optional Studies  
 
The following specimens and evaluations are optional depending on whether or not the 
patient has signed an informed consent for them. If patient consents, send tumor tissue and 
peripheral blood according to collection and shipping instructions in Section 15.0. 
 
7.5.1 
Biology Specimens 
With Amendment 3, the tissue samples will be utilized as is detailed in Section 2.2 
and Section 9.4. 
 
Study 
Sample 
When  
Gene expression 
microarray 
Snap frozen tumor tissue 
At time of diagnosis and 
second surgery 
Genomic hybridization 
(GCH) array 
Snap frozen or paraffin 
embedded tumor tissue 
 
Peripheral Blood (5 cc in 
a green top tube [sodium 
heparin]) 
 
Peripheral Blood (5 cc in 
a yellow top tube [ACD]) 
 
Peripheral Blood (5 cc of 
blood in a purple top tube 
[EDTA]) 
At diagnosis 
 
 
Prior to treatment and at 
time of second surgery 
 
 
Prior to treatment and at 
time of second surgery 
 
 
Prior to treatment and at 
time of second surgery 
 
Telomere length 
Snap frozen tumor tissue 
 
At diagnosis 
 
Telomerase activity, 
(all consenting patients) 
Snap frozen tumor tissue 
 
At time of second 
surgery 
hTert expression, and 
hTERC 
Paraffin block 
At time of resection(s) 
gammaH2AX  
Paraffin block 
At time of resection(s) 
  
7.5.2 
Neuropsychologic Evaluations 
Patients who consent to participate on ALTE07C1 will be assessed at three times 
points, in accordance with the COG Standard Neuropsychological Battery: At 
9 months (± 3 months) post cancer diagnosis; at 30 months (± 3 months) post 
diagnosis, and again at 60 months (± 3 months) post diagnosis. Age appropriate 
tests will be used and will include measures of broad cognitive functioning 
(Wechsler Abbreviated IQ) and specific areas of neuropsychological functioning 
(i.e., Visual-motor processing speed (Wechsler Processing Speed Index)), 
Working memory (Wechsler Working Memory Index), Auditory-verbal (list 
learning, CVLT and narrative memory CMS tasks) and Visual (dot location and 
faces from CMS learning and memory), emotional-behavioral functioning (BASC-
2 internalizing and externalizing composite scores), functional adaptive skills 
(ABAS-II General Adaptive Composite, a global measure of adaptive (practical, 
conceptual, social) daily living skills), and quality of life (PedsQL Physical and 
Psychosocial Summary Scores). Total testing time should be approximately 1 hour 
at each assessment point. 

 
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7.6 
Follow-up 
 
Required Observations Following Protocol Therapy for all patients other than Observation Arm 
 
 
Observations 
(Dated from Completion of 
Therapy) 
 
4 
Months 
 
8 
Months 
 
 
12 
Months 
 
16 
Months 
 
20 
Months 
 
24 
Months 
 
28 
Months 
 
32 
Months 
 
36 
Months 
 
42 
Months 
 
48 
Months 
 
54 
Months 
 
60 
Months 
Then 
Annually 
History, Physical Exam 
(incl. Ht, Wt, VS) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MR Brain with gadolinium 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Neurologic Assessment 
X 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
MR Spine1  with 
gadolinium  
 
 
X 
 
 
X 
 
 
 
 
 
 
 
Audiogram or BAER  
 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
Ophthalmology 
Evaluation 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
Endocrine Evaluation2 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
1. 
Perform at the indicated time points and repeat if new symptoms develop. 
2. 
Endocrine evaluation to include: TSH/free T4 or alternative and growth hormone annually. Tanner Stage and LH/FSH and Estradiol/testosterone 
at baseline if child has delayed puberty or precocious puberty before age 8 in girls or 9 in boys and then at end of therapy/annually beginning at 
age 11 or with signs of precocious puberty.  Cortisol (8 am) at end of therapy/annually - begin screening at age 11 or with signs of precocious 
puberty. 
 
See COG Late Effects Guidelines for recommended post treatment follow-up http://www.survivorshipguidelines.org 
 

 
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8.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA  
 
8.1 
Criteria for Removal from Protocol Therapy 
 
a) 
Development of distant progressive disease at any point during study 
b) 
Local disease progression at any time during the study EXCEPT patients with sub-
total resection (STR) who experience local disease progression prior to maintenance 
chemotherapy. These patients will NOT be removed from protocol therapy (see 
definition in Section 10.4). 
c) 
Refusal of further protocol therapy by patient/parent/guardian. 
d) 
Completion of planned therapy. 
e) 
Physician determines it is in patient’s best interest. 
f) 
Development of a second malignancy. 
g) 
Treating physician chooses to proceed with treatment according to the institutional 
review rather than the results from rapid central review.  
h) 
Supratentorial patients who do not have an ependymoma on rapid central pathology 
review. 
 
Patients who are off protocol therapy are to be followed until they meet the criteria for Off 
Study (see below).  
 
8.2 
Off Study Criteria 
 
a) 
Death. 
b) 
Lost to follow-up. 
c) 
Patient enrollment onto another COG study with tumor therapeutic intent (e.g., at 
recurrence). 
d) 
Withdrawal of consent for any further data submission. 
e) 
Tenth anniversary of the date the patient was enrolled on this study. 
 
 
9.0 
STATISTICAL CONSIDERATIONS 
 
9.1 
Study Design 
 
After initial surgery, all patients with a total or near total resection (GTR1/GTR2/NTR), 
except those with classic supratentorial disease and GTR1, will be randomized to radiation 
therapy followed by maintenance chemotherapy, or radiation therapy followed by 
observation. Patients with classic supratentorial disease and GTR1 will be on observation 
only. All patients with incomplete resection (STR) after initial surgery will receive 
induction chemotherapy.  
 
At the end of induction chemotherapy, those achieving a CR after induction chemotherapy, 
except those with classic supratentorial disease, will be randomized to radiation therapy 
followed by maintenance chemotherapy or radiation therapy followed by observation. 
Patients with SD/PR or local progression after induction chemotherapy will undergo 
second surgery when possible; patients with GTR/NTR after second surgery, except those 
with classic supratentorial disease and GTR1, will then be randomized to radiation therapy 
followed by maintenance chemotherapy or radiation therapy followed by observation. 
Patients with classic supratentorial disease who achieve either CR after induction 
chemotherapy or GTR1 after second surgery will be non-randomly assigned to observation 

 
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only. Patients with residual disease after second surgery, or with SD/PR or local 
progression after induction chemotherapy but not amenable for second surgery, will be 
non-randomly assigned to receive radiation therapy followed by maintenance 
chemotherapy. 
 
The primary aim of the study is to evaluate whether the addition of maintenance 
chemotherapy (VCEC) given after conformal radiation will have an impact on event free 
survival (EFS) and overall survival (OS) in newly diagnosed patients with intracranial 
ependymoma. Randomization between VCEC and observation arm will be stratified by 
2 groups below based on when they become eligible for randomization: 1) patients with 
GTR/NTR after initial surgery; 2) patients with incomplete resection after initial surgery 
and then CR after induction chemotherapy, or patients with GTR/NTR after second 
surgery.  
 
Secondary aims include estimating EFS and OS for: (1) incompletely resected patients who 
are non-randomly assigned to receive post radiation maintenance chemotherapy because 
of failure to achieving a CR after induction chemotherapy or incomplete resection at second 
surgery; (2) patients with supratentorial classic disease who achieve either GTR1 after 
surgery (initial or second) or CR after induction chemotherapy and therefore are assigned 
to observation only. 
 
9.2 
Patient Accrual and Expected Duration of Trial 
Per Amendment #1D and based on CTEP recommendations, the study design was 
converted from a maximum-time design to a maximum-information design. More 
specifically, barring early stopping, the primary analysis will be done when 85 events (as 
defined under EFS below) have been observed. Maximum number of eligible and evaluable 
patients to be accrued and randomized for the primary objective remains 320, as originally 
planned. If 85 events have not yet been observed by the time 320 patients have been 
randomized for the primary objective, accrual will be considered complete and we will 
follow patients until 85 events have been observed before initiating the primary analysis of 
the trial data. In the unlikely event that 85 events are not observed 3 years after the last 
patient enrolls on the study, we will nevertheless conduct the primary analysis on pragmatic 
grounds. 
 
ACNS0121, the predecessor study to ACNS0831, enrolled at least 90 patients per year, 
which was the projected accrual rate for this study at the time of its initial design. However 
the observed accrual rate to date on the current trial has been slower than that of ACNS0121 
and thus the expected accrual rate has been reduced to 60 patients per year as per 
Amendment #1D. With an estimated 70% randomization rate, to achieve 320 randomized 
patients, the target maximum accrual for the entire trial is 460 patients and the accrual 
duration is estimated to be approximately 8 years. The maximum accrual for the study is 
extended from the expected number of 460 to a maximum of 500 to accommodate 
ineligible enrollments (up to 8%) and slight fluctuation in the rate of randomization. Note 
however that since the primary analysis will be done at the time 85 events have been 
observed, in the randomized cohort, accrual to the study may be terminated prior to 
enrolling 500 patients. Furthermore given that the study design incudes interim analyses 
for efficacy as well as futility, early stopping is certainly possible. Estimated accrual and 
study duration under various scenarios are detailed in the next section under ‘Monitoring 
for Outcomes’. 
 

 
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9.3 
Statistical Analysis Methods 
 
Endpoints 
 
Event-free survival (EFS), defined as time to the first occurrence of any of the 
following events: disease progression, disease recurrence, second malignant neoplasm, 
or death from any cause. For this endpoint, local disease progression in patients with 
sub-totally resected disease prior to maintenance will not be classified as disease 
progression in the primary analyses, although they may be so classified for some 
secondary analyses.  
 
 Overall survival (OS), defined as time to death from any cause. 
 
Power Considerations 
In the previous study, ACNS0121, we observed about 80% complete resection rate 
(GTR/NTR) following initial surgery. After excluding patients with supratentorial classic 
disease who were completely resected (GTR1) and would go on observation only, which 
was expected to be about 5% of the total eligible enrollments, we estimated that we would 
have approximately 75% of enrolled patients eligible for randomization after initial 
surgery. Among the 20% of patients with incomplete resection after initial surgery, we 
assumed a 10% CR rate after induction chemotherapy which was similar to what was 
observed on ACNS0121. Among the patients who achieved < CR after induction 
chemotherapy, we assumed that 50% would go through 2nd surgery and 40% would have 
complete resection after 2nd surgery. Therefore the percentage of patients who became CR 
after chemotherapy or had complete resection after second surgery was estimated to be 
20%*10%+20%*90%*50%*40%=6% of total eligible enrollments. It was assumed that 
~5% among these 6% would be patients with supratentorial classic disease with CR or 
GTR1 who would go on observation only; which resulted in approximately 6% of total 
enrollments being eligible for randomization through this path. Combining with the 75% 
patients eligible for randomization after the initial surgery, altogether we had projected that 
about 80% of the enrollment cohort would be eligible for randomization. Since the study 
activation, however, only around 70% of the enrolled patients have been eligible for 
randomization. This is partially due to the fact that 10% of enrollments to date (twice as 
many as projected based on ACNS0121) have been patients with supratentorial classic 
disease that were completely resected (GTR1) making them eligible for observation only 
arm. Another contributing factor for lower than expected rate of randomization has been 
patient refusal or early termination of treatment prior to randomization. Therefore, per 
Amendment #1A, we are revising the projected rate of randomization for this study to be 
70%.   
At the time of the initial development of this protocol, the outcome data on ACNS0121 
was not yet available because the study was still under DSMC monitoring. An earlier 
ependymoma protocol CCG 9942 had enrolled 84 patients; where patients without residual 
tumor were treated with irradiation only and patients with residual tumor received pre-
irradiation chemotherapy. The overall 2 year EFS on CCG 9942 was about 70%; the group 
of 43 patients who had irradiation alone (because of no residual tumor) and the group of 
21 patients who achieved some response (CR/PR) after pre-irradiation chemotherapy had 
slightly higher 2 year EFS at about 75%. Therefore, for the post radiation observation arm 
we had assumed 2 year EFS of 75% (4-year EFS 66%; long term EFS 60%) under a cure 
model with an exponential failure rate for the patients who fail. These assumptions appear 
to be reasonable based on the later released data from ACNS0121. Per the 2014 ISPNO 
abstract of ACNS0121, 5-year EFS estimates for 281 patients treated with immediate post-

 
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operative CRT was 67.3%±4.5%  for patients with near-total or macroscopic gross-total 
(GTR2) resection (stratum 3, treatment 3); was 69.5%±3.8% for those with WHO grade 
III, supratentorial or any grade, infratentorial after GTR1 (stratum 4, treatment 3). When 
combined with the 25 additional patients who achieved CR after induction chemotherapy 
or GTR after second look surgery, the 5-year EFS estimate for the entire cohort was slightly 
lower at around 67%. Additional failures beyond 5 years were also observed supporting 
the slightly declining outcome assumption for the long term. With a maximum of 160 
patients per arm accrued over 8 years and with up to 2 years of additional follow up after 
the last patient enrollment, we will have about 93% power for detecting a higher EFS in 
the post-radiation VCEC arm when it has 2 year EFS of 87% (4-year EFS 81%; long term 
EFS 76%). The test considered is a 1-sided log rank test with type I error of 0.05. A loss to 
follow-up of 10% by the end of year 5 under an exponential model is included for each 
arm; the assumed loss to follow-up is approximately 2% every year for the first 5 years.  
 
If on each randomized arm 10% of the patients are non-compliant and switch to the other 
arm, in the intent-to-treat analysis where we include patients in their assigned arm rather 
than the treated arm the power is reduced to about 80%. The intent-to-treat analysis suffers 
because the observed difference between the 2 arms becomes smaller; with 10% switch-
over the 2-year EFS for the post-radiation observation arm becomes 76% instead of 75%, 
while the 2-year EFS on post-radiation VCEC arm reduces to 86% instead of 87%. In this 
case intent-to-treat analysis maintains the comparability of the 2 groups of patients by 
randomization but has lower power than the as-treated analysis. Similarly, the power for 
intent-to-treat analysis is approximately 75% if 20% of the treatment arm patients switch 
to control treatment while none of the control arm patients are non-compliant; the power 
is approximately 82% if 20% of the control arm patients switch to the treatment arm and 
none of the treatment arm patients are non-compliant. 
 
Monitoring for Toxic Death 
There were no toxic deaths observed on ACNS0121 (eligible n=356). The study committee 
will review any occurrence of toxic death observed on this study for safety evaluations and 
report the results to the DSMC in DSMC report as well as in the study progress report. 
Based on the findings, the study committee may propose appropriate actions if necessary 
such as study modification or suspension; at any time DSMC may make their own safety 
assessments and recommendations. DSMC reports and study progress reports will be 
prepared every 6 months for the first 2 years of the study, and later upon DSMC approval 
will be generated once every year if the study goes smoothly during the first 2 years.  
 
Monitoring for Randomization Rate and Randomization Compliance 
The percentage of patients that are randomized will be reported at each progress report and 
will be monitored approximately once every year after the opening of the study. Note 
however that the composition of the patient cohort enrolled on this study is unpredictable 
which has already been observed as of Amendment #1D in the notably larger than expected 
‘observation only’ patient cohort: 23 out of 226 eligible enrollments (10.2%) at the time of 
Amendment #1D for ACNS0831 vs. only 11 in 355 (3.1%) eligible patients on ACNS0121. 
Thus, as of Amendment #1D, we will monitor the randomization rate among patients who 
were eligible for randomization and are enrolled after the activation of Amendment #1D. 
We consider a randomization rate of 90% or higher among patients who are eligible to be 
randomized to be acceptable. We will use a 1-sided 95% exact CI to assess the adequacy 
of the randomization rate once at least 40 patients have been randomized. If the 95% UB 
estimate of the randomization rate is lower than 90% we will detail the reasons for the 

 
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lower than expected randomization rate and seek the DSMC’s input regarding what actions 
may need to be taken. 
 
We will also examine the rate of non-compliance for randomization (i.e., patients receiving 
treatment of the opposite arm, not the assigned arm) on each arm and report these rates to 
the DSMC as part of the regularly scheduled DSMC reports. We consider a compliance 
rate of 90% or higher among randomized patients to be acceptable. We will use a 1-sided 
95% exact CI to assess the adequacy of the compliance rate once at least 40 patients have 
been randomized. If the 95% UB estimate of the compliance rate is lower than 90% we 
will detail the reasons for the lower than expected compliance rate and seek the DSMC’s 
input regarding what actions may need to be taken.  
 
If the randomization percentage is inadequate or the non-compliance rate is unacceptably 
high, DSMC may consider study suspension or modification, taking into account factors 
such as the observed issue, its magnitude, potential reasons and the number of patients 
remaining to be enrolled, etc.  
 
Monitoring for Outcomes 
Interim monitoring on the randomization comparison will be performed and will be based 
on 1-sided log rank tests. Monitoring will be performed once a year coinciding with the 
annual DSMC reports, and monitoring boundaries will be calculated based on the observed 
number of events via Lan-Demet’s method with spending function αt2. The expected 
maximum number of interim analyses to be conducted post Amendment #1D is 6.  
 
Since the study was converted from a time-based design to an information based design as 
part of Amendment #1D, and some of the type 1 error (i.e., 0.0023) was spent on interim 
analyses prior to this conversion, 0.0023 will be subtracted from the original overall type 
1 error rate (0.05) and the rejection boundaries for interim analyses post Amendment #1D 
will be calculated based on alpha=0.0477 in order not to cause an inflation in the study-
wide type 1 error. Note that this small reduction in alpha results in virtually no change in 
the overall power of the study (0.930 vs. 0.925).     
 
Given the information based design that has been implemented as per Amendment #1D, 
the assumptions made about accrual as well as EFS distributions and the above described 
interim analyses for early stopping for efficacy, if the alternative hypothesis is true, the 
expected duration of the trial is approximately 6.5-7 years after initiating enrollment. In 
other words if the RT+chemotherapy arm is superior to the RT-only arm in the randomized 
cohort at the level that was hypothesized in the study design (i.e., HR≈0.5), then we expect 
that we will stop accrual to the study following one of the interim analyses. We estimate 
that on average this will happen approximately 6.5-7 years after initiating enrollment based 
on an estimated 53 events. If on the other hand the null hypothesis is true and there is no 
appreciable difference in the two arms in terms of efficacy, we expect to observe 85 events 
shortly after the accrual is complete, at about 8 years. This estimate does not include the 
additional interim monitoring for futility described below which may allow us to stop 
enrollment earlier under the null hypothesis. While various forms of non-compliance do 
not affect the estimate of trial duration under the null hypothesis, under the alternative 
hypothesis the overall effect of non-compliance is to prolong the study by up to 6 months, 
on average. 
 
A futility monitoring will be performed at the same time as the efficacy interim analyses 
and will be based on the conditional probability of detecting the EFS difference between 

 
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the 2 randomized arms at the end of the study given the current observed data. Failure 
pattern for future patients and current patients who are still at risk will be simulated under 
the alternative hypothesis. In the simulations, if the conditional probability of detecting the 
difference between the 2 arms given the current observed data falls below 10%, the study 
will be referred to the DSMC for study modification or suspension. 
 
We will also perform interim informal monitoring on the outcome for patients with 
supratentorial classic disease that were on observation only following a complete resection 
or CR to induction chemotherapy. ACNS0121 data on such patients have become available 
as of Amendment #1D. Eleven eligible patients were enrolled on ACNS0121 in the 
observation arm out of a total of 355 eligible enrollments. Per 2014 ISPNO abstract, there 
were 5 events among the 11 patients with 5-year EFS of 61.4% (±14.4%). Importantly 
however the 5-year OS rate is 100% in these patients. We will estimate EFS for 
observation-only patients on our study and compare that to the estimates from ACNS0121. 
We will use the most up to date data on ACNS0121 for these comparisons until the data 
for the primary manuscript of that study are frozen, after which we will use those frozen 
data for our comparisons. Informal monitoring will be based on whether the 95% 
confidence intervals for the 1-year and 3-year EFS estimates based on a KM approach on 
our study include the corresponding estimates from ACNS0121. This informal monitoring 
rule will serve as a guideline for continued monitoring of outcome on this group of patients, 
and is not to be interpreted literally as a formal rule for terminating or modifying treatment 
for this group of patients. The informal monitoring on observation only patients will be 
performed at the same time as the monitoring on the primary study comparison on the 
randomized patients.  Monitoring results will be presented to the DSMC along with the OS 
outcome. 
 
Informal monitoring will also be performed for the subset of patients who are non-
randomly assigned to receive maintenance chemotherapy due to achieving less than CR 
after induction chemotherapy or due to incomplete resection after second surgery, by 
comparing the outcome of such patients to that of similar patients from ACNS0121 who 
were treated without post-radiation maintenance chemotherapy. We will use the most up 
to date data on ACNS0121 for these comparisons until the data for the primary manuscript 
of that study are frozen, after which we will use those frozen data for our comparisons. 
Monitoring will be based on a 1-sided log rank test and the observed p-value will be 
reported without a benchmark since no effect size has been specified for this comparison 
and the control cohort is from a previous trial. This monitoring is informal in nature and 
serves as basis for continued assessment for outcome in this group, since such comparison 
is not the primary study question. This informal monitoring will be performed at the same 
time as the monitoring on the primary study comparison on the randomized patients. 
Monitoring results will be presented to the DSMC. 
 
Analysis Plans for Primary Objective 
We will use Kaplan-Meier curves to estimate the observed EFS and OS for the 
two randomization arms (post-radiation Maintenance arm and post-radiation Observation 
only arm). Log rank tests will be used to compare the observed EFS and OS between the 
two randomization arms. Stratified log rank test will also be performed to examine the 
treatment difference with consideration and adjustment for the randomization groups. If 
outcome data on ACNS0121 or this study suggest a difference or a different pattern in 
outcome between the 2 randomization strata, then we will supplement the primary analyses 
with log-rank tests performed separately in each stratum in order not to confound the 
overall conclusions of the study with respect to the effect of maintenance therapy. 

 
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Furthermore, if significant non-proportionality is apparent in the survival curves (e.g., 
crossing of the curves) we may also use parametric or cure model approaches to 
supplement the primary analyses based on the log-rank test. For the comparative survival 
analysis on randomized patients, the EFS and OS will be calculated from the time of 
randomization. 
 
The primary analysis will be based on intent-to-treat. In the event that the non-compliance 
rate is relatively high (>5% in either arm), we will also perform an as-treated analysis to 
examine potential changes in the overall trial conclusions from the primary intent-to-treat 
analysis. 
 
Analysis Plans for Exploratory Clinical Objectives 
Kaplan-Meier curves will also be used to estimate the EFS and OS for the subset of patients 
who were non-randomly assigned to receive maintenance chemotherapy after incomplete 
resection; this group includes those who remain less than CR after induction chemotherapy 
and those do not achieve complete resection with second
 
surgery. Exploratory log rank test 
will be performed to compare the outcome in this group of patients to similar patients 
treated on ACNS0121 without post-radiation chemotherapy to assess the effect of post-
radiation maintenance chemotherapy in such patients. Similar log rank test will be 
performed to see if this group of incompletely resected patients who were assigned to 
receive maintenance chemotherapy has lower EFS/OS than the patients who are 
randomized to maintenance chemotherapy because of complete resection or CR after 
induction chemotherapy. 
 
 
EFS and OS will also be estimated using Kaplan-Meier curves for the subset of patients 
with supratentorial classic disease that achieve complete resection or CR to induction 
chemotherapy and are assigned to observation only. 
 
Analysis Plan for Neurocognitive and QOL Outcomes 
Barring early stopping, this study expects to randomize 320 patients (160 per arm) between 
radiation only and radiation followed by maintenance chemotherapy. As of the March 31, 
2016 data freeze, of the 214 patients randomized, 69 patients (32%) were co-enrolled on 
the ALTE07C1 study, of these 69, 33 were treated with RT and 36 were treated with 
RT+maintenance chemotherapy. Dropout rate is a bit more difficult to estimate at this time 
since most patients are still within the assessment window. However given the relatively 
low participation rate observed to date, the neurocognitive/QOL objectives were moved 
from secondary to exploratory. For these exploratory analyses, our intent is to describe 
each outcome measures via descriptive summary statistics and plots. Descriptive statistics 
will be used to summarize the neurocognitive and QOL outcome measures at each time 
point and for the different patient subsets. Given the limitations in the number of 
participants and the large number of outcomes to be evaluated, the expectation from these 
data is that they will provide pilot information to estimate potential effect sizes as well as 
variability that can be used to inform future trials. 
 
For the exploratory objective of comparing neurobehavioral outcome collected through 
ALTE07C1 for patients treated with proton beam radiation therapy compared to children 
treated with conventional radiation delivery techniques, similar descriptive approaches will 
be used as described above. 
 

 
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9.4 
Correlative Biology Studies 
The correlative biology studies listed in the secondary objectives are described in Section 
15.0. The associated statistical analyses to be performed are detailed below. 
 
As of Amendment 3, 479 patients have been enrolled on this study and 451 patients are 
eligible. Among the eligible patients, 390/451 (86.5%) have paraffin embedded tissue from 
their primary tumor at the BPC with the following breakdown: 
 
Subjects with Paraffin Embedded 
Tissue 
N 
% of total 
ARM 
 
Unassigned 
13 
65% 
Maintenance 
61 
88% 
Observation 
32 
86% 
Randomization 
284 
87% 
All 
390 
 
 
There are also 146 subjects who have frozen tissue available. 
 
The methodology which will be used to define methylation based subgroups is described 
in Section 15. It is expected that a majority of subjects will be classified in one of the 
4 subtypes below using the methylation approach: ST-RELA, ST-YAP1, PFA and PFB. It 
is not possible to determine the percentage of patients for which this classification will fail 
due to assay or tissue quality problems but based on experience from previous cohorts 
(e.g., medulloblastoma samples from ACNS0331 and ACNS0332) the failure rate is 
expected to be low (~5% of patients with adequate tissue). These subtypes will then be 
incorporated into Cox Regression analyses (or similar models if significant non-
proportionality exists) along with treatment variables in an effort to determine degree and 
nature of associations with clinical outcome as measured by EFS and OS. If notable 
variability exists in outcome based on tumor location, these analyses may be performed 
separately for posterior fossa (PF) and supratentorial (ST) tumors which would then reduce 
the number of variables in the model as well (e.g., 2 subtypes rather than 4, etc.). The 
proposed analyses will be performed separately for the randomized cohort, the observation 
cohort and the cohort assigned to maintenance in order to better account for the treatment 
effect and the design of the study. 
 
The outcome data for ACNS0831 remains under DSMC monitoring; however, the 
statistical design stipulates that the final analysis will be done when 85 EFS events are 
observed in the randomized cohort. Based on the data reported in ACNS0121 (the previous 
COG Ependymoma study), the rate of EFS events in the observation cohort is expected to 
be similar to the RT-only arm of the randomized cohort; whereas the outcome in the cohort 
non-randomly assigned to maintenance is expected to be worse compared to the RT-only 
arm in the randomized cohort. The design assumptions in the randomized RT–only vs. RT 
+ Maintenance arms specify 2-year EFS of 75% vs. 87%, respectively. With 85 events in 
the randomized comparison, the proposed Cox models should be able to incorporate the 
4 Ependymoma subtypes in addition to treatment as part of the analysis. The 4 subtypes 

 
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are location specific (2 for supratentorial and 2 for posterior fossa tumors) and the current 
information suggests that ~40% of the randomized subjects have supratentorial tumors and 
60% have posterior fossa tumors. If the event distribution does not allow for a single model 
for the entire randomized cohort, location-specific models are also incorporated into the 
analysis plan for these exploratory biology objectives. Since the observation and 
maintenance cohorts are much smaller in sample size, these will be analyzed descriptively 
as separate cohorts. 
 
Similar analyses will be performed for IHC based analyses for H3 K27 status for 
identifying PFA vs. PFB tumors and these will be contrasted against methylation based 
analyses. H3 K27M status will also be correlated with outcome. Similarly the detection 
rate of copy number variants for 1q gain and CDKN2A as assessed by DNA methylation 
profiling vs. interphase fluorescence in situ hybridization (iFISH) will be compared by 
cross tabulation methods and the association of these variants (1q gain in PF and CDKN2A 
loss in ST ependymomas) with EFS and OS will be evaluated using similar methods as 
described above which will incorporate treatment variables. We will also perform similar 
analyses to summarize frequencies of specific genetic alterations that include RELA 
fusions, specifically C11orf95-RELA fusions; YAP1 fusions and H3 K27M mutation. 
 
As further exploratory analyses, we will study associations of the biomarkers listed above 
with WHO grade, tumor location, extent of resection, age and other demographic variables 
and incorporate these additional variables in outcome analyses for EFS and OS along with 
treatment, as feasible and appropriate. 
 
9.5 
Gender and Minority Accrual Estimates 
 
The gender and minority distribution of the study population is expected to be: 
 
 
Accrual Targets 
 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
31 
40 
71 
Not Hispanic or Latino 
179 
250 
429 
Ethnic Category: Total of all subjects 
210 
290 
500 
Racial Category 
 
American Indian or Alaskan Native 
1 
0 
1 
Asian 
13 
15 
28 
Black or African American 
19 
35 
54 
Native Hawaiian or other Pacific Islander 
2 
1 
3 
White 
175 
239 
414 
Racial Category: Total of all subjects 
210 
290 
500 
 
 
 
 
 
This distribution was derived from study ACNS0121. 
 
 

 
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10.0 
EVALUATION CRITERIA 
 
10.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
This study will utilize version 5.0 of the CTCAE of the National Cancer Institute (NCI) for 
toxicity and performance reporting. A copy of the CTCAE version 5.0 can be downloaded 
from the CTEP website 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). 
Additionally, toxicities are to be reported on the appropriate case report forms. 
 
Please note: ‘CTCAE v5.0’ is understood to represent the most current version of CTCAE 
v5.0 as referenced on the CTEP website (i.e., v5.02 and all subsequent iterations prior to 
version 6.0). 
 
10.2 
Methodology to Determine Tumor Measurement 
In order to completely document the assessment of response, the measurements of the 
longest tumor dimension, and its perpendicular, of all target lesions upon which the 
assessments of tumor response are based should be explicitly noted in the radiology report 
for the baseline and all subsequent follow-up exams.  Reports for the follow-up exams 
should reiterate the measurements obtained at baseline for each target lesion.  Non-target 
lesions or newly occurring lesions should also be enumerated in these reports, and changes 
in non-target lesions should be described. 
 
Tumor response criteria are determined by changes in size using the longest tumor 
dimension, and it’s perpendicular. Either T1 or T2 weighted images are used - which ever 
gives the best estimate of tumor size. The following section describes the methodology. 
 
(See drawing below for illustration) 
 
1. Longest diameter of target lesion(s) should be selected in the axial plane only for CT. 
For MRI imaging, the longest diameter can be measured from the axial plane or the 
plane in which the tumor is best seen or measured, provided the same plane is used in 
follow ups. This longest measurement of the tumor is referred to as the width (W).  

 
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2. The perpendicular measurements should be determined - transverse (T) measurement, 
perpendicular to the width in the selected plane.  
 
3. The cystic or necrotic components of a tumor are not considered in tumor 
measurements. Therefore only the solid component of cystic/necrotic tumors should 
be measured. If cysts/necrosis compose the majority of the lesion, the lesion may not 
be “measurable”.   
Options: 
- 
if the cyst/necrosis is eccentric, the W and T  of the solid portion should be 
measured, the cyst/necrosis excluded from measurement 
- 
if the cyst/necrosis is central but represents a small portion of the tumor (< 25%), 
disregard and measure the whole lesion 
- 
if the cyst/necrosis is central but represents a large portion of the tumor, identify a 
solid aspect of the mass that can be reproducibly measured 
4. Leptomeningeal tumor spread is usually not a target lesion, and usually cannot be 
measured accurately. Presence and location of leptomeningeal tumor spread should be 
noted, change in extent/thickness assessed on follow up studies. 
5. Overall Response Assessment 
The overall response assessment takes into account response in both target and non-
target lesion, and the appearance of new lesions, where applicable, according to the 
criteria described in the table below.  The overall response assessment is shown in the 
last column, and depends on the assessments of target, non-target, and new lesions in 
the preceding columns. 
Z
AXIS
W
T
A
B
C
D
E
COG GUIDELINE: TUMOR SIZE
MEASUREMENT BASED ON
CROSS-SECTIONAL IMAGING
• A, B, C, D, & E are contiguous
parallel slices in the X-Y plane
(usually axial) showing the tumor
• W and T are the maximal
perpendicular diameters on the slice
(C in this example) showing the
largest surface area
• Tumor length in the Z-axis (L)
(perpendicular to X-Y plane) can be
obtained either by the [a] (difference
in table position of the first and last
slices showing the tumor + one slice
thickness), or [b] the product of (slice
thickness + gap) and the number of
slices showing the tumor
X-Y
PLANE
L

 
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CR – Complete Response 
PR – Partial Response 
SD – Stable Disease 
PD – Progressive Disease 
IR – Incomplete Response 
 
The sections that follow discuss the selection and evaluation of each of these types 
of lesions. 
 
 
10.3 
Selection of Target and Non-Target Lesions 
1. 
For most CNS tumors, only one lesion/mass is present and therefore is considered a 
“target” for measurement/follow up to assess for tumor progression/response.  
2. 
If multiple measurable lesions are present, up to 5 should be selected as “target” 
lesions. Target lesions should be selected on the basis of size and suitability for 
accurate repeated measurements.  All other lesions will be followed as non-target 
lesions (including CSF positive for tumor cells).   
3. 
The lower size limit of the target lesion(s) should be at least twice the thickness of the 
slices showing the tumor to decrease the partial volume effect (e.g., 8 mm lesion for 
a 4 mm slice). 
4. 
Any change in size of non-target lesions should be noted, though does not need to be 
measured. 
 
10.4 
Response Criteria for Target Lesions 
1. 
Response criteria are assessed in 2 dimensions – the product of W x T.  
2. 
To assess response/progression, the ratio is calculated: 
W x T (current scan)  
W x T (reference scan) 
 
3. 
Development of new disease or progression in any established lesions is considered 
progressive disease, regardless of response in other lesions – e.g., when multiple 
lesions show opposite responses, the progressive disease takes precedence. 
 
4. 
Response Criteria for target lesions: 
 
Complete Response (CR): Disappearance of all target lesions.  
 
Partial response (PR): ≥ 50% decrease in the sum of the products of the two perpendicular 
diameters of all target lesions (up to 5), taking as reference the initial baseline 
measurements 
 
 
Target 
Lesions 
 
Non-target Lesions 
 
New Lesions 
 
Overall Response 
CR 
CR 
No 
CR 
CR 
IR/SD 
No 
PR  
PR 
 CR, IR/SD 
No 
PR 
SD  
 CR, IR/SD 
No 
SD  
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 

 
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Stable Disease (SD): Neither sufficient decrease in the sum of the products of the two 
perpendicular diameters of all target lesions to qualify for PR (taking as reference the initial 
baseline measurements), nor sufficient increase in a single target lesion to qualify for PD, 
(taking as reference the smallest disease measurement since the treatment started). 
 
Progressive Disease (PD): 25% or more increase in the product of perpendicular diameters 
of ANY target lesion, taking as reference the smallest product observed since the start of 
treatment, or the appearance of one or more new lesions.  
 
Local progression is defined as progression of known residual tumor or the appearance of 
tumor at known prior sites of disease that were at some point without evidence of disease.  
 
Distant progression is defined as the appearance of tumor at sites other than known prior 
sites of disease. Distant progression most often occurs in the subarachnoid space and may 
occur at any point within the neuraxis. Although rare, extra-CNS metastasis represents 
distant failure.  
 
Combined local and distant progression is defined when evaluation of the entire neuraxis 
reveals local and distant progression. 
 
10.5 
Response Criteria for Non-target Lesions 
Complete Response (CR): Disappearance of all non-target lesions.  
 
Incomplete Response/Stable Disease (IR/SD):  The persistence of one or more non-
target lesions.  
 
Progressive Disease (PD): The appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  
 
 
 
 
 
11.0 
ADVERSE EVENT REPORTING REQUIREMENTS  
 
11.1 
Purpose 
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of patients enrolled in the studies as well as those who 
will enroll in future studies using similar agents.  
 
11.2 
Determination of Reporting Requirements 
Reporting requirements may include the following considerations: 1) the characteristics of 
the adverse event including the grade (severity); 2) the relationship to the study therapy 
(attribution); and 3) the prior experience (expectedness) of the adverse event. 
 
Commercial agents are those agents not provided under an IND but obtained instead from 
a commercial source. In some cases an agent obtained commercially may be used for 
indications not included in the package label. In addition, NCI may on some occasions 
distribute commercial supplies for a trial. Even in these cases, the agent is still considered 
to be a commercial agent and the procedures described below should be followed. 
 
Determine the prior experience Expected events are those that have been previously 
identified as resulting from administration of the agent. An adverse event is considered 

 
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unexpected, for reporting purposes only, when either the type of event or the severity of 
the event is not listed in:  
 
 
the current known toxicities for each commercial agent as provided in the Drug 
Information for Commercial Agents Used by the Children’s Oncology Group posted 
on the COG website; or 
 
the drug package insert. 
 
11.2.1 Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous 
malignancy (e.g., treatment with investigational agent/intervention, radiation or 
chemotherapy). A metastasis of the initial neoplasm is not considered a secondary 
malignancy.  
 
All secondary malignancies that occur following treatment need to be reported via 
CTEP-AERS. Three options are available to describe the event:  
 
Leukemia secondary to oncology chemotherapy   
 
Myelodysplastic syndrome  
 
Treatment related secondary malignancy 
 
Any malignancy possibly related to cancer treatment (including AML/MDS) 
should also be reported via the routine reporting mechanisms outlined in each 
protocol.  
 
11.2.2 Second Malignancy 
A second malignancy is one unrelated to the treatment of a prior malignancy (and 
is NOT a metastasis from the initial malignancy). Second malignancies require 
ONLY routine reporting via CDUS unless otherwise specified. 
 
11.3 
Reporting of Adverse Events for Commercial Agents – via CTEP AERS 
abbreviated pathway 
Expedited AE reporting must use CTEP-AERS (Adverse Event Expedited Reporting 
System), accessed via https://eapps-ctep.nci.nih.gov/ctepaers 
 
Commercial reporting requirements are provided in Table B. The commercial agent(s) used 
in this study are listed in the front of this protocol immediately following the Study 
Committee roster.  
 
 
COG requires the CTEP-AERS report to be submitted within 7 calendar days of 
learning of the event.  
 
Use the NCI protocol number and the protocol-specific patient ID provided during 
trial registration on all reports. 
 
 
CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0 will be utilized for AE reporting. All appropriate treatment areas should have access to 
a copy of the CTEP Active Version of CTCAE version 5.0. A copy of the CTCAE version 
5.0 can be downloaded from the CTEP website at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
 
 

 
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Table B  
Reporting requirements for adverse events experienced by patients on study who 
have NOT received any doses of an investigational agent on this study. 
 
CTEP-AERS Reporting Requirements for Adverse Events That Occur During 
Therapy with a Commercial Agent or Within 30 Days1 
 
Attribution 
Grade 4 
Grade 5 
 
Unexpected 
Expected 
 
Unrelated or 
Unlikely 
 
 
CTEP-AERS 
Possible, 
Probable, 
Definite 
CTEP-AERS 
 
CTEP-AERS 
1This includes all deaths within 30 days of the last dose of treatment with a 
commercial agent, regardless of attribution. Any death that occurs more than 
30 days after the last dose of treatment with a commercial agent which can 
be attributed (possibly, probably, or definitely) to the agent and is not due to 
cancer recurrence must be reported via CTEP-AERS 
 
11.4 
Routine Adverse Event Reporting 
 
Note: The guidelines below are for routine reporting of study specific adverse events on 
the COG case report forms and do not affect the requirements for CTEP-AERS 
reporting. 
 
The NCI defines both routine and expedited AE reporting. Routine reporting is 
accomplished via the Adverse Event (AE) Case Report Form (CRF) within the study 
database. For this study, routine reporting will include all Grade 4 and higher non-
hematologic Adverse Events (any attribution). 
 
As of Amendment #1D, routine reporting will include Grade 3 Central Nervous System 
Necrosis (retrospective and prospective) for 2 years after study enrollment. Imaging and 
reports must be submitted for all patients with reported Grade 3 or above CNS System 
Necrosis for 2 years after study enrollment. 
 
 
12.0 
RECORDS AND REPORTING 
 
See the Case Report Forms posted on the COG web site with each protocol under “Data 
Collection/Specimens”. A submission schedule is included. 
 
12.1 
CDUS 
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0. 
Cumulative protocol- and patient-specific CDUS data will be submitted quarterly to CTEP 
by electronic means. Reports are due January 31, April 30, July 31 and October 31. CDUS 
reporting is not a responsibility of institutions participating in this trial. 
 
 

 
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13.0 
NEUROSURGICAL GUIDELINES  
  
13.1 
General 
When feasible, an attempt will be made to perform a gross total resection; if not feasible, 
an attempt will be made to remove as much tumor as possible without jeopardizing the 
patient. Biopsy alone, with no attempt at resection, may be associated with statistically 
worse survival and local progression during chemotherapy and should not be done. No 
patient will be eligible for this study without a pathologic diagnosis and histological 
confirmation. 
 
 
13.2 
Imaging Confirmation of Extent of Resection 
All patients will have confirmation of the neurosurgical staging of the extent of resection 
with a postoperative MRI with and without contrast. Post-operative imaging of the brain 
should be done within 72 hours of surgery and prior to the onset of edema or gliosis which 
can make measurements of residual tumor difficult. If imaging cannot be obtained at this 
time or is difficult to interpret, the scan should be repeated 10 or more days after surgery. 
 
13.3 
Peri-operative Corticosteroids 
 
13.3.1 
Some patients with large tumors may require initiation of corticosteroid therapy pre-
operatively to reduce associated cerebral edema or improve neurologic function.  
 
13.3.2 
Usual corticosteroid dosage is 0.25 to 1 mg/kg/day of dexamethasone, in divided doses, 
every 4-6 hours. 
 
13.3.3 
Corticosteroids may be continued during the peri-operative period. Every attempt should 
be made to taper and discontinue corticosteroid therapy as soon as clinically feasible 
(7 days). 
 
13.4 
Initial Surgery 
 
13.4.1 
The guidelines for surgery are provided with the recognition that many patients on this 
study will have had their first operation prior to referral to the oncology service. Control 
of significant hydrocephalus in the perioperative period may be achieved with placement 
of either a ventriculostomy or ventriculoperitoneal shunt at the discretion of the 
neurosurgeon. Patients are allowed to have had more than one attempt at resection prior to 
enrollment. 
 
13.4.2 
For infratentorial tumors, suboccipital craniotomy or craniectomy should be performed 
using standard neurosurgical procedures. Midline tumors are best approached by a midline 
incision extending to the upper cervical region. When appropriate, the posterior arch of C-
1 should be removed as well so that the tonsils and brainstem can be decompressed. A wide 
dural opening will permit exposure of the cerebellar vermis, tonsils, medulla, both 
cerebellar hemispheres, and the upper cervical region. Careful search for extension of 
disease in the arachnoid and leptomeninges should be made. Biopsies of these sites should 
be performed if disease extension is suspected. Evidence of brainstem invasion should be 

 
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sought and noted in the operative report if present. Replacement of overlying bone and 
posterior vertebral body elements should be reported. The use of Surgicel (Johnson & 
Johnson, Somerville, NJ) and other hemostatic products should be reported. The site of 
origin should be sought and described in the operative report. 
 
13.4.3 
Tumor should be removed and hemostasis achieved using standard techniques. The 
surgeon should try to remove as much of the tumor as is safely possible, without 
comprising function. If resection cannot be complete, surgeons should estimate in their 
reports the percentage of tumor removed. 
 
13.4.4 
As much tissue as possible should be submitted intact to the pathologists for review. At the 
time of diagnosis and at the second surgery (if applicable), specimens outlined in Section 
14.0 of the protocol must be sent to the Biopathology Center (BPC). Unsafe tumor 
resection should not be undertaken for the purposes of tissue banking; however, removed 
tumor tissue should not be discarded. 
 
13.4.5 
Techniques for bone and dura closure will be left to the discretion of the neurosurgeon. 
Post-operatively, patients should be monitored for hematoma formation and 
hydrocephalus. A decision concerning placement of a permanent VP shunt should be made 
within two weeks of tumor removal. 
 
13.5 
Second Operation 
 
13.5.1 
The definition of second surgery in this study is surgery performed after the 
administration of Induction chemotherapy and prior to radiation therapy. The 
purpose of the second operation is to safely remove as much tumor as possible that persists 
after induction chemotherapy. If it is determined pre-operatively that residual tumor cannot 
be removed in its entirety, serious consideration should be made to resect the tumor to a 
minimum level of disease. Second surgery should be performed within 14 days after 
completing Induction Cycle B chemotherapy (Day 21). Conformal radiation therapy may 
then be given within 30 days after completing chemotherapy or second surgery. The 
timelines for the performance of second surgery and conformal radiation therapy are not 
rigid. 
 
13.5.2 
There is no limit to the number of surgery procedures performed prior to enrollment or 
following chemotherapy. We expect to see cases where “second” surgery is performed and 
post-operatively the institutional team determines that additional surgery is feasible or 
necessary prior to radiation therapy.  
 
13.5.3 
Guidelines for this operation are similar to those for the first operation; however, control 
of increased intracranial pressure and ventriculomegaly should not be concerns at this time. 
An approach most suitable to the child should be taken. The direction of approach can be 
either similar to the first operation or different from it depending on the site of residual 
disease and the judgment of the surgeon. 
 
 

 
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13.6 
Extent of Resection Definition and Treatment 
See Section 4.1. 
 
 
14.0 
NEUROPATHOLOGY GUIDELINES AND CENTRAL PATHOLOGY REVIEW 
SPECIMEN REQUIREMENTS 
 
14.1 
Histological Grading 
 
14.1.1 Classic Ependymoma – WHO II 
Classic ependymoma (EP) will be the classic lesion in which perivascular 
pseudorosettes are a requisite feature. Less cell-dense, more fibrillary regions may 
be present. Necrosis may be common. Unless very focal, and unaccompanied by 
regions of higher cellularity and mitotic activity, vascular endothelial proliferation 
is not permitted in this category. 
 
14.1.2 Anaplastic Ependymoma (AEP) – WHO III  
Anaplastic ependymoma will include only tumors with clearly defined ependymal 
differentiation, in the form of perivascular pseudorosettes. The defining features 
of “anaplasia” will be: 1) widespread regions of high cell density, 2) cytological 
atypia, and 3) microvascular proliferation. The hypercellularity may be diffuse or 
multifocal, the latter in the form of circumscribed regions that abut those of lower 
cell density. Atypia may be expressed as cells with increased nuclear 
pleomorphism and coarse chromatin. Vascular proliferation, of the glomeruloid 
variety, should be found within or just outside the hypercellular regions. The 
cellular anaplastic regions may be mitotically more active than those of lesser 
cellularity, although mitotic activity has not been quantified, nor has any threshold 
mitotic index been determined to direct the lesion into the AEP category. Grading 
may be difficult, because of variation in cell density and mitotic activity across the 
tumor. For this reason, we require vascular proliferation for this category, except 
in the few cases where overt atypia and abundant mitotic activity are clearly 
present.  
 
14.2 
Central Pathology Review Required for All Patients 
The classification and grading of the tumors will be performed according to the WHO 
criteria.49 A modification of these has been applied to a series of ependymoma with 
significant differences in outcome in patients with classic (WHO grade II) ependymoma 
and anaplastic (WHO grade III) ependymoma. The submission of pathology material shall 
be made directly from the participating institutions. Review pathologists may utilize 
unstained sections for a variety of supplementary tests, e.g., Ki-67. The remaining slides 
shall be kept as back-up material, or shall be used to perform additional staining as needed.  
 
If pathologic interpretation relating to a patient being considered for ACNS0831 is 
considered difficult, it is possible to consult on the pathology with the central review 
pathologist, Dr. David Ellison at St. Jude Children's Research Hospital, ahead of 
enrollment and the submission of materials for central pathology review according to 
protocol. However, this request for a second clinical opinion is arranged in the usual way, 
from pathologist to pathologist, and not through the Biopathology Center. If the patient is 
subsequently enrolled on ACNS0831, the submission of pathology materials to the 
Biopathology Center must be followed; the consultation does not count as the central 

 
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pathology review and does not remove the need to submit specimens to the Biopathology 
Center.  
 
 
Required Materials for Central Pathology Review (Rapid or Standard Central Review): 
1) 1 x H&E stained slide and 1 x unstained spare from ALL available paraffin blocks  
2) Representative paraffin embedded tissue block. If block is not available, submit 
10 unstained slides from the most representative block.  
3) Institutional pathology reports  
4) Operative report(s)  
5) COG Specimen Transmittal Form to accompany each shipment:  Please use current 
form from https://www.cogmembers.org/site/prot/generic.aspx. 
 
Please label all pathology review materials with patient’s COG Patient ID Number and the 
Surgical Path ID (SPID Number) and block number from the corresponding pathology 
report. 
 
It is the responsibility of the Principal Investigator enrolling a patient on this trial to request 
from the submitting pathologist that s/he send the appropriate set of forms, local pathology 
report and all required specimens to the Biopathology Center. The PI must enroll the patient 
onto the trial concurrently with this submission, so that a diagnosis can be entered on-line 
when rapid pathology review is undertaken for those patients with supratentorial 
ependymoma (see Section 14.2.1).  
 
 
 
 
 
Please see below for information on whether to send a case for Rapid or Standard Central 
Review. Cases sent for Rapid Central Review must be marked for RAPID REVIEW and 
shipped FedEx Priority Overnight within 5 days of enrollment using the COG FedEx 
account (https://www.cogmembers.org/_files/reference/FEDEXmemo.pdf).  Cases for 
Standard Central Review are shipped by regular mail or using your institution’s courier 
account within 10 days of enrollment to: 
 
COG Biopathology Center 
Nationwide Children’s Hospital 
700 Children’s Drive, WA1340* 
Columbus, OH  43205 
Phone: (614) 722-2865 
Fax: (614) 722-2897 
Email: BPCParaffinTeam@nationwidechildrens.org 
 
*Be sure to include the room number. Packages received without the room number may 
be returned to the sender. 
 
14.2.1 Rapid Central Pathology Review for Patients with Supratentorial Primary Tumors 
Only those patients with a supratentorial primary tumor location will require rapid 
central pathology review at study entry. Cases must be marked for rapid review 
and sent within 5 days of enrollment by Federal Express Priority Overnight to the 
Biopathology Center. Results of rapid central review will generally be available 
within 5 working days of the receipt of pathology review materials.   
 
All supratentorial STR patients regardless of histology will receive induction 
chemotherapy. Only supratentorial patients who have Classic Histology confirmed 

 
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by central review and GTR1 will be assigned to observation; all other GTR 1/2 
and NTR supratentorial patients will be randomized between a) (cRT) and 
maintenance chemotherapy OR b) (cRT) and Observation including: 
 
 
Classic Histology by central review with GTR2, NTR; OR   
 
Anaplastic Histology by central review with GTR1, GTR2, NTR; OR 
 
Rapid central pathology review cannot be performed for any reason; OR 
 
Tumor histologic grade is indeterminate by central review 
 
Second Opinion for Discordant Diagnoses 
In the event that a diagnosis other than ependymoma is returned at pathology 
review, the principal central review pathologist will liaise with the trial PI and 
registering center’s pathologist about the diagnostic considerations, and the back-
up central review pathologist will be consulted as appropriate. 
 
GTR 1 Patients 
Patients with supratentorial tumor location, extent of resection GTR1 and with a 
diagnosis of classic ependymoma (WHO grade II) by rapid central review will be 
assigned to Observation only.  
 
In the event that a discordant grade is returned at pathology review, i.e., classic 
instead of anaplastic/indeterminate or vice versa, the principal central review 
pathologist will liaise with the trial PI and registering center’s pathologist about 
diagnostic considerations, and the back-up central review pathologist will be 
consulted as appropriate. If the final assessment is classic ependymoma, the patient 
will be observed; if the final assessment is anaplastic ependymoma or indeterminate 
histology, the patient will be randomized. If the treating physician chooses to 
proceed with treatment according to the institutional review rather than the final 
central review, the patient will be removed from protocol therapy (see Section 8.1). 
 
 
 
14.2.2 Standard Central Review of Pathological Data (Initial and Second Resection) 
Within 10 days of enrollment, for patients with infratentorial primary tumor 
locations, institutions must submit materials for Standard Central Review. For all 
patients undergoing second surgery, institutions must submit materials for 
Standard Central Review within two weeks of second surgery.  
 
 
15.0 
OPTIONAL BIOLOGY STUDIES 
 
Participation in optional biology studies is strongly encouraged. In addition, institutions are 
encouraged to enroll and submit specimens for APEC14B1, Project:EveryChild A Registry, 
Eligibility Screening, Biology and Outcome Study. 
 
15.1 
Biology Specimen Requirements 
Process tumor specimens from first and second surgeries according to the guidelines below. 
Send snap frozen tissue and matched control blood specimens to the Biopathology Center 
in Columbus, Ohio. Portions of the tissue will be used for the correlative biology studies 
listed in Section 15.2. 
 

 
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15.1.1 Required Materials 
At the time of diagnosis and second surgery, tumor tissue must be sent to the 
Biopathology Center for Biology Studies: 
1)  
Frozen Tumor Tissue: As many 100 mg pieces of tissue as possible 
should be frozen in foil in liquid nitrogen within 10 minutes of removal. 
Frozen tissue should be sent on dry ice to the BPC. A minimum tumor 
tissue > 0.5 cm2 is preferred. 
- 
If frozen tumor is not available, formalin-fixed block with >80% 
tumor should be sent although this will compromise the studies 
being performed. (Paraffin blocks will be retained at the BPC 
unless return is requested.)  
- 
If frozen tumor is not available and the institution cannot release 
blocks; three to ten 50 µm scrolls should be sent and 10 unstained 
slides. (Please indicate percent tumor represented.) 
2)  
Peripheral Blood: 5 cc of peripheral blood in a green top tube (sodium 
heparin), 5 cc of peripheral blood in a yellow top tube (ACD) and 5 cc of 
blood in a purple top tube (EDTA) should be sent at room temperature any 
time before the initiation of therapy. Do not send if the patient has had a 
whole blood transfusion. For second surgeries, please send blood at this 
time also. 
3) 
COG Specimen Transmittal Form must accompany each shipment. 
Please use current form available at  
 
https://www.cogmembers.org/site/prot/generic.aspx 
 
Please label blood and frozen tissue with the patient’s COG Patient ID Number, 
collection date and specimen type. Label block or slides with the COG Patient ID 
number, Surgical Pathology ID and block number. Include the corresponding 
pathology report with each shipment of tissue. 
 
15.1.2 Specimen Shipment 
The BPC will provide a dual chamber specimen procurement kit upon request. Kits 
are ordered via the BPC Kit Management system accessed via the following link: 
https://ricapps.nationwidechildrens.org/KitManagement/. The dual chambered kit 
allows for the shipment of room temperature and frozen specimens in the same 
container. Dry ice may be placed in either compartment of the kit, but should not be 
put in both. For packing and shipping instructions please see Shipping Specimens 
in a Dual Chambered Kit at 
https://www.cogmembers.org/_files/reference/labs/ShippingSpecimensDual.pdf. 
 
Biology specimens may be shipped to the BPC using a FedEx shipping label 
provided by the BPC. Access the Kit Management application to print a shipping 
label. Please note that the BPC does not pay for shipments of blocks or slides when 
they are sent separately. Ship to: 
 
COG Biopathology Center 
Nationwide Children’s Hospital 
700 Children’s Drive, WA1340* 
Columbus, OH  43205 
Phone: (614) 722-2865 
Fax: (614) 722-2897 
Email: BPCBank@nationwidechildrens.org 

 
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*Be sure to include the room number. Packages received without the room number 
may be returned to the sender. 
 
15.2 
Special Studies Performed on Samples 
 
All specimens will be banked and processed at the COG Biopathology Center (BPC) 
and distributed from there as well. 
 
Special studies will be performed on tumor tissue specimens collected from first and 
second surgeries and from the peripheral blood samples obtained prior to initiation of 
therapy and from any second surgeries. 
 
Samples of the snap frozen tissue and samples of the matched control blood specimens will 
be used for the molecular genetic studies, by Dr. David Ellison and Dr. Nicholas Foreman 
and others as described below. The tissue will be collected centrally and distributed based 
on priority of the biologic correlative studies (see Section 15.3 below for priority list of 
studies). 
 
15.3 
Priority List of Special Biology Studies  
The experimental approach is designed to make optimal use of tissue submitted to the COG 
Biopathology Center. In order to optimally interpret the trial’s clinical data, molecular 
biomarkers in three categories will be assessed: 
 
Study #1: Molecular groups as defined by DNA methylation profiling and 
immunohistochemistry. 
 
 
RELA (ST-RELA) 
 
YAP1 (ST-YAP1) 
 
PFA 
 
PFB 
 
Study #2: Copy number variants 
 
 
1q gain in posterior fossa ependymomas 
 
CDKN2A loss (homozygous deletion) in supratentorial ependymomas  
 
Study #3: Specific genetic alterations 
 
 
RELA fusions, specifically C11orf95-RELA fusions 
 
YAP1 fusions 
 
H3 K27M mutation 
 
15.4 
Sample Processing at the BPC 
Peripheral blood mononuclear cells (PBMCs) will be studied via flow cytometry. Blood 
will be processed to remove red blood cells (ficol or lyse), and the resulting PBMC will be 
viably frozen using freezing media. 
 

 
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15.5 
Methodology 
Molecular groups will be determined by DNA methylation profiling using DNA extracted 
from FFPE tissue and Illumina EPIC (850K) arrays. Immunohistochemistry for 
H3 K27-me3 will also be used to identify PFA and PFB tumors.33 The copy number 
variants 1q gain and CDKN2A loss can be assessed as part of the analysis of data from 
DNA methylation profiling arrays and will also be evaluated by interphase fluorescence in 
situ hybridization (iFISH).36 iFISH with break-apart probes to RELA and YAP1 loci on 
11q13 and 11q22, respectively, can be used to detect gene rearrangements and is a 
surrogate marker of RELA and YAP1 gene fusions in supratentorial ependymomas.31 
H3 K27M mutation can be detected by immunohistochemistry with a mutation-specific 
antibody that has found significant utility in diagnostic laboratories for identifying diffuse 
midline gliomas.32 
 
Immunohistochemistry and interphase fluorescence in situ hybridization (iFISH) 
Clinical standard operating procedures, as used in the Anatomic and Molecular Pathology 
sections of the St. Jude Pathology department, will be used for immunohistochemistry and 
iFISH. The following antibodies and probes will be used: 
 
Immunohistochemistry: 
 
RevMab Biosciences anti-histone H3 K27M (clone – RM192) 
 
Cell Signaling anti-histone H3 K27-trimethylation 
 
iFISH: 
Break-apart probes are used in the evaluation of the C11orf95, RELA, and YAP1 loci. 
Copy number at the EXO1 (1q) and CDKN2A loci is assessed with reference to a 
control probe on the other chromosome arm. 
 
CTD-3241G19 
1p (control) 
RP11-610O24 
1q (EXO1) 
 
 
CH17-384P01 
CDKN2A 
RP11-235C23 
9q (control) 
 
 
CH17-215P06 
C11orf95  ba-c 
CH17-67K13 
C11orf95  ba-c 
CH17-388O01 
C11orf95  ba-t 
 
 
CH17-14J18 
RELA  ba-c 
RP11-642F7 
RELA  ba-c 
CH17-211O12 
RELA  ba-t 
 
 
CH17-380G02 
YAP1  BA-c 
RP11-11N20 
YAP1  BA-c 
RP11-1082I13 
YAP1  BA-t 
 
 
 

 
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DNA methylation profiling for determination of molecular group and assessment of copy 
number variation 
Genomic DNA extracted from available FFPE tissue samples using a QIAamp DNA FFPE 
Tissue Kit (Qiagen) will be used to generate DNA methylation data on Illumina Infinium 
MethylationEPIC BeadChip arrays according to the manufacturer’s instructions. DNA 
samples will be checked for quality using the Infinium HD FFPE QC Assay Protocol, 
followed by bisulfite conversion using EZ-96 DNA Methylation™ Kit (Zymo Research 
Corp). The purified converted DNA will then be restored, following the Infinium HD FFPE 
Restore Protocol, to a state amplifiable by the Infinium HD FFPE methylation whole 
genome amplification protocol. After whole genome amplification, endpoint fragmentation 
and cleanup, the DNA samples will be hybridized onto the BeadChips, followed by 
washing, single-base extension and staining. Finally, the BeadChips will be scanned by the 
iScan System in the setting of Methylation NXT. 
 
All computational analyses will be performed in R. Raw signal intensities will be obtained 
from IDAT-files using the minfi Bioconductor package. Each sample will be normalized 
by performing a background correction (shifting of the 5% percentile of negative control 
probe intensities to 0) and a dye-bias correction (scaling of the mean of normalization 
control probe intensities to 10,000) for both color channels. Beta-values will be calculated 
from the retransformed intensities using an offset of 100 (as recommended by Illumina). 
Before unsupervised clustering analysis the following filtering criteria will be applied: 
removal of probes targeting the X and Y chromosomes (n=11,551), removal of probes 
containing a single-nucleotide polymorphism (dbSNP132 Common) within five base pairs 
of and including the targeted CpG-site (n=7,998), and probes not mapping uniquely to the 
human reference genome (hg19) allowing for one mismatch (n=3,965). 
 
15.6 
Future Studies with Remaining Banked Biospecimens 
Prior to the use of any remaining banked samples following the correlative studies 
described in Section 15.3, a protocol amendment or separate biology proposal will be 
submitted to CTEP, NCI for review and approval according to NCTN guidelines. 
Amendments to the protocol and/or proposals for use of banked tissue or blood samples 
will include the appropriate background, experimental plans with assay details, and a 
detailed statistical section. Samples for testing will not be released for testing until the 
appropriate NCI approvals have been obtained. 
 
 
 
16.0 
NEUROPSYCHOLOGICAL FUNCTION STUDY 
Enrollment onto the neuropsychological function study ALTE07C1 is strongly encouraged. If the 
family agrees to participate in ALTE07C1, a separate informed consent for ALTE07C1 must be 
signed. Please refer to the ALTE07C1 protocol for eligibility requirements. 
 
Because of the high risk of neurodevelopmental problems in young children treated for 
ependymoma, assessment of functional and neuropsychological status will be completed to obtain 
information about tumor and treatment related morbidity.  The premise of this study is that newer 
radiation planning and delivery techniques are capable of reducing neuropsychological sequelae 
for all children, including the very young.  While it has historically been difficult to obtain 
neuropsychometric data in a cooperative group study, these data are nonetheless critical to the 
success of this treatment approach and its acceptance by patients, parents and the neuro-oncology 
community. 
 

 
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17.0 
NEUROIMAGING STUDIES REQUIRED AND GUIDELINES FOR OBTAINING 
 
 
 
 
 
 
 
 
 
 
 
17.1 
Rapid Central Review 
All patients will have Central Review, however, Rapid Central Review will be performed 
at 2 time points ONLY FOR PATIENTS WHO HAVE SUB-TOTAL RESECTION 
after initial surgery: 1) After induction chemotherapy to determine response and 2) After 
second surgery to determine extent of resection.  MRI scans must be submitted for rapid 
Central Review within 3 days.  Results will be available on the RDE system within 1 week 
after IROC RI (QARC) has received a reviewable copy of the scans. See Section 17.6 
regarding submission guidelines for central review. 
 
Studies to be submitted for rapid central review with radiology and operative reports: 
o Pre-op and post-op brain MRI (If not previously submitted) 
o Pre-op or post-op spine MRI with radiology (If not previously submitted) 
o Brain MRI at the end of Induction 
o Brain MRI after second surgery 
 
MRI studies must be submitted for rapid Central Review in Dicom format on a CD or 
electronically. Film copies will not be accepted.  
 
In instances in which the Central Review differs from that of the institution, a second 
central radiology reviewer will examine the films and will function as an adjudicator in 
order to facilitate appropriate stratification.   If such discrepancies cannot be immediately 
resolved, a web-based or phone conference will be organized by IROC RI (QARC) to 
expedite resolution of any discrepancies in interpretation of the imaging data.  
 
17.2 
Neuroimaging 
The neuroimaging (MR) examination is the basis for determining the extent of resection 
and/or induction chemotherapy response, and subsequent therapy. The determination of 
residual disease is based on abnormal anatomy. Ependymoma has a mixed pattern of 
enhancement and requires evaluation with all available imaging sequences including 
enhanced and non-enhanced, T1 – weighted, T2 – weighted, Fluid Attenuated Inversion 
Recovery (FLAIR) techniques capable of water suppression to define residual tumor, as 
well as diffusion MR, where available.  
 
17.3 
MR Brain With and Without Contrast 
To document the degree of residual tumor, pre and post-operative MR imaging of the brain 
with and without contrast (gadolinium) must be performed. Post-operative imaging of the 
brain should be done within 72 hours of surgery and prior to the onset of edema or gliosis 
which can make measurements of residual tumor difficult. If imaging cannot be obtained 
at this time, or the scan obtained within 72 hours is difficult to interpret, the scan should be 
repeated 10 or more days after surgery. 
 
Timing of protocol therapy administration, response assessment studies, and surgical interventions are 
based on schedules derived from the experimental design or on established standards of care.  Minor 
unavoidable departures (up to 72 hours) from protocol directed therapy and/or disease evaluations (and 
up to 1 week for surgery) for valid clinical, patient and family logistical, or facility, procedure and/or 
anesthesia scheduling issues are acceptable per COG Administrative Policy 5.14 (except where explicitly 
prohibited within the protocol).  

 
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Required sequences 
1. Sagittal T1 localizer; 4 mm skip 0.4 mm 
2. Axial FSE T2; 4 mm,  skip 0.4 mm  
3. Axial T2 FLAIR; 4 mm skip 0.4  
4. Axial diffusion; 4-5 mm skip 0 (single shot, matrix 128 x 128 or 128 x 192, 
B=1000) 
5. Axial T1; 4 mm skip 0.4 mm  
6. Axial T1 with contrast; 4 mm skip 0.4 mm 
7. Sagittal T1 with contrast; 4 mm skip 0.4 mm 
8. Axial T2 FLAIR with contrast; 4 mm skip 0.4  
 
Optional sequences (depending on tumor) 
Precontrast: 
1. Axial gradient echo (susceptibility sequence); 4-5 mm skip 1-2 mm. TE=20, flip 
angle =20.  
2. Sagittal or coronal FSET2; 4 mm skip 0.4 mm, depending on tumor 
configuration/orientation 
3. Axial diffusion tensor, 30 directions, 2.5-5 mm skip 0 (1 NEX, matrix 96 x 96, 
FOV = 24, B = 1000) 
 
Post contrast: 
1. Coronal T1: 4mm skip 0.4 
2. T1-weighted gradient echo volume sequence (SPGR or equivalent) 
3. Axial Perfusion (see optional sequences, 
 
Notes:  
1. DO NOT INTERLEAVE T1 weighted sequences 
2. Flow compensation should not be used / not on all T1 enhanced sequences 
3. Fat Saturation not necessary 
 
17.4 
Tumor Measurements 
The dimensions of the tumor will be recorded for the L-R, A-P and S-I dimensions. 
Measurements of combined solid tumor and cyst will be obtained in its maximum 
dimension as well as through 2 perpendicular planes. 
 
 
17.5 
MR Spine Imaging 
Pre-operative or post-operative MRI must be performed within 10 days prior to surgery or 
10 or more days after surgery. It is preferable to have a Spine MRI with and without 
gadolinium, however, we recognize that many sites only perform post-operative spine MRI 
with gadolinium. This is acceptable if it is of good quality and no hemorrhage is present. 
The MRI of the spine should include the entire spine and must be performed in at least two 
planes. If there is significant motion artifact and/or hemorrhage, then the scan is not 
evaluable and should be repeated. 
 
At a minimum, MRI of the entire spine should be obtained in the sagittal plane with both 
post gadolinium T1-weighted imaging and T2-weighted images, to assess for the presence 
of drop metastases. If present, the largest dimension of the largest metastasis will be 
measured. 
 
1. Whole spine sagittal T1; 3 mm skip 0 – 0.3 mm.  
Technical notes: 

 
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- 
Phase direction AP, frequency direction SI 
- 
Acquire 2 separate acquisitions (one cervical and upper thoracic, the second 
lower thoracic and lumbosacral) to optimize placement of presaturation pulse.  
- 
Place anterior saturation pulse close to the anterior margin of the spinal column - 
to minimize motion artifacts from chest/abdomen. 
- 
Pixel size 1 mm2 or less (example: for 26 cm FOV, use 256 x 256 matrix)  
- 
Keep TE to minimum (<15 msecs) 
- 
Do not use fat saturation 
2. Axial T1 images through the entire spine; 4-5 mm thick, skip 1-2mm.  
Technical notes: 
- 
Phase direction RL, frequency direction AP 
- 
Keep TE to minimum (< 15 msecs) 
- 
DO NOT INTERLEAVE 
 
For primary tumors of the spinal cord, add: 
1. Whole spine sagittal T2; 3 mm skip 0mm.  
Technical notes: 
- 
Can keep Phase direction AP, frequency direction SI, with anterior saturation 
pulses; or switch phase direction SI, frequency direction AP, with inferior and 
superior saturation pulses if that produces better images (less CSF pulsation 
artifacts) 
- 
Pixel size 1 mm2 or less (example: for 26 cm FOV, use 256 x 256 matrix)  
2. Axial FSE T2, 4-5mm skip 0-1 mm, through tumor 
 
NOTE: 
In the routine evaluation for subarachnoid metastatic dissemination from brain tumors to 
the spine: 
1. High quality T1 images are essential - without artefacts from physiologic motion 
(cardiac, respiratory) or from CSF pulsation.  
2. T2 weighted sequences (sagittal or axial) are not needed. They are optional.  
 
17.6 
Central Review 
Central review will be performed to confirm eligibility, response and relapse by the study 
neuroradiologists.  As of Amendment #1D, imaging during follow-up (retrospective and 
prospective) will be submitted for all patients who received radiation therapy. 
 
Please see Section 17.1 for guidelines regarding Rapid Central Review for patients who 
have sub-total resection.  The following scans should be submitted for central review for 
all patients in addition to the operative report: 
Head MR: Axial T1-weighted images without contrast; axial T1-weighted images 
with contrast; T2-weighted images; FLAIR images, coronal and sagittal post 
gadolinium T1-weighted images.  Post contrast T1-weighted images should 
preferably be 4 mm thick slices with no skip 
Spine MR: pre or post-operative sagittal post-contrast T1-weighted and T2-weighted 
images at a minimum.   
 
The size of the tumor and metastases will be recorded to assess response. 
 

 
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The following scans and reports must be submitted with the operative report(s): 
                        Scan 
 
 
 
Brain  
Spine 
1) 
Preoperative (initial) 
 
 
X 
 
X (pre or post-op) 
2) 
Postoperative 
 
 
 
X 
 
X (pre or post-op) 
3) 
Post Induction Chemotherapy 
 
X 
 
X 
(Cycle B Days 21-29) 
4) 
Post Second Surgery (If applicable) 
X 
 
- 
5) 
Post RT (4 weeks post RT) 
 
X 
 
- 
6) 
End of Maintenance Chemotherapy 
X 
 
X 
7) 
Relapse 
 
X 
 
X 
 
Note: As of Amendment #1D, patients with reported Grade 3 or above CNS system 
necrosis within 2 years of study enrollment must submit imaging and reports for central 
review within 2 weeks of completion. Patients who experience toxicity must continue to 
have imaging submitted up to 2 years after study enrollment. See Section 11.4. 
 
The study committee requests submission of pre and post-operative imaging from any and 
all surgeries performed to resect tumor in addition to those noted above. This includes 
patients who have more than one surgery prior to enrollment or more than one surgery after 
induction chemotherapy. Please also include any repeat Brain MRs done prior to starting 
treatment. 
 
17.7 
Address Information 
Copies of the required studies for central review should be forwarded to: 
 
IROC Rhode Island  
Building B, Suite 201 
640 George Washington Highway 
Lincoln, RI 02865-4207 
Phone: (401) 753-7600 
Fax: 
(401) 753-7601 
 
 
Submission of Diagnostic Imaging data in digital format is required. Digital files must be 
in DICOM format. These files can be submitted via sFTP. Information for obtaining an 
sFTP account and submission instructions can be found at http://irocri.qarc.org/. Follow 
the link labeled digital data. Alternatively, if sFTP is not feasible, the imaging may be 
burned to a CD and mailed to IROC RI (QARC) at the address below. Multiple studies for 
the same patient may be submitted on one CD; however, please submit only one patient 
per CD. Sites using Dicommunicator may submit imaging via that application. Contact 
IROC RI (QARC) with questions or for additional information. 
 
 
 
18.0 
RADIATION THERAPY GUIDELINES  
 
Radiation Therapy (RT) can only be delivered at approved RT facilities (COG administrative 
policy 3.9).  
 
 
 
 
 
Timing of protocol therapy administration, response assessment studies, and surgical 
interventions are based on schedules derived from the experimental design or on established 
standards of care.  Minor unavoidable departures (up to 72 hours) from protocol directed therapy 
and/or disease evaluations (and up to 1 week for surgery) for valid clinical, patient and family 
logistical, or facility, procedure and/or anesthesia scheduling issues are acceptable per COG 
Administrative Policy 5.14 (except where explicitly prohibited within the protocol). 

 
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18.0.1 General Guidelines 
The indications and sequencing of radiation therapy for this protocol will be based on 
extent of resection and tumor grade and location. Patients enrolled on this protocol after 
subtotal resection will receive induction chemotherapy for seven weeks followed by second 
surgery and radiation therapy. Patients enrolled after gross-total or near-total resection will 
receive immediate post-operative radiation therapy unless they have microscopic gross-
total resection (GTR1) and supratentorial, classic ependymoma. Maintenance 
chemotherapy after radiation therapy will be mandated for certain patients and randomized 
for others. This study specifies a 5mm clinical target volume margin and mandates the use 
of CT-MR registration to define the target volumes. The allowed treatment methods are 
restricted to conformal or intensity-modulated radiation therapy using photons or proton 
beam therapy and electronic data submission is required. 
 
18.0.2 Treatment Planning Specifics 
The guidelines for this study were developed based on the performance of COG 
investigators when executing the guidelines for ACNS0121 and the experience from St. 
Jude Children’s Research Hospital prospectively monitoring the side effects of conformal 
radiation therapy in young children with ependymoma. The prescribed dose for 
ependymoma has evolved to a standard of 59.4 Gy when using a clinical target volume 
margin of 1cm for all children except those under the age of 18 months treated with gross-
total resection. There are ample data demonstrating that these prescribed doses and target 
volumes are reasonable and safe. The data suggest that further volume reductions are 
warranted because of the correlation between radiation dose, treatment volume and a 
variety of functional outcomes. In this study, the clinical target volume has been reduced 
to 0.5 cm with the expectation that the dose will be lower to normal tissues and side effects 
will be reduced. To achieve the protocol specified dose of 59.4 Gy and respect normal 
tissue tolerances, with emphasis on dose to the spinal cord, brainstem and optic chiasm, 
prior protocols have emphasized a two phase approach. The two phase approach included 
54 Gy administered during the first phase followed by a second phase reduction in the 
treatment volume to exclude spinal cord, brainstem or optic chiasm, when indicated. 
Because of the association of the brainstem and the target volume in patients with 
infratentorial ependymoma, prior studies using photons have not specified brainstem dose-
volume constraints and few unexpected adverse events have been observed in these 
patients. Children with ependymoma tend to be young and vulnerable from the events 
leading to diagnosis and neurosurgery. We continue to place an emphasis on reducing dose 
to normal tissues and have designed a new algorithm to follow that specifies a volume-
based change in treatment after 54 Gy. The goal is to achieve a minimum dose level of 54 
Gy to the planning target volume before further reducing dose to spinal cord, brainstem 
and optic chiasm, when indicated.50,51 We will continue to limit the total dose to 54 Gy for 
children under the age of 18 months at the start of irradiation provided that they have 
undergone gross-total resection. Additional limitations in radiation dose and volume will 
be applied for patients treated using proton therapy. 
 
18.0.3 Credentialing Requirements 
Radiation therapy will be administered using protons or photons. Allowable photon 
methods include 3D-conformal radiation therapy (3D-CRT) or intensity modulated 
radiation therapy (IMRT). Proton therapy may be delivered using passively scattered 
proton or scanning beams provided that the specific beam line has been approved for use 
in clinical trials by IROC Houston (RPC). Centers participating in this protocol using 3D-
CRT are required to complete the 3D benchmark; those using IMRT and not previously 

 
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credentialed for use of IMRT in COG trials must irradiate the IMRT Head and Neck 
Phantom available from IROC Houston (RPC). See http://rpc.mdanderson.org for 
information regarding the phantom irradiation and other credentialing requirements.  All 
centers participating in this protocol must complete the IROC RI (QARC) CT/MR image 
fusion 
benchmark, 
which 
is 
available 
from 
the 
IROC 
RI 
QA 
Center  
(http://iroc.qarc.org/ ).  
 
18.0.4 Guidelines and Requirements for the Use of IMRT 
Investigators using IMRT will be required to comply with the guidelines developed for the 
use of IMRT in National Cancer Institute sponsored cooperative group trials. These 
guidelines are available through http://iroc.qarc.org/. These guidelines require that the 
protocol explicitly state their requirements and methods for localization and 
immobilization; the use of volumetric imaging; target and organ motion management; 
nomenclature, definitions and rationale for targets and organs at risk; target volume 
coverage and normal tissue dose constraints; effects of heterogeneity in tissues; and quality 
assurance. 
 
18.0.5 Guidelines and Requirements for the Use of Proton Beam Therapy 
Investigators using proton beam therapy will be required to comply with the guidelines for 
the use of protons in National Cancer Institute sponsored cooperative group trials. These 
guidelines are available at http://www.irocri.qarc.org and http://rpc.mdanderson.org. The 
guidelines specify the following for the participating institution: both scattered and scanned 
proton beams may be used provided that the specific beam line has been approved by IROC 
Houston; the IAEA TRS 398 protocol shall be used for beam calibration; dose reporting 
will be in Cobalt Gy Equivalent (1 CGE = 1 proton Gy * 1.1). Radiation doses shall be 
prescribed using protocol specified definitions for gross (GTV) and clinical (CTV) target 
volumes. For set-up uncertainties and target motion, additional margin, smearing, range of 
modulation will be added on a per beam basis as appropriate. The proton institution is 
required to participate in on-site and remote review according to COG guidelines.52-54 
 
18.0.6 Rationale for Limiting Radiation Dose and Volume to the Brainstem Using Proton 
Therapy 
Local failure is predominant mode of failure in children treated with post-operative 
radiation therapy for ependymoma. Beginning with the POG-9132 study (1991-1994) the 
primary site dose was escalated to 69.6 Gy using a hyper-fractionated approach (1.2 Gy 
BID) and later to 59.4 Gy (1.8 Gy daily) consistent with the treatment of other aggressive 
or high-grade brain tumors. Based on the reported experience at St. Jude,20 which included 
a high-rate of gross-total resection (>80%), the cumulative incidence of local failure was 
approximately 16.3% (9.6-23.0, 95% CI) when measured at 5-7 years. 
 
The following table (Table 18.0) provides information about photon and proton therapy 
trials for children with ependymoma. The number of children treated using 54 Gy is small 
in any of the north American series; however, for the European series (55,56 – presented at 
ESTRO 2015) better rates of tumor control are observed in patients treated with the higher 
dose regimens.  

 
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Table 18.0 
Source 
Treatment 
Dates 
Age 
Restriction 
Target 
Volume 
CTV 
Margin 
Dose 
Regimens 
cGy/CcGE 
Total 
Irradiated 
Location Ratio 
(IT/ST) 
Modality 
US Cooperative Group Studies 
POG-913257 
 
1991-1994 
>36mo 
Pre-op 
2.0cm 
69.6/1.2 
BID 
31 
 
31/0 
Photon 
CCG-9942 15 
 
1995-1999 
>36mo 
Pre-op 
1.5cm 
59.4/1.8 
55.8/1.8* 
84 
 
49/35 
Photon 
ACNS0121 
 
2003-2007 
>12mo 
Post-op 
1.0cm 
59.4/1.8 
54.0/1.8** 
378 
 
258/96† 
Photon-
Proton 
ACNS0831 
2010-
Present 
>12mo 
Post-op 
0.5cm 
59.4/1.8 
54.0/1.8** 
>300 
  
Not yet known Photon-
Proton 
Single or Multi-Institution Studies 
St. Jude 20 
1997-2003 
>12mo 
Post-op 
1.0cm 
59.4/1.8 
54.0/1.8** 
153 
 
122/31 
Photon 
PSI 58 
2004-2013 
>12mo 
Post-op 
1.0-
0.5cm 
59.4/1.8 
50 
 
36/14 
Proton-PBS 
only 
French 
Cohort 55 
2000-2013 
>36mo 
No details 
No 
details 
59.4/1.8 
54.0/1.8 
177 
 
136/41 
Photon-
Proton 
Italian 
Cohort56 
2003- 
>36mo 
No details 
No 
details 
59.4/1.8 
67.8/1.8-
2.0*** 
160 
 
110/50 
Photon 
Legend:  
IT = infratentorial, ST = supratentorial, †-2 patients had trans-tentorial tumors  
*Patients with GTR and infratentorial tumors, or residual tumor (infratentorial or supratentorial) received 59.4 cGy.  
Patients with GTR and supratentorial tumors received 55.8 cGy. 
 ** - Patients less than 18  months of age at resection and GTR1 (gross total resection with no visible residual tumor 
identified at surgery or on post-operative imaging) or GTR2 (microscopically visible residual tumor identified at 
surgery an no evidence of disease on post-operative imaging) received 54 Gy. 
 
 
The following graph compares the ACNS0121 Stratum 2 (sub-total resection/
chemotherapy/second surgery when feasible/radiation therapy) proton and photon patients. 
There were two local failures amongst 5 patients. 
 

 
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The following graph compares the ACNS0121 Stratum 3+4 (near- or gross-total 
resection/radiation therapy) proton and photon patients. There were 4 distant and 2 local 
failures amongst 13 patients. 
 

 
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Summary of ACNS0121 proton review – there are too many different groups and clinical 
factors to suggest that a deviation in radiation dose of less than 10% has any impact on 
outcome. 
 
Among patients with infratentorial tumors who received either 54 GyE (n=4) or 59.4 GyE 
(n=8) proton therapy on ACNS0121, one of 4 patients who received 54GyE experienced 
distant progression; 6 of 8 patients who received 59.4 cGyE experienced progression (3 
local and 3 distant).  
 
The investigators further narrowed the subgroup of patients receiving 54 GyE or 59.4 GyE 
proton therapy on ACNS0121 to include only those patients with infratentorial tumors with 
a gross/near total resection (strata 3 and 4) (total n=8). One of 3 patients who received 54 
cGyE experienced progression (distant) and 4 of 5 patients who received  
59.4 cGyE experienced progression (1 local and 3 distant).  
 
The RT guidelines for the ACNS0831 protocol (activated 3/29/2010) were developed 
based on the guidelines used in the ACNS0121 protocol. The ACNS0121 protocol 
guidelines were widely accepted. There are notable differences between the ACNS0121 
and ACNS0831 RT guidelines. In ACNS0831 the investigators reduced the clinical target 
volume margin from 1.0 cm to 0.5 cm, there was a mandated target volume reduction after 

 
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5400 cGy, quantitative normal tissue constraints were included, and the guidelines for 
proton therapy were more specific.  
 
Review of the patients that have been treated thus far on ACNS0831 reveals that there is 
some evidence that investigators are reluctant to treat patients with infratentorial tumors 
using doses in excess of 54 Gy on this study even though the initial target volume margins 
are smaller (CTV1=0.5cm and PTV1=0.3cm) than for the prior study (CTV=1.0cm and 
PTV=0.5cm) and there is a mandated volume reduction for treatment from 54 Gy to 59.4 
Gy and investigators are allowed to prioritize normal tissue dose constraints over target 
volume (PTV2) coverage. Without considering the rate of enrollment, investigator 
reluctance to use doses > 54 Gy does not appear to have reached a level that affects current 
protocol performance, compromises disease control, or risks poor functional outcomes. 
The modification of the guidelines previously proposed was meant to strengthen, clarify, 
and increase acceptance of existing guidelines. The intent was not to compromise treatment 
of the initial target volume to a minimum of 54 Gy. The goal was to allow for supplemental 
(“boost”) irradiation of at highest risk for local tumor recurrence to 59.4 Gy prioritizing a 
more stringent brainstem dose constraint and highlighting that investigators could limit the 
CTV expansion into the brainstem.  
 
The Study Committee has amended the protocol with Amendment #1D to reflect this shift 
in practice which will help provide uniformity going forward and a way to look at the data 
on the patients already treated to provide helpful data in future COG studies to answer the 
questions posed about toxicity and tumor control. 
 
18.1 
Indications for Radiation Therapy  
Patients enrolled on this protocol after subtotal resection will receive induction 
chemotherapy for seven weeks followed by second surgery and radiation therapy (except 
for supratentorial classic patients with GTR1 after second surgery, who will not be 
irradiated). 
 
Patients enrolled after gross-total or near-total resection will receive immediate post-
operative radiation therapy unless they have microscopic gross-total resection (GTR1). 
 
Patients enrolled after microscopic gross-total resection (GTR1) and supratentorial, classic 
ependymoma will not be irradiated. 
 
18.2 
Timing 
 
18.2.1 All patients who will require irradiation should be seen in consultation by a radiation 
oncologist at the time of study enrollment. The purpose of the consultation is to 
participate in staging and to review the adequacy of the initial diagnostic imaging 
studies that will be used for subsequent RT planning. 
 
18.2.2 There are no contraindications to radiation therapy. Patients taking phenytoin should 
be weaned and/or switched to a different anticonvulsant as soon as feasible.  
 
18.3 
Emergency Irradiation 
Patients are not allowed to have received radiation therapy prior to enrollment on this 
protocol and urgent irradiation is not envisioned under any circumstance.  
 

 
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18.4 
Equipment and Methods of Delivery and Verification 
 
Equipment 
Photons 
(any energy) 
IMRT 
(4-10MV) 
Protons 
Linear Accelerator 
X 
X 
 
Proton Beam  
 
 
X 
 
18.4.1 Treatment planning 
CT (volumetric) based planning is required to optimize dose to the PTV while 
protecting normal tissues. Organs at risk within the irradiated volume should be 
contoured including those required. A DVH is necessary to determine target 
coverage and evaluate dose to normal tissues. CT section thickness should be 
≤ 5mm although 23mm is preferred. 
 
 
18.4.2 In-room verification of spatial positioning 
 
18.4.2.1 Portal imaging is the most common system used to verify patient position, 
in particular when the target volume is believed to possess a fixed spatial 
relationship with visualized bony anatomy. Orthogonal paired (AP and 
lateral) portal images (MV or kV) are required for IMRT and 3-D CRT to 
verify that the isocenter is in correct alignment relative to the patient 
position. 
 
18.4.2.2 Volumetric imaging is allowed in this study. This includes in-room kV or 
MV cone beam or conventional CT imaging. A printout or screen capture 
of representative axial images showing the isocenter and the correct 
alignment in relationship to the patients’ position will be considered 
documentation of positioning. For CT tomography where isocenters are 
not used, a printout of the isodoses overlaid on the fused CT images can 
be printed to demonstrate in room verification. 
 
 
18.5 
Target Volumes 
 
18.5.1 General comments 
International Commission on Radiation Units and Measurements (ICRU) Reports 
50, 62, and 78 (https://icru.org/) define prescription methods and nomenclature 
that will be utilized for this study. Although the MRI obtained immediately prior 
to radiation therapy should be used for treatment planning, the target volumes for 
this study will be determined by the collective information that delineates the 
extent of disease before and after surgical resection. Most patients with 
ependymoma require a combination of pre- and post-operative MR sequences to 
delineate the extent of disease. MR pre- and post-gadolinium contrast T1, T2, and 
FLAIR sequences should be reviewed. The sequence that best defines the extent 
of residual disease and post-operative tumor bed should be registered to the 
treatment planning CT and used to determine the GTV. The GTV, CTV and PTV 
and normal tissues must be outlined on all axial imaging slices on which the 
structures exist.  
 
The target volume definitions for this protocol are similar to those used in the 
ACNS0121 study with notable exceptions: the clinical target volume margin is 

 
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5mm and there is a mandatory target volume reduction after 54 Gy. On the 
ACNS0121 study the clinical target volume margin was 10 mm and there was not 
a target volume reduction. The most practical way to comply with this protocol 
would be to follow the steps outlined below and consider the information contained 
in the more formal definitions of the target volumes. 
 
Practical Targeting Guidelines for GTV1, CTV1, and PTV1 
 
Obtain a treatment planning CT using a 23 mm image section thickness. 
Contrast is not required. 
 
Register the pre-operative MR sequences that best demonstrate the full extent 
of disease. Most often this would be the T2 or FLAIR MR sequences. In some 
cases, the post-contrast T1-weighted MR sequences will be useful. 
 
Contour the pre-operative tumor (GTV_PREOP) on the registered MR data to 
satisfy the protocol requirement to delineate this volume. 
 
Register the post-operative or more recently acquired (when available) pre-
irradiation T1-weighted MR image data to the treatment planning CT. Register 
other imaging data sets as required to delineate post-operative residual disease 
and the tumor bed. 
 
Contour GTV1 which is defined the post-operative residual disease and the 
edge of the (often collapsed) post-operative tumor bed. The edge of any 
structure in contact with the pre-operative tumor (GTV_PREOP) should be 
included as part of GTV1. 
 
Expand GTV1 geometrically by 5mm to create CTV1. The physician should 
modify CTV1 at non-neural and neural interfaces where invasion is unlikely. 
This would include the inner-table of the skull, base of skull and tentorium for 
non-neural structures. For neural structures this would include brainstem, 
uninvaded ventricle wall, and borders associated with mass effect. 
 
Expand the final form of CTV1 geometrically by 3 or 5 mm to create PTV1 
(Section 18.5.8). 
 
Practical Targeting Guidelines for GTV2, CTV2, and PTV2 
 
GTV2 may be the same as GTV1 or modified from GTV1 depending on the 
clinical scenario as defined in Section 18.5.5. 
 
There is no CTV2. 
 
Expand GTV2 geometrically by 3 or 5 mm to create PTV2 (see Section 
18.5.9). 
 
18.5.2 Photon definitions for GTV, CTV, and PTV 
 
Gross tumor volume (GTV) is based on the post-operative MR examination 
and includes gross residual tumor and the tumor bed at the primary site. In 
defining the GTV, the investigator should consider the initial pre-operative 
imaging examination that defined the extent of tumor and the tissues involved 
anatomically. The GTV in most cases will be a contracted or collapsed tumor 
bed. Tissue defects resulting from surgical approaches will not be included as 
part of the GTV when not previously involved by tumor. Investigators should 
register the pre-operative MR imaging sequence that demonstrated tumor and 
contour the structure to be identified as GTV_preop to assist in the delineation 
and evaluation of the GTV. 
 

 
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 
Clinical target volume (CTV) includes the GTV with an added margin that is 
meant to treat subclinical microscopic disease and is anatomically confined 
(i.e., the CTV is limited to the confines of the bony calvarium, falx, and 
tentorium where applicable or extends up to but not beyond neuroanatomic 
structures through which tumor extension or invasion is certain not to have 
occurred); the CTV margin will be 5mm for all patients. When the GTV 
approaches the boundary of an anatomic compartment, the CTV will extend 
up to and include the boundary. The CTV margin chosen for this study requires 
treatment planning MR and/or diagnostic MR imaging data with image section 
thickness ≤ 5mm. In the setting where the target volumes interface with 
the brainstem, the expansion of the CTV into the brainstem should be 
limited to 3mm. 
 
 
Planning target volume (PTV) includes a margin which is added to the CTV 
in 3-dimensions to create the PTV. It is geometric and not anatomically 
defined. The PTV has two components, the internal margin (IM) and the set-
up margin (SM). The IM is meant to compensate for all movements and 
variations in size and shape of the tissues contained within the CTV. The SM 
is meant to account for set-up, mechanical and dosimetric uncertainties related 
to daily patient positioning, treatment equipment and software. For this study, 
the PTV margin should be 3 or 5mm. The use of a PTV margin of 3mm 
requires written documentation that image-guided radiation therapy (IGRT) 
methods are used on a daily basis or alternatively that a head fixation system 
or verification system was used with weekly or more frequent imaging. For 
this study, IGRT is defined as 2- or 3-dimensional digital imaging positioning. 
Given that the CTV is generally confined to the intracranial space, the PTV 
may extend into or beyond bone but is unlikely to extend beyond the surface 
of the patient. The PTV margin chosen by the treating investigator requires 
treatment planning MR and/or diagnostic MR imaging data with imaging 
section thickness ≤ the chosen PTV margin. 
 
 
18.5.3 Proton definitions for GTV, CTV, and PTV 
 
GTV is the same for protons and photons. 
 
CTV is the same for protons and photons. 
 
PTV is the same as photons and will be used to select the appropriate beam 
size and beam arrangements to achieve lateral coverage of the targeted volume 
and to minimize heterogeneity. The PTV will not be used to determine the 
distal range for the individual proton beams but will be used to report dose 
according to ICRU Report-78. The proton distal target margin will be 
determined per beam using the guidelines in Section 18.6.3. 
 
18.5.4 Gross Tumor Volume 1 (GTV1) 
GTV1 will include the post-operative resection margin of tissues initially involved 
with disease and the entirety of residual tumor defined on post-operative MR with 
consideration given to the pre-operative imaging evaluation. In the setting of gross-
total resection, the post-contrast T1-weighted MR sequence is generally the most 
useful. In the setting of non-enhancing residual disease, T2-weighted imaging may 
be required. GTV1 will take into account changes in brain anatomy resulting from 
tumor resection or CSF shunting.  
 

 
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 
GTV1 is the volume of tissue containing the highest concentration of tumor 
cells. 
 
GTV1 includes the post-operative tumor bed which is the edge of the resection 
cavity. 
 
GTV1 includes residual disease defined by post-operative neuroimaging. 
 
The surgical corridor should not be included in the delineation of the GTV 
unless suspected to contain tumor. 
 
When there is discrepancy between imaging studies or intra-operative 
findings, the larger volume will define GTV1. 
 
18.5.5 Gross Tumor Volume 2 (GTV2) 
The purpose of GTV2 is to administer radiation dose to the volume of tissue 
containing the highest concentration of tumor cells and allow the investigator to 
limit dose to the spinal cord, brainstem and optic chiasm after the initial phase of 
treatment to 54 Gy. There are several options to define GTV2: GTV2 may be the 
same as GTV1 when the composite plan dose distributions to the optic chiasm and 
spinal cord do not exceed the recommendations in Section 18.8. When the 
recommended spinal cord dose distribution might be exceeded, GTV2 should be 
equal to GTV1 minus the any portion of GTV1 caudal to the intracranial aspect of 
the foramen magnum. When the recommended optic chiasm dose distribution 
might be exceeded, GTV2 should be equal to GTV1 minus the optic chiasm with 
a planning organ at risk (PRV) margin equal to the margin chosen for PTV1. When 
both the spinal cord and optic chiasm dose distributions might be exceeded, both 
of the outlined procedures should be followed. 
 
Option 1: GTV2 = GTV1 
 
Option 2: GTV2 = GTV1 minus the GTV1 volume caudal to the foramen 
magnum 
 
Option 3: GTV2 = GTV1 minus (optic chiasm + PRV margin chosen for 
PTV1) 
 
Option 4: GTV2 = combined procedure used for options 2 and 3 
 
18.5.6 Clinical Target Volume 1 (CTV1) 
 
CTV1 is defined as the volume of tissue containing subclinical microscopic 
disease 
 
CTV1 for this protocol is the GTV1 with an anatomically confined margin of 
0.5cm 
 
CTV1 should be tailored at tissue interfaces where invasion/infiltration is not 
likely 
 
CTV1 extent in brainstem should be limited to 3mm 
 
CTV1 may be manually moved inward to the inner table of the bony calvarium 
 
18.5.7 Clinical Target Volume 2 (CTV2) 
 
CTV2 = There is no CTV2 
 
18.5.8 Planning Target Volume 1 (PTV1) 
The PTV-1 will include the CTV-1 plus a geometric margin of 3 or 5mm in all 
dimensions. The PTV may extend beyond bone margins and the skin surface. 
There are two options for PTV1 depending on the institutional method for daily 

 
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localization, verification and interventions performed to reduce the set-up 
uncertainty. 
 
Option 1: PTV1 = 3mm (requires daily digital imaging and intervention or 
equivalent, 18.5.2) 
 
Option 2: PTV1 = 5mm (no special requirements) 
 
18.5.9 Planning Target Volume 2 (PTV2) 
 
The PTV2 will include GTV2 with an additional margin equal to the margin 
used to create PTV1. PTV2 may extend beyond bone margins and the skin 
surface. 
 
Option 1: PTV2 = 3mm (requires daily digital imaging and intervention or 
equivalent, 18.5.2) 
 
Option 2: PTV2 = 5mm (no special requirements) 
 
There is no PTV2 for children under the age of 18 months at the start of 
irradiation if their extent of resection has been characterized as gross-
total resection. 
 
 
18.6 
Target Dose 
 
18.6.1 Dose Definition 
Photon dose is to be specified in centigray (cGy)-to-muscle. For proton beam, the 
absorbed dose is specified in CGE, which is the same as ICRU 78 DRBE using a 
standard RBE of 1.10 with respect to water.  
 
18.6.2 Prescribed dose and fractionation 
 
Planning Target Volume 1 (PTV1): The total dose to the PTV1 prescription 
isodose surface will be 5400 cGy administered in 30 fractions of 180 cGy. The 
patient should be treated with one fraction per day.  All fields should be treated 
each day in photon treatments. Simultaneous integrated boost is not allowed. 
 
 
Planning Target Volume 2 (PTV2): The total boost dose to the PTV2 
prescription isodose surface will be 540 cGy administered in 3 fractions of 180 
cGy. The cumulative dose will be 5940 cGy. The patient should be treated with 
one fraction per day.  All fields should be treated each day in photon 
treatments. Simultaneous integrated boost is not allowed. Children under the 
age of 18 months at the start of irradiation will not receive boost treatment 
after 54 Gy provided their extent of resection has been characterized as 
gross-total resection. 
 
Table 18.6.2 Prescribed Doses and Fractionation 
Nominal Dose by Site 
Target Volume 
Dose/fraction 
Number of 
Fractions 
Primary Site 5400 cGy 
PTV1 
180 cGy 
30 
Primary Site Boost 540 cGy† 
PTV2 
180 cGy 
3 
† Primary site boost treatment will not be administered to children under the age 
of 18 months at the start of irradiation if their extent of resection has been 
characterized as gross-total resection. 
 

 
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18.6.3 Dose uniformity 
For photons, at least 95% of the protocol-specified dose should encompass 100% 
of the PTV1/PTV2 and no more than 10% of PTV1 or PTV2 should receive greater 
than 110% of the protocol dose as evaluated by DVH. The 100% isodose should 
be equal to the protocol specified dose. Wedges, compensators and other methods 
of generating more uniform dose distributions are encouraged. 
 
 
For protons, at least 95% of the protocol-specified dose should encompass 100% 
of the PTV1/PTV2 and no more than 10% of PTV1 or PTV2 should receive greater 
than 110% of the protocol dose as evaluated by DVH. The 100% isodose should 
be equal to the protocol specified dose. The PTV; however, will be only be used 
to select the appropriate beam size and beam arrangements to achieve lateral 
coverage of the targeted volume and to minimize heterogeneity. The lateral margin 
for proton beam therapy should be 3 or 5 mm according to Section 18.5.8 or 
Section 18.5.9. The PTV will not be used to determine the distal range for the 
individual proton beams. The proton distal target margin will be determined per 
beam based on the distal aspect of the CTV and additional margin(s) meant to 
account for range uncertainty and the SM and IM components of the PTV which 
are understood for this group of patients and which may affect the proton distal 
range.‡   
 
Proton Distal Target Margin† = CTV + Range Uncertainty + Set-up Margin + 
Internal Margin 
 
CTV = the distal aspect of the CTV 
 
Range Uncertainty = 1.5% of the water-equivalent range of the CTV at max 
depth 
o > 1 mm 
 
Set-up Margin = set-up, mechanical and dosimetric uncertainties 
o Protons are relatively unaffected by set-up uncertainty in axis of beam 
o Uncertainty in hardware and software – no assigned value available 
 
Internal margin = compensates for all variations in site, size and shape of the 
tissues contained in or adjacent to the CTV 
o > 1 mm 
 
†The proton distal range may be adjusted at the discretion of the treating radiation 
oncologist based on normal tissue dose concerns.  
‡The uncertainty of distal margin has been estimated to be as large as 4 mm. 
 
When pencil beam scanning techniques are used with scenario based optimization 
(also known as robust optimization), the plan may be optimized for 100% of the 
CTV to receive 95% of the protocol-specified dose. The protocol-defined PTV 
should be reviewed to confirm sufficient coverage. 
 
18.6.4 Tissue heterogeneity 
Calculations must take into account tissue heterogeneity and should be performed 
with CT-based treatment planning to generate dose distributions and treatment 
calculations from CT densities. For questions about heterogeneity corrections or 
approved algorithms, please contact IROC RI (QARC) (http://iroc.qarc.org/). 
 
 

 
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18.6.5 Interruptions, Delays and Dose Modifications 
There will be no planned rests or breaks from treatment, and once radiation therapy 
has been initiated, treatment will not be interrupted except for any life threatening 
infection or severe hematological toxicity defined as ANC < 300/L or platelets less 
than 40,000/L during the course of treatment. Blood product support should be 
instituted according to institutional/protocol guidelines. The reason for any 
interruptions greater than 3 treatment days should be recorded in the patient treatment 
chart and submitted with the QA documentation. There should be no modifications 
in dose fractionation due to age or field size. 
 
18.7 
Treatment Technique 
 
18.7.1 Beam Configuration 
Every attempt should be made to minimize dose to organs at risk without 
compromising coverage of the target volume. Three-dimensional conformal 
therapy (coplanar or non-coplanar) or IMRT are required to minimize dose to 
normal tissues.  
 
 
 
18.7.2 Selection of proton beam arrangements 
Proton beams have two uncertainties at the distal edge of the beam that affect 
planning. The first is the physical uncertainty of the exact location of the stopping 
edge. This is accounted for in Section 18.6.3. The second is the biologic 
uncertainty of the distal range of the proton beam in which the RBE may be greater 
than 1.1; therefore, single proton beam plans which stop in a critical organ will not 
be allowed.   
 
18.7.3 Field Shaping 
Field shaping for photons will be done with either customized cerrobend blocking 
or multileaf collimation. For passive scattering or uniform scanning proton 
techniques, field shaping will be done with either brass apertures or proton-specific 
multileaf collimation. 
 
18.7.4 Simulation including patient positioning and immobilization 
 
18.7.4.1 Patient positioning  
Reproducible setups are critical and the use of immobilization devices is strongly 
encouraged.  The patient may be treated in any appropriate, stable position. 
Consideration should be given to implications for inter and intrafraction motion 
when using non-standard position approaches. 
 
 
18.7.4.2 Immobilization devices 
Standard immobilization devices for the torso, extremities or head and neck are to 
be used.  For IMRT delivery approaches, the methods used for localization and 
immobilization of both patient and tumor are critical. The imaging studies should 
provide a clear assessment of the target volume with the patient in the treatment 
position.  
 
18.7.5 Special considerations 
Anesthesia or sedation may be required in certain patients, such as very young 
patients, to prevent movement during simulation and daily treatments.  

 
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18.7.6 Motion Management and Margins to Account for Target Volume Changes During 
Treatment 
Considering motion of normal tissues and target volumes is important. The internal 
target volume (ITV) is defined as the CTV surrounded by the IM component of 
the PTV and is meant to account for potential motion or changes in the CTV. The 
planning organ at risk volume (PRV) includes the corresponding organ at risk 
(OAR) volume surrounded by a margin to compensate for motion or physiologic 
change in the OAR. If adequate clinical data do not exist to define the IM 
component of the PTV or the PRV margin, the following suggestions are provided: 
 
 
A margin matching the PTV margin may be added to any OAR to form the 
PRV. 
 
Brain tumors susceptible to cyst expansion should be monitored closely. 
 
Any change in clinical condition or anatomy related to hydrocephalus, VP 
shunt placement, subdural fluid, pseudomeningocele or steroid use should be 
monitored carefully and with repeat imaging when indicated. 
 
 
18.7.7 Treatment Planning Procedures 
Table 18.7.7 
 
 
18.8 
Organs at Risk 
The organs at risk guidelines in this section are recommendations. If the recommended 
doses to the organs at risk are exceeded because of target volume coverage requirements 
or other conditions, an explanation should be included in the quality assurance 
documentation. In some cases, photon IMRT may be the preferred treatment method to 
meet these recommendations and the required target volume coverage guidelines.  
 
Treatment Planning CT 
Section thickness: < 3mm 
Volume: thoracic inlet-top of head 
↓ 
Register MR Imaging 
Pre-op (post-Gd T1WI or T2WI) 
Post-op (post-Gd T1W1) 
↓ 
Required Contours 
GTV_preop 
GTV1, CTV1, PTV1 (Section 18.4) 
GTV2, CTV2=PTV2 (Section 18.4) 
Normal Tissue Contours (Section 18.8) 
↓ 
Radiation Treatment Planning 
Target Volume Coverage (Section 18.5) 
Normal Tissue Dose Recommendations (Section 18.7) 
↓ 
Data Submission to IROC RI (QARC) 
Due Day 3 and End of Treatment (Section 18.9) 
Electronic and Hard Copy Data (Section 18.9) 

 
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18.8.1 Cochleae 
 
D50% <  3500 cGy – Goal (single cochlea) 
 
D50% < 2000 cGy – Preferred (single cochlea) 
 
Comment – There is no dose limit for the cochleae. 
 
Structure definition - Each cochlea will be contoured on the treatment planning 
CT as a circular structure within the petrous portion of the temporal bone.  The 
contour should appear on at least two successive CT images. 
 
18.8.2 Optic Globes 
 
D50% < 1000 cGy and D10% < 3500 cGy – Goal 
 
D50% < 2000 cGy and D10% < 5400 cGy – Maximum 
 
Comment – Effort should be made to avoid direct treatment of the anterior 
chamber of the eye and minimize dose to the entire eye without compromising 
target volume coverage during treatment of PTV1. In the event that the 
recommended maximum dose constraints provided in this section would be 
exceeded as a result of treatment of PTV2, the treating radiation oncologist 
may use their discretion to reduce target volume coverage. 
 
Structure definition - Each eye should be separately contoured on the treatment 
planning CT or MR as a circular structure from the most superior to inferior 
aspect. 
 
18.8.3 Optic Nerves and Chiasm 
 
D50% < 5400 cGy and D10% < 5600 cGy – Goal 
 
D50% < 5600 cGy and D10% < 5800 cGy – Maximum 
 
Comment – Effort should be made to avoid direct treatment of the optic nerves 
and chiasm without compromising target volume coverage during treatment of 
PTV1. In the event that the recommended maximum dose constraints provided 
in this section would be exceeded as a result of treatment of PTV2, the treating 
radiation oncologist may use their discretion to reduce target volume coverage. 
 
Structure definition – The optic nerve may be contoured on CT or MR.  The 
contour should appear on at least two successive CT or MR images. 
 
18.8.4 Spinal Cord 
 
D50% < 2600 cGy and D10% < 5700 cGy  Goal 
 
D50% < 5000 cGy and D10% < 5900 cGy – Maximum 
 
Comment – Effort should be made to minimize dose to the spinal cord without 
compromising target volume coverage during treatment of PTV1. If any 
portion of the spinal cord receives the prescription dose during the treatment 
of PTV1, it is preferable to allow that portion of the spinal cord to receive 5400 
cGy during the first 30 fractions of treatment.  
 
Investigator discretion may be used during the initial phase of treatment 
(05400 cGy) for exceptional cases to minimize the dose to the upper cervical 
spinal cord and reduce target volume coverage after 5040 or 5220 cGy. 
 
During treatment of PTV2, the entire spinal cord volume should receive no 
more than 70% or 126 cGy per fraction during each of the last three treatments 
to achieve the recommended maximum dose constraints provided in this 
section. 
 
Structure Definition - For the purposes of this study, the upper aspect of the 
spinal cord begins at the inferior border of the foramen magnum and should 
be contoured on the treatment planning CT. For purposes of comparison and 

 
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consistency with dose volume data, the spinal cord should be contoured on a 
number of images to be determined by the image section thickness (CT section 
thickness, n=number of images; 2mm, n=30; 2.5 mm, n=24; 3 mm, n=20). 
Using these guidelines, only the superior-most 6cm of anatomic spinal cord is 
contoured. 
 
18.8.5 Brainstem – Photon Therapy 
 
D50% < 6100 cGy and D10% < 6300 cGy  Goal 
 
D50% < 6200 cGy and D10% < 6400 cGy – Maximum 
 
Comment – Effort should be made to minimize dose to the brainstem without 
compromising target volume coverage during treatment of PTV1. In the event 
that the recommended maximum dose constraints provided in this section 
would be exceeded as a result of treatment of PTV2, the treating radiation 
oncologist may use their discretion to reduce target volume coverage. 
 
Structure Definition - The brainstem may be contoured on the treatment 
planning CT or MR and will include the midbrain, pons and medulla. The 
cranial extent will be inferior to the IIIrd ventricle and optic tracts. The caudal 
extent will end at the foramen Magnum. 
 
18.8.6 Brainstem – Proton Therapy 
 
D50% < 5240CcGE and D0.1cc < 5660CcGE  – Goal 
 
D50% < 5400CcGE and D0.1cc < 5800CcGE  – Maximum 
 
Comment – Effort should be made to minimize dose to the brainstem without 
compromising target volume coverage during treatment of PTV1. In the event 
that the recommended maximum dose constraints provided in this section 
would be exceeded as a result of treatment of PTV2, the treating radiation 
oncologist may use their discretion to reduce target volume coverage. 
 
Structure Definition - The brainstem may be contoured on the treatment 
planning CT or MR and will include the midbrain, pons and medulla. The 
cranial extent will be inferior to the IIIrd ventricle and optic tracts. The caudal 
extent will end at the foramen Magnum. 
 
18.9 
Dose Calculations and Reporting 
 
18.9.1 Prescribed Dose 
The prescribed dose for each target volume and/or phase of treatment shall be 
submitted using the RT-1 Dosimetry Summary Form or Proton Reporting Form. 
If IMRT or proton therapy is used, the monitor units generated by the 
IMRT/ proton therapy planning system must be independently checked prior to the 
patient’s first treatment. Measurements in a QA phantom can suffice for a check 
as long as the patient’s plan can be directly applied to a phantom geometry. The 
total dose delivered shall be calculated and reported on the RT-2 Radiotherapy 
Total Dose Record.  
 
18.9.2 Normal Tissue Dosimetry 
The dose to the critical organs indicated should be calculated whenever they are 
directly included in a radiation field. The appropriate dose-volume histograms 
should be submitted. If IMRT is used for the primary tumor, a DVH must be 
submitted for a category of tissue called “unspecified tissue,” which is defined as 
tissue contained within the skin, but which is not otherwise identified by 

 
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containment within any other structure. A DVH for “Body” shall also be submitted 
to enable calculation of the required volumes in Table 18.9b. “Body” is defined as 
the outer contour of the patient on the treatment planning CT data set. 
 
Table 18.9a Required DVH data regardless of primary treatment site 
Required DVH 
Optic Chiasm 
Brainstem 
Spinal Cord 
Right Cochlea 
Left Cochlea 
Body 
Unspecified Tissue 
 
Treated Volume (mL), Irradiated Volume (mL) and Conformity Index (CI) 
The treated volume (TV) is the tissue volume that receives therapeutic dose. For 
the purpose of this protocol this would include the prescribed total dose of  
59.4 Gy and 95% of the prescribed dose or 56.4 Gy. This information may be used 
by the investigators, along with the absolute volume of the PTV, to calculate the 
conformity indexes (CI) CI100% and CI95%, respectively. The irradiated volume (IV) 
is the tissue volume that receives a dose that is considered significant in relation to 
normal tissue tolerance. The descriptive statistics for these and other tissue 
volumes maybe used for correlation with unusual side effects or to develop 
practical guidelines for future high-grade brain tumor protocols. 
 
Table 18.9b Required Volumetric Information 
Required Volumes (ml) 
TV95%=V56.4 Gy 
TV100%=V59.4 Gy 
IV35=V35 Gy 
IV45=V45 Gy 
IV54=V54 Gy 
PTV 
CTV 
GTV 
Entire Brain 
Unspecified Tissue 
 
18.10 Quality Assurance Documentation 
 
Institutions are required to submit the treatment plan as DICOM RT.  
Digital data must include treatment planning CT, structures, plan, and dose files. 
Submission may be by sFTP or CD.  Submission by sFTP is encouraged to ensure prompt 
review.  Instructions for data submission by sFTP or CD are on the IROC RI (QARC) web 
site at http://iroc.qarc.org/ under "Digital Data." Any items on the list below that are not 
part of the digital submission may be included with the transmission of the digital RT data 
or submitted separately. Screen captures are preferred to hard copy for items that are not 
part of the digital plan. 
 

 
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Within three days of the start of radiation therapy, detailed treatment data shall be 
submitted for on treatment review. 
 
Please submit the following for the Primary Site Target Volume: 
External beam Treatment Planning System  
 
RT treatment plan including CT, structures, dose, and plan files. These items 
are included in the digital plan. 
 
Dose volume histograms (DVH) for the composite treatment plan for all 
target volumes and required organs at risk. A DVH shall be submitted for 
the organs at risk specified in Section 18.8.  When using IMRT, a DVH shall 
be submitted for a category of tissue called “unspecified tissue.” This is 
defined as tissue contained within the skin, but which is not otherwise 
identified by containment within any other structure. DVHs are included in 
the digital plan. 
 
Treatment planning system summary report that includes the monitor unit 
calculations, beam parameters, calculation algorithm, and volume of interest 
dose statistics. 
 
MRI studies that have been fused with the planning CT should be submitted 
along with the digital RT data. The corresponding spatial registration files 
should also be submitted, if available. 
 
 
 
Supportive Data 
 
All diagnostic imaging and reports used to plan the target volume. This 
includes CT or MRI PRIOR to attempted surgical resection of the primary 
tumor. Digital format is preferred. 
 
For protons, a description of the rationale for the PTV margins.   
 
If the recommended doses to the organs at risk are exceeded, an explanation 
should be included for review by the IROC RI (QARC) and the radiation 
oncology reviewers. 
 
If a PTV margin of 3 mm is used, written documentation that image-guided 
radiation therapy (IGRT) methods are used on a daily basis or alternatively 
that a head fixation system or verification system was used with weekly or 
more frequent imaging. See Section 18.5.2 
 
Forms 
 
RT-1/IMRT Dosimetry Summary Form; or 
 
Proton Reporting Form (whichever is applicable). 
 
Within 1 week of the completion of radiotherapy, the following data shall be 
submitted for all patients: 
 
 
The RT-2 Radiotherapy Total Dose Record form. 
 
A copy of the patient’s radiotherapy record including prescription, and the 
daily and cumulative doses to all required areas and reference points 
 
Documentation listed above showing any modifications from original 
submission. 
 

 
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Data not included with the digital submission should be forwarded to: 
 
IROC Rhode Island 
Building B, Suite 201 
640 George Washington Highway 
Lincoln, Rhode Island 02865-4207 
Phone: (401) 753-7600 
Fax: 
(401) 753-7601 
Email: DataSubmission@qarc.org 
 
Questions regarding the dose calculations or documentation should be directed to: 
 
COG Protocol Dosimetrist 
IROC Rhode Island 
Phone: (401) 753-7600 
Email: physics@qarc.org 
 
18.11 Definitions of Deviations in Protocol Performance 
 
 
DEVIATION 
 
Minor 
Major 
Prescription Dose (0-5400 cGy/CcGE) 
 
Difference in prescribed or 
computed dose is 6-10% of 
protocol specified dose 
Difference in prescribed or 
computed dose is > 10% of 
protocol specified dose 
Dose Uniformity (0-5400 cGy/CcGE) 
 
>10% PTV received > 110% 
of the prescription dose 
or 
95% isodose covers < 100% of 
CTV 
90% isodose covers < 100% of 
CTV 
Volume (0-5400 cGy/CcGE) 
 
CTV1 or PTV1 margins are less 
than the protocol specified 
margins in the absence of 
anatomic barriers to tumor 
invasion (CTV1) or without 
written justification (PTV1) 
GTV1 does not encompass 
MR-visible residual tumor 
Organs at Risk 
 
Will be assessed at time of data 
review 
Will be assessed at time of data 
review 
 
18.12 Patterns of Failure Evaluation 
The patterns of failure for patients with localized ependymoma may be described as local, 
distant or a combination of local and distant and are based primarily on imaging evaluation 
of the neuraxis. Local failure is defined as progression of known residual tumor or the 
appearance of tumor at known prior sites of disease that were at some point without 
evidence of disease. Distant failure is defined as the appearance of tumor at sites other than 
known prior sites of disease. Distant failure most often occurs in the subarachnoid space 
and may occur at any point within the neuraxis. Although rare, extra-CNS metastasis 

 
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represents distant failure. Combined local and distant failure is defined when evaluation of 
the entire neuraxis reveals local and distant failure. The present study involves treatment 
of the primary site only and the prescription dose will be confined to a limited volume 
encompassing the tumor and/or tumor bed. It is possible that the volume that receives the 
prescription dose will not subtend the entire area at risk and that the rate of failure for 
patients treated using the guidelines of this protocol will be higher than that observed for 
patients treated with conformal radiation therapy using the same prescription dose and a 
larger CTV margin (ACNS0121 or historical data). If the treatment volume did not include 
the entire area at risk one would expect an increase in the rate of failure and a change in 
the pattern of failure with local failure as a component of failure occurring at a higher than 
expected rate. The monitoring of EFS will assess the rate of failure.  Determining the 
patterns of failure will require an assessment of tumor recurrence with respect to targeting 
and dosimetry. Failure may be described as in-field, marginal or out-of-field when focal 
irradiation techniques are used. Out-of-field failure is recurrence that occurs entirely 
outside of the CTV and is synonymous with distant failure. In-field failure is recurrence 
that originated entirely within the volume that was targeted to receive the prescription dose 
(CTV). Marginal failure is recurrence originating on the margin of the volume targeted to 
receive the prescription dose (CTV) and may be described in terms of location or the dose 
received. 
 
There is no universally accepted analytical method to assess pattern of failure and to determine 
whether failure is in-field, marginal or out-of-field. For this study, the pattern of failure will 
be assessed qualitatively and quantitatively by registering MR data obtained at the time of 
failure to the dosimetry from the original treatment plan.21 Failures will be determined 
qualitatively to be “in-field” when the recurrence appears to have originated from within and 
remains confined to the CTV, “marginal” when a portion of the recurrence is within the CTV 
but the majority of the recurrence is outside of the CTV, “distant” when the recurrence does 
not involve the CTV. Recurrences will be quantitatively categorized as in-field, marginal, or 
out-of-field based on the proportion of the recurrence that received at least 95% of the 
prescription dose.59 This requires contouring of the recurrence and computation of the dose-
volume histogram. Marginal failure occurs when between 20 and 80% of the recurrence 
volume receives more than 95% of the prescription dose, thus, in-field failure occurs when 
more than 80% of the recurrence volume receives more than 95% of the prescription dose and 
out-of-field failure occurs when less than 20% of the volume received more than 95% of the 
prescription dose. Any method has significant limitations, however, since the point of origin 
for tumor recurrence cannot be ascertained with absolute certainty and does not explicitly 
determine marginal failure. Because of this finding, we are not certain of the best method to 
define the patterns of failure at this time. 
 
 
 

 
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Page 105 
APPENDIX I: YOUTH INFORMATION SHEETS 
 
INFORMATION SHEET REGARDING RESEARCH STUDY- ACNS0831 
(for children from 7 through 12 years of age) 
 
A Study of Treating Newly Diagnosed Ependymoma without X-Ray Treatment 
 
1. We have been talking with you about your brain tumor which is called ependymoma. Ependymoma 
is a type of cancer that grows in the brain. After doing tests, we have found that you have this type 
of cancer. 
 
2. We are asking you to take part in a research study because you were just diagnosed with 
ependymoma. A research study is when doctors work together to try out new ways to help people 
who are sick. This study will see if a new treatment will work better to get rid of ependymoma than 
the normal treatment.  
 
The normal treatment is an operation to take out as much of the tumor as possible. Then, after the 
operation children also get x-ray treatment to kill any cancer cells that may still be in the brain. But, 
this x-ray treatment can cause bad health problems. Study doctors want to see if not giving x-ray 
treatment will help keep children from having bad health problems in the future from the x-ray 
treatment without having the tumor grow back. 
 
3. Children who are part of this study had a tumor that was completely taken out by an operation. The 
tumor is also a kind that doctors think will probably not grow back. Because of these things, study 
doctors do not want to give you any treatments but they want to watch you closely. You will have 
tests and exams to check for any signs that the tumor may be coming back. This “careful watching” 
is sometimes done for children who are not part of this study. If your tumor does come back, study 
doctors will talk to you about other treatments at that time. 
 
4. Sometimes good things can happen to people when they are in a research study. These good things 
are called “benefits”. We hope that a benefit to you of being part of this study is that you will not 
have any bad health problems from the x-ray treatment when you are older. But, we do not know 
for sure if there is any benefit of being part of this study. 
 
5. Sometimes bad things can happen to people when they are in a research study. These bad things 
are called “risks”. The risk to you from this study is that your tumor may come back because you 
are not getting the x-ray treatment. If this happens, you would need other treatment to try to get rid 
of the tumor. Other things may happen to you that we do not yet know about. 
 
6. Your family can choose to be part of this study or not. Your family can also decide to stop being 
in this study at any time. There may be other treatments for your illness that your doctor can tell 
you about. Make sure to ask your doctors any questions you have. 
 
7. We would like your “okay” to collect some extra blood. We will take the extra blood when other 
normal blood tests are done, so there will be no extra needle sticks. We would also like your “okay” 
to collect any tumor tissue that is left over from any operations you have while you are part of this 
study. We want to see if there are ways to tell how the cancer will react to treatment. You can still 
take part in this study even if you do not allow us to collect the extra blood or tumor tissue for 
research.  
 

 
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Page 106 
INFORMATION SHEET REGARDING RESEARCH STUDY – ACNS0831 
(for teens from 13 through 17 years of age) 
 
A Study of Treating Newly Diagnosed Ependymoma without X-Ray Treatment 
 
1. We have been talking with you about your brain tumor which is called ependymoma. Ependymoma 
is a type of cancer that grows in the brain. After doing tests, we have found that you have this type 
of cancer. 
 
2. We are asking you to take part in a research study because you have a newly diagnosed 
ependymoma tumor. A research study is when doctors work together to try out new ways to help 
people who are sick. This study will see if a new treatment will work better to get rid of 
ependymoma than the standard treatment.  
 
The standard treatment is surgery to remove as much of the tumor as possible. Then, after the 
operation children and teens also get radiation therapy (the use of high-energy x-rays) to kill any 
cancer cells that may still be in the brain. However, the radiation therapy can cause bad health 
problems (also called side effects) that show up when you are older. Study doctors want to see if 
not giving radiation therapy will help keep children and teens from having side effects from the 
radiation therapy without having the tumor grow back. 
 
3. Children and teens who are part of this study have had their tumor completely removed. The tumor 
is also a kind that doctors think is unlikely to grow back. Because of these things, study doctors do 
not want to give you any treatments but they want to watch you closely. You will have tests and 
exams regularly to check for any signs that the tumor may be coming back. This “careful watching” 
is sometimes done for children and teens who are not part of this study. If your tumor does come 
back, study doctors will talk to you about other treatments at that time. 
 
4. Sometimes good things can happen to people when they are in a research study. These good things 
are called “benefits”. We hope that a benefit to you of being part of this study is that you will avoid 
side effects from radiation therapy, but we do not know for sure if there is any benefit of being part 
of this study. 
 
5. Sometimes bad things can happen to people when they are in a research study. These bad things 
are called “risks”. The risks to you from this study are that your cancer may come back because 
you will not be receiving radiation therapy. If the tumor does come back, you would need other 
treatment to try to get rid of the tumor. There is also a risk that surgery may not be possible or that 
the tumor will come back and spread throughout the brain and spine. Other things may happen to 
you that we do not yet know about. 
 
6. Your family can choose to be part of this study or not. Your family can also decide to stop being 
in this study at any time once you start. There may be other treatments for your illness that your 
doctor can tell you about. Make sure to ask your doctors any questions that you have. 
 
7. We are asking your permission to collect extra blood. We will take these samples when other 
standard blood tests are done, so there will be no extra needle sticks. We are also asking your 
permission to collect any tumor tissue that is left over from any surgeries you have while you are 
part of this study. We would like to use the blood and tumor tissue to do tests to see if there are 
ways to tell how the cancer will respond to treatment. If there is any tumor tissue left over from 
these tests, we would like to save it for other research tests in the future. You can still be treated on 
this study even if you do not allow us to collect the extra blood and tumor tissue or save the leftover 
tumor tissue for research. 
 

 
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INFORMATION SHEET REGARDING RESEARCH STUDY- ACNS0831 
(for children from 7 through 12 years of age) 
 
A Study of Adding Anti-Cancer Drugs to Treatment for Newly Diagnosed Ependymoma 
 
1. We have been talking with you about your brain tumor which is called ependymoma. Ependymoma 
is a type of cancer that grows in the brain. After doing tests, we have found that you have this type 
of cancer. 
 
2. We are asking you to take part in a research study because you had an operation and the doctor was 
able to take out all but a very small bit of the tumor. A research study is when doctors work together 
to try out new ways to help people who are sick. This study will see if a new treatment will work 
better to get rid of ependymoma than the normal treatment. 
 
The normal treatment is an operation to take out as much of the tumor as possible. Then, after the 
operation children also get x-ray treatment to kill any cancer cells that may still be in the brain. 
Study doctors want to try a new treatment that gives anti-cancer drugs after the x-ray treatment. 
Study doctors hope this new treatment will work better than the normal treatment to kill cancer 
cells that are still in the brain. 
 
3. All children who are part of this study will get x-ray treatments. One group of children in this study 
will then get anti-cancer medicines after the x-ray treatment. One group of children will not. The 
group you will be in will be decided by chance, like flipping a coin for “heads” or “tails”. If you 
are in the group that gets the anti-cancer medicines, you will be treated with the medicines for about 
12 weeks. If you are in the other group, you will not have any more treatment during the rest of this 
study. You will be watched carefully and have regular tests done. 
 
4. Sometimes good things can happen to people when they are in a research study. These good things 
are called “benefits.” If you get the new treatment, we hope that a benefit to you of being part of 
this study is that you get a treatment that works better than the normal treatment to get rid of the 
tumor. But, we do not know for sure if there is any benefit of being part of this study. 
 
5. Sometimes bad things can happen to people when they are in a research study. These bad things 
are called “risks”. If you get the new treatment, the risk to you from this study is that you may have 
bad health problems from the anti-cancer drugs. If this happens you may need treatment for the 
problems. If you are in the group that gets the normal treatment, the risk to you is that you may not 
get a treatment that is better at getting rid of the tumor. Other things may happen to you that we do 
not yet know about. 
 
6. Your family can choose to be part of this study or not. Your family can also decide to stop being 
in this study at any time. There may be other treatments for your illness that your doctor can tell 
you about. Make sure to ask your doctors any questions you have. 
 
7. We are asking your “okay” to collect some extra blood. We will take the extra blood when other 
regular blood tests are done, so there will be no extra needle sticks. We are also asking your “okay” 
to collect any tumor tissue that is left over from any operations you have while you are part of this 
study. We want to see if there are ways to tell how the cancer will react to treatment. You can still 
take part in this study even if you do not allow us to collect the extra blood or tumor tissue for 
research.  

 
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Page 108 
INFORMATION SHEET REGARDING RESEARCH STUDY – ACNS0831 
(for teens from 13 through 17 years of age) 
 
A Study of Adding Chemotherapy to Treatment for Newly Diagnosed Ependymoma 
 
1. We have been talking with you about your brain tumor which is called an ependymoma. 
Ependymoma is a type of cancer that grows in the brain. After doing tests, we have found that you 
have this type of cancer. 
 
2. We are asking you to take part in a research study because you had surgery and doctors were able 
to remove all but a very small amount of the ependymoma tumor. A research study is when doctors 
work together to try out new ways to help people who are sick.  This study will see if a new 
treatment to get rid of ependymoma will work better than the standard treatment. 
 
The standard treatment is surgery to take out as much of the tumor as possible. After surgery, 
radiation therapy (treatment with high-energy X-rays) is used to kill any cells that are still in the 
brain. Study doctors want to see if giving chemotherapy (anti-cancer drugs) after radiation therapy 
will work better to get rid of the cancer or keep it from growing. 
 
3. All children and teens who are part of this study will be treated with radiation therapy. You will 
get radiation therapy 5 days a week for about 6 weeks. Half of the children and teens will also be 
treated with chemotherapy. The process to decide who gets chemotherapy is called 
“randomization”. It is a lot like flipping a coin for “heads” or “tails”, except it is done by computer. 
If you are in the group that will be treated with chemotherapy, you will be treated with several 
drugs for about 12 weeks. If you are in the group that does not get chemotherapy, you will not have 
any more treatment while you are on this study. You will be watched carefully and have regular 
tests done. 
 
4. Sometimes good things can happen to people when they are in a research study. These good things 
are called “benefits.” If you receive chemotherapy, we hope that a benefit to you of being part of 
this study is getting a treatment that works better to get rid of your tumor than the standard 
treatment.  But, we do not know for sure if there is any benefit of being part of this study. 
 
5. Sometimes bad things can happen to people when they are in a research study. These bad things 
are called “risks.” If you receive chemotherapy, the risks to you from this study are bad effects, 
called “side effects” from the drugs. These side effects include fewer red blood cells, white blood 
cells, and platelets in your blood, which can make it easier to get an infection, make you feel tired, 
and cause you to bruise and bleed more easily. If you have side effects, you may need treatment for 
them. If you are in the group that gets the standard treatment, the risk to you is that you may not 
get a treatment that is better at getting rid of the tumor. Other things may happen to you that we do 
not yet know about. 
 
6. Your family can choose to be part of this study or not. Your family can also decide to stop being 
in this study at any time once you start. There may be other treatments for your illness that your 
doctor can tell you about. Make sure to ask your doctors any questions you have. 
 
7. We are asking your permission to collect extra blood. We will take these samples when other 
standard blood tests are done, so there will be no extra needle sticks. We are also asking your 
permission to collect any tumor tissue that is left over from any surgeries you have while you are 
part of this study. We would like to use the blood and tumor tissue to do tests to see if there are 

 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ACNS0831 
Version Date: 2/27/2020 
 
Page 109 
ways to tell how the cancer will respond to treatment. If there is any tumor tissue left over from 
these tests, we would like to save it for other research tests in the future. You can still be treated on 
this study even if you do not allow us to collect the extra blood and tumor tissue or save the leftover 
tumor tissue for research.  
 

 
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Page 110 
INFORMATION SHEET REGARDING RESEARCH STUDY- ACNS0831 
(for children from 7 through 12 years of age) 
 
A Study of Adding Anti-Cancer Medicines and Second Surgery to Treatment for Newly Diagnosed 
Ependymoma  
 
1. We have been talking with you about your brain tumor that is called an ependymoma.  
Ependymoma is a type of cancer that grows in the brain.  After doing tests, we have found that you 
have this type of cancer. 
 
2. We are asking you to take part in a research study because you had an operation and the doctor was 
able to take out most of the tumor but not all of it. A research study is when doctors work together 
to try out new ways to help people who are sick. This study will see if a new treatment will work 
better to get rid of ependymoma than the normal treatment for this disease. 
 
The normal treatment for this kind of tumor is an operation to take out as much of the tumor as 
possible. After the operation children also get x-ray treatment to kill any cells that are still in the 
brain. Study doctors want to see if giving anti-cancer medicines after the operation can help kill 
any tumor that is still in the brain. Study doctors also hope that giving anti-cancer medicines will 
make it easier for doctors to take out the rest of the tumor in another operation. 
 
3. All children who are part of this study will be treated with anti-cancer medicines. Then, study 
doctors will do scans to see how well the anti-cancer medicines worked to kill the tumor. What 
happens next depends on what the scans show and the kind of cells that are in the tumor. You may 
be watched carefully, have a second operation, or get x-ray treatments. You may also have more 
anti-cancer medicines after the x-ray treatments. The process to decide who gets anti-cancer 
medicines after x-ray treatments is called “randomization”. It is a lot like flipping a coin for “heads” 
or “tails”, except it is done by computer. Your doctor will tell you what treatments you will have 
while you are on this study. 
 
4. Sometimes good things can happen to people when they are in a research study. These good things 
are called “benefits.” If you get the anti-cancer medicines, we hope that a benefit to you of being 
part of this study is that you get a treatment that works better to get rid of the tumor than the normal 
treatment. But, we do not know for sure if there is any benefit of being part of this study. 
 
5. Sometimes bad things can happen to people when they are in a research study. These bad things 
are called “risks”. A risk to you from this study is bad health problems from the anti-cancer 
medicines. If this happens you may need treatment for the problems. There is also the risk that the 
tumor may grow while you are taking the anti-cancer medicines. If this happens, there is a risk that 
another operation may not be possible. There is also a risk that the tumor may spread into other 
areas of your brain or spine. Other things may happen to you that we do not yet know about. 
 
6. Your family can choose to be part of this study or not. Your family can also decide to stop being 
in this study at any time. There may be other treatments for your illness that your doctor can tell 
you about. Make sure to ask your doctors any questions you have. 
 
7. We are asking your “okay” to collect some extra blood. We will take the extra blood when other 
regular blood tests are done, so there would be no extra needle sticks. We are also asking your 
“okay” to collect any tumor tissue that is left over from any operations you have while you are part 
of this study. We want to see if there are ways to tell how the cancer will react to treatment. You 
can still take part in this study even if you do not allow us to collect the extra blood and tumor 
tissue for research.

 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ACNS0831 
Version Date: 2/27/2020 
 
Page 111 
INFORMATION SHEET REGARDING RESEARCH STUDY – ACNS0831 
(for teens from 13 through 17 years of age) 
 
A Study of Adding Chemotherapy and Second Surgery to Treatment for Newly Diagnosed 
Ependymoma  
 
1. We have been talking with you about your brain tumor which is called ependymoma. Ependymoma 
is a type of cancer that grows in the brain. After doing tests, we have found that you have this type 
of cancer. 
 
2. We are asking you to take part in a research study because you had surgery and the doctor was able 
to remove most of the tumor but not all of it. A research study is when doctors work together to try 
out new ways to help people who are sick. This study will see if new treatments will work better to 
get rid of ependymoma than the standard treatment for this disease. 
 
The standard treatment for this kind of tumor is an operation to take out as much of the tumor as 
possible. After the operation children and teens also get radiation therapy (the use of high-energy 
x-rays) to kill any tumor cells that are still in the brain. Study doctors want to see if giving 
chemotherapy (anti-cancer drugs) can help shrink any leftover tumor so that a second operation can 
remove most if not all of the tumor before treatment with radiation therapy is done. Study doctors 
also want to see if giving chemotherapy after radiation therapy will help get rid of the tumor for as 
long as possible. 
 
3. All children and teens who are part of this study will be treated first with chemotherapy. This 
chemotherapy lasts 7 weeks and includes several drugs. Then, study doctors will do scans to see 
how well the chemotherapy worked to kill the tumor. What happens next depends on what the scans 
show and the kind of cells that are in the tumor. You may be watched carefully, have a second 
operation, or have radiation therapy. Also, if you have radiation therapy, you may or may not have 
more chemotherapy after it. (The process to decide who gets chemotherapy after radiation therapy 
is called “randomization”. It is a lot like flipping a coin for “heads” or “tails”, except it is done by 
computer.)  
 
If you have radiation therapy, it will be given 5 days a week for about 6 weeks. If you have the 
second chemotherapy, it will last for 12 weeks and includes four drugs. If you have a second 
operation and the doctors are able to take out all of the tumor and you do not have one certain kind 
of tumor, you will go on to have either radiation therapy and more chemotherapy, or radiation 
therapy only. For some children and teens who have a certain type of tumor that the doctors are 
able to remove completely, there will be no more treatment. Your doctor will tell you what 
treatments you will have while you are on this study. 
 
4. Sometimes good things can happen to people when they are in a research study. These good things 
are called “benefits”. We hope that a benefit to you of being part of this study is that the new 
treatments work better to get rid of the tumor than the standard treatment. However, we do not 
know for sure if there is any benefit of being part of this study. 
 
5. Sometimes bad things can happen to people when they are in a research study. These bad things 
are called “risks.” A risk to you from this study is having side effects from the chemotherapy. These 
side effects include fewer red blood cells, white blood cells, and platelets in your blood, which can 
make it easier to get an infection, make you feel tired, and cause you to bruise and bleed more 
easily. If you have side effects, you may need treatment for them. There is also the risk that the 

 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ACNS0831 
Version Date: 2/27/2020 
 
Page 112 
tumor may grow while you are on the first part of chemotherapy. If this happens, there is a risk that 
another operation may not be possible, or that the tumor may spread into other areas of your brain 
or spine. Other things may happen to you that we do not yet know about. 
 
6. Your family can choose to be part of this study or not. Your family can also decide to stop being 
in this study at any time once you start. There may be other treatments for your illness that your 
doctor can tell you about. Make sure to ask your doctors any questions you have. 
 
7. We are asking your permission to collect extra blood. We will take these samples when other 
regular blood tests are done, so there will be no extra needle sticks. We are also asking your 
permission to collect any tumor tissue that is left over from any surgeries you have while you are 
part of this study. We would like to use the blood and tumor tissue to do tests to see if there are 
ways to tell how the cancer will respond to treatment. If there is any tumor tissue left over from 
these tests, we would like to save it for other research tests in the future. You can still be treated on 
this study even if you do not allow us to collect the extra blood and tumor tissue or save the leftover 
tumor tissue for research.  

 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
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Version Date: 2/27/2020 
 
Page 113 
APPENDIX II: TANNER STAGING CRITERIA 
 
 
 
Classification of Sex Maturity Stages in Girls 
 
(Adapted from:  Marshall WA, Tanner JM.  Variations in the pattern of pubertal changes in girls.  Arch Diseases in Childhood 44:291, 1969) 
SMR 
Stage 
Pubic Hair 
 
1 
Preadolescent with vellus over the pubic area no more profuse than on the abdomen. 
 
2 
Sparse growth of long, slightly pigmented downy hair which is straight or only 
slightly curled, and appearing usually at the base of the penis or along the labia. 
 
3 
Pubic hair is darker, courser and more curly, and the hair is spreading sparsely over 
the pubic area. 
 
4 
Further spread of the pubic hair, still considerably less than in the adult, and no 
extension of hair bilaterally up to the middle of the thigh. 
 
5 
Adult in amount and type of hair. 
 
 
Breasts (Females) 
 
1 
Preadolescent, with coloration of the papilla only. 
 
2 
Breast bud stage:  breast and papilla are elevated above the chest in a small mound, 
without enlargement of the areolar diameter. 
 
3 
Further elevation and enlargement of the breast and areola but no separation of the 
contours. 
 
4 
The areola and papilla project from the breast to form a secondary mound. 
 
5 
Adult state:  projection of the papilla only, due to recession of the areola to the 
general contour of the breast. 
 
Classification of Sex Maturity Stages in Boys 
 
(Adapted from:  Marshall WA, Tanner JM.  Variations in the pattern of pubertal changes in boys.  Arch Diseases in Childhood 45:13, 1970) 
SMR 
Stage 
Pubic Hair 
 
1 
Preadolescent with vellus over the pubic area no more profuse than on the abdomen. 
 
2 
Sparse growth of long, slightly pigmented downy hair which is straight or only 
slightly curled, and appearing usually at the base of the penis or along the labia. 
 
3 
Pubic hair is darker, courser and more curly, and the hair is spreading sparsely over 
the pubic area. 
 
4 
Further spread of the pubic hair, still considerably less than in the adult, and no 
extension of hair bilaterally up to the middle of the thigh. 
 
5 
Adult in amount and type of hair. 
 
 
Genitalia (Males) 
 
1 
Preadolescent:  Testes, scrotum, and penis are of about the same size and proportion 
as in early childhood. 
 
2 
Beginning enlargement of the scrotum and testes; reddening of the scrotum, and 
changes in its texture. 
 
3 
Penile enlargement (mm) with increase in length and further growth of the scrotum 
and testes (mm). 
 
4 
Further increase in penile size; growth in breadth and development of the glans.  
Further enlargement of the testes and scrotum and continued darkening of the scrotal 
skin. 
 
5 
Adult genitalia in size and shape. 
 

 
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APPENDIX III:  CTEP AND CTSU REGISTRATION PROCEDURES 
 
CTEP INVESTIGATOR REGISTRATION PROCEDURES 
 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy 
require all individuals contributing to NCI-sponsored trials to register and to renew their registration 
annually. To register, all individuals must obtain a Cancer Therapy Evaluation Program (CTEP) 
Identity and Access Management (IAM) account (https://ctepcore.nci.nih.gov/iam). In addition, 
persons with a registration type of Investigator (IVR), Non-Physician Investigator (NPIVR), or 
Associate Plus (AP) (i.e., clinical site staff requiring write access to OPEN, RAVE, or TRIAD or 
acting as a primary site contact) must complete their annual registration using CTEP’s web-based 
Registration and Credential Repository (RCR) (https://ctepcore.nci.nih.gov/rcr). Documentation 
requirements per registration type are outlined in the table below. 
 
Documentation Required 
IVR 
NPIVR 
AP 
A 
FDA Form 1572 
 
 
Financial Disclosure Form 
 
 
 
NCI Biosketch (education, training, 
employment, license, and certification) 
 
 
 
HSP/GCP training 
 
 
 
Agent Shipment Form (if applicable) 
 
CV (optional) 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all CTEP 
and CTSU (Cancer Trials Support Unit) websites and applications.  In addition, IVRs and NPIVRs 
must list all clinical practice sites and IRBs covering their practice sites on the FDA Form 1572 in 
RCR to allow the following: 
 Added to a site roster 
 Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in 
OPEN 
 Act as the site-protocol PI on the IRB approval 
 Assigned the Clinical Investigator (CI) role on the Delegation of Tasks Log 
(DTL). 
 
Additional 
information 
can 
be 
found 
on 
the 
CTEP 
website 
at 
https://ctep.cancer.gov/investigatorResources/default.htm. For questions, please contact the RCR 
Help Desk by email at RCRHelpDesk@nih.gov. 
 
 

 
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CTSU REGISTRATION PROCEDURES 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU).  
 
Downloading Site Registration Documents: 
 
Site registration forms may be downloaded from the ACNS0831 protocol page located on the 
CTSU members’ website. Permission to view and download this protocol and its supporting 
documents is restricted and is based on person and site roster assignment housed in the CTSU RSS. 
 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM username 
and password 
 
Click on the Protocols tab in the upper left of your screen 
 Either enter the protocol # in the search field at the top of the protocol tree, or 
 
Click on the By Lead Organization folder to expand 
 
Click on the COG link to expand, then select trial protocol #ACNS0831 
Click on LPO Documents, select the Site Registration documents link, and download and 
complete the forms provided. 
 
Requirements For ACNS0831 Site Registration: 
 
• 
IRB approval (For sites not participating via the NCI CIRB; local IRB documentation, an IRB-
signed CTSU IRB Certification Form, Protocol of Human Subjects Assurance 
Identification/IRB Certification/Declaration of Exemption Form, or combination is accepted ) 
• 
IROC Credentialing Status Inquiry (CSI) Form 
NOTE: For studies with a radiation and/or imaging (RTI) component, the enrolling site must 
be aligned to a RTI provider.  To manage provider associations access the Provider Association 
tab on the CTSU website at https://www.ctsu.org/RSS/RTFProviderAssociation, to add or 
remove associated providers.  Sites must be linked to at least one IROC credentialed provider 
to participate on trials with an RT component.   
 
Submitting Regulatory Documents: 
 
Submit required forms and documents to the CTSU Regulatory Office, where they will be entered 
and tracked in the CTSU RSS.  
 
Regulatory Submission Portal: www.ctsu.org  (members’ area)  Regulatory Tab 
Regulatory Submission  
 
When applicable, original documents should be mailed to: 
CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU Regulatory 
Office immediately at 1-866-651-2878 in order to receive further instruction and support. 
 
Checking Your Site’s Registration Status: 
 
You can verify your site registration status on the members’ section of the CTSU website. (Note: 
Sites will not receive formal notification of regulatory approval from the CTSU Regulatory Office.) 
 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM username 

 
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and password 
 
Click on the Regulatory tab at the top of your screen 
 
Click on the Site Registration tab 
 
Enter your 5-character CTEP Institution Code and click on Go 
 
Note: The status given only reflects compliance with IRB documentation and institutional 
compliance with protocol-specific requirements as outlined by the Lead Network. It does not reflect 
compliance with protocol requirements for individuals participating on the protocol or the enrolling 
investigator’s status with the NCI or their affiliated networks. 
 

 
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Page 117 
APPENDIX IV:  POSSIBLE DRUG INTERACTIONS 
 
The lists below do not include everything that may interact with chemotherapy. Study Subjects and/or 
their Parents should be encouraged to talk to their doctors before starting any new medications, using 
over-the-counter medicines, or herbal supplements and before making a significant change in diet. 
 
Carboplatin 
 
Drugs that may interact with carboplatin* 
 Antibiotics like gentamicin or tobramycin 
 Anti-seizure medications like fosphenytoin or phenytoin 
 Arthritis medications like leflunomide, tofacitinib 
 Some chemotherapy (be sure to talk to your doctor about this) 
 Other medications like clozapine or natalizumab 
 
Food and supplements that may interact with carboplatin** 
 Echinacea 
 
*Sometimes these drugs are used with carboplatin on purpose.  Discuss all drugs with your 
doctor. 
 
**Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, 
capsules, pills, or dried herbs. All forms should be avoided.   
 
 
Cisplatin: 
 
Drugs that may interact with cisplatin* 
 Antibiotics like gentamicin or tobramycin 
 Anti-seizure medications like fosphenytoin or phenytoin 
 Arthritis medications like leflunomide or tofacitinib 
 Some chemotherapy (be sure to talk to your doctor about this) 
 Other medications like bumetanide, clozapiner, furosemide, natalizumab 
 
Food and supplements that may interact with cisplatin** 
 Echinacea 
 
*Sometimes these drugs are used with cisplatin on purpose.  Discuss all drugs with your 
doctor. 
 
**Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, 
capsules, pills, or dried herbs. All forms should be avoided.  
 

 
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Cyclophosphamide: 
 
Drugs that may interact with cyclophosphamide* 
 
Allopurinol 
 
Chloramphenicol 
 
Cyclosporine 
 
Digoxin 
 
Etanercept 
 
Hydrochlorothiazide 
 
Indomethacin 
 
Nevirapine 
 
Pentostatin 
 
Warfarin  
 
Food and supplements that may interact with cyclophosphamide** 
 
St. John’s Wort 
 
Drinks, food, supplements, or vitamins containing “flavonoids” or other “antioxidants” 
 
*Sometimes these drugs are used with cyclophosphamide on purpose.  Discuss all drugs with 
your doctor. 
 
**Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, 
capsules, pills, or dried herbs. All forms should be avoided.  
 
 
 
 

 
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Etoposide 
 
Drugs that may interact with etoposide* 
 Antibiotics  
 
Clarithromycin, erythromycin, nafcillin, rifabutin, rifampin, telithromycin 
 Antidepressants and antipsychotics  
 Aripiprazole, clozapine, nefazodone 
 Antifungals  
 Fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole 
 Arthritis medications  
 Leflunomide, tofacitinib 
 Anti-rejection medications 
 Cyclosporine, tacrolimus 
 Antiretrovirals and antivirals  
 Atazanavir, boceprevir, darunavir, delaviridine, efavirenz, etravirine, fosamprenavir, 
indinavir, lopinavir, nelfinavir, nevirapine, ritonavir, saquinavir, Stribild, telaprevir, 
tipranavir 
 Anti-seizure medications  
 
Carbamazepine, oxcarbazepine, phenobarbital, phenytoin, primidone 
 Heart medications  
 Amiodarone, dronedenarone, verapamil 
 Some chemotherapy (be sure to talk to your doctor about this) 
 Many other drugs, including the following: 
 
Aprepitant, atovaquone, bosentan, deferasirox, dexamethasone, ivacaftor, lomitapide, 
mifepristone, natalizumab, pimozide, sitaxentan 
 
Food and supplements that may interact with etoposide** 
 Echinacea 
 Glucosamine 
 St. John’s Wort 
 Grapefruit, grapefruit juice, Seville oranges, star fruit 
 
*Sometimes these drugs are used with etoposide on purpose.  Discuss all drugs with your 
doctor. 
 
**Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, 
capsules, pills, or dried herbs. All forms should be avoided.   
 
 
 

 
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Vincristine: 
 
Drugs that may interact with vincristine* 
 Antibiotics  
 
Clarithromycin, erythromycin, nafcillin, rifabutin, rifampin, telithromycin 
 Antidepressants and antipsychotics  
 Aripiprazole, nefazodone, trazodone 
 Antifungals  
 
Fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole 
 Arthritis medications  
 Leflunomide, tocilizumab, tofacitinib 
 Anti-rejection medications 
 Cyclosporine, tacrolimus 
 Antiretrovirals and antivirals  
 
Atazanavir, boceprevir, darunavir, delaviridine, efavirenz, etravirine, fosamprenavir, 
indinavir, lopinavir, nelfinavir, nevirapine, ritonavir, saquinavir, Stribild, telaprevir, 
tenofovir, tipranavir 
 Anti-seizure medications  
 
Carbamazepine, oxcarbazepine, phenobarbital, phenytoin, primidone 
 Heart medications  
 
Amiodarone, digoxin, dronedenarone, propranolol, verapamil 
 Some chemotherapy (be sure to talk to your doctor about this) 
 Many other drugs, including the following: 
 
Aprepitant, deferasirox, ivacaftor, lomitapide, mifepristone, natalizumab, pimozide, 
warfarin  
 
Food and supplements that may interact with vincristine** 
 Echinacea 
 St. John’s Wort 
 Grapefruit, grapefruit juice, Seville oranges, star fruit 
 
*Sometimes these drugs are used with vincristine on purpose.  Discuss all drugs with your 
doctor. 
 
**Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, 
capsules, pills, or dried herbs. All forms should be avoided.  
 
 
 

 
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