A Phase II Trial of Surgery and Fractionated Re-Irradiation for Recurrent Ependymoma
Phase: PHASE2
Conditions: Ependymoma
Sponsor: St. Jude Children's Research Hospital

Official Study Title: A Phase II Trial of Surgery and Fractionated Re-Irradiation for 
Recurrent Ependymoma   
 
CTG Number: NCT02125786 
 
Document Date: 2/1/2023 
 

Rev. 3.2  dated:   1/19/2023
IRB Approval date:  
Protocol document date: 1/19/2023
St. Jude
RERTEP
Initial version, dated:  12/10/2013 Resubmitted to IRB: 3/17/2014 (IRB Approved: 3/18/2014) 
Activated: 04/21/2014
Rev 0.1, dated: September 3, 2015 (IRB Approved: 10/22/2015)   Activated: November 2, 2015 
Amend 1.0, dated: September 1, 2016 (IRB Approved: 12/06/2016) Activated: December 14, 2016 
Rev. 1.1 dated: July 28, 2017 (IRB Approved: 8/30/2017) Activated: September 7, 2017
Amend 2.0, dated: January 11, 2019 (IRB Approved 08-09-2019  Activated: August 19, 2019 
Amend 3.0 dated:   June 30, 2020 (IRB Approved:  08-11-2020)  Activated:  September 20, 2020                                 
Rev. 3.1, dated: September 14, 2020 (IRB Approved: 10-27-2020)  Activated:November 11, 2020
Rev. 3.2, dated January 19, 2023 (IRB Approved 02-01-2023)Activated: February 28, 2023
A PHASE II TRIAL OF SURGERY AND FRACTIONATED RE-IRRADIATION FOR 
RECURRENT EPENDYMOMA 
IND #104987
Principal Investigator
Thomas E. Merchant, DO, PhD
Department of Radiation Oncology
St. Jude Children’s Research Hospital
262 Danny Thomas Place, MS 210
Memphis, TN 38105
Phone: (901) 595-3604
Fax: (901) 595-3113
Email: thomas.merchant@stjude.org
St. Jude Children's Research Hospital
IRB NUMBER: Pro00004349
IRB APPROVAL DATE: 02/01/2023

Rev. 3.2  dated:   1/19/2023                                                   IRB Approval date:  
Protocol document date: 1/19/2023                                
St. Jude Co-Investigators
David Ellison, MD, PhD
Department of Pathology
St. Jude Children’s Research Hospital
262 Danny Thomas Place, MS 250
Memphis, TN 38105
Phone: (901) 595-3538
Fax: (901) 595-3100
Email: david.ellison@stjude.org
Noah Sabin, MD
Diagnostic Imaging
St. Jude Children’s Research Hospital
262 Danny Thomas Place, MS 220
Memphis, TN 38105
Phone: (901) 595-6526
Fax: (901) 595-3981
Email: noah.sabin@stjude.org
Chia-ho Hua, PhD
Department of Radiation Oncology
St. Jude Children’s Research Hospital
262 Danny Thomas Place, MS 210
Memphis, TN 38105
Phone: (901) 595-3610
Fax: (901) 595-3981
Email: chia-ho.hua@stjude.org
Kirsten Ness, PhD
Division of Epidemiology
Department of Cancer Prevention and Control
St. Jude Children’s Research Hospital
262 Danny Thomas Place, MS 735
Memphis, TN 38105
Phone: (901) 595-5157
Fax: (901) 595-5845
Email: kiri.ness@stjude.org
Belinda Mandrell, PhD
Nursing Research
St. Jude Children’s Research Hospital
262 Danny Thomas Place, MS 738
Memphis, TN 38105
Phone: (901) 595-4209
Fax: (901) 595-2866
Email: belinda.mandrell@stjude.org
Johnnie Bass, AuD
Rehabilitation Services
St. Jude Children’s Research Hospital
262 Danny Thomas Place, MS 113
Memphis, TN 38105
Phone: (901) 595-6696
Fax: ( 901) 595-2961
Email: johnnie.bass@stjude.org
Heather M. Conklin, PhD
Department of Psychology
St. Jude Children’s Research Hospital
262 Danny Thomas Place, MS 740
Memphis, TN 38105
Phone: (901) 595-3585
Fax: (901) 595-4701
Email: heather.conklin@stjude.org
Austin Faught, PhD
Radiation Oncology
St. Jude Children’s Research Hospital
262 Danny Thomas Place, MS 210
Memphis, TN 38105
Phone: (901) 595-1121
Fax: (901) 595-3113
Email: austin.faught@stjude.org 
Amar Gajjar, MD
Division of Neuro-Oncology
Department of Oncology
St. Jude Children’s Research Hospital
262 Danny Thomas Place, MS 260
Memphis, TN 38105
Phone: (901) 595-2615
Fax: (901) 521-9005
Email: amar.gajjar@stjude.org
Paul Klimo, MD
Division of Neurosurgery
Department of Surgery
St. Jude Children’s Research Hospital
262 Danny Thomas Place
Memphis, TN 38105
Email: paul.klimo@stjude.org
Raja Bicky Khan, MD
Division of Neurology
Barry Shulkin, MD
Department of Diagnostic Imaging
St. Jude Children's Research Hospital
IRB NUMBER: Pro00004349
IRB APPROVAL DATE: 02/01/2023

Rev. 3.2  dated:   1/19/2023                                                   IRB Approval date:  
Protocol document date: 1/19/2023                                
St. Jude Children’s Research Hospital
262 Danny Thomas Place, MS 220
Memphis, TN 38105
Phone: (901) 595-8024
Fax: (901) 595-8548
Email: raja.khan@stjude.org
St. Jude Children’s Research Hospital
262 Danny Thomas Place, MS 220
Memphis, TN 38105
Phone: (901) 595-3347
Fax: (901) 595-3981
Email: barry.shulkin@stjude.org
Ibrahim Qaddoumi, MD
Division of Neuro-Oncology
Department of Oncology
St. Jude Children’s Research Hospital
262 Danny Thomas Place, MS 260
Memphis, TN 38105
Phone: (901) 595-4925
Fax: (901) 521-9005
Email: ibrahim.qaddoumi@stjude.org
Yimei Li, PhD
Biostatistics
St. Jude Children’s Research Hospital
262 Danny Thomas Place, MS 768
Memphis, TN 38105
Phone: (901) 595-6735
Fax: (901) 595-8843
Email: yimei.li@stjude.org
Christopher Tinkle, MD, PhD
Radiation Oncology
St. Jude Children’s Research Hospital
262 Danny Thomas Place, MS 210
Memphis, TN 38105
Phone: (901) 595-8735
Fax: (901) 595-3113
Email: christopher.tinkle@stjude.org 
John Lucas, MD
Radiation Oncology
St. Jude Children’s Research Hospital
262 Danny Thomas Place, MS 210
Memphis, TN 38105
Phone: (901) 595-8664
Fax: (901) 595-3113
Email: john.lucas@stjude.org
Contents of this document may not be extracted without permission from the Principal Investigator
St. Jude Children's Research Hospital
IRB NUMBER: Pro00004349
IRB APPROVAL DATE: 02/01/2023

Rev. 3.2  dated:   1/19/2023                                                   IRB Approval date:  
Protocol document date: 1/19/2023                                
 
 Protocol Summary
Protocol MNEMONIC and Title:  RERTEP - A Phase II Trial of Surgery and 
Fractionated Re-irradiation for Recurrent Ependymoma 
Principal Investigator: Thomas E. Merchant, DO, PhD 
IND Holder: 11C-methionine, IND 104987, Sponsor of IND: St. Jude Children’s Research 
Hospital
Brief Overview: There is a need to determine the role of re-irradiation in patients with 
recurrent ependymoma after prior therapy that includes fractionated radiation therapy 
administered with curative intent. Outcomes reported from St. Jude Children’s Research 
Hospital suggest that a proportion of children with recurrent ependymoma after prior 
irradiation may be successfully treated with additional surgery and a second course of 
irradiation; however, there are a number of unanswered questions about this approach 
including portability, morbidity and mortality, and the biological basis for success. 
Responding to these questions requires prospective study of outcomes and tumor biology.
Intervention: Neurosurgery and fractionated irradiation. 
Brief Outline of Treatment Plan: The goal of this study is to determine the feasibility and 
safety of treating recurrent ependymoma with a second course of irradiation using 
cumulative doses that exceed those used in routine clinical practice.  Surgery is an important 
part of this study and will be used to document recurrent ependymoma and reduce the tumor 
burden when feasible. Patients with local failure after prior surgery and focal irradiation will 
undergo surgery and focal re-irradiation; however, those age > 3 years with tumors having 
1q gain will be offered craniospinal irradiation. Those with metastatic disease limited to the 
neuraxis will receive craniospinal irradiation after surgery. Patients with combined local and 
distant failure will be treated with surgery and craniospinal irradiation. Patients will be 
stratified for outcome according to diagnosis and prior therapy. All patients will be 
evaluated for the effects of the treatment regimen.  
St. Jude Children's Research Hospital
IRB NUMBER: Pro00004349
IRB APPROVAL DATE: 02/01/2023

Rev. 3.2  dated:   1/19/2023                                                   IRB Approval date:  
Protocol document date: 1/19/2023                                
Primary Objective:
1.1 To estimate the progression-free and overall survival distributions for children and 
young adults with recurrent ependymoma treated with a second course of irradiation while 
monitoring for excessive central nervous system necrosis.
Responsible Investigator: Thomas E. Merchant
Biostatistician: Yimei Li and Shengjie Wu
Estimated date for completion of data collection:  10-11 years after activation.
Secondary and Exploratory Objectives:
1.2 To explore potential associations of clinical and treatment factors with the incidence and 
severity of neurological, endocrine and cognitive deficits in children and young adults with 
ependymoma treated with a second course of irradiation.
Responsible Investigators: Heather M. Conklin and Thomas E. Merchant
Biostatisticians: Hui Zhang and Shengjie Wu
Estimated date for completion of data collection: 10-11 years after activation.
1.3 Using specific measures of sleep quality, excessive daytime sleepiness, daytime activity, 
fatigue, symptom distress, and quality of life, explore associations of sleep, fatigue and quality 
of life with other measures of CNS effects, clinical and treatment factors in children and 
young adults with ependymoma treated with a second course of irradiation.
Responsible Investigator: Belinda Mandrell
Biostatisticians: Hui Zhang
Estimated date for completion of data collection: 10-11 years after activation.
1.4 To describe physical performance and movement in children, adolescents and young 
adults with ependymoma treated with a second course of irradiation.
Responsible Investigator: Kirsten Ness
Biostatisticians: Yimei Li 
Estimated date for completion of data collection: 10-11 years after activation.
1.5 Estimate and compare the response of recurrent tumor and the incidence and severity of 
macrostructural, microstructural, physiologic and vascular effects on brain tissue in children 
and young adults with ependymoma after treatment with a second course of irradiation using 
specific methods of diffusion, contrast-enhancement, magnetization transfer, vascular 
neuroimaging, and explore the association between these and other measures of CNS effects 
and clinical and treatment factors.
Responsible Investigators: Julie Harreld and Chia-ho Hua
St. Jude Children's Research Hospital
IRB NUMBER: Pro00004349
IRB APPROVAL DATE: 02/01/2023

Rev. 3.2  dated:   1/19/2023                                                   IRB Approval date:  
Protocol document date: 1/19/2023                                
Biostatisticians: Yimei Li 
Estimated date for completion of data collection: 10-11 years after activation.
1.6 Estimate the avidity of ependymoma to 18F-fluorodeoxyglucose (FDG) and 11C-
methionine positron emission tomography (IND # 104987) prior to radiation therapy and 
correlate change in avidity 12, 24 and 36 months after a second course of irradiation with 
tumor progression.
Responsible Investigator: Barry Shulkin
Biostatisticians: Yimei Li 
Estimated date for completion of data collection:  10-11 years after activation.
1.7 Measure growth factor and cytokine responses in children and young adults with 
ependymoma after treatment with a second course of irradiation, and explore associations 
between these and other measures of CNS effects and clinical and treatment factors. 
Descriptively compare findings to similar growth factors and cytokines evaluated in historic 
patients during their initial course of irradiation.
Responsible Investigator: Thomas E. Merchant
Biostatistician: Yimei Li
Estimated date for completion of data collection: 10-11 years after activation.
 
1.8 Conduct molecular analyses on tumor samples (and blood where a germline control is 
required) with the aim of studying associations between tumor molecular subgroup and 
treatment response and various side effects, including vasculopathy, hearing loss, cognitive 
deficits, growth hormone deficiency, and other measures as appropriate.
Responsible Investigator: David Ellison
Biostatistician: Yimei Li
Estimated date for completion of data collection: 10-11 years after activation.
1.9 To explore the association of chemotherapy given prior to re-irradiation with PFS and 
OS distributions.
Responsible Investigator: Thomas E. Merchant
Biostatistician: Yimei Li
Estimated date for completion of data collection: 10-11 years after activation.
Hypotheses: 
1.1.1
Hypothesis for Primary Objective – Ependymoma recurrent after prior therapy that 
included irradiation is genetically distinct from the untreated tumor. The effectiveness 
of a second course of irradiation depends on tumor biology and the pattern of initial 
tumor progression.
St. Jude Children's Research Hospital
IRB NUMBER: Pro00004349
IRB APPROVAL DATE: 02/01/2023

Rev. 3.2  dated:   1/19/2023                                                   IRB Approval date:  
Protocol document date: 1/19/2023                                
1.1.2
Hypothesis for Secondary Objective - A second course of irradiation may be safely 
administered to patients with recurrent ependymoma after prior irradiation. The 
incidence and severity of side effects after second irradiation correlate with relevant 
clinical factors and treatment parameters, including radiation dose to normal tissue 
volumes. The selection of patients for re-irradiation can be improved by models that 
include clinical and treatment factors and longitudinal measures of CNS effects.
Criteria for Evaluation: Disease control will be evaluated using MR imaging performed 
during regular intervals after enrollment. Patients will be considered to have progressive 
disease when there is progressive growth of any component of the tumor based on serial 
imaging.
Study Design: Phase II study assessing the rate of failure for patients with ependymoma 
treated with surgery and a second course of irradiation.
Inclusion Criteria: 
1. Progressive intracranial ependymoma after prior focal irradiation
2. Patients aged 1-21 years at the time of enrollment
3. Adequate performance status (ECOG < 3) and research participant does not require 
mechanical ventilation
4. Interval from start of initial radiation therapy to enrollment > 9 months
Exclusion Criteria:
1. Prior craniospinal irradiation
2. Pregnant women are excluded from this study because radiation therapy is an agent 
with the potential for teratogenic or abortifacient effects.
3. Any patient with both metastatic ependymoma and age <3 years at the time of 
enrollment.
Sample Size: Accounting for ineligible patients, the total number of patients to be accrued 
to this study is estimated to be 99.  We expect to enroll about 12 patients per year for a 
period of 8-9 years.
Randomization: N/A
Data Analyses: 
Primary Aim:
To estimate the progression-free and overall survival distributions for children and young 
adults with recurrent ependymoma treated with a second course of irradiation while 
monitoring for excessive central nervous system necrosis.
Secondary Aims: 
Evaluate functional outcomes and host and tumor biology in patients with recurrent 
ependymoma treated with a second course of irradiation.
Primary Anticipated Completion Date: May, 2023
Anticipated Study Completion Date:  May, 2028
Timeframe for Primary Outcome Measure:  Five years after last patient has been 
enrolled.
St. Jude Children's Research Hospital
IRB NUMBER: Pro00004349
IRB APPROVAL DATE: 02/01/2023

Rev. 3.2  dated:   1/19/2023                                                   IRB Approval date:  
Protocol document date: 1/19/2023                                
Data Management: Data management will be provided by the clinical research staff in the 
Department of Radiation Oncology at St. Jude Children’s Research Hospital and all data 
will be entered and maintained in the St. Jude CRIS database.
Human Subjects: The risks to subjects treated with surgery and re-irradiation are expected 
to be higher when compared to initial surgery and radiation therapy. Patients previously 
treated with surgery and radiation therapy have accepted the burden of risk associated with 
those treatments including neurological, endocrine, cognitive and somatic dysfunction. We 
estimate that these risks will be magnified depending on whether the volume for the second 
course of irradiation is limited to the primary tumor bed or craniospinal. The effects of 
craniospinal irradiation are known to be largely dependent on age at the time of treatment. 
Regardless of treatment approach, the short term side effects may include nausea, vomiting, 
fatigue, loss of appetite, hair loss and headache. Common late effects include hormone 
deficiencies and weight gain, fatigue and sleep disorders, cognitive effects (memory, 
attention, behavior, learning, global intelligence), headache and permanent hair loss. Less 
common late effects are secondary tumor formation (benign or malignant), vasculopathy 
and stroke, neurological effects such as hearing loss, vision loss and seizures, and structural 
effects such as necrosis or myelopathy that may lead to permanent disability or death. 
Patients will be informed of this and other possible side effects during informed consent. 
Adverse events will be monitored, reported, and treated appropriately. The risks to subjects 
may be increased from surgery include all of the side effects listed above in addition to 
delayed wound healing, infection and stroke. The use of chemotherapy at any time may 
increase the side effects of re-irradiation.
St. Jude Children's Research Hospital
IRB NUMBER: Pro00004349
IRB APPROVAL DATE: 02/01/2023

Rev. 3.2  dated:   1/19/2023                                                   IRB Approval date:  
Protocol document date: 1/19/2023                                
Table of Contents
1.0
OBJECTIVES......................................................................................................................1
1.1
Primary Hypothesis and Objective ..........................................................................1
1.2
Secondary Hypotheses and Secondary Objectives..................................................1
1.3
Exploratory Objectives ............................................................................................2
1.4
Definitions ...............................................................................................................2
2.0
BACKGROUND AND RATIONALE................................................................................3
2.1
Problem Definition ..................................................................................................3
2.2
Neurological, Endocrine and Cognitive Studies....................................................10
2.3    Psychology Studies and Neurocognitive Outcomes..............................................11
2.4
Sleep Disorders, Fatigue and Quality of Life ........................................................12
2.5
Physical Performance and Movement ...................................................................17
2.6
Neuroimaging ........................................................................................................23
2.7     Rationale for 18F-Fluorodeoxyglucose and 11C-Methionine PET to Detect 
Ependymoma and Monitor Response to Radiation Therapy.................................27
2.8 
Growth Factor and Cytokine Responses to Radiation Therapy.............................27
2.9  
Rationale for Genomic Analysis of Untreated and Recurrent Ependymoma and 
Evaluation of Host Factor Susceptibility to Treatment-Related Side Effects .......28
2.10 
Pathology and Biological Studies..........................................................................35
2.11
PET Activation ......................................................................................................36
3.0
ELIGIBILITY CRITERIA AND STUDY ENROLLMENT ............................................36
3.1
Inclusion Criteria ...................................................................................................37
3.2
Exclusion Criteria ..................................................................................................37
3.3
Recruitment............................................................................................................37
3.4
Enrollment on Study..............................................................................................37
3.5
Enrollment Instructions for Collaborative Sites ....................................................38
4.0
TREATMENT AND PLAN STRATIFICATION ............................................................38
4.1
Overview................................................................................................................38
4.2
Surgery...................................................................................................................40
4.3
Stratification for Treatment ...................................................................................42
4.4
Radiation Therapy .................................................................................................42
4.5
Chemotherapy........................................................................................................42
5.0
RADIATION THERAPY GUIDELINES.........................................................................43
5.1
General Guidelines ................................................................................................43
St. Jude Children's Research Hospital
IRB NUMBER: Pro00004349
IRB APPROVAL DATE: 02/01/2023

Rev. 3.2  dated:   1/19/2023                                                   IRB Approval date:  
Protocol document date: 1/19/2023                                
5.2
Treatment Planning and Specifics .........................................................................43
5.3
Indications for Radiation Therapy.........................................................................44
5.4
Timing....................................................................................................................44
5.5
Emergency Irradiation ...........................................................................................44
5.6
Treatment Planning................................................................................................44
5.7
Target Volumes .....................................................................................................46
5.8  
Definitions for GTV, CTV and PTV .....................................................................47
5.9  
Target Dose............................................................................................................49
5.10  Treatment Technique.............................................................................................52
5.11  Treatment Planning Procedures.............................................................................54
5.12  Organs at Risk........................................................................................................54
5.13  Dose Calculations and Reporting ..........................................................................56
5.14  Patterns of Failure Evaluation ...............................................................................57
5.15
Management of Radiation Necrosis.......................................................................58
5.16
PET for Dose Verification of Proton Therapy.......................................................59
6.0
REQUIRED EVALUATIONS, TESTS AND OBSERVATIONS...................................59
6.1 
Physical Examination ............................................................................................60
6.2 
Neurology ..............................................................................................................61
6.3 
Ophthalmology ......................................................................................................61
6.4 
Audiology ..............................................................................................................61
6.5  
Endocrinology........................................................................................................62
6.6  
Neuropsychological Testing ..................................................................................63
6.7  
Sleep, Fatigue and Quality of Life Measures ........................................................73
6.8 
Physical Performance ............................................................................................74
6.9  
Diagnostic and Investigational MR Imaging.........................................................80
6.10
Pathology and Biological Studies..........................................................................83
6.11
Patient Support.......................................................................................................86
7.0
EVALUATION CRITERIA..............................................................................................90
8.0
REMOVAL FROM PROTOCOL AND OFF-STUDY CRITERIA.................................92
8.1
Off-Study Criteria..................................................................................................92
8.2
Collaborating Sites Notification ............................................................................92
9.0
SAFETY AND ADVERSE EVENT REPORTING REQUIREMENTS..........................92
9.1  
Reporting Adverse Experiences and Deaths to St. Jude IRB ................................92
9.2  
Serious Adverse Events (SAE) or Adverse Events (AE) felt to be related to 11C-
methionine (IND #104987)....................................................................................95
St. Jude Children's Research Hospital
IRB NUMBER: Pro00004349
IRB APPROVAL DATE: 02/01/2023

Rev. 3.2  dated:   1/19/2023                                                   IRB Approval date:  
Protocol document date: 1/19/2023                                
9.3  
Recording Adverse Events and Serious Adverse Events ......................................97
9.4
Process for Reporting Adverse Events from and to Collaborative Sites...............97
9.5  
Radiation Safety Committee..................................................................................98
10.0
DATA COLLECTION, STUDY MONITORING, AND  CONFIDENTIALITY ...........98
10.1
Data Collection ......................................................................................................98
10.2  Study Monitoring...................................................................................................99
10.3 
Confidentiality .....................................................................................................100
11.0
STATISTICAL CONSIDERATIONS ............................................................................100
11.1 
Statistical Analysis of Primary Objective 1.1......................................................112
11.2
Statistical Analysis of Secondary Objective 1.2.1 Neurological, Endocrine and 
Cognitive..............................................................................................................114
11.3 
Statistical Analysis of Secondary Objective 1.2.2 Sleep, Fatigue and Quality of 
Life.......................................................................................................................116
11.4 
Statistical Analysis of Secondary Objective 1.2.3 Physical Performance...........117
11.5 
Statistical Analysis of Secondary Objective 1.2.4 Neuroimaging.......................119
11.6 
Statistical Analysis of Exploratory Objective 1.3.1 Avidity to FDG and C-MET
.............................................................................................................................119
11.7 
Statistical Analysis of Exploratory Objective 1.3.2 Growth Factor and Cytokine 
Responses ............................................................................................................120
11.8 
Statistical Analysis of Exploratory Objective 1.3.3 Radiogenomics...................120
11.9
Statistical Analyses of Exploratory Objective 1.3.4: Association of prior 
chemotherapy with PFS and OS distributions.....................................................122
11.10 Statistical Analyses of Exploratory Objective 1.3.5: To compare the progression-
free and overall survival distributions for children (age > 3 years) and young 
adults with recurrent ependymoma and 1q gain treated with a second course of 
irradiation (focal or craniospinal) while monitoring for excessive central nervous 
system necrosis. ...................................................................................................122
11.11 Monitoring Outcomes for the Retrospective Cohort ...........................................124
12.0
OBTAINING INFORMED CONSENT..........................................................................125
12.1
Consent/Assent at Enrollment .............................................................................125
12.2 
Consent at Age of Majority .................................................................................125
13.0
REFERENCES ................................................................................................................126
APPENDICES .............................................................................................................................148
Appendix I:    Evaluation Schedules................................................................................148
Appendix II:   Evaluations During Radiation Therapy at St. Jude ..................................150
Appendix III:  Research Tests .........................................................................................150
Appendix IV:  RERTEP Ophthalmology Form...............................................................152
St. Jude Children's Research Hospital
IRB NUMBER: Pro00004349
IRB APPROVAL DATE: 02/01/2023

Rev. 3.2  dated:   1/19/2023                                                   IRB Approval date:  
Protocol document date: 1/19/2023                                
St. Jude Children's Research Hospital
IRB NUMBER: Pro00004349
IRB APPROVAL DATE: 02/01/2023

RERTEP
1
Rev. 3.2  dated:   1/19/2023                                                   IRB Approval date:  
Protocol document date: 1/19/2023                                
1.0
OBJECTIVES
1.1
Primary Hypothesis and Objective
Hypothesis: Ependymoma recurrent after prior therapy that included irradiation is 
genetically distinct from the untreated tumor. The effectiveness of a second 
course of irradiation depends on tumor biology and the pattern of initial tumor 
progression.
1.1.1
To prospectively estimate the progression-free and overall survival 
distributions for children and young adults with recurrent ependymoma 
treated with a second course of irradiation while monitoring for excessive 
central nervous system necrosis.
 
1.2
Secondary Hypotheses and Secondary Objectives
Hypotheses: A second course of irradiation may be safely administered to patients 
with recurrent ependymoma after prior irradiation. The incidence and severity of 
side effects after second irradiation correlate with relevant clinical factors and 
treatment parameters, including radiation dose to normal tissue volumes and the 
use of chemotherapy before or after second irradiation. The selection of patients 
for re-irradiation can be improved by models that include clinical and treatment 
factors and longitudinal measures of CNS effects.
1.2.1
To explore potential associations of clinical and treatment factors with the 
incidence and severity of neurological, endocrine and cognitive deficits in 
children and young adults with ependymoma treated with a second course 
of irradiation.
1.2.2
Using specific measures of sleep quality, excessive daytime sleepiness, 
daytime activity, fatigue, symptom distress, and quality of life, explore 
associations of sleep, fatigue and quality of life with other measures of 
CNS effects, clinical and treatment factors in children and young adults 
with ependymoma treated with a second course of irradiation.
1.2.3
To evaluate and explore differences in physical performance and 
movement in children and young adults with ependymoma treated with a 
second course of irradiation.
1.2.4
Estimate and compare the response of residual tumor and the incidence 
and severity of structural, physiological, and vascular effects of normal 
brain in children and young adults with ependymoma after treatment with 
a second course of irradiation using specific methods of diffusion, 
contrast-enhancement, magnetization transfer, vascular and functional 
St. Jude Children's Research Hospital
IRB NUMBER: Pro00004349
IRB APPROVAL DATE: 02/01/2023

RERTEP
2
Rev. 3.2  dated:   1/19/2023                                                   IRB Approval date:  
Protocol document date: 1/19/2023                                
neuroimaging, and explore the association between these and other 
measures of CNS effects and clinical and treatment factors. Determine the 
time course of gray matter and white matter tract injury and recovery post 
irradiation and the association between imaging metrics derived from 
serial quantitative neural imaging and radiation dosimetry as well as 
neuro-cognitive outcomes.
1.3
Exploratory Objectives
1.3.1
Estimate the avidity of ependymoma to 18F-fluorodeoxyglucose (FDG) 
and 11C-methionine positron emission tomography (IND # 104987) prior 
to radiation therapy and correlate change in avidity 12, 24 and 36 months 
after a second course of irradiation with tumor progression.
1.3.2
Measure growth factor and cytokine responses in children and young 
adults with ependymoma after treatment with a second course of 
irradiation, and explore associations between these and other measures of 
CNS effects and clinical and treatment factors. Descriptively compare 
findings for patients treated with an initial course of irradiation.
1.3.3
To conduct a variety of exploratory molecular analyses on tumor samples 
(and blood where a germline control is required), including but not limited 
to broad (genome-wide / array-based) or focused (gene-specific) analyses 
at the DNA, RNA, or protein level and next generation (whole genome, 
exome, transcriptome) sequencing in an effort to improve our 
understanding of ependymoma biology, and to explore associations 
between molecular findings and treatment response and various side 
effects including vasculopathy, hearing loss, cognitive deficits, and growth 
hormone deficiency and other measures as appropriate.
1.3.4
To explore the association of chemotherapy given prior to re-irradiation 
with progression-free survival and overall survival distributions.
1.3.5
To compare the progression-free and overall survival distributions for 
children (age > 3 years) and young adults with recurrent ependymoma and 
1q gain treated with a second course of irradiation (focal or craniospinal) 
while monitoring for excessive central nervous system necrosis.
1.4
Definitions
1.4.1
Clinical factors include but are not limited to vital statistics, auxological 
measures and tumor variables that uniquely identify the patient and the 
natural history of their disease. Clinical factors also include laboratory 
measures of host and tumor biology and response to treatment.
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1.4.2
Treatment factors include but are not limited to type and extent of surgical 
interventions including operative complications. Treatment factors also 
include the full extent of radiation therapy treatment planning and delivery 
parameters and chemotherapy before or after radiation therapy.
1.4.3
Measures of CNS effects refers to the broad categories of different 
objective clinical or laboratory methods used to evaluate the acute and late 
effects of radical surgery or limited surgery and radiation therapy in this 
protocol (neuropsychological, growth factor and cytokines, endocrine, 
physical performance and movement, host and tumor genetics, structural, 
functional and vascular imaging, audiology, neurology and 
ophthalmology, sleep, fatigue and quality of life, and positron emission 
tomography). Each of these categories includes smaller or more specific 
measures. Some of these measures may be used to evaluate tumor 
response to treatment (cytokines, tumor and host genomics and 
neuroimaging).
2.0
BACKGROUND AND RATIONALE
2.1
Problem Definition
Children with ependymoma who experience disease progression after surgery and 
radiation therapy have few options: chemotherapy may prolong survival but is not 
curative and surgeons are reluctant to approach recurrent disease without effective 
adjuvant therapy. Fractionated re-irradiation may be a potential treatment for 
these patients; however, guidelines have not been established, relative benefits 
and risks are unknown, a most reported series include diverse diagnoses and 
combine adult and pediatric patients [1, 2]. Single fraction radiosurgery has been 
used in selected cases of locally recurrent or metastatic ependymoma with mixed 
results: morbidity has been high and durable disease control has not been clearly 
demonstrated [3, 4]. Fractionated re-irradiation has not been systematically 
explored for ependymoma mainly because it affects the very young and pediatric 
oncologists are not familiar with re-irradiation as a treatment option. In this study, 
we propose to irradiate children with ependymoma that is recurrent after prior 
fractionated focal irradiation and to investigate clinical and biologic features that 
may be associated with subsequent disease control and toxicity.
The rationale for this study is based on the St. Jude experience with re-irradiation 
for recurrent ependymoma [5]. Thirty-eight patients with initially localized 
ependymoma at the time of definitive radiation therapy underwent a second 
course of radiation therapy at St. Jude Children's Research Hospital after local 
(n=21), metastatic (n=13) or combined (n=4) treatment failure. The re-irradiation 
method included radiosurgery (SRS, n=6), focal fractionated (FFRT, n=13) or 
craniospinal irradiation (CSI, n=19). SRS resulted in significant brainstem 
toxicity and one death using a median SRS dose of 18Gy. There was only one 
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long-term survivor. Focal fractionated re-irradiation was used in 13 patients who 
were followed for a median of 30 months. Three failed with metastatic disease 
and the 3-year event-free (EFS) and overall survival (OS) was 71% + 14% and 
67% + 16%, respectively. There were no cases of necrosis with a median 
combined dose of 111.6Gy localized primarily to the brainstem and cerebellum. 
The outcome suggested a high-rate of local control for re-irradiation with limited 
adverse effects. CSI was administered to 12 patients with isolated metastatic 
failure after metastasectomy. The median combined dose at any point of overlap 
with prior irradiation was 99Gy. The 3 year EFS was 53% + 20% for patients 
with a median follow-up of 32 months. These data suggested that some patients 
with extensive recurrent disease may be salvaged with CSI, provided that surgery 
is a component of therapy. CSI was also administered to 4 patients with a history 
of combined local and metastatic failure: 3 of 4 patients subsequently failed 
demonstrating a potential limitation to this approach in patients who have more 
clinically aggressive disease. In summarizing this experience, it appears that SRS 
should have a limited role in the treatment of recurrent ependymoma and that 
patients with locally recurrent EP have durable local tumor control but remain at 
risk for metastasis. Salvage of isolated metastatic EP failures may be possible 
using CSI; however, those who have combined local and metastatic failure fare 
poorly despite aggressive surgery and re-irradiation.
To design this study we updated the experience at St. Jude Children’s Research 
Hospital which included more than 47 children treated with fractionated re-
irradiation after 2000. The 3 year EFS and OS rates were 49% + 8% and 70% + 
8%, respectively. More and less favorable subgroups were identified considering 
initial pattern of failure, duration of initial disease control, neuropathology at 
initial recurrence, extent of resection at initial recurrence. The value of this 
approach is further supported by the lack of significant surgery-related 
complications and acceptable late effects of irradiation. We retrospectively 
reviewed 32 patients who underwent surgery prior to a second course of 
irradiation, 43% had no surgical complications and facial nerve weakness in 6 
patients (21%) lead the list of identifiable complications including CSF 
leak/pseudomeningocele (7%), lower cranial nerve weakness (7%), cerebellar 
ataxia (7%), hemiparesis (7%), tracheostomy/gastrostomy (3%) and subdural 
effusion requiring shunt (3%). Late complications have not been systematically 
reviewed for these patients.
The St. Jude approach to re-irradiation has been partly validated by investigators 
at the University of Toronto. From their institutional experience including the 
years 1986 – 2010, they analyzed the outcomes from 47 patients with recurrent 
disease [5]. Twenty-nine patients were treated with various combinations of 
surgery and/or chemotherapy and 18 were treated with a second course of 
irradiation. Re-irradiation included ≥54Gy focal irradiation, with or without 
craniospinal irradiation and with or without surgery. Three-year OS was 7% ± 6% 
and 81% ± 12% for non-re-irradiated and re-irradiated patients (P < 0.0001). Time 
to second progression after re-irradiation was significantly longer than time to 
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first progression. There was improved progression-free survival (PFS) for tumors 
with evidence of DNA damage (n=15; p=0.002). Overall treatment effects 
appeared limited. A decline in intellectual function was observed in assessed 
patients.
The aggressive nature of salvage therapy using surgery and re-irradiation for 
relapsed ependymoma requires consideration of the clinical characteristics of the 
patients. Children with ependymoma tend to be young. Most are under the age of 
4 years at the time of initial treatment. Children in this age range are vulnerable to 
the effects of radiation therapy and its use in frontline management has only 
recently been adopted. Historically, the pattern of failure for children with 
ependymoma treated with surgery and radiation therapy has been local. With 
improving rates of gross-total resection and high dose irradiation with doses 
ranging from 54-59.4Gy, the pattern of failure has become mixed with a higher 
proportion of patients failing with metastatic disease [6]; nevertheless, local 
failure as a component of failure remains high. The recent use of conformal 
radiation therapy has reduced the volume of normal tissue receiving the highest 
dose leaving open the possibility of re-irradiation in the setting of failure [7]. The 
potential young age of these patients at the time of failure should be considered 
among the indications for re-irradiation and suggestions with regard to dose and 
volume.
The indications for re-irradiation require exploration and dose and volume 
guidelines need to be established. The St. Jude experience defined three clinical 
risk groups that might help select patients for a particular treatment. Patients who 
progress at the primary site with no evidence of metastatic disease should be 
eligible for resection and re-irradiation using focal fractionated or craniospinal 
methods. Craniospinal irradiation might be considered for older patients based on 
the risk for metastatic progression. Focal fractionated irradiation should be the 
only option for younger patients to minimize the side effects of treatment. Patients 
with local failure should be offered both treatment options with recommendations 
dependent on patient age, prior treatment and morbidity and other factors 
balancing the potential for cure with the risk of long-term effects. The low 
negative predictive value of CSF cytology and neuraxis imaging affect the 
selection of treatment for this group of patients. Improving the negative predictive 
value of these tests may be considered in this study. Patients who progress with 
metastatic disease but who remain controlled at the primary site should be 
considered for metastasectomy and craniospinal irradiation. This group of patients 
may have disease burdens ranging from the resectable oligometastasis to 
extensive and unresectable neuraxis disease. Controlling metastatic disease 
requires a combination of craniospinal irradiation to neuraxis tolerance and 
supplemental irradiation to areas at highest risk for disease progression. Definitive 
treatment of these patients often requires exceeding generally acceptable normal 
tissue tolerance limits for brain and spinal cord. Patients who progress with 
combined local and metastatic failure, or diffuse neuraxis metastatic disease after 
prior radiation therapy appear to fare poorly with a second course of radiation 
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therapy although the number of patients with these clinical features appears to be 
small. Nevertheless, they should be considered for this treatment protocol that 
will set the stage for future experimental therapy including a combined modality 
approach that would involve craniospinal irradiation.
Patients who progress with local failure require careful neuraxis surveillance for 
metastatic disease and aggressive local resection with definitive evidence that the 
recurrence was indeed local. The nature and timing of the local failure may 
provide helpful clues about the risk of neuraxis dissemination and move 
caregivers to recommend focal or craniospinal treatment. The specter of 
metastatic disease may be reduced in a patient who experiences disease 
progression where residual tumor was known to remain after initial surgery or in a 
patient who develops obvious local failure relatively late > 3 years after radiation 
therapy. The clinical condition and age of a patient also require consideration, 
very young or debilitated patients may not fare well with craniospinal irradiation. 
Drawing a parallel to the frontline treatment for medulloblastoma, we do not 
propose a lower age cutoff for craniospinal irradiation but consider it to be a 
reasonable option in children over the age of 3 years since craniospinal irradiation 
is a treatment option for newly diagnosed and similarly aged children with 
medulloblastoma on frontline trials.
Exploring normal tissue tolerance with re-irradiation can lead to lethal 
complications or tremendous morbidity. This is readily apparent in patients 
treated with radiosurgery when the treatment volume included portions of the 
brainstem. Toxicity is always a concern for patients treated with fractionated re-
irradiation regardless of the follow-up interval. While changes on imaging, and to 
a lesser extent with symptoms, may be apparent in some patient, most appear to 
avoid major effects. Those who do not have complications tend to be those with a 
negative history for prior treatment complications and a long interval between the 
first and second course of irradiation. There are several maneuvers to limit the 
side effects of treatment including the timely treatment of necrosis or potential 
necrosis. Our technique of re-irradiation using a combination of CSI and boost 
treatment seeks comprehensive coverage of the neuraxis. Shielding large volumes 
of previously irradiated tissue invites re-seeding. We have successfully limited 
side effects in patients with radiation necrosis and transient myelopathy using 
hyperbaric oxygen therapy. The time interval between courses of radiation is 
recognized along with other clinical factors, such as the specific region of the 
brain or spinal cord, as an important variable to consider when offering 
retreatment [8]. Although investigators have shown by experimentation or in 
clinical studies that the spinal cord may tolerate re-irradiation to relatively high-
doses [9, 10], we have restricted retreatment to the spinal cord when 
administering craniospinal irradiation to patients who had prior infratentorial 
irradiation that involved the upper cervical spinal cord. The addition of 
craniospinal irradiation to a dose of 39.6Gy and to regions treated to less than 
30% of the previously prescribed 54Gy achieves a biologic effective dose (BED) 
of approximately 96Gy2 whereas overlap of the entire cervical cord with the 
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combined doses of 54Gy and 39.6Gy would achieve a BED of approximately 
246Gy2. The former value falls within the lower range and the latter falls within 
the upper range of the previously reported cumulative spinal cord doses of 102-
181.5Gy2 where the risk of myelopathy was estimated at 25%. In our patients, 
categorized as intermediate risk based on the cumulative dose, the BED of the 
first course of treatment was about 129Gy2 [9].
Re-irradiation for recurrent primary brain tumors has been a long-standing 
treatment option with investigators recognizing the attendant risks of necrosis or 
neurologic complication [1, 11]. One published series reported a 9% risk of 
necrosis and overall complication rate of 29% among 34 patients with primary 
brain tumors, including children, undergoing fractionated re-irradiation to a 
median combined dose of 79.7Gy (range 43.2-111Gy) [1]. This series showed 
only a modest palliative and survival benefit in a diverse group of patients. A 
more specific evaluation of combined re-irradiation and lomustine was conducted 
in a small cohort of patients with high-grade glioma demonstrating a median OS 
of 13.7 months. The re-irradiation dose was limited to 34.5Gy in 23 fractions with 
a median interval between first and second courses of irradiation of approximately 
14 months [12]. With the advent of conformal radiation therapy investigators have 
attempted to minimize the dose to normal tissues when re-irradiation is attempted. 
One series included 20 patients with primary brain tumors unsuitable for 
brachytherapy or radiosurgery, predominantly high grade glioma. With a median 
re-irradiation dose of 36Gy (30.6-59.4Gy), and combined doses ranging from 
80.6-119.4Gy, neurologic improvement and stabilization of disease was observed 
in more than 67% of patients [13]. Different dose and fractionated schemes have 
been attempted for similar patients. For example, low-dose (36Gy) fractionated 
re-irradiation has been applied successfully to predominantly adult patients with 
low and high-grade astrocytoma. The lack of observed toxicity might be 
attributable to the long interval between courses (median 50 months) for the low-
grade patients and relatively short time to progression for the high-grade patients 
[14, 15]. Similar low, hypo-fractionated, doses have been applied in patients with 
high-grade glioma  and ependymoma [16] with modest results. Focal fractionated 
re-irradiation and radiosurgery for medulloblastoma appears to be safe, provided 
the doses are relatively low, and locally effective; however, the overall results are 
poor in a tumor system prone to metastatic failure not unlike ependymoma [2].
To minimize the risks to the patient, there should be a 9-month interval between 
the start of the first course of radiation therapy and the start of the second course. 
The rational for this eligibility inclusion criteria including  avoiding treatment of 
patients who have not passed the usual time period after the initial course of 
radiation therapy when necrosis might begin to appear and increasing the time 
interval between the start of the first course of radiation therapy and the second 
course, a known factor to precipitate necrosis. Brainstem radiation necrosis after 
the initial course of radiation therapy usually occurs within 6 months of 
completing radiation therapy or less than 8 months after the start of irradiation [6]. 
We would not want to initiate a second course of treatment for a patient that has 
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not passed this phase. Because the follow-up of children with ependymoma may 
vary between 3 and 4 months, it is reasonable to be conservative and specify an 
interval of 9 months. Further, patients who experience necrosis after a second 
course of irradiation appear to have a higher risk when the interval from first to 
second RT course is shorter than 6 months. This has been documented in two 
series [9, 17]. Fortunately, tumor progression during the first year after the initial 
course of radiation therapy is uncommon.
Patients treated with a second course of irradiation at St. Jude have not been 
systematically evaluated for late effects. Among the 23 patients who had not 
failed salvage therapy, we observed that 4 had notable disabilities. The remaining 
patients continue to be followed and the magnitude of side effects has been 
greatest among those treated with craniospinal irradiation. Given the very small 
volume that is targeted for focal fractionated re-irradiation, barring structure 
damage to the brainstem, the risks of endocrinopathy, hearing loss and cognitive 
decline do not appear to be significantly greater that that observed after the initial 
treatment course.
There are five domains of investigation which combine to support the primary and 
secondary objectives of this study. These include 1) the statistical design to 
estimate outcome (PFS and OS) which encompasses the evaluation of extent of 
disease, stratification, treatment and how disease progression is defined, 2) 
investigational imaging using MR imaging and PET, 3) clinical and neurological 
evaluation not limited to neuro-cognitive testing, ophthalmology and audiology, 
4) biological studies and 5) functional outcomes including quality of life.
Three-year PFS and OS endpoints are appropriate for this protocol. The endpoint 
of PFS is based on data from our recent series suggesting that most newly 
diagnosed patients experience progression within the first 3 years after radiation 
therapy [6], regardless of whether progression is local or distant. Most of the 
patients enrolled on this study will have had their initial progression during this 
time interval. This will allow us to calculate of a ratio of time to second 
progression (PFS2) to time to initial progression (PFS1) [17]. The endpoint for 
OS is based on our unpublished experience which suggests that few patients live 
more than 24 months after recurrence when treated with chemotherapy alone.
Correlating clinical and biological factors with PFS and OS is aimed at learning 
more about the biology of ependymoma and risk factors for initial and second 
progression. By nature, patients treated on this study will be considered a high-
risk group. Many will have had subtotal resection prior to the initial course of 
radiation therapy. It will be important to review the initial treatment for these 
patients and consider that some might have fared better after their initial course of 
irradiation, had surgery or radiation therapy been further optimized. For example, 
patients with initial subtotal resection who develop local progression and through 
this protocol achieve gross total resection will be considered amongst those who 
were not optimized surgically prior to their initial course of irradiation. Patients 
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initially treated with doses lower than 50Gy, especially in the setting or residual 
disease would also fit this category. These patients will be ineligible for this 
protocol. Other factors such as targeting for the initial treatment and subsequent 
pattern of local-regional failure will be considered.
Tissue acquisition (initial and recurrent) will enable a number of unique 
opportunities. Patients with local progression treated with surgery prior to their 
second course of irradiation will have their tissue acquired for biology study. 
These patients will be considered to have less radiosensitive and more aggressive 
tumors. The pattern of failure for these patients after second irradiation will 
provide unique insight into their inherent radioinsensitivity (local failure) or 
metastatic potential (neuraxis failure). Another unique opportunity will be to 
study metastasectomy specimens. These tissues will likely represent metastatic 
tumor that has not been exposed to irradiation and may be considered virulent by 
nature of its metastatic potential unless iatrogenic.
There is significant variability of extent of disease at the time of initial treatment 
failure. One of the primary concerns among caregivers is morbidity. The toxicity 
of this regimen requires careful evaluation with attention to the early and late 
effects of treatment. While the attribution of toxicity to prior treatments, surgery 
performed as a part of this study, and radiation therapy dose and volume is of 
academic importance, it is more important to consider the toxicity of the 
combined regimen to determine the overall value of this approach. Indeed, some 
consider metastasectomy to be an extreme maneuver; however, in our experience, 
the morbidity of resection of locally recurrent tumor, which is more widely 
accepted, may be greater than that for metastasectomy. Sites at which tumor 
resection is not feasible will be monitored for therapy response and used to fulfill 
secondary imaging objectives. In monitoring response to therapy, sites will be 
classified based on prior treatment with metastatic sites providing a unique 
opportunity to quantitatively monitor response to irradiation in a treatment-naïve 
setting.
Composite radiation planning data is critical to the evaluation of these patients. 
The tolerance of the nervous system to high-dose irradiation is remarkable. The 
underlying effects of high-dose irradiation on structure and function will be 
studied. We support the hypothesis that normal tissue tolerance is dependent on 
both radiation dose and volume, that the tolerance of any volume to high-dose 
irradiation is dependent on the proportional volume of the entire organ exposed to 
radiation dose, the so called dose “bath and shower” effect. To study this more 
thoroughly, we have acquired hardware and software to accept the treatment 
planning data from most commercial systems so that patients initially irradiated at 
other centers will have their volumetric dose data combined with those of this 
study for a more accurate representation of volumetric dose to normal tissue. This 
is an important maneuver since registration of follow-up imaging with composite 
dose-volume data will be requisite to monitoring response to therapy and 
evaluating structural and functional changes.
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We need to determine clinically significant side effects in the context of prior 
treatment, prior treatment complications, pattern of failure and disease burden, 
and radiation dose integrated over the central nervous system and specific 
functional subunits. Considering clinical factors that predict morbidity, there are 
critical combinations of tumor, surgery and radiotherapy effects that will lead to 
clinically significant morbidity after a second course of irradiation. There are 
critical events leading to initial diagnosis, critical events in the peri-operative 
period and critical radiation dose and irradiated volume tolerance levels that will 
predict for side effects after a second course of irradiation. A detailed medical 
history with supportive clinical data is required for safe second irradiation and 
exposes clinical factors that predict for morbidity. Our greatest concern is for 
patients with infratentorial tumor location and necrosis of the brainstem, 
cerebellum, spinal cord or other central intra-axial structures. History and 
supportive documentation may include but should not be limited to the following: 
presenting signs and symptoms and their duration; tumor imaging features at 
presentation: size, location, displacement and invasion of normal structures; 
hydrocephalus: extent, treatment and complications including temporary or 
permanent ventriculostomy and subsequent complications, infections, revisions 
and ventricle response; peri-operative factors: extent and number of surgeries, 
surgical complications including infections, transfusions and anesthesia records 
detailing brainstem neurological and vital functions including heart and 
respiratory rate and rhythm, blood pressure and required management and 
medications; post-operative neurological function, imaging findings and clinical 
course of recovery. Similar detailed information is required at the time of 
recurrence including patient demographic data, serial imaging and clinical 
evaluations, documented radiotherapy history including electronic record of 
dosimetry (radiation dose and volume, normal tissue and target volumes, dose 
heterogeneity), history of chemotherapy, and time course of functional deficits 
affecting neurological (neurological examinations, hearing and vision testing), 
endocrine (deficits and replacements) and cognitive systems (fundamental 
psychology and developmental data). These data will help us to assess the 
morbidity of surgery after prior irradiation.
2.2
Neurological, Endocrine and Cognitive Studies
Neurological, endocrine and cognitive effects of irradiation are the most common 
focus of concern for caregivers. Neurological effects most often include cranial 
nerve, motor and cerebellar dysfunction. The effects of surgery and irradiation on 
neurological function have been previously described for children with 
ependymoma initially treated with aggressive surgery and irradiation [18]. There 
is little doubt that patients who experience tumor recurrence and undergo 
additional surgery and radiation therapy will experience or be susceptible to 
treatment effects. These have not been formally documented. Such documentation 
will be the goal for this study both to describe the morbidity of the condition as 
well as to identify clinical covariates that impact other measures of CNS effects. 
Neurological deficits include transient and permanent damage to hearing and 
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vision and loss of neurological function associated with surgery, radiation therapy 
and in the extreme – necrosis of brain or spinal cord.
The endocrine effects of retreatment may compound the existing risk for any 
endocrinopathy which ranges up to 25% among patients successfully or 
unsuccessfully treated with initial surgery and irradiation [7]. Because most 
recurrences after initial treatment occur about 18-26 months after treatment, 
patients enrolled on this study may have ongoing endocrine deficiencies that need 
to be addressed and document to assess the toxicity of the proposed treatment 
regimen. Children will undergo endocrine evaluation and provocative assessment 
of growth hormone and adrenal axis hormones.
2.3    Psychology Studies and Neurocognitive Outcomes
Children who receive radiation therapy for ependymoma are at increased risk for 
impairments in cognitive functioning [19]. There is strong evidence to suggest 
that total radiation dose and volume of irradiated brain play a significant role in 
cognitive outcomes, with lower doses of cranial radiation associated with less 
intellectual impairment [20, 21]. Given this finding, it is predicted that re-
irradiation may be associated with additional cognitive morbidity; thus, it is 
imperative that cognitive outcomes be closely monitored. Cognitive monitoring 
conducted within the context of this protocol could significantly impact 
determinations regarding the acceptability of this treatment approach.
A progressive decline in intellectual functioning (IQ) after radiation therapy for 
childhood brain tumors has been well-established [22-25]. Increased utilization of 
special education services has also been reported and cranial irradiation has been 
associated with poor academic performance on standardized measures in 
childhood brain tumor survivors [21, 23, 26, 27]. Further, studies have found 
declines in academic functioning for children 2 to 5 years after irradiation [28, 
29]. Previously reported findings from the RT-1 protocol indicate that reading, in 
particular, may be more vulnerable than other academic skills and may decline 
despite stable intellectual functioning in children treated for ependymoma with 
conformal radiation therapy [30]. 
More recently, research investigators have tried to identify specific cognitive 
deficits that may underlie global declines in intellectual function or academic 
achievement. Reports of deficits in attention [31], working memory (online 
maintenance and manipulation of information) [32], and processing efficiency 
[33] are most prevalent. These emerging areas of core deficit are informative as 
nearly half of age-related improvements in IQ can be accounted for by 
developmental improvements in working memory and processing speed [34]. 
Accordingly, these cognitive domains will be the focus of serial monitoring.
Radiation therapy is a well-established cause of changes in cerebral white matter 
[35]. There is accumulating evidence to suggest that reduced cerebral white 
matter accounts for a significant proportion of the observed decline in IQ among 
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survivors of childhood brain tumors. For example, in a longitudinal study 
examining the impact of two craniospinal irradiation doses (conventional [36Gy] 
and reduced [23.4Gy]) in the treatment of medulloblastoma, Reddick and 
colleagues found a significant decrease in cerebral white matter volumes, in 
contrast to expected developmental maturation [36]. Further, the rate of white 
matter decrease was more rapid in patients who received the higher radiation 
dose. Reddick and colleagues have also demonstrated that a primary implication 
of reduced cerebral white matter volumes in children treated for brain tumors is 
compromised attention abilities that lead to a decline in IQ and academic 
achievement [37].
Risk factors most consistently associated with cognitive problems following 
treatment for childhood brain tumors include not only treatment intensity (i.e., 
radiation dose/volume) but also younger age at treatment [38], longer time since 
treatment [39], female gender [40] and complicating medical factors [41]. 
Findings from children treated for ependymoma on the RT-1 protocol revealed 
that tumor location, number of surgical resections, longer symptomatic interval, 
pre-irradiation chemotherapy, pre-existing endocrine deficiencies, hydrocephalus 
and younger age at treatment were associated with greater cognitive problems [30, 
42]. Accordingly, relevant demographic and clinical factors will be included in 
models investigating the effect of re-irradiation on cognitive outcomes.
2.4
Sleep Disorders, Fatigue and Quality of Life
Survivors of ependymoma retreatment are known to have neuroendocrine 
deficiencies, visual deficits, seizure disorders and hypothalamic obesity due to the 
number of surgery procedures, dose and volume of radiation therapy and tumor 
location.  Damage caused by repeated and aggressive surgeries and radiation also 
results in sleep disturbances, daytime hypersomnolence, defective-short-term 
memory, limited concentration span, and other symptoms. Reports of sleep 
disturbances and long term outcomes in pediatric ependymoma patients are 
limited; however, adult patients with ependymoma report moderate to severe 
symptoms including fatigue and sleep disturbance [43].
The literature is limited regarding sleep disturbance and symptoms among 
pediatric patients re-irradiated for recurrent brain tumors. A recently published 
review of patients with recurrent medulloblastoma described toxicities and noted 
an increased risk of necrosis among patients re-irradiated compared to 
nonirradiated [44]. The brain tumor retreatment was suggestive of prolonged 
survival, with the benefit best for those initially treated as standard risk. However, 
the literature is limited in describing patient reported outcomes of 
symptomatology.
This study provides an opportunity to investigate the potential relationships 
between characteristics of sleep quality and daytime sleepiness/fatigue, quality of 
life, and treatment symptoms within a large cohort of extensively treated brain 
tumor survivors.  Clinical experience suggests that a variety of clinical sleep 
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disorders may be present in this patient group including insomnia, obstructive 
sleep apnea, daytime sleepiness, circadian rhythm dysfunction and/or fatigue.  
Sleep has a restorative function for healthy and ill children and adolescents as it 
provides a period of increased protein synthesis, cellular division, and growth 
hormone release that contributes to tissue renewal [45, 46] and compensates for 
energy deficits acquired during daily functions [47, 48]. Sleep patterns reflect 
neurological maturation, but stability in those patterns in terms of total night sleep 
and night awakenings occurs by age 4 or 5 years [47, 48]. A gradual reduction in 
nocturnal movement intensity occurs in children and adolescents [49, 50] with 
minimal differences being found between children who are 3 – 5 years of age, 8 – 
12 years or young adults who are 18 –  24 years of age [51]. When self-report 
methods are used in sleep studies, significant gender differences are noted in sleep 
quality with females reporting significantly lower sleep efficiency than do males 
[52]. Weight has also been associated with sleep quality. Overweight children and 
adolescents have documented shorter sleep time, later sleep onset and more 
disturbed sleep than healthy controls [53]. Academic grades are adversely 
affected by short or poor sleep [54, 55]. Finally, children with a confirmed 
diagnosis of depression were also found to have poorer sleep quality [56]. Given 
these important child or adolescent characteristics associated with sleep, we will 
collect information on patient age, gender, weight (BMI), and other clinical 
factors at diagnosis and will examine the association of each with sleep, daytime 
activity and fatigue outcomes.
Modulation of sleep/wake patterns and sleep architecture is orchestrated by 
specific neuronal populations and pathways that involve the brainstem, 
diencephalon, and thalamus [52, 57, 58]. In healthy individuals, neuroanatomical 
and neurophysiological systems provide the substrate for well-organized and 
predictable sleep/wake cycles.  Restorative sleep is typically experienced during 
the night and sustained wakefulness across the day.  Wakefulness is promoted by 
several systems that include the reticular formation (RF) of the brainstem (ventral 
medullary, central pontine, and midbrain reticular formation), the posterior 
hypothalamus, and the basal forebrain [52, 59]. Neurophysiological expression of 
wakefulness is characterized by desynchronication of cortical activity.  From a 
neurochemical perspective, catecholamine- and acetylcholine-containing neurons 
modulate the activity of subcortical and cortical neurons during wakefulness.  
Histamine, hypocretin [60], and a variety of other neuropeptides elaborated by the 
posterior hypothalamus enhance wakefulness.  Circulating blood-borne 
neurochemicals such as epinephrine, histamine, and glucocorticoids can also 
serve to enhance wakefulness. Another neurochemical, melatonin is produced by 
the pineal gland and is important in the hypothalamic and pituitary regulatory 
functions. Melatonin secretion occurs at night and insufficient secretion has been 
associated with disorders in delay of sleep, with an influence on circadian rhythm 
[61]. 
Non-rapid eye movement (NREM) sleep is characterized by synchronized 
neuronal activity that is modulated by several integrated neuronal systems.  
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Neurons involved in NREM sleep are located in the solitary tract of the medulla, 
raphe nuclei of the brain stem, reticular thalamic nuclei, anterior hypothalamus, 
preoptic area, basal forebrain, and the orbitofrontal cortex [52, 57, 62].  Thalamo-
cortical projections and networks support the synchronized cortical activity that 
comprises NREM sleep [63, 64].  This neuronal network is GABAergic in 
character.  Serotonin-containing neurons of the brain stem raphe serve to dampen 
sensory input and inhibit motor activity, which promotes the emergence of deep 
NREM (slow wave) sleep.  Adenosine neurons are located in the hypothalamus, 
promote NREM sleep, and are blocked by caffeine and xanthines.  GABA, 
opiates, somatostatin, and alpha-melanocyte-stimulating hormone facilitate 
NREM sleep.  Benzodiazepines bind with GABA receptors to enhance NREM 
sleep.  CSF-borne factors such as opiate peptides (beta-endorphin, enkephalin, 
and dynorphin) play roles in sensory modulation and analgesia and these 
processes are related to sleep onset and maintenance.  Several blood-borne factors 
also promote NREM sleep including muramyl peptides from intestinal gut 
bacteria (stimulating production of interleukin-1 and other cytokines), 
cholecystokinin, and insulin [52].
Rapid eye movement (REM) sleep alternates with NREM sleep in a predictable 
and periodic fashion across the major sleep period.  REM sleep is supported 
primarily by neuronal populations in the dorsolateral pons and caudal midbrain 
[65]. During REM sleep muscle atonia occurs as a normal and expected 
phenomenon [66, 67]. This process is mediated by neurons in the midbrain 
perilocusceruleus region with connections to the medullary reticular nucleus via 
the tegmentoreticular tract.  In addition to muscle atonia, a variety of other REM 
related phenomena occur under normal circumstances including dream mentation 
and imagery, rapid eye movements, fluctuations in heart rate, respiratory rate and 
depth, hippocampal theta [68] activity, and relative loss of thermoregulatory 
ability.  The precise function of REM sleep is not fully understood.
The sleep architecture of NREM and REM periods alternate throughout each 
night of sleep in cycles of 90 to 110 minutes for children, adolescents and young 
adults. The three stages of NREM together take approximately 36 to 75 minutes 
and REM approximately 5 minutes [69, 70]. Sleep experts generally suggest a 90-
minute sleep cycle for children and adolescents [71].
Given the critical importance of the neuroanatomical, neurophysiological, and 
neurochemical systems for modulation of sleep/wake states, it is apparent that 
anatomic lesions in key locations of the brainstem, diencephalon, and thalamus 
may lead to functional disruption of sleep and/or wakefulness.  Loss of 
wakefulness can occur with lesions in the pontine and midbrain tegmentum, in the 
glutamatergic neurons of the reticular formation, in the noradrenergic locus 
coeruleus neurons, in the posterior hypothalamus (histaminergic or 
hypocretinergic neurons), or in the cholinergic basal forebrain neurons.  Loss of 
natural sleep can occur in association with lesions of the lower brainstem or 
preoptic area in the forebrain [72].
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The literature regarding cerebral neoplasms and sleep is limited by the small 
number of reports, small sample sizes, and the observational and retrospective 
nature of the studies.  Few reports involve children. Several reports provide 
information about the “hypersomnolence syndrome” that occurs after cranial 
radiation treatment [73, 74] and several others describe the association of brain 
lesions and cataplexy [75], and brain lesions and obstructive or central sleep 
apnea [76-78]. One study provides polysomnographic (sleep study) data from 
patients who were studied before and after surgery [79]. In a retrospective report 
by Rosen et al, 14 children with CNS tumors are characterized regarding the 
range of sleep problems and disorders that are present following surgical 
resection, cranial radiation, and in some cases, chemotherapy [80]. This proposal 
would be the largest study describing the trajectory of sleep complaints and 
disturbances among a cohort of patients with recurrent ependymoma. 
A recent study evaluated adult survivors of brain and spine ependymoma 
assessing the impact of symptoms on their daily life [43]. The patients reported 
the most severe symptoms to include fatigue (44%), numbness/tingling (39%), 
pain (36%), and disturbed sleep (34%). The specific sleep disturbance among 
patients with ependymoma was not examined nor the specific sleep symptoms. 
This proposal will assess for prevalence of fatigue and sleep disruption and 
associated symptomatology.  We will assess for excessive complaints of daytime 
sleepiness that may be secondary to obstructive sleep apnea or may indicate 
secondary narcolepsy due to the medical condition.  Excessive sleep complaints 
will be measured with the Symptom Distress Scale and Epworth Sleepiness. 
Quality of Life will be measured with the Peds QL Brain Tumor. Fatigue will be 
measured with the Peds Multidimensional Fatigue Scale.
Sleep efficiency, latency, and total sleep time will be assessed with actigraphy. 
The actigraph has been used in monitoring sleep in children and adolescents 
because it is a low cost, non-intrusive yet keenly sensitive measurement approach. 
Actigraphy has been used to validate parental reports of their child’s sleep 
abnormalities [81] while producing more objective and accurate data as compared 
to parental reports [82, 83].  Functionally, the actigraph detects and records 
movement. Movement triggering the actigraph is relatively high during 
wakefulness and decreases to near-zero values during sleep. Analysis of 
actigraphic records reveals sleep-wake patterns that correlate closely with patterns 
obtained via polysomnographic recordings and behavioral observations [81, 84, 
85]. Sleep-wake scoring algorithms from actigraphic data from the dominant and 
nondominant hands of 16 adolescents were determined to be essentially the same; 
similarly, the overall agreement rates from actigraphic data from both hands with 
polysomnography scoring during one laboratory night was between 91 and 93% 
[82, 86].  Actigraphy has been used to document the efficacy of behavioral 
interventions designed to correct sleep disturbances in well infants and toddlers 
[81, 86] and to document the hyperactive state and response to therapy in children 
with attention-deficit hyperactivity disorder [87, 88]. In summary, actigraphy is 
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able to sensitively capture change in sleep-wake patterns before and after 
behavioral or medical interventions, and actigraphic data from either wrist is 
highly similar.
We will assess sleep quality with actigraphy at baseline and yearly over a 5 day 
assessment period with measurement of the following. 
Actigraph Terms
Duration
Minutes from start to end of 
interval
Activity Mean
Mean activity score (counts/epoch)
Activity Median
Median activity score 
(counts/epoch)
Activity SD
SD of Activity mean
Wake Minutes
Total minutes scored as Wake
Sleep Minutes
Total minutes scored as Sleep 
(Sleep + Light Sleep)
% Sleep
Percent minutes scored Sleep 
(100*(Sleep + Light 
Sleep)/Duration)
Light Sleep
Total minutes scored Light Sleep 
(Sadeh Infant Algorithm)
Sleep Efficiency
(100 * Sleep Minutes/(O-O 
duration))
Sleep Latency
Minutes to start of first 20 minute 
block with > 19 minutes sleep
Wake After Sleep Onset (WASO)
Wake minutes during O-O interval
Acceleration Index
% epochs with > 0 activity score
Bad Epochs
Total bad epochs
Wake Episodes (WE)
Number of blocks of contiguous 
wake epochs
Mean Wake Episode
Mean duration of WE (minutes)
Long Wake Episodes
WE >= value in Options: Sleep: 
Sleep Statistics Criteria text box
Longest WE
Duration of longest WE (minutes)
Sleep Episodes (SE)
Number of blocks of contiguous 
sleep epochs
Mean Sleep Episode
Mean duration of SE (minutes)
Long Sleep Episode
SE >= value in Options: Sleep: 
Sleep Statistics Criteria text box
Longest SE
Duration of longest SE (minutes)
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Acceleration Index—the acceleration index (AI) is calculated by the formula:
AI=2p-1
Where p is the proportion of the interval required for 50% of the total activity in 
the interval to be completed.  For example, for a 1-hour interval, if the activity 
total for the interval was 1000 and 800 counts occurred in the first 20 minutes of 
the interval, p would be 20/60 or 0.33.  Doubling p and subtracting 1 scale the 
index form -1 to +1.  Thus, negative values represent slowing during the interval, 
0 represents uniform distribution of activity during the interval, and positive 
values represent acceleration during the interval.
Epoch—this is the time interval used for activity sampling.  It is usually set to 60 
seconds, though for some actigraphs, it is programmable from one second to 
many minutes.  The epoch duration determines the maximum temporal resolution 
of the activity data.  For sleep estimation, the epoch duration must be 60 seconds, 
or an integer factor of 60 seconds. Down intervals—represent the major sleep 
period of the day, when subjects are in bed and trying to sleep.  These intervals 
are sometimes called “In-Bed” intervals. Up intervals—represent the times 
between successive Down intervals.  Thus there will always be one fewer Up 
Interval than Down Intervals. O-O intervals—are sub-intervals of the Down 
Intervals that estimate the true sleep period.  It represents the time from sleep 
Onset (as defined by the sleep latency) to sleep Offset (the end of the last sleep 
episode in the Down Interval).  Thus an O-O interval represents the Down 
Interval minus the sleep latency and any terminal wake in the down interval.
Each patient will be provided with a postage paid return mailer for actigraphy 
return. Once the actigraphy has been returned to the Division of Nursing 
Research, each participant will receive a $25 gift card to reimburse for the time 
and any inconvenience experienced as a result of taking part in the sleep study.
2.5
Physical Performance and Movement
Physical function is goal directed.  Movement takes place within the environment 
as a mechanism for survival, adaptation, learning, and interaction [89]. When 
individuals are limited in their abilities to move, they are less likely to be able to 
meet every day needs.  For example, someone who cannot reach overhead may 
not be able to get a glass or plate out of the cupboard to set the table.  A person 
with weak legs may not be able to get up and down from the floor or in and out of 
the bathtub and a person with poor cardiopulmonary fitness may not be able to 
walk up and down the aisles of a grocery store, or up and down the stairs in front 
of a church.  Movement is an essential part of everyday life.  Mobility limitations 
interfere with participation in roles at home, work and in the environment [90]. 
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During infancy and childhood, both the size of the body and the maturity of the 
body systems define and limit physical performance abilities.  Early development 
is survival oriented and includes lifting and turning the head, coordinating 
sucking, swallowing, and breathing, crying to indicate needs, and making facial 
expressions to interact with the caregiver.  As children grow and gain control of 
movement, they begin to explore their environments and gain initial independence 
with everyday physical tasks, like eating, dressing and playing.  Throughout 
childhood and adolescence, the body continues to grow and mature until all 
systems are optimized, designed to operate at peak efficiency.  Movement 
practice allows refinement of motor skills so that participation in recreational 
physical activities like track, swimming, baseball, basketball, ballet and 
gymnastics is possible [89, 91, 92]. 
In typically developing children, societal roles, lifestyle changes and eventually 
aging impact the development and maintenance of optimal physical function [93].  
Decreased exposure to physical activity because of time spent indoors, watching 
television, or in front of the computer, accompanied by poor dietary choices may 
result in overweight or obesity and make movement difficult and undesirable [94].  
Cardiopulmonary fitness and muscle strength may not be fully optimized, 
resulting in poor endurance and weakness [95].  Progression into adulthood with 
less than optimal physical function can be problematic, as both a habitual 
sedentary lifestyle, and the requirements of work specialization, for example, 
sitting at a desk, may perpetuate and contribute to declining physical efficiencies 
over time [96]. 
Function, physical performance and participation in everyday tasks
Function is an umbrella term that considers health and health related status as an 
interaction of a person with society.  Physical performance is one component of 
function, and when limited, may contribute to disability. Normal function 
includes the ability to perform movement related tasks required for everyday 
activities.  Typical physical performance progresses from infancy to toddlerhood 
as head lifting, rolling, crawling, sitting, pulling to stand, and walking.  Toddlers 
learn to run, jump, hop and skip, so that by age 5 or 6, they can participate in 
vigorous play activities and organized physical recreation.  Motor skills are 
refined throughout childhood and movement force is optimized in adolescence.  
Young adults typically have all of the skills and capacity necessary for 
participation in everyday tasks including activities that require extreme movement 
coordination, like bathing and dressing, and activities that require a fair amount of 
physical capacity like running and participation in sport.  Refined skill and 
capacity vary across the normal population; not everyone has the capacity to 
climb Mount Everest.  However, most people can bath, dress, get out of a chair, 
walk several blocks, climb stairs and perform the physical tasks required for them 
to maintain their households or do their jobs.
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Physical performance is dependent on the structural integrity and physiologic 
function of the nervous, musculoskeletal and cardiopulmonary systems, to 
provide a foundation upon which normal movement for everyday tasks can be 
accomplished.  Movement created by the coordination of these three systems is 
also dependent on the health of the other body systems; that is, on intact skin to 
protect the body, on the gastrointestinal and urinary systems to process nutrients 
and body waste, and on the endocrine system to regulate metabolism.  The 
general composition of the body is extremely important to movement as it 
governs the strength of the skeleton upon which movement occurs, the amount of 
lean muscle available to produce force, and the amount of body fat that must be 
carried while performing daily tasks.  The structure and functions of the systems 
that govern movement are typically measured by assessing flexibility, balance, 
coordination, power, and cardiopulmonary fitness [89].  Lack of capacity can be 
defined for these measures.  Impaired capacity in these systems is typically 
associated with overall physical performance limitations.
1. Flexibility is the capacity to bend and is based on the pliability of the muscles, 
connective tissue and skin, and on the ability of a joint to move through its 
range of motion.  Girls are typically more flexible than boys [89, 92, 97]. 
2. Balance is the ability to maintain center of gravity over a base of support, 
thereby maintaining an upright posture either at rest or during movement [98].  
Balance improves throughout childhood, is better in girls than boys during 
childhood, and plateaus in adolescence where young men’s skill surpasses that 
of young women [99]. 
3. Coordination implies that the nervous and musculoskeletal system work 
together to produce smooth, efficient movement.  It implies that the muscles 
work at the right time with the right intensity [100] to produce movement.  
Coordination is needed to get button or zip clothing, run, skip, and drive a car.
4. Power is the rate at which work is done and includes both muscle strength and 
speed of movement.  It requires a muscle to develop tension and produce the 
force to move a body part through range of motion.  Power increases during 
childhood and peaks during adolescence and young adulthood [101]. 
5. Cardiopulmonary fitness is the ability of the cardiac and pulmonary systems to 
provide muscles with an adequate supply of oxygen for work.  Capacity 
increases across childhood with age and peaks during young adulthood.  
Exercise capacity is typically quantified as maximal oxygen uptake (Vo2max) 
and is a product of maximal cardiac output (liters of blood per minute) and 
arterial-venous oxygen difference (milliliters of oxygen per liters of blood).  
Fitness levels across populations vary primarily from differences in maximal 
cardiac output.  Therefore, this measure closely corresponds to the functional 
capacity of the heart [102-107]. 
Physical performance in children treated for recurrent ependymoma
While early research has documented the impact of changing treatment on 
survival [17, 108] and some late cognitive late effects [30], little work has been 
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done to either specifically and objectively evaluate and describe physical 
performance, or to look at the impact of improved surgical and radiotherapy 
management techniques on physical disability in this population. A longitudinal 
assessment of physical performance and of movement related impairments among 
children undergoing retreatment for ependymoma, either with focal retreatment or 
craniospinal irradiation after additional surgery is important as it will provide 
insight into the specific nature and timing of physical disability in this population.  
It will help assess the effectiveness of this therapy, balancing disease control 
against functional outcomes, including movement related morbidity in long term 
survivors, and provide information for targeted rehabilitation interventions 
designed to restore physical function, teach compensatory strategies that 
overcome functional loss, or adapt the environment so survivors with persistent 
disability can participate optimally in life roles.
Childhood cancer survivors treated for brain tumors with radiation report 
increased rates of physical disability when compared to their siblings [109, 110], 
and demonstrate limitations in mobility, strength, flexibility, and cardiopulmonary 
fitness when evaluated with objective physical performance measures [111].  
Long term physical disability is problematic.  It interferes with play and family 
interaction in the young child, with school attendance and social participation in 
the school aged child, with normal adolescent activities and school participation 
in older children, and with normal social and work roles in young adults.  
Childhood cancer survivors with physical disability report reduced quality of life 
and are less likely to attend college, gain employment or get married than are their 
siblings [112, 113].  Unfortunately, in some cases of recurrent brain tumor, 
including ependymoma, the cost of curative therapy has been permanent physical 
disability, as radiation induced necrosis destroys a portion of the nervous system 
necessary to achieve normal movement [17, 114, 115]. 
Evaluation of the potential positive impact of new modalities and mechanisms to 
treat recurrent tumor on physical performance outcomes is important.  Positive 
clinical outcomes provide evidence to support the use of emerging and state of the 
art technology, and identification of both positive and negative predictors of long-
term outcome provide foundational information for future development of 
rehabilitation type intervention trials in those children and adolescents who might 
most benefit from an early plan to maintain their ability, mobility and long-term 
physical abilities. Mechanisms to optimize physical performance after surviving 
recurrent ependymoma, developed in response to the information gained when 
evaluating this clinical outcome, can be designed to allow these young survivors 
to become productive members of their communities and society.
From a global perspective, little information is available about physical 
performance outcomes among children treated for brain tumors, and almost no 
information specifically characterizes these outcomes among children who are 
treated with re-irradiation for recurrent ependymoma.  In studies designed to 
measure short or long-term clinical outcome, these patients are usually a small 
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subset among a larger group of children with brain tumors, and are often 
evaluated only in a cross sectional, or one time point assessment.  Very rarely, 
objective, person level function is measured.  Most data comes from self- or 
proxy report questionnaires or from general clinician generated global scales of 
function.  Nevertheless, there is some information in the literature describing 
overall brain tumor survivor outcomes that indicates that physical disability 
prevalence rates are potentially elevated in this population.  Gains from the 
investigation proposed here will add to this literature.  Knowledge of expected 
long-term clinical outcome may inform parents and clinicians during the 
treatment process, so they know what to expect and when and if to seek 
restorative rehabilitation services.  This work will identify specific person and 
treatment related characteristics that predict poor outcomes, and potential physical 
impairments in this population that may be amenable to a rehabilitation type 
intervention.  
Two reports from the Childhood Cancer Survivor Study enumerate self or proxy 
reported physical performance and functional outcomes in adult survivors of 
childhood brain tumors, and provide some indication of the impact of large 
radiation doses on long-term physical disability.  The first report, published in 
2005, indicated that physical performance limitations are prevalent among 26.6% 
of childhood brain tumor survivors, a rate 2.5 times higher than among siblings.  
In this cohort, treatment with radiation was associated with a 70% increased 
chance of reporting poor physical performance when compared to treatment with 
surgery alone [110].  In a subsequent manuscript from the same cohort, 
Armstrong et al. [109] completed a cross sectional analysis of long-term outcomes 
among adult survivors of central nervous system malignancies.  This manuscript 
included 148 survivors of ependymoma.  Both chronic medical conditions (82%) 
and functional loss were prevalent in this large cohort.  Brain tumor survivors 
were 19.5 times more likely than siblings to report functional impairment, and 
36.2 times more likely than siblings to report activity limitations.  Weakness, 
sensory loss, pain, problems with balance and paralysis were common, and 
continued to develop, even at time points beyond 5 years off treatment.  Higher 
doses of cranial radiation, particularly doses >50Gy, were associated with lower 
educational attainment, unemployment, never being married, and incomes of less 
than $20,000 per year.  The brain tumor survivors characterized in these two 
manuscripts were treated between 1970 and 1986, prior to the advent of more 
contemporary imaging and radiotherapy techniques.  
However, these data are supported by an investigation of measured physical 
performance outcomes in a more contemporary cohort of brain tumor survivors 
treated at the University of Minnesota or at St. Jude Children’s Research Hospital 
[111].  Participants (n=78) and age, gender, and zip code matched controls (n=78) 
were compared on measures of muscle strength, mobility and cardiopulmonary 
fitness.  Among brain tumor survivors who were, on average, 22 years of age, 
estimates of grip strength, knee extension strength and peak oxygen uptake were 
similar to expected values of individuals in their seventh decade of life.  Radiation 
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to the posterior fossa or occipital/parietal lobes was associated with poor 
outcomes. Poor physical performance was associated with not living 
independently and with not attending college.
Only a few authors have specifically included survivors of ependymoma in 
investigations, and have usually document physical ability simply as one 
component of global clinical outcome [116]. At least one investigation has been 
longitudinal, but did not include children with recurrent disease [18].  Benesch et 
al [116] included 6 children with ependymoma when they developed the LESS 
scoring system for clinicians to use when quantifying late effects in children after 
radiation and chemotherapy for brain tumor.  Neurological, endocrine, 
visual/auditory and an “other” category are included on this severity rating scale.  
Children with higher scores on this rating scale had lower quality of life scores 
than did those with lower scores, indicating an association between neurological 
outcome and overall quality of life.  Morris et al [18] evaluated neurological 
morbidity in 96 children with ependymoma within 3 months of conformal cranial 
irradiation and every 6-12 months thereafter until 120 months post radiation.  
Assessments were performed by a neurologist and included a four point grading 
of multiple neurologic outcomes including muscle strength and strength, motor 
control, coordination and gait.  Neurologic impairments were most prevalent at 
baseline and decreased over time.  However, at 60 months post treatment, 
participants still had an average of 2.2 neurological deficits.  There were 17 
patients with at least one severely compromised function 60 months post therapy.  
We could identify only one study among children with recurrent ependymoma 
who treated with re-irradiation that very briefly described performance type 
outcomes.  Liu et al, [108] in a study designed to evaluate the curative impact of 
hypofractionated re-irradiation in 6 children with local recurrence of 
ependymoma, reported that 3 children had imaging changes consistent with 
necrosis 7-8 months after treatment.  Among these 3 children, 1 had no physical 
symptoms, 1 had ataxia that resolved, and 1 had headache related pain treated 
with over the counter medication.  
The literature describing function among survivors of childhood ependymoma is 
limited not only because of few papers and lack of longitudinal data, but also 
because functional outcomes are generally good after frontline therapy.  The 
determination of disability has generally depended on clinician report rather than 
on measured values or on patient reported outcome.  These issues make it difficult 
to determine either the real prevalence of physical disability, or the specific 
impairments that survivors have that contribute to their physical disability.  
Demographic and clinical characteristics have been reported to be associated with 
poor overall global function.  However, because investigations have not 
specifically measured physical performance, risk factors for these specific 
outcomes are unknown.  Information about the extent and nature of physical 
performance limitations, and about the risk factors for poor outcomes, is 
important for determining the need for resources and the type of resources that 
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might be needed to optimize functional outcomes.  Knowledge about the timing 
of and the specific risk factors for poor outcomes may help identify those patients 
in particular need of interventions designed to prevent long term functional loss. 
2.6
Neuroimaging
Patterns of recurrence of ependymoma have been little studied in the literature, 
but may provide valuable information regarding efficacy of initial 
radiotherapeutic target volumes.  It would be expected that, given the history of 
prior focal RT, the pattern of recurrent disease would differ from that typically 
seen at initial presentation.  Initial, pre-treatment conventional imaging and post-
recurrence conventional MR imaging will be analyzed for spatial distribution of 
disease, compared to each other and compared to initial radiation dosimetry maps 
to evaluate how the disease pattern is altered in the post-irradiation brain.
Evidence of tissue damage, including atrophy and encephalomalacia, has been 
observed in untreated brain in initially successfully treated patients who, though 
initially without clinical evidence of function loss, subsequently experienced 
complications.  By assessing alterations in structural, microstructural and 
physiologic properties of both treated and untreated brain tissue over time and 
comparing to dose distribution and measures of cognition and function over time, 
imaging-based biomarkers predictive of treatment-related functional or cognitive 
compromise may be established.  Evaluation of response of primary site and 
metastatic disease to radiation therapy will be assessed using quantitative MR 
imaging and PET.
2.6.1
Magnetization-Transfer Imaging
As early damage to brain tissue can appear deceptively normal on conventional 
anatomic MR images [117], reliance on visual inspection may be insufficient to 
appreciate the true extent of microstructural damage.  Diffusion tensor imaging 
has proved effective in delineating white matter tracts, and has demonstrated 
changes in fractional anisotropy (FA) and other diffusion parameters in normal-
appearing white matter following radiation therapy above a certain threshold dose 
[118]. These changes in water diffusivity have been shown to correlate with 
damage to structural components of the white matter tracts [119].
Magnetization-transfer (MT) MR techniques offer an alternative approach toward 
evaluation of brain tissue integrity, via evaluation of macromolecular content. In 
this technique, the protons of MR-invisible macromolecules are saturated by 
manipulation of the radiofrequency (RF) pulse [120].   These protons then 
exchange their saturation by various mechanisms with the water peak. This results 
in a decrease in the detectable water signal, serving as an indirect marker of the 
size of the macromolecular “pool”.  Because in white matter this pool is presumed 
to be largely due to myelin, changes in the magnetization-transfer ratio (MTR, 1-
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Ssat/So) are felt to be representative in changes in myelination.  Indeed, changes 
in magnetization-transfer ratio have been shown to correlate to white matter 
damage and recovery in multiple sclerosis and other white matter disorders [121, 
122].  Changes in MTR in normal-appearing white matter (NAWM) have been 
found to precede the development of lesions in multiple sclerosis (MS); changes 
in MTR in normal-appearing gray matter [123] may have an even stronger 
correlation with clinical course [124, 125]. There is a strong possibility that, as in 
MS, invisible gray matter alterations may be a more sensitive predictor of clinical 
course following radiation injury.  Though MT imaging has the potential to detect 
these changes in both gray matter and white matter prior to manifestation on 
standard MR sequences, there is a dearth of studies of MT in this setting, likely 
due to the historically long image acquisition time (~12 minutes for MT sensitized 
and non-MT sensitized sequences) limiting routine utilization [117]. However, 
this limitation has been overcome by the recent development of bSSFP –based 
MT techniques requiring on the order of 3.5 minutes total acquisition time, quite 
feasible for inclusion in a routine imaging protocol [120, 126].
Magnetization-transfer imaging with bSSFP technique in this protocol will serve 
three purposes: 1) comparison to DTI regarding sensitivity for radiation-induced 
white matter changes, 2) assessment of early cortical gray matter damage, not 
possible with DTI, and 3) comparison of gray matter and white matter damage. In 
addition, information derived from MT imaging will be complementary to DTI, as 
the former relies primarily on neuronal density and the latter on directionality 
[127]. FMRIB Software Library (FSL) [128] will be utilized for segmentation of 
gray matter from white matter for analysis of MT data, which will then be 
correlated with radiation field maps, perfusion and DTI data.  Comparison will 
also be made to grading of gray and white matter damage on conventional 
imaging.
2.6.2
Diffusion-Tensor Imaging (DTI)
DTI is the most important magnetic resonance imaging technique to investigate 
brain white matter development and injury in vivo. Numerous lines of evidence 
support the use of DTI in studying treatment effects on brain structures composed 
predominantly of white matter tracts [129-132]. Animal histological studies 
demonstrated strong correlation between changes in DTI metrics and radiation-
induced demyelination, axonal degeneration, and necrosis in the brain [119]. DTI 
metrics were also found to be significantly related to neurological deficits in 
patients [133-136]. Brainstem and cerebellar white matter pathways will be 
studied with DTI in this protocol due to their proximity to posterior fossa tumors 
and susceptibility to radiation injury. When craniospinal irradiation is delivered 
for patients with distant metastasis, supratentorial white matter tracts are likely to 
be affected and will be studied as well.
For ependymoma recurrent in the posterior fossa, white matter tracts in the 
brainstem and cerebellum are particularly vulnerable to therapy-induced injury. 
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Radiation dose delivered to these critical organs from previous radiation 
treatments often reach their tolerance estimated to be in the range of 54-60Gy 
[137]. Severe motor and sensory deficits could occur if irradiated fiber tracts have 
not been repaired sufficiently from prior irradiation at the time of second 
irradiation. We will perform baseline DTI studies prior to re-irradiation to 
evaluate the recovery status of brainstem and cerebellum white matter tracts. The 
results will be compared to age-related benchmark values previously obtained 
from healthy volunteer children. Serial DTI studies will also be performed at each 
follow-up visit to monitor the evolution of therapy-induced injury and recovery in 
white matter structural integrity.
For recurrent brain tumors, DTI can be helpful in assessing the tumor infiltration 
into the peritumoral white matter regions [138, 139]. DTI has also been used to 
differentiate recurrent brain tumors from radiation injury [140]. These potentials 
will be explored in this unique pediatric population. For normal tissue protection, 
changes in normal white matters adjacent to tumor or tumor bed due to surgical 
resection and reirradiation in children were rarely documented. Long term effects 
of re-irradiation on cerebral white matter development in children were not 
clearly understood. Serial DTI studies performed in this trial will be analyzed to 
answer above questions for reducing the knowledge gap. Collected DTI data will 
help estimate the radiation tolerance of cerebral white matters and the brain in 
children.   
DTI will be acquired with a double spin echo EPI pulse sequence which applies 
diffusion-encoding gradients along 12 non-linear, non-coplanar directions in 
space. To facilitate comparisons with magnetization transfer imaging and 
previously acquired benchmark data in healthy children, examinations will be 
preferentially performed at 3T but may be performed at 1.5T if imaging at 3T is 
contraindicated. Each DTI study will contain 4 repetitions of the same diffusion 
pulse sequence to improve signal to noise ratio. These 4 imaging datasets will be 
spatially registered to a raw image dataset without diffusion gradient encoding 
(b=0) to correct for patient motion and linear system drift during acquisition 
before performing diffusion tensor calculation. Voxel-based DTI metrics which 
can be calculated for quantitative analysis include apparent diffusion coefficient 
(ADC), fractional anisotropy (FA), relative anisotropy (RA), parallel and 
perpendicular eigenvalues (λ// and λ). ADC and FA values represent the 
magnitude and directionality of water diffusion in each tissue voxel, respectively. 
ADC has the unit of mm2/s. FA is dimensionless and ranges from 0 (isotropic 
diffusion) to 1 (highly directional). To determine if DTI reflects and predicts 
treatment toxicity, changes in these imaging metrics from serial DTI 
measurements will be correlated with results of longitudinal neurological 
outcomes and radiation dosimetry.
2.6.3   Dynamic Susceptibility Contrast-enhanced (DSC) Imaging
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DSC MRI is a magnetic resonance imaging technique which quantifies blood 
perfusion in cerebral tumors and brain tissues by measuring the changes in 
relaxation time T2* due to the signal dephasing associated with the susceptibility-
induced gradients surrounding the paramagnetic contrast agent. It involves a rapid 
injection of a bolus of paramagnetic contrast agent into a vein following 1-2 min 
baseline data collection and the continuous tracking of the transient signal loss 
during the passage of the contrast agent through the tissue of interest. The 
dynamic data acquisition typically utilizes a heavily T2*-weighted sequence with 
a temporal resolution of 2 s or less. The more commonly used sequences are 
echo-planar imaging (EPI) and fast low-angle single-shot (FLASH) [141]. The 
latter sequence has less image distortions in regions of high magnetic 
susceptibility gradients such as tissue-air interfaces. Voxel-based DSC MRI 
metrics include relative cerebral blood flow (rCBF), relative cerebral blood 
volume (rCBV), and mean transit time (MTT). These derived DSC MRI metrics 
are often used for disease state characterization and therapeutic efficacy 
assessment [142-146].
In this protocol, we will focus on investigating radiation effects on perfusion of 
brainstem by examining relative differences in blood flow and blood volume 
between patients and longitudinal changes within the same subjects. These 
perfusion changes will be compared to diffusion changes in white matter tracts 
and to tests of neurological function to determine if therapy-induced perfusion 
and diffusion changes in brainstem can be detected before the manifestation of 
neurological signs and symptoms. DSC perfusion imaging is also clinically useful 
in differentiating between recurrent tumor and radiation necrosis. In such cases, 
and depending on the ability to perform a whole-brain examination, DSC 
perfusion imaging will require repositioning to center on the region of clinical 
interest. 
2.6.4
Susceptibility-weighted Imaging (SWI)
This technique was originally developed to noninvasively assess the vascular 
architecture of brain parenchyma. The unique potential of SWI lies in its ability to 
exquisitely highlight vascular structures based on differences between magnetic 
susceptibility in blood (BOLD effect) and surrounding tissues. SWI also has the 
potential to detect, and perhaps even quantify extremely small amounts of 
magnetically susceptible substances within brain parenchyma and thereby detect 
the presence of microscopic hemorrhages. Potential uses of SWI include tissue 
characterization through visualization of architecture within brain lesions and 
monitoring such susceptibility changes as an indicator of treatment response or 
disease progression. SWI also allows detection of small amounts of blood 
degradation products that would otherwise not be detectable at imaging.  This 
aspect of the technique may permit early detection of radiation induced vascular 
changes within the brain, such as venous anomalies and associated cavernous 
malformations, and possibly allow prevention of hemorrhagic complications from 
these lesions.
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2.7     Rationale for 18F-Fluorodeoxyglucose and 11C-Methionine PET to Detect 
Ependymoma and Monitor Response to Radiation Therapy
Because ependymoma is amenable to imaging using to positron emission 
tomography (PET) with 18F-fluorodeoxyglucose (FDG) or 11C-methionine (MET, 
both of which are under study for the evaluation of brain tumors for the purposes 
of detection, staging and monitoring response to treatment, PET has tremendous 
potential and value in evaluating residual or recurrent disease and radiation 
necrosis. We have demonstrated that ependymoma is avid to FDG. We will 
explore the utility of FDG and other compounds to image residual tumor and 
investigate whether the level of avidity before treatment correlates with tumor 
progression after a second course of irradiation or may be used to differentiate 
between tumor progression and radiation necrosis. Knowledge of the limitations 
of this modality will enhance or curb its use. Although it may be difficult to 
define boundaries using PET because of its resolution, it may be useful to define 
some aspects of the tumor volume for targeting because local failure is the 
principal mode of failure.
Ependymoma is a tumor found within the CNS and should be amenable to 
positron emission tomography with 18F-fluorodeoxyglucose or 11C-methionine 
(IND # 104987), both of which are under study for the evaluation of brain tumors 
for the purposes of detection, staging and monitoring response to treatment. We 
have demonstrated that ependymoma is avid to FDG and will explore the utility 
of FDG and other compounds to imaging visible residual tumor, differentiate 
between tumor and necrosis, and investigate whether the level of avidity 12, 24 
and 36 months after irradiation correlates with tumor progression. Knowledge of 
the limitations of this modality will enhance or curb its use. Although it may be 
difficult to define boundaries using PET because of its resolution, it may be useful 
to define some aspects of the tumor volume using PET because local failure is the 
principal mode of failure.
2.8 
Growth Factor and Cytokine Responses to Radiation Therapy
Our previous work in patients with the brain tumors (ependymoma and low-grade 
glioma) and pediatric soft-tissue sarcoma (Ewing sarcoma, rhabdomyosarcoma 
and non-rhabdomyosarcoma soft-tissue sarcoma) has shown that cytokine and 
growth factors levels measured in serum before, during and after radiation therapy 
correlate with clinical factors, tumor types and disease control [147-149]. Levels 
of pro-inflammatory cytokines have been used to predict side effects in normal 
tissues after radiation therapy, monitor tumor and normal tissue responses to 
treatment, and demonstrate the differences between tumor and normal tissue 
responses where the latter serves as an indicator of the systemic effects of 
irradiation. Serum cytokines also appear to correlate with disease groups, patterns 
of treatment and the volume of residual disease in patients with soft-tissue tumors. 
Growth factor and cytokine responses to irradiation will be measured and 
modeled to investigate associations between their levels and disease control and 
side effects that exist for patients with craniopharyngioma. On treatment 
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monitoring will allow us to explore associations between growth factors and 
cytokines and cyst formation.  Monitoring after treatment will help us to study the 
systemic nature of the radiation response and the correlation with neurological, 
endocrine and cognitive/quality of life parameters.
Cytokines are hormonal messengers responsible for modulating biological effects 
in normal tissues and the immune system. They can be divided into two groups: 
those that are proinflammatory (Th1 cytokines) and those that are anti-
inflammatory (Th2 cytokines). Th1 cytokines perpetuate autoimmune responses, 
promote tissue damage and may be responsible for fatigue and promoting chronic 
diseases [150-153]. Th2 cytokines have anti-inflammatory effects and may 
balance Th1 responses. Diseases resulting from excess inflammation may be 
prevented through a variety of means; therefore, understanding changes in 
cytokines after irradiation may provide opportunities for secondary prevention. 
We will investigate the possible correlation between the change in cytokine levels 
and factors such as radiation dose and irradiated volume, time since irradiation, 
tumor volume, tumor response, surgical and host factors, etc.  We will also 
evaluate the association between cytokine responses and measures of sleep, 
fatigue and function. The actual volume of blood for the cytokine studies is 6 ml 
per time point. There are eight time points: baseline, weeks 3 and 6 of radiation 
therapy and 5 additional time points during follow-up.
2.9  
Rationale for Genomic Analysis of Untreated and Recurrent Ependymoma 
and Evaluation of Host Factor Susceptibility to Treatment-Related Side 
Effects
By identifying genetic predictors of neurotoxicity in ependymoma patients before 
irradiation it will be possible to recognize those individuals who are most 
vulnerable and alter their medical management and follow-up. By focusing our 
research inquiry on a homogenous sample of patients, that is, patients with 
ependymoma who have the similar tumor pathology and treatment, we can 
examine the multiple factors that contribute to outcome that may have 
implications for other, less common, brain tumors in children as well as other 
pediatric malignancies. There is significant inter-individual variation in neuro-
toxicity in brain tumor patients [154-156].
This variation is likely related to the many variables that influence outcome. 
Factors that may influence outcome can be divided into tumor (presenting 
symptoms, tumor size, tumor location, pathological/molecular type), treatment 
(extent of resection, repeat surgery, radiation dose and dosimetry, chemotherapy, 
time since treatment), host (age at diagnosis and treatment, gender, genetic 
determinants), and environment (socio-economic status) related predictors. For 
example, larger tumor size, greater medical complications following initial 
surgery, higher radiation dose and larger treated volume, younger age at 
diagnosis, and longer time since treatment all predict for neuro-cognitive deficits 
and white matter damage [25, 157, 158]. Other factors that may influence 
outcome are not known prior to treatment and/or may be confounded with 
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treatment. To take the next step in predicting outcome and use this knowledge for 
individualizing and optimizing therapy in order to reduce late effects it is 
important to identify those variables that we can assess prior to – or at least very 
early in - the medical management of children with recurrent ependymoma. For 
example, patient age is already considered in decisions regarding the use of 
cranial radiation because of the particular vulnerability of the very young brain 
[159]. In order to further modify treatment in the most vulnerable patients and 
ensure early intervention, biomarkers of outcome that can be obtained early 
following diagnosis are necessary. Variability in outcome is likely due in part to 
genetic variation in individuals that renders them especially susceptible or 
resilient to injury. Delineating genetic markers that identify individuals at risk or 
resilient to treatment induced toxicity provides the foundation for maximizing 
individualized treatment de-escalation and targeting neuro-protection. We will 
therefore, perform selective candidate gene analysis to define patients at risk 
neurocognitive and other clinical aspects of radiation induced neurotoxicity. We 
will perform this using germline gene SNPs and analysis of peritumoral normal 
brain tissue for specific damage. From the candidate genetic markers we will 
evaluate will be prioritized within two categories. As a first priority we will 
examine markers known to predict the physiological response to treatment for 
cancer and vulnerability to toxicity Genes [160] have been identified where 
polymorphisms are related to toxicity following treatment with radiation for brain 
tumors, including intellectual impairment [161]. Polymorphisms in the ATM, 
TGFB1, CYP2D6, LIG4, XRCC1, XRCC3, hHR21 genes have been shown to be 
associated with an increased risk of developing an adverse reaction to 
radiotherapy in normal tissue [162-165]. In general, cytokines or genes involved 
in DNA repair and apoptosis may be involved in toxicity response to radiation. As 
a secondary priority we will also examine genetic markers associated with brain 
integrity and vulnerability to neuronal insult which may predispose an individual 
to greater toxicity following treatment. High resolution genomic assays have been 
used to reveal novel genes and other complex genetic abnormalities (i.e., ASAH1, 
PTCHD1, CDH8, MBD5, SHANK2, MACROD2) associated with intellectual 
disability, neuro-developmental disorders and cognitive deficits [166-170]. Such 
predictors of overall cognitive function may help determine which patients will do 
better or worse following treatment. Likewise, genetic anomalies associated with 
white matter disease, neuro-degenerative disorders, and response to brain injury 
[162-165] may be useful in predicting patients vulnerable to late effects of 
treatment for recurrent ependymoma. We will also assess normal tissue for 
evidence of DNA damage, vascular insufficiency and damage [171, 172] and for 
expression of any of the “protective candidate genes”.
2.9.1  Biological Correlates of Vasculopathy, Hearing Loss, Cognition Effects, 
Growth Hormone Deficiency and Disease Control.
Normal blood samples will be acquired by protocol collaborators prior to 
initiation of treatment. Germline will be isolated and analyzed by SNP 
microarrays and re-sequencing analysis in conjunction with tumor specimens in 
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order to pinpoint the genetic events occurring during tumor initiation and 
development. Since the analyses of these samples won’t take place for at least 5-6 
years from the initiation of enrollment, it is likely that substantial changes will 
take place in available technology to process the samples as well as in methods to 
analyze the data. Further additional insights in the biology of these tumors may 
become available which may influence the analyses to be performed. Therefore it 
is not possible to state precisely the types of analyses which will be pursued.
The goal of radiogenomics is to identify genetic variations that predict for side 
effects from radiation therapy with the long-term aim of screening susceptible 
patients prior to irradiation and to study the biology of late effects. Assays to 
predict radiosensitivity developed in the past have not been useful nor have they 
been easy to implement in the general population including in children. The 
ability to assess genetic variation through the evaluation of single nucleotide 
polymorphisms has been considered a breakthrough and reasonable entry point 
from which to collect information to study inherent radiosensitivity. This has been 
successful in the study of radiation-related effects in adult patients with breast and 
prostate cancer, and it is considered one of the key steps in delivering limited-
toxicity personalized medicine to children with cancer. Our track record of 
treatment and follow-up, annotation of patient specimens, consistency of care and 
the number of patients included in this study will increase the likelihood that such 
an association may be detected, if it exists. Genomic studies will be performed to 
evaluate constitutional DNA from whole blood samples. The goal will be to 
evaluate the latent systemic effect of radiation therapy. Our objective is to 
investigate which genetic polymorphisms may be associated with radiation-
related side effects in children. Some specific approaches to addressing this 
objective are outlined below. This list is not exhaustive, however, and at the time 
of analysis, additional insights may be available which could change the direction 
of and approach to these analyses. Clinical genomics testing may be ordered for 
all patients including germ line testing. The data may be used to explore the 
associated outcomes outlined in this protocol document. In the setting where there 
is insufficient tumor available for clinical genomics, the patient may be scheduled 
for genetics counseling with the appropriate clinic at which time germ line testing 
alone may be ordered. The data obtained from this route of germ line testing may 
be used to explore the associated outcomes outlined in this protocol document. 
2.9.2  Genetic Abnormalities Associated with Vasculopathy
Pediatric stroke has a variety of presentations, including headache, seizure and 
acute neurological deficits including hemiparesis.  There are several gene-specific 
disorders with a significantly high predisposition for stroke including sickle cell 
disease (SCD), homocystinuria, progeria, and neurofibromatosis.
It is known that the predisposition for stroke is related to the HgS genotype in 
SCD [173], however, other candidate genes that may play a role in stroke 
susceptibility have been identified in this population [174].  Children with SCD 
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were phenotyped into large-vessel (LV) and small-vessel (SV) stroke subgroups 
by magnetic resonance imaging and angiography and genotyped for 
polymorphisms associated with blood pressure regulation, cellular adhesion, 
inflammation, and lipid metabolism.  Polymorphisms in IL4R, TNF, and ADRB 
genes were associated with stroke risk in the LV subgroup, while VCAM-1 and 
LDLR gene polymorphisms were associated with SV stroke risk, suggesting a 
basis for which population screening and targeted intervention may aid in the 
prevention of stroke in SCD patients.
A number of candidate genes that may contribute to pediatric stroke in the general 
pediatric population have also been identified [175].  Polymorphisms in genes 
underlying thrombophilia (Factor II, Factor V, MTHFR, and PAI-1) appear to be 
risk factors for venous sinus thrombosis and arterial ischemic stroke [176].  More 
recently, a polymorphism within the promoter region of the GPx-3 gene that 
compromises plasma antioxidant and antithrombotic activities was identified as a 
risk factor for arterial ischemic stroke in children and young adults [177].
The majority of gene identification for intracranial aneurysm (IA) risk has been 
performed in adults.  One candidate gene that may contribute to IA is the elastin 
(ELN) gene, a major component in the blood vessel wall.  Researchers showed 
that the presence of the Mm INT20/INT23 haplotype occurred more frequently in 
patients with IA compared to controls [178].  The collagen α2(I) gene [179], 
important for vascular wall elasticity, may also serve as a candidate gene for IA 
risk as the Ala459Pro SNP was observed with higher frequency in familial IA 
patients [179].  The TNFRSF13B gene encodes a TNF receptor that plays a role 
in inflammation.  Single nucleotide polymorphisms identified within the 
TNFRSF13B gene were associated with IA, suggesting that TNFRSF13B may 
also serve as a candidate gene for IA susceptibility [180].
One study attempted to identify genes that were associated with aneurysms 
(though not intracranial) in children.  In children with Kawasaki disease, coronary 
artery aneurysms will develop if untreated.  Researchers identified an SNP within 
the inositol 1,4,5-triphosphate 3-kinase C [181] gene associated with Kawasaki 
disease susceptibility and formation of coronary artery aneurisms in both Japanese 
and US children [181].
Moya-moya syndrome is defined as bilateral severe stenosis or occlusion of the 
internal carotid arteries with collateral formation [182]. The same Moya-moya-
type appearance is seen in a number of vastly different clinical settings including 
sickle cell disease, neurofibromatosis, Down syndrome, Morning Glory 
abnormality, and post-irradiation. The common underlying pathophysiology has 
yet to be clearly elucidated. To determine the pathogenesis of Moya-moya, 
children and adults were angiographically confirmed for Moya-moya then human 
leukocyte antigen (HLA)-serotyped [183].  Their results showed that Moya-moya 
was associated with HLA-AW24, -BW46, and -BW54 serotypes.
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2.9.3  Genetic Abnormalities Associated with Hearing Loss
Nonsyndromic hereditary impaired hearing (NSHIH) accounts for 60-70% of 
congenital impaired hearing [184].  A disorder restricted to the ear and vestibular 
system (as opposed to syndromic HIH which may occur as part of a multisystem 
disease), NSHIH is caused almost exclusively by cochlear defects, resulting in 
sensorineural hearing loss.  There are a number of gene mutations that contribute 
to NSHIH (Table 1) [184].  Mutations of the GJB2 gene are the major cause of 
NS autosomal recessive and sporadic deafness [185] and are ethnic-specific.  The 
most frequent mutation observed in patients with European ancestry is 35delG 
[186], while 235delC occurs most frequently in the Japanese population [187]. 
Aminoglycoside antibiotics, such as gentamycin, streptomycin, and tobramycin, 
are widely used to treat gram-negative bacterial infections.  Aminoglycosides are 
well-known for their dose-limiting effects on hearing loss [188].  Studies have 
shown that some people have a genetic predisposition that renders them extremely 
sensitive to the ototoxic effects of aminoglycosides [189].  Mutations in the 
mitochondrial 12S ribosomal RNA gene account for most cases of 
aminoglycoside-induced ototoxicity with A1555G occurring most frequently 
[190].  Due to the high frequency of this mutation, as well as GJB2, researchers 
have developed a molecular screening test for these genes to aid in the early 
identification of hereditary hearing loss and genetic susceptibility to 
aminoglycoside-induced ototoxicity for the Chinese population [191].
There have been a few attempts to identify associations between hearing gene 
mutations and cancer treatment-induced ototoxicity in patients.  Cisplatin is often 
used to treat pediatric solid tumors, but one of the dose-limiting side effects is 
sensorineural hearing loss [192].  To test whether mutations in genes responsible 
for cisplatin detoxification contribute to cisplatin-induced ototoxicity, cisplatin-
treated testicular cancer survivors were retrospectively assessed for functional 
polymorphisms in genes coding for glutathione S-transferase enzymes [193].  
Their results indicate that SNPs within the GSTP1 gene contributed to cisplatin-
induced ototoxicity and suggest that the GSTP1 gene may impact an individual’s 
susceptibility to cisplatin-induced ototoxicity.  Another study sought to test 
whether there was an association between cisplatin-induced ototoxicity and 
megalin mutations [194].  Megalin is an endocytotic receptor that has been 
associated with the uptake of aminoglycosides which are similar to cisplatin in 
their ototoxic effects.  Patients who did and did not develop hearing loss after 
cisplatin treatment were analyzed for megalin SNPs.  Their results demonstrate 
that SNPs within the megalin gene occurred at a higher frequency in those 
patients who developed hearing loss after cisplatin treatment and suggest that the 
megalin gene may impact an individual’s susceptibility to cisplatin-induced 
ototoxicity.
In contrast, one study showed no association between hearing genes and 
susceptibility to cisplatin-induced ototoxicity [195].  Using buccal washes from 
11 children who developed hearing loss after cisplatin treatment, the authors 
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performed retrospective mutation screening of GJB2, SLC26A4, MTRNR1, 
MTTL1, and MTTS1 but found no association.  However, there are weaknesses in 
this study: 1) small cohort and 2) method of patient selection which was based on 
self-reported hearing loss with no audiometric measurement.  The authors state 
that the lack of an association may also be confounded by the large number of 
survivors in whom deafness may have been more a function of the tumor or 
radiation therapy than of cisplatin treatment.
In our own experience, we understand that hearing loss is uncommon and 
predictable in patients with craniopharyngioma when baseline hearing is normal. 
Among 75 children with craniopharyngioma followed longitudinally with 
audiograms that we reviewed for hearing loss in preparation for this protocol, we 
identified 2 with pre-existing hearing loss (intermediate and high-frequencies) 
that could not be attributed to known clinical or host factors. 
2.9.4  Genetic Abnormalities Associated with Cognitive Deficiencies
The polygenic nature of cognitive ability has made it difficult to identify specific 
genes underlying normal cognition; however, nonsyndromic mental retardation 
(NSMR) may serve as the best example from which to assess genes involved in 
cognitive deficiencies since similar conditions are associated with purely 
cognitive phenotypes and are not secondary to other abnormalities that constitute 
a particular syndrome.
A number of genes have been identified that appear to play a role in NSMR 
(Table 3) [196].  Three genes are involved in Rho GTPase signaling: GDI1, 
oligophrenin, and PAK3.  GDI1 encodes a guanine nucleotide dissociation 
inhibitor which prevents the deactivation of a small GTP-binding protein that 
plays a role in synaptic vessel recruitment for exocytosis.  Oligophrenin is a 
rhoGAP protein that stimulates the intrinsic GTPase activity of certain small G 
proteins.  PAK3 encodes p21-activated kinase which links Rac to Cdc42 and to 
transcriptional activation.  Altogether, mutations in any of these genes may 
disrupt the normal development of axonal connections or compromise synapse 
function [197].  Other genes shown to be involved in NSMR include FMR2, 
IL1RAPL, TM4SF2, VCX-A, and ARHGEF6, all of which can lead to neuronal 
dysfunction if mutated [197].  More recently, polymorphisms of GPC3, GPC4, 
and HTR2A genes were identified in families with NSMR [198].
Another gene that may contribute to normal cognition is the SNAP-25 gene.  
SNAP-25 encodes a presynaptic terminal protein important for regulation of 
neurotransmitter release from neurons with high expression in the hippocampus, a 
brain structure central to learning and memory processes.  One study genotyped 
children and adults with variable IQ phenotypes for SNAP-25 SNPs and found 4 
SNPs in intron 1 of the SNAP-25 gene that were significantly associated with IQ 
which suggests that functional polymorphisms within noncoding regulatory 
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sequences may also be associated with expression of genes underlying cognitive 
function [199].
There is a disorder associated with severity-dependent changes in cognitive ability 
known as obstructive sleep apnea (OSA).  Since the severity of OSA accounts for 
only 40% of the variance in cognitive performance, researchers have sought to 
determine if there was a genetic determinant of individual susceptibility that may 
contribute to cognitive dysfunction [200].  The APOE gene encodes 
apolipoprotein E, a lipoprotein that may have neuroprotective and anti-
inflammatory effects in the brain [201].  Adult patients with OSA displayed more 
severe cognitive dysfunction when the APOE ε4 allele was present than those 
patients with other APOE alleles.  To test whether the presence of the APOE ε4 
allele accounted for increased cognitive dysfunction in children, children with 
OSA were genotyped for the ε4 allele [200].  Their data showed that the 
frequency of the ε4 allele was higher in children with OSA, particularly in those 
children with cognitive deficiencies.  These data suggest that not only is the 
presence of the APOE ε4 allele associated with increased risk for OSA, but also 
with increased risk for cognitive dysfunction.
The neurocognitive effects of cancer treatment can markedly impact QOL in 
children with cancer, but it is not known why some children fare worse than 
others.  To date, there are few studies that have attempted to identify genes that 
may contribute to cognitive dysfunction susceptibility in these children.  Because 
the chemotherapeutic agent methotrexate (MTX) contributes to cognitive 
dysfunction via homocysteinemia, one such study attempted to test whether 
polymorphisms in genes responsible for maintenance of homocysteine levels 
contributed to cognitive decline in children treated with cranial irradiation (CI) for 
acute lymphoblastic leukemia (ALL) [202].  Their results showed that IQ decline 
was apparent among children with the NOS3 (endothelial nitric oxidase synthase) 
894TT genotype who received CI, suggesting that NOS3 may serve as a predictor 
for children that are susceptible to cognitive decline following radiation therapy.
Investigators at St. Jude have assessed the relationship between dopamine and the 
dopamine degrading enzyme Catechol-O-Methyltransferase (COMT), changes in 
frontal brain white matter and the effects of CNS directed therapy including 
children treated with focal irradiation [203]. They found that patients with the 
Met/Val genotype performed significantly better in tests of executive function 
than those with the Val/Val or Met/Met genotype suggesting that COMT 
genotype is associated with working memory performance and may indicate 
resiliency against late effects.
2.9.5   Genetic Abnormalities Associated with Hormone Deficiencies
Gene polymorphisms that may be associated with response to treatment and 
toxicity are under investigation to discriminate between individuals at risk for 
endocrine effects of cancer therapy including radiation therapy. The roles of 
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glutathione S-transferase enzymes, which detoxify normal tissues, are viewed as 
key molecules for the role that they play in oxidative stress. Genetic aberrations in 
GST (GSTM1, GSTP1, GSTT1) increase the risk of relapse of certain cancers and 
modulate response to therapy [160]. Pediatric investigators in New South Wales 
have shown that children age less than 14 years with a null allele for GSTM1 who 
undergo radiation therapy may have increased susceptibility to growth hormone 
deficiency. Considering that there may be an important proportion of children 
with this type of genetic make-up and that even low-dose hypothalamic 
irradiation [204] will ultimately result in growth hormone deficiency, testing the 
hypothesis that GST deficiency modulates growth hormone in children would be 
both feasible and rewarding. Treatment with glutathione has been shown to confer 
a neuroprotective effect against neurotoxic chemotherapy such as oxaliplatin 
[146].
2.10 
Pathology and Biological Studies
Pathological evaluation will be used to confirm the diagnosis of ependymoma 
and, therefore, patient eligibility, but beyond this the collection of tumor material 
as part of the present trial represents an opportunity to study several aspects of the 
pathology and biology of both primary and recurrent ependymomas.  
No reliable prognostic or predictive biomarker currently exists for the therapeutic 
stratification of ependymoma; even the clinical utility of the WHO pathological 
classification of this tumor is controversial. However, recent studies at St. Jude 
and elsewhere have begun to reveal molecular abnormalities in ependymoma that 
might serve either as outcome indicators of disease or as targets for ‘small 
molecule’ therapies. In particular, genomic analyses have revealed both key 
recurrent molecular alterations in supratentorial ependymomas and molecular 
subgroups among both supratentorial and infratentorial tumors. Supratentorial 
ependymomas form two molecular subgroups, with tumors characterized or not 
by a C11orf95-RELA fusion gene; approximately 70% of supratentorial 
ependymomas harbor this fusion gene, which is associated with up-regulation of 
the NF-B pathway, a potential therapeutic target [205]. Posterior fossa 
ependymomas also form two molecular subgroups [206], and data from this first 
study suggest that the two subgroups have distinct genetic alterations and 
outcomes. St. Jude data on childhood posterior fossa ependymomas also suggest 
that there are two molecular subgroups [207].  
Aim 1. Anecdotal evidence suggests that ependymomas may or may not show 
increasing signs of histologic anaplasia upon recurrence, but a detailed analysis of 
histologic features in paired primary and recurrent tumors has not been previously 
undertaken. In addition to standard indices of anaplasia - tumor cell density and 
nuclear pleomorphism, mitotic count, microvascular proliferation, and necrosis, 
the presence or absence of tumor cell invasion into adjacent parenchyma will be 
evaluated in formalin-fixed paraffin-embedded (FFPE) sections from primary and 
recurrent tumors. Pathological features will be related to several clinical indices: 
site of recurrent disease - local or metastatic, progression-free interval, and 
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outcome. 
Aim 2. We have developed assays to determine molecular subgroup from FFPE 
material. The presence or absence of a C11orf95-RELA fusion gene in a 
supratentorial tumor can be detected by interphase fluorescence in situ 
hybridization (iFISH) in FFPE tissue sections [205], while the two posterior fossa 
ependymoma subgroups can be detected by a Quantigene assay using RNA 
extracted from FFPE sections [207]. Molecular subgroup will be determined for 
primary and recurrent disease to test the hypothesis that molecular subgroup does 
not change with tumor recurrence, as is the case for medulloblastoma [208]. In 
addition, associations between molecular subgroup and the following 
clinicopathological variables will be sought - site of recurrent disease - local or 
metastatic, PFS, and outcome. 
2.11
PET Activation
We will investigate the feasibility of using post-treatment PET as an in-vivo 
dosimetric, distal edge, and linear energy transfer (LET) verification system for 
pediatric patients with ependymoma.  Factors that may limit the practicality of 
this system are loss of signal intensity due to activation decay of relevant isotopes 
and loss of resolution due to biological washout and patient motion.  
Conventional radiation therapy uses X-rays to deposit dose within a patient. Dose 
deposition occurs predominantly through photon-electron interactions in tissue.  
Proton therapy uses a subatomic particle known as a proton.  Protons also interact 
with electrons in tissue to deposit dose; however, because of their physical 
characteristics, protons have a significant probability of interacting with atomic 
nuclei. During proton therapy it is possible to convert stable 16O, 14N and 12C 
atoms within tissue to the short-lived positron emitters [209] 15O, 13N and 11C.  
These positron emitters (primarly 11C) can be imaged using a clinical PET [210, 
211] system.  A correlation between the dose deposited by protons and the PET 
image can be obtained via Monte Carlo simulations[212], leading to in-vivo 
dosimetry and distal edge verification of the proton beam.  Based on the decay 
characteristics of the activated isotopes, PET imaging after multiple sequential 
treatment beams may not adequately image the beam path of the earliest beams in 
the series.  Methods have not been fully developed to separate the contribution of 
multiple beams in activation imaging. To remedy these uncertainties, activation 
studies will be limited to individual beam measurements.
3.0
ELIGIBILITY CRITERIA AND STUDY ENROLLMENT 
According to institutional and NIH policy, the study will accession research 
participants regardless of gender and ethnic background.  Institutional experience 
confirms broad representation in this regard.
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3.1
Inclusion Criteria
•
Progressive  intracranial ependymoma after prior focal irradiation
•
Patients aged 1-21 years at the time of enrollment
•
Adequate performance status (ECOG < 3) and research participant does not 
require mechanical ventilation
•
Interval from start of initial radiation therapy to enrollment > 9 months
3.2
Exclusion Criteria
•
Prior craniospinal irradiation
•
Pregnant women are excluded from enrollment on this study because radiation 
therapy is an agent with the potential for teratogenic or abortifacient effects
•
Any patient with both metastatic ependymoma and age < 3 years at the time of 
enrollment
3.3
Recruitment 
The statistical design of this trial requires that 90 eligible patients be enrolled over 
a 9 year period. Accounting for ineligible patients, which are expected to be at 
most 10%, the total number of patients to be accrued to this study may be 99.  We 
expect to enroll about 12 patients per year for approximately 9 years. The study 
will enroll patients with ependymoma and progressive disease. There is no 
exclusion to enrollment based on the time interval between initial tumor 
progression and enrollment. In the event that the accrual of patients is slower than 
expected, we will consider collaborating with other centers that specialize in the 
treatment of ependymoma. Patients with a prior history of radiosurgery may be 
excluded from protocol enrollment if the principal investigator or his designee 
determines that the risk of injury associated with fractionated retreatment is 
excessive.
  
  
3.4
Enrollment on Study
A member of the study team will confirm potential participant eligibility as 
defined in Section 3.1-3.2, complete and sign the ‘Participant Eligibility 
Checklist’.  The study team will enter the eligibility checklist information into the 
Patient Protocol Manager (PPM) system. Eligibility will be reviewed, and a 
research participant-specific consent form and assent document (where 
applicable) will be generated. The complete signed consent/assent form(s) must 
be faxed or emailed to the CPDMO at 595-6265 to complete the enrollment 
process.
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The CPDMO is staffed 7:30 am-5:00 pm CST, Monday through Friday.  A staff 
member from the Milli helpline is on call Saturday, Sunday, and holidays from 
8:00 am to 6:00 pm.  If you have a therapeutic research enrollment and need 
assistance releasing your consent, please call the Milli helpline (901-338-0596) on 
call number.
3.5
Enrollment Instructions for Collaborative Sites
Collaborating Site research participants should be registered at St. Jude within 72 
hours of enrollment at the site. The completed Eligibility Checklist and entire 
signed Informed Consent should be faxed to 901-595-6265. Please call 901-595-
2568 if confirmation of the enrollment information is needed. The Protocol 
Eligibility Coordinator will then register the research participant in the St. Jude 
CTMS.
 
4.0
TREATMENT AND PLAN STRATIFICATION
4.1
Overview
Patients will be enrolled on this protocol at St. Jude Children’s Research Hospital 
(SJCRH) if they meet the eligibility criteria outlined in section 3.0. Patients may 
be enrolled before or after surgery performed at the time of recurrence. 
Enrollment prior to surgery is preferred to prospectively obtain peri-operative 
information about surgical morbidity and to facilitate the acquisition of tissue for 
biology studies. This protocol allows for co-enrollment on other protocols for 
recurrent ependymoma including those that might administer chemotherapy after 
irradiation. Chemotherapy concurrent with radiation therapy will not be allowed. 
Patients will be jointly evaluated by treatment teams representing neuro-oncology, 
radiation oncology and neurosurgery. 
In the event that collaborative sites are allowed to join this trial, SJCRH will not 
be financially responsible for the cost of surgery, radiation therapy or follow-up 
for patients enrolled at collaborative sites. All patients are expected to undergo 
clinically indicated follow-up measures at the enrolling institution or at their 
routine point of care. Collaborative sites are expected to perform the research 
outlined in the protocol unless otherwise specified. The PI and protocol team at 
SJCRH will establish appropriate and legal (HIPAA) compliant communication 
with the enrolling institutions and the routine point of care for each patient.
Patients will be considered for enrollment if they have progressive disease after 
prior therapy that included surgery and focal irradiation with or without 
chemotherapy. There is no limit regarding the time interval from initial treatment 
failure to enrollment on this protocol which means that patients may choose other 
forms of therapy prior to enrollment on this protocol. Multiple episodes of 
progression will be allowed. The most common enrollment scenario will be the 
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patient who has been diagnosed with asymptomatic recurrence noted on 
surveillance neuroimaging. This patient will be consented for the study and will 
undergo pre-operative evaluations. Post-operatively, the studies necessary for 
treatment planning and to assess the impact of resection will be performed or 
repeated.
It is expected that some patients will have surgery for local recurrence or 
metastasectomy prior to enrollment. Enrollment before surgery is preferred to 
facilitate tumor-related imaging studies, tissue procurement and baseline 
evaluation of neurological function.  Regardless, studies performed prior to 
enrollment and tissue from any surgery performed prior to enrollment will be part 
of the protocol data set.
Patients will be enrolled if initial or post-irradiation pathology or imaging reports 
confirm a diagnosis of ependymoma or suggest a differential diagnosis that might 
include ependymoma. Limited tissue availability from initial and subsequent 
surgeries along with expanding efforts to sub-classify tumors may lead pathology 
reviewers to consider a range of diagnoses for which identical interventions and 
treatments would be considered. These patients will be enrolled after review by 
the principal investigator and treating physicians.
At the time of enrollment, patients will undergo extent of disease evaluation that 
will include MR imaging of the brain and spine and CSF cytology. To reduce cost 
and in consideration of the patient, the extent of disease evaluation may be waived 
with PI approval if a similar and adequate evaluation was performed within 3 
weeks of enrollment. It should be noted that for patients who proceed directly to 
irradiation, specific sequences will be required for radiation therapy treatment 
planning of intracranial disease if not present in the prior extent of disease 
evaluation. For patients who undergo further surgery, extent of disease evaluation 
after surgery is required; only CSF cytology may be waived based on safety 
concerns or for patients with obvious neuraxis metastases noted on imaging.
Optimally, patients will undergo surgery to achieve minimal residual disease. It is 
our hope, but not required, that they will experience limited morbidity from 
surgery and proceed to irradiation within 12 weeks of last surgery. The pre- and 
post-operative neuroimaging and clinical assessments will be completed to satisfy 
the secondary objectives for the study, aid in the treatment planning process, and 
provide information for longitudinal assessment of toxicity.
Surgery performed prior to registration will not preclude enrollment and treatment 
on this protocol but does limit the toxicity assessment which will be retrospective 
with regard to the pre-operative baseline. Resection prior to enrollment will also 
limit the imaging evaluation because not all patients will have, preoperatively, the 
MR sequences that are specified for longitudinal follow-up. We would hope that 
patients enrolling on the study prior to surgery will have the protocol-specified 
clinical and neuroimaging evaluation.
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Occasionally, surgery may not be feasible or the patient and their parents will 
refuse. These patients should have a small volume of residual tumor. Although it 
is preferable to perform surgery to achieve minimal residual disease and acquire 
tissue for correlative analysis, surgery will be recommended, but not required. A 
general guideline is that the thickness measurement of residual disease should not 
exceed 5mm.
Neuraxis staging is commonly performed when patients are suspected to have 
recurrent tumor and prior to surgery; however, if neuraxis staging is not 
performed before resection of recurrent tumor, the patient will be eligible, 
because the same staging procedure will be recommended prior to the initiation of 
radiation therapy on this study.
Resection undertaken in a previously irradiated patient is difficult and significant 
morbidity may result. The intent of the protocol is to document operative 
morbidity clinically and by neuroimaging. There is no required time interval from 
the time of surgery to the initiation of radiation therapy. This will provide for a 
period of recovery for injured patients and assessment of performance status and 
morbidity factors that would make re-irradiation potentially dangerous or increase 
the risk of necrosis. Neurological evaluation and performance status assessment 
will be required. When surgical morbidity is significant and the patient is made 
ventilator dependent, unresponsive or there is no prospect for a meaningful 
recovery, they will be removed from study.
Neuroimaging review is required to proceed with treatment. Pathology review is 
required to centrally confirm the diagnosis and compare the recurrent tumor grade 
to that documented at the time of initial diagnosis. Patients cannot proceed with 
enrollment on this study unless sufficient records of prior irradiation can be 
obtained. Electronic records of prior irradiation (imaging and objects) will be 
requested with the help of the patient and their family. In the absence of electronic 
data from the initial course of radiation therapy; hard copy data will suffice 
provided a review is conducted by the PI and approved. The most common 
commercial planning systems will be available to the PI and other software or 
methods to electronically import treatment planning data for the evaluation of 
treatment and normal tissue effects. Tissue is strongly recommended to achieve 
the biology goals of the study. Tumor tissue from the initial surgery, recurrence(s) 
and any other time points will be acquired for biological evaluation. 
4.2
Surgery
In addition to a detailed history along with physical and neurologic examinations, 
the preoperative evaluation should include, when appropriate, ophthalmologic 
examination, including visual field assessment and endocrinology consultation. 
Preoperative imaging should include a MRI of the brain.
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The goal of surgical intervention should be to improve tumor control with 
minimal morbidity.  Common indications for surgical intervention directed at the 
tumor will include establishing a tissue diagnosis and tumor control by radical 
resection.
Beyond the need to establish a diagnosis of recurrent ependymoma, patients will 
be selected for surgery based on the neurosurgeon’s assessment that a GTR or 
meaningful resection may be achieved with acceptable postoperative morbidity. 
This protocol does not dictate the extent or type of surgery.  This decision will be 
left to the treating neurosurgeon and the patient and parents or guardians 
following a discussion about the risks and benefits of surgery. It is recognized that 
in certain cases, the feasibility of radical surgery may initially require exploration. 
Patients who have been treated at other institutions will commonly undergo 
surgery prior to learning about this protocol. In some cases the extent of resection 
will be in determinant and the details of surgery vague. Because of the impact of 
radical surgery on outcome, we advise exploration, resection and wall biopsies 
where feasible to clearly define the extent of resection. Patients will be 
characterized as having undergone GTR based on an assessment of pre- and post-
operative imaging and the report from the neurosurgeon.
An important exploratory objective of this protocol is to evaluate the impact of 
surgery on disease control and functional outcomes.  Neurologic, endocrine, and 
functional outcomes as discussed in previous sections will be assessed at study 
enrollment and again after surgical intervention.  Disease control will be 
monitored as discussed in previous sections, and factors affecting surgical 
outcomes will also be monitored.  These will include previous surgical 
procedures, extent of disease, tumor location and tumor related effects including 
hydrocephalus and CSF shunt status.
Other surgeries not directly on the tumor but related to the disease will include 
CSF diversion procedures for hydrocephalus. Complications related to these 
surgeries will also be tracked. Surgical planning discussion for a patient with 
recurrent ependymoma will include a frank discussion of the risks and benefits of 
radical surgery.
Surgery to resect residual tumor during the first 12 months after the initiation of 
radiation therapy is allowed when the same residual tumor was present at the 
initiation of radiation therapy. There are instances when residual tumor, present 
and deemed unresectable at the initiation of radiation therapy, is observed to 
coalesce and become more demarcated as a result of treatment. This should not be 
misinterpreted as disease progression, which is highly unusual during the first few 
months after radiation therapy. Advice should be sought from the principal 
investigator. Likewise, during this time, viable residual tumor in the specimen 
does not constitute disease progression. Examples include non-enhancing residual 
tumor that enhances after radiation therapy, residual tumor more apparent on T2-
weighted MR imaging after treatment, tumor adjacent to the brainstem or 
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involving the cerebellar peduncles or within the internal auditory meatus 
becoming more apparent after treatment. The same principles have been applied 
in recent front-line studies for ependymoma.
4.3
Stratification for Treatment
Stratification for treatment of ependymoma will be determined when radiation 
therapy planning is initiated. There is no limit to the number of participants in 
each stratum. 
Stratum 1 (initial pattern of failure is local); disease confined to primary site; age 
>12 months at time of enrollment to < 21 years. Treatment: focal irradiation.
Stratum 2 (initial pattern of failure is metastatic); neuraxis metastatic disease 
without equivocal evidence of local failure; age > 36 months at time of enrollment 
to < 21 years. Treatment: craniospinal irradiation.
Stratum 3 (initial pattern of failure is both local and metastatic): neuraxis 
metastatic disease with unequivocal evidence of local failure; age > 36 months at 
time of enrollment to < 21 years. Treatment: craniospinal irradiation.
Stratum 4 (initial pattern of failure is local): disease confined to primary site; age 
>36 months at time of enrollment to < 21 years; tumor shows presence of 1q gain. 
Treatment: craniospinal irradiation (optional).
4.4
Radiation Therapy
Radiation therapy will be started once a final treatment plan has been developed 
and approved. There is no time limit for the interval from enrollment to when 
irradiation commences.
4.5
Chemotherapy
The use of chemotherapy prior to or after re-irradiation will be allowed for 
patients enrolled on this study. The use of chemotherapy during the initial 
management of ependymoma has become more commonplace as investigators 
seek to determine the role of chemotherapy for patients with initially unresectable 
ependymoma [213] or in patients after gross-total resection [214]. The impact of 
chemotherapy on disease control and complications will be considered in the 
statistical design. It is envision that as combined modality therapy becomes more 
common for children, with ependymoma, the novel agents [215] tested in 
conjunction with re-irradiation will vary over time and according to specific 
clinical and biological parameters.
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5.0
RADIATION THERAPY GUIDELINES
5.1
General Guidelines
Radiation therapy on this protocol will be based on extent of disease, extent of 
resection and location. The allowed treatment modalities include conformal or 
intensity-modulated radiation therapy using photons or proton therapy using all 
available methods.
 5.2
Treatment Planning and Specifics
The guidelines for this study were based on the experience treating patients with 
ependymoma at St. Jude Children’s Research Hospital. This includes patients 
treated with radiation therapy at the time of initial diagnosis as well as recurrence 
after prior focal irradiation. Patients with local failure will be treated with surgery 
and a second course of focal irradiation. The total dose for the second course of 
irradiation for most cases will be 54Gy. The total dose may be attenuated for 
patients with prior history of significant treatment-related complications or in the 
setting of significant dose heterogeneity or high-dose treatment volumes. Patients 
with metastatic failure will be treated with metastasectomy and craniospinal 
irradiation. Craniospinal irradiation (36-39.6Gy) will include focal boost 
treatment of primary and metastatic sites (50.4-59.4Gy) depending on location, 
extent of resection and target volume. Patients with combined local failure will 
undergo metastasectomy, primary site resection and craniospinal irradiation.
Targeting the primary site for retreatment follows the principle of minimizing 
dose to normal tissue, irradiating only the site of known recurrent disease and not 
irradiating the entirely of the tumor bed at the time of initial diagnosis. It is 
anticipated that some tissues will receive a combined dose 59.4Gy + 54Gy ~ 
114Gy from the first and second courses of irradiation, respectively.
The prescribed dose for ependymoma has evolved to a standard of 59.4Gy 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. In the setting of recurrent disease and prior irradiation, the dose of 59.4Gy is 
appropriate for previously untreated brain and the limit for previously irradiated 
tissue will be 54Gy. The neuraxis dose for metastatic ependymoma has been 
chosen to achieve the highest level of disease control; however, there may be 
instances when portions of the neuraxis will receive less than 36Gy owing to 
concerns about potential risks. 
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The CSI component of treatment is planned and administered in a relatively 
conventional manner; however, limited volume irradiation of the primary site or 
metastatic sites after CSI is amenable to a spectrum of conformal planning and 
delivery techniques. The guidelines for this study are generalized to provide 
consistency in the targeting, dosimetry and reporting. 
Investigator discretion will be used in various minor aspects of treatment 
including the total dose prescribed to the previously irradiated cervical spinal cord 
and brainstem, the total neuraxis dose, total spinal and intracranial dose for 
metastatic sites, and total primary site dose.
 5.3
Indications for Radiation Therapy
Patients enrolled on this protocol will receive radiation therapy after documented 
evidence of tumor progression or recurrence. In most cases, surgery will be 
performed for diagnostic and therapeutic purposes prior to irradiation. The goal of 
surgery is to achieve gross total resection of all imaging visible residual tumor.
5.4
Timing
The general goal is to initiate radiation therapy within 12 weeks of last surgery 
performed at the time of recurrence; however, there is no required time interval 
from the time of surgery to the initiation of radiation therapy.
There are no contraindications to radiation therapy; however, patients taking 
phenytoin should be weaned and/or switched to a different anticonvulsant as soon 
as possible.
5.5
Emergency Irradiation
Urgent irradiation is not envisioned under any circumstance.
Equipment and Methods of Delivery and Verification: all photon and proton 
therapy modalities will be allowed on this protocol including all energy of photon 
and proton beams. Photon treatment may be indicated when proton systems are 
not available.
5.6
Treatment Planning
CT (volumetric) based planning is required to optimize dose to the neuraxis or 
target volume(s) while protecting normal tissues. Organs at risk within the 
irradiated volume should be contoured including those required. A dose-volume 
histogram (DVH) is necessary to determine target coverage and evaluate dose to 
normal tissues. CT section thickness should be < 2-3mm when planning for 
treatment of focal targets in the brain and < 5mm for craniospinal irradiation.
5.6.1   Treatment Planning
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CT (volumetric) based planning is required to optimize dose to the target while 
protecting normal tissues. Organs at risk within and external to the irradiated 
volume should be contoured. A DVH is necessary to assess target coverage and 
evaluate dose to normal tissues. Three-dimensional imaging data will be the basis 
for treatment planning and will be used to define target volumes and organs at 
risk. The size, shape and location of the target volume and its relationship to the 
surrounding anatomy will be incorporated into the decision regarding the use of 
the specific planning method and the goals of treatment which include target 
volume coverage, normal tissue sparing, feasibility of delivery and the potential 
for verification. Target coverage and dose to critical structures will be evaluated 
by examining isodose distributions and dose-volume histograms for the target 
volumes and normal tissue structures. Based on these evaluations, the optimal 
plan that maximizes conformity of treatment and minimizes dose to normal 
tissues will be selected. The homogeneity of dose will be optimized across the 
targeted volumes.
5.6.2
 CT Data
At the outset of this protocol, CT data will be obtained in the treatment position as 
the fundamental data set to which MR data will be registered for treatment 
planning and measurements of brain shift, target volume change and patient’s 
positioning. The fundamental data set will include the volume from the vertex to 
the base of the skull and will hopefully encompass all tissues down to the level of 
the sternal notch. Each slice thickness will be approximately < 2mm throughout 
the volume. Intravenous contrast may be used unless it is contraindicated or 
deemed unnecessary by the treating radiation oncologist. The use of proton 
therapy necessitates a non-contrast CT in addition to a contrast-enhanced CT 
when acquired.
5.6.3
 MR Data
MR data will be registered to CT data for planning and evaluation. MR data 
includes imaging obtained pre and post-operatively and studies performed as part 
of the planning process. Diagnostic imaging MR data (DIMR) will include 2- 
and/or 3-dimensionally acquired T1-weighted pre- and post-contrast imaging, T2-
weighted imaging and post-contrast FLAIR sequences to identify tumor. 
Radiation oncology MR data (ROMR) will include imaging studies performed for 
planning purposes and during treatment to monitor for changes in target and 
normal tissue volumes and patient positioning. 
5.6.4
Immobilization and Simulation
Patients will be immobilized according to their level of cooperation, clinical 
condition and the suitability of available devices relative to their tumor location 
and the goals of treatment. Daily general anesthesia will be used when required to 
achieve satisfactory immobilization and localization. At the outset of this 
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protocol, supine-position immobilization devices will be used. Fiducial markers 
may be placed prior to therapy when requested.
5.6.5 Verification Simulation
After treatment planning, the patient may need to be repositioned at the treatment 
isocenter (as defined by the treatment plan) for verification. This may take place 
in the simulator (CT or MR) or using the verification imaging systems associated 
with the treatment device.
5.6.6
Verification of Spatial Positioning 
Portal and volumetric mV or kV imaging are interchangeably used to verify 
patient position. 
5.7
Target Volumes
General Comments International Commission on Radiation Units and 
Measurements (ICRU) [216-218] Reports 50,  62 and 78  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 
of recurrent tumor. 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 used to determine the GTV and registered to the treatment planning 
CT. Registration of the PET studies may also be useful. The GTV, CTV and PTV 
and normal tissues must be outlined on all axial imaging slices on which the 
structures are visible.
5.7.1
Targeting for patients with local recurrence
Primary Site Irradiation
The patient with recurrent disease at the primary site and no evidence of 
metastasis will receive focal irradiation of the primary site using the targeting 
guidelines provided below. Exceptions will include patients with tumors 
demonstrating the presence of 1q gain at any point in their treatment history. They 
will be given the option of craniospinal irradiation and will follow targeting 
guidelines similar to those who have metastatic disease. 
5.7.2  Targeting for patients with metastatic disease
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Craniospinal Irradiation (CSI): The CSI volume includes the entire subarachnoid 
volume with special attention to identification and inclusion of the cribriform 
plate and temporal fossae intracranially; the full width of the spinal subarachnoid 
space intraspinally and the inferior aspect of the thecal sac. CSI will be reserved 
for patients with evidence of neuraxis dissemination based on evaluation of CSF 
cytology or imaging of the brain and spine and will be given according to the 
guidelines provided below.
Primary Site Irradiation: Patients with metastatic disease may also have evidence 
of primary site failure and will receive supplemental irradiation to the primary site 
immediately following craniospinal irradiation. Targeting guidelines for the 
treatment of the primary site in this setting will follow the guidelines used for 
primary site irradiation in the absence of metastatic disease.
Metastatic Site Irradiation: Treatment of metastatic disease requires investigator 
discretion. All resected lesions and overt metastatic disease >0.3cm in maximal 
thickness should receive supplemental irradiation in addition to CSI when 
practical. Smaller lesions may also be treated at the discretion of the treating 
physician. This will include lesions in the brain and spine and using the guidelines 
outlined below.
5.8  
Definitions for GTV, CTV and PTV
5.8.1 Gross Tumor Volume
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 pre-operative imaging examination 
that defined the extent of recurrent 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. 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. The GTV will 
take into account changes in brain anatomy resulting from tumor resection or CSF 
shunting. 

GTV is the volume of tissue containing the highest concentration of tumor 
cells.

GTV includes the post-operative tumor bed which is the edge of the resection 
cavity.

GTV includes residual disease defined by post-operative neuroimaging.
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
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 GTV.
5.8.2  Clinical Target Volume
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 anatomy, dura, 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 should not exceed 0.5cm and should generally include 0.3cm of 
normal tissue. 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 ≤ 0.5cm.

CTV is defined as the volume of tissue containing subclinical microscopic 
disease

CTV for this protocol is the GTV with an anatomically confined margin of < 
0.5cm

CTV should be tailored at tissue interfaces where invasion/infiltration is not 
likely

CTV may be manually moved inward to the inner-table of the bony calvarium

CTV may be limited to the brainstem surface which is < 0.2-0.3cm depth of 
the brainstem contour.
5.8.3  Planning Target Volume
Planning target volume (PTV) is a concept associated with photon therapy  
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 0.2-0.3cm. The use of a PTV 
margin of 0.2-0.3cm requires image-guided radiation therapy methods are used on 
a daily basis or alternatively a fixation system or verification system with similar 
performance. 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. In summary, the PTV will include the 
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CTV plus a geometric margin of 0.2-0.3cm in all dimensions.  The PTV may 
extend beyond bone margins and the skin surface.
Craniospinal Irradiation (CSI): The CSI volume includes the entire subarachnoid 
volume with special attention to identification and inclusion of the cribriform 
plate and temporal fossae; the full width of the spinal subarachnoid space and the 
inferior aspect of the thecal sac.
Craniospinal Irradiation-CT Planning: CT studies obtained uniquely for the CSI 
planning process are allowed and may also serve as the basis for planning boost 
treatment. CT studies will be performed whenever possible and the information 
used for craniocaudal intensity modulation. For the cranial component of 
treatment, the external contours of the skull and neck are viewed in the AP 
direction and points are chosen to divide the cranial field into 2-4 fields to achieve 
a field-within-a-field plan and lateral homogeneity over the craniocervical 
junction. For the spinal component of treatment, the spinal cord and canal are 
contoured and viewed laterally and points are chosen to divide the spinal field 
into 4-6 fields to achieve field-within-a-field plan and antero-posterior 
homogeneity over the spinal cord and thecal sac. The following parameters are 
suggested: volume - cranial vertex to perineum; section thickness < 5mm; image 
matrix - 5122. The administration of IV contrast is not required.
Patients may have one or more metastatic lesions. These lesions may or may not 
be surgically removed. The nomenclature for the targeted volumes will follow 
those used for primary site irradiation with additional descriptors mean to assist in 
the evaluation of the case after the completion of treatment. For example, 
MGTV1_intracranial or MGTV1_right_lateral ventricle and subsequent 
modifications for CTV and PTV will be helpful.
Relevant to proton therapy, the PTV may 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 noted in this protocol. 
5.9  
Target Dose
5.9.1  Dose Definition
Photon dose is to be specified in centigray (cGy)-to-muscle. For proton therapy, the 
absorbed dose is specified in CGE, which is the same as ICRU 78 DRBE [218] 
using a standard RBE of 1.10 with respect to water. The units of Gy and CGE will 
be interchangeable with reference to prescription dose, normal tissue constraints, 
etc.
5.9.2  Prescribed dose and fractionation
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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.
Table Prescribed Doses and Fractionation
Total Dose by Site
Target Volume
Dose/fraction
Number of Fractions
Neuraxis 3600-3960CcGE/cGy
CTVCSI/PTVCSI
180CcGE/cGy
20-22
Primary Site 5040-5400cGy
CTVPS/PTVPS
180CcGE/cGy
10-30
Metastases 5040-5940cGy
CTVX/PTVX
180CcGE/cGy
5-13
The total dose to the target volume CTV (proton) or PTV (photon) prescription 
isodose surface will be 5400CcGE/cGy administered in 30 fractions of 
180CcGE/cGy.  The patient should be treated with one fraction per day.  All fields 
should be treated each day in photon treatments. Exceptions will include 
unanticipated changes in patient’s clinical condition, logistical considerations 
owing to holidays, weather, equipment failure and the need to complete the course 
of treatment in the least number of elapsed days. Two treatments in one calendar 
day will be discouraged. We will consider a single fraction reduction in the dose 
regimen for cases where significant dose heterogeneity are encountered. 
Investigator discretion may be used to alter the dose per fraction 150-200CcGE/cGy 
per day when indicated and requires PI approval. The total dose may be attenuated 
– 3420CcGE/cGy instead of 3600CcGE/cGy CSI or 5040CcGE/cGy instead of 
5400CcGE/cGy primary site - for patients with prior history of significant 
treatment-related complications or in the setting of significant dose heterogeneity 
or high-dose treatment volumes. We will also consider alterating the craniospinal 
dose when there are concerns about excessive risks regarding treatment-related 
complications,
5.9.3  Dose Uniformity
Photon Therapy Goals: At least 95% of the protocol-specified dose should 
encompass 100% of the PTV and no more than 10% of PTV should receive 
greater than 110% of the protocol dose as evaluated by DVH. The 100% isodose 
should be equal to the protocol specified dose. All methods of generating more 
uniform dose distributions are encouraged. For craniospinal treatments, the dose 
will be measured at the midplane of the cranial volume and at the posterior border 
of the vertebral body the spinal field(s) including the dose at the central ray. 
Effort should be made to minimize inhomogeneity at the craniocervical junction 
when possible and the gradient of dose across the spinal cord.
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Proton Therapy Goals: At least 95% of the protocol-specified dose should 
encompass 100% of the CTV and no more than 10% of CTV 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 may 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 
therapy should be approximately 3mm. 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 = 3% of the water-equivalent range of the CTV at max 
depth 
o
> 1mm

Set-up Margin = set-up, mechanical, dosimetric and registration uncertainties
o
Protons are relatively unaffected by set-up uncertainty in axis of beam. 
Setup errors for brain in general do not have an impact on range per se. 
o
Uncertainty in hardware and software – no assigned value available 
Uncertainty in accuracy of image registration

> 1mm

Internal margin = compensates for all variations in site, size and shape of the 
tissues contained in or adjacent to the CTV. We assume no internal organ 
motion.
o
> 1mm
†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 3-4mm.
For the rare case treated using photon therapy due to equipment failure, at least 
95% of the protocol-specified dose should encompass 100% of the PTV and no 
more than 10% of PTV should receive greater than 110% of the protocol dose as 
evaluated by DVH. The 100% isodose should be equal to the protocol specified 
dose. Methods of generating more uniform dose distributions are encouraged.
When pencil beam scanning techniques are used with scenario-based optimization 
(e.g., robust optimization), the plan may be optimized for 100% of the CTV to 
receive 95% of the protocol-specified dose. The protocol-defined PTV may be 
reviewed to confirm coverage. 
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5.9.4  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.
5.9.5  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 20,000/L during the course of treatment. Blood product 
support is not required.  The reason for any interruptions greater than 3 treatment 
days should be recorded in the patient treatment chart.  There should be no 
modifications in dose fractionation due to age or field size. 
Sequencing Contingencies:  CSI will generally be given first, followed by boost 
therapy. Boost therapy may be initiated prior to craniospinal irradiation if required 
by the medical condition. In all cases when CSI is deferred, it should be initiated 
as soon as medically feasible, before the completion of boost therapy if feasible.  
If CSI is interrupted for >4 days for medical reasons, the boost should be started 
until CSI can be resumed.
5.10  Treatment Technique
5.10.1  Beam Configuration
Every attempt should be made to minimize dose to organs at risk without 
compromising coverage of the target volume. Three-dimensional conformal or 
intensity-modulated radiation therapy using photons or protons are required to 
minimize dose to normal tissues.
5.10.2  Field Shaping
Photon field shaping will be done with multileaf collimation.
5.10.3  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 intra-fraction motion 
when using non-standard position approaches.
5.10.4  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 
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provide a clear assessment of the target volume with the patient in the treatment 
position. 
5.10.5  Special considerations
Anesthesia or sedation may be required in certain patients, such as very young 
patients, to prevent movement during simulation and daily treatments. 
5.10.6  Motion Management and Margins to Account for Target Volume
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:

Margin matching the PTV margin may be added to 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.

Portal and volumetric imaging may be performed at the completion of 
individual treatment sessions to assess the individual patient’s set-up 
uncertainty and prescribe the appropriate margins to account for set-up 
uncertainty. 
5.10.7  Radiosurgery
Under certain circumstances patients will be treated with primary radiosurgery.  
These patients will be treated with tumor ablative doses according to institutional 
and cooperative group guidelines. Tolerances to normal tissue structure according 
to the same guidelines will also be observed.
Radiosurgery is a standardized procedure and will be considered for the primary 
or boost treatment of selected patients with residual primary or metastatic disease. 
This treatment may be carried out using the linear accelerator or Gamma Knife. 
Patients will undergo a CT or MR scan for stereotactic localization following the 
placement of a neurosurgical head frame. A dose in the range of 1000-1500cGy 
will be delivered to the patients receiving boost treatment and generally 1500-
2100cGy to patients receiving primary radiosurgery. The dose selected depends 
on the size of the target volume. The treatment will be single fraction and the dose 
will be described to the isodose line encompassing the target volume. In general, 
the target volume will be encompassed by the 80-90% isodose surface for linac-
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based radiosurgery and the 50-60% isodose surface for Gamma Knife. The 
brainstem dose will be less than 1200cGy and the dose to the chiasm will be 
limited to 800cGy.
5.11  Treatment Planning Procedures
Craniospinal Irradiation: Patients may be simulated and treated in the prone or 
supine position using customized immobilization devices that allow for 
verification of cranial and spinal field junctions. Treatment will be given using 
standard techniques, encompassing the entire subarachnoid volume (both brain 
and spine). The technique should assure coverage at the cribriform plate and 
temporal fossae intracranially; the full width of the spinal subarachnoid space 
(dosimetrically to include the medial aspect of the neural foramina) down to the 
bottom of the thecal space (as indicated by sagittal spinal MR).
Infratentorial Irradiation: Consideration should be given to minimizing dose to the 
brainstem and spinal cord.
Supratentorial Irradiation: Consideration should be given to minimize dose to the 
optic apparatus including the eyes, nerves and chiasm.
Metastatic Site Irradiation: MR visible intracranial metastatic disease should be 
treated concurrently with the primary site and when feasible joined to the primary 
site volume. The decision to treat separate or combined primary and metastatic 
boost volumes should be based on limiting normal tissue irradiation. Spinal 
metastatic disease should be treated concurrently with the primary site treatment. 
5.12  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. Note these guidelines are for the current 
treatment protocol and do not represent cumulative target doses.
5.12.1  Cochleae
D50% < 3500cGy – Goal (single cochlea)
D50% < 2000cGy – 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.
5.12.2  Optic Globes
D50% < 1000cGy and D10% < 3500cGy – Goal
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D50% < 2000cGy and D10% < 5400cGy – 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. In the event that the recommended maximum dose 
constraints provided in this section would be exceeded, 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.
5.12.3  Optic Nerves and Chiasm
D50% < 5400cGy and D10% < 5600cGy – Goal
D50% < 5600cGy and D10% < 5800cGy – Maximum
Comment – Effort should be made to avoid direct treatment of the optic nerves 
and chiasm without compromising target volume coverage. In the event that 
the recommended maximum dose constraints provided in this section would be 
exceeded, 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.
5.12.4  Spinal Cord
D50% < 2600cGy and D10% < 5700cGy - Goal
D50% < 5000cGy and D10% < 5900cGy – Maximum
Comment – Effort should be made to minimize dose to the spinal cord without 
compromising target volume coverage. In the event that the recommended 
maximum dose constraints provided in this section would be exceeded, the 
treating radiation oncologist may use their discretion to reduce target volume 
coverage.
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 
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; 2.5mm, n=24; 3mm, n=20). 
Using these guidelines, only the superior-most 6cm of anatomic spinal cord is 
contoured.
5.12.5  Brainstem
D50% < 6100cGy and D10% < 6300cGy - Goal
D50% < 6200cGy and D10% < 6400cGy – Maximum
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Comment – Effort should be made to minimize dose to the brainstem without 
compromising target volume coverage. In the event that the recommended 
maximum dose constraints provided in this section would be exceeded, 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. A brainstem core representing tissue > 
3mm depth from the brainstem surface may be contoured when indicated.
5.13  Dose Calculations and Reporting
5.13.1  Prescribed Dose
The dose should be prescribed to an isodose surface that encompasses the CTV 
(proton) or PTV (photon) and allows the dose uniformity requirements to be 
satisfied.
5.13.2  Normal Tissue Dosimetry
The dose to the critical organs indicated should be calculated whenever they are 
directly included in a radiation field. 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 containment within any other 
structure. A DVH for “Body” shall be submitted to enable calculation of the 
required volumes. “Body” is defined as the outer contour of the patient on the 
treatment planning CT data set.
Required DVH data regardless of primary treatment site
Required DVH
Optic Chiasm
Brainstem
Spinal Cord
Right Cochlea
Left Cochlea
Body
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Unspecified Tissue
Treated Volume, Irradiated Volume 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 54-
59.4Gy and 95% of the prescribed dose. 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 brain tumor protocols.
Required Volumetric Information

Required 
Volumes 
TV95%=V56.4
Gy
TV100%=V59.
4Gy
IV35=V35Gy
IV45=V45Gy
IV54=V54Gy
PTV
CTV
GTV
Entire Brain
Unspecified 
Tissue
5.14  Patterns of Failure Evaluation
The patterns of failure for patients with ependymoma may be described as local, 
distant or a combination of local and distant based on imaging evaluation of the 
neuraxis. Local failure is defined as progression or recurrence of tumor at the 
primary site of disease. Distant failure is defined as the progression or recurrence 
of tumor at a location other than the primary site. Distant failure 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 failure is defined when evaluation of the entire neuraxis reveals 
synchronous local and distant failure.
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The present study involves treatment of the primary site only, neuraxis with or 
without supplemental primary and metastatic site irradiation. Because 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 will be driven by targeting. 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. 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. 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 
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.
5.15
Management of Radiation Necrosis
When early signs of progressive parenchymal changes are present on imaging we 
will consider referral for hyperbaric oxygen therapy (HBOT). HBOT may be 
recommended when progressive parenchymal changes are associated with mild to 
moderate symptoms. Steroid therapy, most often dexamethasone, may be initiated 
and tapered according to symptoms. When the dose of dexamethasone has been 
tapered to approximately 0.5mg daily, a taper of hydrocortisone will be initiated 
at approximately 25mg daily administered in divided doses. Dexamethasone will 
be discontinued within 2-3 days of the initiation of the hydrocortisone. Patients 
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are not required to remain on steroid therapy during HBOT. In the setting of 
severe symptoms, medical oncology may be consulted to consider other measures 
including the use of bevacizumab.
5.16
PET for Dose Verification of Proton Therapy
The number of PET activation studies will equal the number of proton treatment 
beams, which is estimated to be 3 for the majority of cases. On the day of the PET 
evaluation, the patient will be treated with a single beam corresponding to the 
activation beam under study. A separate plan may be developed to ensure the 
prescription dose to the target using a single beam on that day and that a critical 
normal tissue volume will not be compromised by the end of range uncertainty in 
RBE. The beam on time and duration for each of the single field treatment 
fractions will be recorded. The duration of the single beam fraction is estimated to 
be 10 to 15 minutes shorter than the conventional fraction. At the end of the single 
beam fraction, the patient will be transported to the PET-CT; estimated time 
required is 10 minutes. For PET attenuation correction and anatomic localization 
purposes, a CT of the cranium will be obtained; estimated time required is 5 
minutes. The PET activation study will then be acquired for 30 minutes; the start 
time will be recorded. Based on the treatment plan, a Monte Carlo simulation of 
the positron activation locations and intensities will be created. The predicted 
image and acquired image will be compared and analyzed.
Alternatively, the patient may be treated with one beam, have the PET activation 
study and then complete the treatment with the remaining beams.
6.0
REQUIRED EVALUATIONS, TESTS AND OBSERVATIONS
Instructions regarding the logistics of baseline evaluations
Surgery→enrollment→no surgery→ radiation therapy
If surgery was performed prior to enrollment and the patient does not require 
additional surgical intervention, similar to the preceding section, they should be 
enrolled on protocol and undergo baseline evaluation prior to radiation therapy. 
Surgery→enrollment→surgery→ radiation therapy
Regardless of prior surgical history, patient who will undergo additional surgery 
should be enrolled on protocol and undergo baseline evaluation prior to surgery. 
If they are unable to complete the required baseline evaluations prior to surgery, 
partial evaluation will be accepted and the remaining baseline evaluations should 
be completed after surgery (i.e., partial evaluations prior to and following surgical 
intervention will be accepted). Investigators should consider repeating aspects of 
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the baseline evaluation (e.g., diagnostic imaging, neurological examination, 
ophthalmology, etc.) that may be altered by surgery. 
Instructions Regarding the Logistics of Follow-up Evaluations
It is the intent of the investigators to perform follow-up evaluations to meet the 
primary objectives and research the exploratory aims (Table 6.0.2). Performance 
will be regularly monitored according to institutional guidelines and by the 
principal investigator. Principal Investigator will closely monitor compliance and, 
when necessary, will establish contact with primary care providers and engage 
home health nursing, to ensure completion of protocol-specified evaluations. It is 
a requirement that all patients enrolled at St. Jude undergo all evaluations. 
Patients enrolled at collaborative sites may have evaluation requirements tailored 
to the availability of local resources.
Sponsorship
In the event that patients are enrolled at collaborative sites, the costs associated 
with research, treatment, follow-up and routine medical care will be the 
responsibility of the enrolling institution, patient and their family. 
Protocol Performance
Despite the intent to adhere as closely as possible to the guidelines of this study, it 
is understood that unforeseeable circumstances may dictate postponement, 
cancellation or minor deviation in protocol guidelines because of intercurrent 
illness, logistical problems, and the absence of care providers or investigators, 
shortages in time and materials and lack of funding. Exceptions to the evaluation 
scheme will be made at the discretion of the Principal Investigator when clinical 
or logistical considerations preclude protocol-timely evaluation.
Research Data
The exploratory data derived from this study will be collected, analyzed and 
reported while the study is ongoing and with the approval of the Principal 
Investigator. The analyzed data will be reported and presented at institutional and 
scientific meetings and at invited presentations with the approval of the Principal 
Investigator. Use of the protocol data and publication of analyzed data is 
anticipated prior to completion of the study in the form of ongoing or preliminary 
reports and will be done only with approval of the Principal Investigator.
6.1 
Physical Examination
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Physical examination will be performed before, during and after radiation therapy. 
The patient height, weight and body-mass index will be recorded and converted to 
percentiles based on age and gender.
6.2 
Neurology
At baseline and with each visit the pediMIDAS form will be completed. Grade 3-
5 neurological complications will be reported using the NCI Common Toxicity 
Criteria v4.0.
6.3 
Ophthalmology
At the specified time points and when clinically indicated, patients will be 
assessed in the ophthalmology clinic. The ophthalmologic examination may 
consist of an assessment of external signs of treatment sequelae, visual acuity, 
current correction, color vision, intraocular pressure, mobility, refraction and 
visual field. The ophthalmology data sheet will no longer be collected in paper 
version. This data will be extracted directly from the patient’s medical record 
clinical documentation and entered directly into the trial database.
6.4 
Audiology
Schedule: Patients will be referred for audiological testing prior to radiation 
therapy and annually dated from the start of RT. More frequent evaluations may 
be considered by the treating physician or audiologist based on results of prior 
evaluations and the potential risk for hearing loss.
Tests and Outcome Measurements: At each evaluation tympanometry will be 
performed to assess integrity of the conductive mechanism, distortion product 
otoacoustic emissions will be assessed to determine cochlear outer hair cell 
function, a pure tone audiogram will be obtained to assess peripheral hearing 
sensitivity, and speech-in-noise testing will be administered to assess performance 
in background noise and to screen for auditory processing disorder in children.  
Each audiogram will include air conduction thresholds at 250, 500, 1000, 2000, 
3000, 4000, 6000, and 8000 Hertz measured in dB HL. Ultra-high frequency 
thresholds will be obtained at 9000, 10000, 11200, 12500, 14000, and 16000 
Hertz in patients older than 5 years.  Bone conduction thresholds will be obtained 
as needed to rule out a conductive component to the hearing impairment. Hearing 
will be categorized as normal if all thresholds are within the 0-20 dB HL range.  If 
a deficit is present, hearing impairment will be categorized by the numerical dB 
HL values. Speech-in-noise testing will be administered to patients older than 5 
years. The QuickSIN speech-in-noise test [219] will be administered to patients 
older than 14 years and the BKB-SIN speech-in-noise test [220] will be used for 
patients 5-14 years and for adults whom the QuickSIN test is too difficult.
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An auditory brainstem response (ABR) evaluation may be substituted for patients 
who are unable to respond to conventional audiometric testing techniques.
Every audiogram or ABR evaluation will be assigned a grade based on the Chang 
and SIOP Ototoxicity Grading Scales.
Ototoxicity Grading Scales*
Chang
SIOP
Grade 0
≤ 20 dB at 1, 2, and 4 kHz
Grade 0
<20 dB HL at all frequencies
Grade 1a
≥ 40 dB at any freq 6  to 12 kHz
Grade 1b
> 20 and < 40 dB at 4kHz
Grade 1
>20 dB HL (i.e., 25 dB HL or 
greater) SNHL above 4000 Hz (i.e., 
6 or 8 kHz)
Grade 2a
≥ 40 dB at 4 kHz and above
Grade 2b
> 20 and < 40 dB at any freq 
below 4kHz
Grade 2
>20 dB HL SNHL at 4000 Hz and 
above
Grade 3
≥ 40 dB at 2 or 3 kHz & above
Grade 3
>20 dB HL SNHL at 2000 Hz or 
3000 Hz and above
Grade 4
≥ 40 dB at 1 kHz and above
Grade 4
>40 dB HL (i.e., 45 dB HL or 
more) SNHL at 2000 Hz and above
*Sensorineural Hearing Threshold (dB HL) bone conduction or air conduction with normal 
tympanogram
6.5  
Endocrinology
To establish a baseline, patients will be evaluated for evidence of endocrinopathy 
and abnormal growth and development. They will be seen by the endocrine 
service at baseline and then at least once annually to document their 
developmental exam and to perform auxological measurements. 
When necessary, the baseline and follow-up developmental exam and auxological 
measurements may be performed by a trained co-investigator.
Endocrine Imaging: Baseline evaluation will include 1) a plain film postero-
anterior X-ray of the left hand and wrist for bone age; 2) quantitative CT; and 3) 
DXA scan for bone mineral density for participants ≥ 3 years of age. These 
examinations will be repeated when deemed necessary by the treating physicians.
Serum Screening Studies: Hypothalamic-pituitary axis function will be assessed 
with static assessments of fasting serum: thyrotropin (TSH), free and total 
thyroxine [212], reverse and total T3, cortisol (obtained by 0800 hours), prolactin, 
insulin-like growth factor binding protein-1 (IGFBP-1, marker of insulin 
resistance) and insulin-like growth factor binding protein-3 (IGFBP-3), IGF-1, 
LH, FSH, insulin, 25(OH)D, serum Comprehensive Metabolic Panel (CMP) and 
complete blood count. These evaluations will be performed with each planned 
follow-up. These screening tests resemble those drawn for routine evaluation.  
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Understanding the pan-endocrine status is critical to interpretation of the GH data 
from the provocative testing.
Provocative Endocrine Testing: Patients will undergo evaluation for growth 
hormone and ACTH secretion abnormality using provocative tests of endocrine 
function. Recent steroid or growth hormone usage by the patient will be reviewed 
by the PI to determine when and if provocative endocrine testing shall be 
performed. GH provocative testing will be performed using arginine and 
carbidopa-levodopa.  ACTH secretion will be tested using the 1 µg ACTH test. 
Similar evaluations will be repeated at 12 and 24 months after irradiation.  The 
protocols used for provocative testing are identical to those used for patients in 
whom endocrinopathy is suspected.  Exceptions to the endocrine testing 
procedures may be made at the discretion the treating physicians.  Testing 
procedures may be omitted or modified: 1) because the patient is receiving 
replacement therapy; 2) when the provocative agent is unavailable; or 3) when the 
procedure is deemed inappropriate based on patient’s clinical condition, 4) the 
intraday timing of the drug administration, or 5) phlebotomy is constrained by 
logistic problems.
6.6  
Neuropsychological Testing
6.6.1  Overview of Neurocognitive Studies – Schedule
Patients will be referred for neurocognitive testing before radiation therapy and 
yearly through 5 years. All measures in the battery described below will be 
administered at yearly time points with the exception of the CVLT-C/CVLT-II, 
which will be administered only at baseline, 2 years post radiation therapy and 4 
years post radiation therapy in order to minimize practice effects. We will not 
perform cognitive assessments on children less than 3 years of age, children for 
whom a language other than English is their primary language, or children with 
premorbid neurological/neurodevelopmental disorders (e.g., Down Syndrome, 
Autism).
6.6.2  Neurocognitive Testing
Children will be assessed at baseline (pre re-irradiation therapy and up to 4 
months after the initiation of treatment) and annually for 5 years. An effort was 
made to select measures that could assess the widest study age range possible. 
Another primary goal was to select a battery that could be administered in a 
circumscribed period of time to reduce the time burden for children, their parents 
and the research team. The administration time for the test battery is estimated at 
2-3 hours, dependent on the age of the child and the speed with which they can 
complete tasks. Therefore, the administration length of the current battery readily 
lies within the standard length of typical clinical and research batteries. All 
selected measures have age-specific norms from large, representative 
standardization samples. Measures also have appropriately demonstrated 
reliability and validity. Given the longitudinal study design, measures were 
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chosen with appropriate test-retest reliability and negligible practice effects for 
the proposed interval between testing time points. Tasks were chosen that balance 
the need to measure global outcomes typically assessed with respect to treatment 
interventions and most useful for educational planning (e.g., IQ and academic 
achievement) with specific areas of deficit most commonly reported in the brain 
tumor literature for children receiving radiation therapy (e.g., attention, 
processing speed and executive functions). See Table 1 for a listing of measures 
by cognitive domain.
Measure of Intellectual Function
Wechsler Intelligence Scale for Children, Fourth Edition (WISC-IV) [221]: The 
WISC-IV is the fourth edition of the WISC and the most commonly used measure 
to assess intelligence in children 6-16:11 years of age. The Wechsler Adult 
Intelligence Scale, Fourth Edition (WAIS-IV) [222] will be administered to 
children 17:0 and older. We propose a shortened administration of 8 subtests that 
provides a prorated full-scale IQ score and also allows for the derivation of the 
Verbal Comprehension, Perceptual Reasoning, Working Memory and Processing 
Speed Indices (60 to 90 minutes). Children ages 3.0-5.11 will complete the age-
appropriate subtests from the Wechsler Preschool and Primary Scale of 
Intelligence, Third Edition (WPPSI-III) [223], which allows for the calculation of 
a Full-Scale IQ, Verbal IQ, Performance IQ, and a Processing Speed Index. (60-
90 minutes)
Attention and Executive Function Measures
CogState [224]:  CogState is a battery of computerized, semi-automated 
assessment measures (www.cogstate.com) that can be administered and proctored 
by examiners/research assistants with minimal training. All responses are 
recorded by the computer system including speed (reaction time) in milliseconds 
thus providing a reliable index of processing speed and psychomotor functioning 
that is highly relevant to this study population. Test batteries can be customized 
for research questions and study populations. The battery included here is 
composed of 5 tasks (Detection, Identification, One-Back, Continuous Paired 
Associate Learning, and Groton Maze) that assess processing speed, visual 
attention, working memory, visual learning and executive functioning. Age-based 
standard scores are computed for each task based on a normative sample. The 
battery is particularly well suited for longitudinal assessment as no practice 
effects have been identified when testing intervals are greater than one month 
[224, 225]. CogState has been used with typically developing children [226] as 
well as individuals diagnosed with attention deficit hyperactivity disorder 
(ADHD) [227], individual with concussions [228] and adult cancer patients [229]. 
The Detection, Identification and One-Back tasks are based on a playing-card 
paradigm. The Detection task is a simple reaction time task that measures 
psychomotor function. In this task, the child is required to press a “yes” button as 
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quickly as possible when the centrally located card turns face-up. The face-up 
card is always the same joker card and the task ends when 35 correct responses 
have been recorded (~2 minutes). The Identification Task is a choice reaction time 
task that measures visual attention. The presentation is similar to the Detection 
task but now the child responds “yes” if the face-up card is red and “no” if it is 
not red. The cards are red and black joker cards and the task ends after 30 correct 
trials (~2 minutes). The One-back task assesses attention and working memory. 
The child is instructed to respond “yes” if the face-up card is exactly the same as 
the immediately previous card or “no” if it is not the same as the previous card. 
The task ends after 30 correct trials (~3 minutes). 
The Groton Maze learning test is a measure of the reasoning and problem solving 
aspects of executive function. In this task, participants are asked to move their 
way through a 10 x 10 grid of square tiles in which a 28-step pathway (with 11 
turns) is hidden. Participants begin from a start location in the upper left corner of 
the grid and are instructed to find their way to the lower right corner of the grid. 
While moving through the hidden maze, participants find the tiles that are part of 
the hidden pathway by clicking on tiles. After each move is made, the computer 
indicates whether they are correct or incorrect. When the participant completes 
the pathway, he or she repeats this process (the same maze pathway) for four 
more trials. Total errors made while navigating the hidden maze across five trials 
is the outcome measure (~5 minutes). The Continuous Paired Associate Learning 
is discussed below under the memory measures.
Working Memory Index: The Digit Span and Letter-Number Sequencing tasks 
from the age-appropriate WISC-IV or WAIS-IV will be administered as measures 
of attention (Digit Span Forward) and working memory (Digit Span Backward; 
Letter-Number Sequencing). Forward span tasks are considered measures of 
attention and immediate recall, whereas backward span and sequencing tasks, 
with the additional requirement of reordering stimuli before responding, are 
regarded as measures of working memory. 
Woodcock-Johnson Tests of Cognitive Abilities, Third Edition (WJ-III-COG) 
[230] Retrieval Fluency: The Retrieval Fluency subtest assesses verbal retrieval 
and fluency by requiring the child to name as many exemplars of a given category 
as they can in one minute.  (3-5 minutes) 
The Behavior Rating Inventory of Executive Function (BRIEF) [231]: The BRIEF 
is a parent questionnaire designed to assess behavioral manifestations of executive 
functioning. Executive functions include goal-directed behaviors, such as the 
ability to plan, organize, sustain performance, and change performance in 
response to feedback. (10-15 minutes)
Visual Spatial/Visual Motor Measures
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The Beery-Buktenica Developmental Test of Visual-Motor Integration (VMI) 
[232]:  The VMI assesses visual-motor skills by requiring children to copy a 
series of increasingly complex shapes and figures as accurately as possible. The 
supplemental test of visual perception requires children to match identicalshapes 
that also become increasingly complex and the supplemental test of motor 
coordination requires children to draw shapes using provided guidelines and  by 
connecting dots. These tests assess visual-motor integration, visual perception and 
motor coordination skills alone. They also assess the relative contribution of 
visual perception and motor factors in a child’s visual motor integration skills and 
differentiate children with motor skills deficits from those without. (10 minutes) 
Memory Measures
California Verbal Learning Test, Children’s Version (CVLT-C) [233]: The 
CVLT-C is a list-learning measure of verbal memory that includes five 
presentations of a list of 15 words comprising three categories. Learning is 
evaluated across the five learning trials as well as following a distracter list, short 
and long delays. Children are also presented with categorical cues and a list of 
target and non-target words from which they must identify those words presented 
on the 15 item list. Process scores allow evaluation of encoding, retrieval, 
retention and recognition abilities. The California Verbal Learning Test, Second 
Edition (CVLT-II) [234] is a comparable version of the test administered to 
individuals 17:0 years of age and older. It comprises sixteen words from four 
semantic categories and provides the same structure, allowing for the examination 
of encoding, retrieval, retention, and recognition. To reduce practice effects, this 
measure will only be administered at baseline, 2 years post and 4 years post. (15-
20 minutes)
CogState [224, 225]:  For the Continuous Paired Associate Learning task, the 
child is asked to learn and remember figures hidden beneath different locations on 
the screen.  The shapes then appear centrally, and initially all appear peripherally 
for matching and remembering where each was located. Thereafter, as each 
picture is revealed centrally, they are required to tap the peripheral location that 
hides the same shape. Total errors is the outcome measure (~6 minutes). 
Processing Speed Measures
Processing Speed Index- WISC-IV:  The Coding and Symbol Search subtests 
from the age appropriate Wechsler scale (WISC-IV or WAIS-IV) will be 
administered as measures of processing speed. 
Motor Measures
Purdue Pegboard: The Purdue Pegboard [235] assesses fine motor speed and 
dexterity by timing participants as they place pegs in holes on a pegboard. 
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Participants complete the task first with their dominant hand, next with their non-
dominant hand and finally with both hands. (5 minutes)
Academic Achievement Measures 
The Woodcock Johnson Tests of Academic Achievement-Third Edition (WJ-III-
ACH) [230]: The WJ-III Achievement allows for interpretation of broad and 
specific academic factors and allows for combining subtests to measure different 
domains. Selected subtests for this study are described in further detail below.
WJ-III-ACH Word Attack:  This task assesses the ability to pronounce pseudo 
words using phonological decoding skills. (3 minutes)
WJ-III-ACH Letter-Word Identification:  This task assesses single letter 
identification for younger children and word reading for older children, thereby 
testing basic letter recognition and word reading skills. (5 minutes)
 
WJ-III-ACH Reading Fluency:  This task assesses reading speed. (3 minutes)
WJ-III-ACH Calculation:  This task assesses the ability to perform simple to 
complex mathematical computations. (5-10 minutes)
WJ-III-ACH Math Fluency:  This task assesses math calculation speed. (3 
minutes)
Bracken Basic Concept Scale, Third Edition, Receptive (BBCS-3:R) [236]: The 
BBCS-3:R assesses early and emerging academic skills. Five individual subtests 
assess knowledge of colors, letters, numbers, amounts, and shapes by requiring 
the child to point to the stimulus requested by the examiner. A School Readiness 
Composite score is produced. This task is only administered to young children for 
whom the WJ-III-ACH measures described above are not yet developmentally 
appropriate. (15 minutes)
Social-Emotional Measures
Behavior Assessment System for Children, Second Edition (BASC-2) [237]: The 
BASC-2 is a questionnaire assessing behavioral, emotional and adaptive 
functioning. The parent form contains 10 clinical scales and 6 adaptive indices. 
The clinical scales include those of the externalizing problems composite (e.g., 
Hyperactivity, Aggression, Conduct Problems), the internalizing problems 
composite (e.g., Anxiety, Depression, Somatization), and the behavioral 
symptoms indices (Atypicality, Withdrawal, and Attention Problems). Adaptive 
scales include Overall Adaptive Skills, Functional Communication, Activities of 
Daily Living, Leadership, Social Skills and Adaptability. (15 minutes)
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Brief Symptom Inventory (BSI) [238]. The BSI is an inventory used to monitor 
parental distress and coping. It includes nine symptom scales: somatization, 
obsessive-compulsive, interpersonal sensitivity, depression, anxiety, hostility, 
phobic anxiety, paranoid ideation and psychoticism. From these scales, three 
global indices are derived- Global Severity Index, Positive Symptom Distress 
Index and Positive Symptom Total. Parents complete this measure. (8-10 minutes)
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Rev 0.1, dated: 9/3/2015    
                                           IRB approval date: 
Protocol document date: 6/7/2016                                                            
Table 1 Neurocognitive Measures by Functional Domain
Cognitive 
Domain
Measure
Broad Skill
Task Characteristics
Age  Range
Admin.
Time
Full Scale 
IQ
1. WPPSI-III
    (Full Battery)
Early Childhood 
Global Cognitive 
Function
Verbal and nonverbal reasoning; Processing 
speed
WPPSI-III=3-
5:11
60 min.
2. WISC-IV/WAIS-
IV
    (8 subtests)*
Global Cognitive 
Function
Verbal reasoning (Vocabulary & 
Similarities), nonverbal reasoning (Block 
Design & Matrix Reasoning), attention/ 
working memory (Digit Span & Letter 
Number Sequencing) & processing speed 
(Coding & Symbol Search)
WISC-IV=6-
16:11
WAIS-IV=17+
60-90 
min.
Attention & 
Executive 
Function
3. CogState
Attention, 
Working Memory, 
Processing Speed
Computerized measure of visual attention 
(Identification, Detection), working memory 
(N-back), psychomotor speed (Detection) & 
executive function (Groton Maze)
  5+
15 min.
4. Wechsler WM 
Index 
    (Digit Span & 
Letter    
    Number 
Sequencing) 
Brief Auditory 
Attention, 
Auditory Working 
Memory
Repeating random digits in strands of 
increasing length both forward and 
backward; Re-sequencing strands of numbers 
and letters presented in mixed order.
WISC-IV=6-
16:11
WAIS-IV=17+
N/A 
above
5. WJ-III-COG 
     Retrieval 
Fluency
Verbal Fluency
Child produces as many items as possible 
belonging to a specified category (e.g., 
animals)
3+
3-5 
min.
6. BRIEF 
Questionnaire
    (Parent Measure)
Executive 
Function
Questionnaire assessing executive 
dysfunction in community
BRIEF-P=3-
5:11
BRIEF=6-
18:11
BRIEF-A=19+
15 min.
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Visual 
Spatial/ 
Visual 
Motor
7. Beery VMI
Visual Perception, 
Motor 
Coordination &
Visual-Motor 
Integration
Blue- Match shapes of decreasing size
Green- Draw shapes of increasing 
complexity
Brown- Draw shapes by connecting dots
3+
15 min.
Memory
8. CVLT-C / 
CVLT-II
Verbal List 
Learning
Learn a novel word-list through multiple 
presentations, interference, delay & 
recognition
CVLT-C=6-
16:11
CVLT-II=17+
15 min.
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Cognitive 
Domain
Measure
Broad Skill
Task Characteristics
Age  Range
Admin.
Time
Full Scale 
IQ
1. WPPSI-III
    (Full Battery)
Early Childhood 
Global Cognitive 
Function
Verbal and nonverbal reasoning; Processing 
speed
WPPSI-III=3-
5:11
60 min.
2. WISC-IV/WAIS-
IV
    (8 subtests)*
Global Cognitive 
Function
Verbal reasoning (Vocabulary & Similarities), 
nonverbal reasoning (Block Design & Matrix 
Reasoning), attention/ working memory (Digit 
Span & Letter Number Sequencing) & 
processing speed (Coding & Symbol Search)
WISC-IV=6-
16:11
WAIS-IV=17+
60-90 
min.
Attention & 
Executive 
Function
3. CogState
Attention, Working 
Memory, Processing 
Speed
Computerized measure of visual attention 
(Identification, Detection), working memory (N-
back), psychomotor speed (Detection) & 
executive function (Groton Maze)
  5+
15 min.
4. Wechsler WM 
Index 
    (Digit Span & 
Letter    
    Number 
Sequencing) 
Brief Auditory 
Attention, Auditory 
Working Memory
Repeating random digits in strands of increasing 
length both forward and backward; Re-
sequencing strands of numbers and letters 
presented in mixed order.
WISC-IV=6-
16:11
WAIS-IV=17+
N/A 
above
5. WJ-III-COG 
     Retrieval Fluency
Verbal Fluency
Child produces as many items as possible 
belonging to a specified category (e.g., animals)
3+
3-5 
min.
6. BRIEF 
Questionnaire
    (Parent Measure)
Executive Function
Questionnaire assessing executive dysfunction in 
community
BRIEF-P=3-
5:11
BRIEF=6-18:11
BRIEF-A=19+
15 min.
Visual 
Spatial/ 
Visual 
Motor
7. Beery VMI
Visual Perception, 
Motor Coordination 
&
Visual-Motor 
Integration
Blue- Match shapes of decreasing size
Green- Draw shapes of increasing complexity
Brown- Draw shapes by connecting dots
3+
15 min.
Memory
8. CVLT-C / CVLT-
II
Verbal List Learning
Learn a novel word-list through multiple 
presentations, interference, delay & recognition
CVLT-C=6-
16:11
CVLT-II=17+
15 min.
9. CogState
Visual Learning
Learn spatial location of hidden objects
6+
5 min.
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Processing 
Speed
10. Wechsler 
      Processing 
      Speed Index 
      (Coding &
      Symbol Search)
Psychomotor & 
Processing Speed
Coding- fill-in symbols using a number-symbol 
code
Symbol Search- identify presence of one of two 
target shapes amongst a group of five search 
shapes
WISC-IV=6-
16:11
WAIS-IV=17+
N/A 
above
Motor
11. Purdue Pegboard
Fine motor speed & 
dexterity
Child places pegs in a pegboard as quickly as 
possible. Scores are obtained for dominant and 
nondominant hands separately, as well as both 
hands in coordination. 
3+
5 min.
Academic 
Skills
12. WJ-III-ACH 
Word  
      Attack, Letter-
      Word 
Identification, 
      Reading Fluency, 
      Calculation, Math 
      Fluency
Reading and Math 
Abilities
Assesses phonologic decoding, single word 
reading, speeded reading, math computation and 
speeded calculation relative to child’s age and 
grade level. 
6+
20-35 
min.
13. BBCS-3:R
School Readiness 
Skills
Child identifies early academic concepts such as 
letters, numbers, colors, and shapes by pointing.
3-5:11
10 min.
Social-
Emotional
14. BASC-II
(Parent Measure)
Psychosocial 
Adjustment
Inquires about 9 behavioral domains including 
attention, conduct problems, anxiety, depression, 
somatization, etc.
3- 21:11
15 min.
15. BSI
(Parent Measure)
Parent Coping & 
Distress
A self-report inventory used to monitor parental 
psychological problems including anxiety, 
depression, interpersonal sensitivity and 
somatization.
3-21:11
8-10 
min.
Table Abbreviations: WPPSI-III: Wechsler Preschool & Primary Scale of Intelligence, Third Edition; WISC-IV: Wechsler Intelligence Scale 
for Children, Fourth Edition; WAIS-IV: Wechsler Adult Intelligence Scale, Fourth Edition; WJ-III-COG: Woodcock-Johnson Tests of 
Cognitive Abilities, Third Edition; BRIEF: Behavior Rating Inventory of Executive Function; VMI: Beery-Buktenica Test of Visual-Motor 
Integration, Fifth Edition; CVLT-C: California Verbal Learning Test, Children’s Version; CVLT-II: California Verbal Learning Test, Second 
Edition; WJ-III-ACH: Woodcock-Johnson Tests of Achievement, Third Edition; BBCS-3:R: Bracken Basic Concept Scale, Third Edition, 
Receptive; BASC-II- Behavior Assessment System for Children, Second Edition; 
*These subtests allow for the derivation of a full scale IQ as well as the four index scores (Verbal Comprehension, Perceptual Reasoning, 
Working Memory and Processing Speed), digit span forward (DSF), and digit span backward (DSB).
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Protocol document date: 6/7/2016                                                            
6.7  
Sleep, Fatigue and Quality of Life Measures
Actigraphy, will be collected annually as described in Section 2.4. Symptom 
Distress, Multidimensional Fatigue Standard Version, Epworth Sleepiness Scale 
and Peds Brain Tumor QoL Generic Version  and Peds QoL Generic Version will 
be administered at baseline and every 3 months for the first 2 years, then every 6 
months to month 60. During radiation the Multidimensional Fatigue Acute, 
Symptom Distress, and Brain Tumor QoL and Peds QoL Acute version 
(measuring QoL over the last 7 days) will be administered weekly. Parental proxy 
will be obtained as indicated or if patient is unable to complete the questionnaires.
Sleep Measures
Wrist Actigraphy: The Micromini Sleep Watch (Ambulatory Monitoring Inc., 
Ardsley, NY) is a wristwatch-style device that contains a biaxial piezoelectric 
sensor and a microprocessor with programmable epoch length.  The system’s 
accompanying software will be used to compute the sleep characteristics. Sadeh’s 
algorithm (previously validated against polysomnography in children [81, 86] is 
the basis of the sleep-wake scoring used in the software program. The actigraph 
will be applied at baseline for a 5 day sleep assessment and at annual visit.
Sleep Diary-Parent/Patient: The sleep diary will be completed daily by the parent 
or study participant while wearing the actigraphy. 
The Peds QL Multidimensional Fatigue Scale: is an 18-item Likert type scale with 
three subscales which include general fatigue, sleep/rest fatigue and cognitive 
fatigue. The patient forms are for three different age groups (5 to 7 year olds, 8 to 
12 year olds, and 13 to 18 year olds). There is a parent proxy for each child 
between the ages of 2-18.
The Symptom Distress Scale (SDS): To be completed by children ≥ 7 years of 
age. The SDS is a 10-item, self-report, Likert type scale developed to measure the 
patient’s degree of discomfort from specific treatment related symptoms (i.e., 
nausea, sleep disturbances, appetite, etc.). In our previous work using the SDS 
with adolescents receiving treatment for cancer, the scale achieved coefficient 
alphas of 0.81 to 0.82. The SDS also was noted to have construct validity, as 
hypotheses predicting negative relationships with measures of hopefulness, self-
esteem, and self-efficacy were all supported. The SDS can be completed in 3 to 5 
minutes.
Epworth Sleepiness Scale:  To be completed in children ≥ 7 years of age. The 
ESS is an 8-item questionnaire that rates the probability of falling asleep on a 
scale of increasing probability from 0 to 3 in eight different situations. A total 
score of 0-9 is normal, while a score of 10 or greater indicates sleep referral. The 
ESS has been validated in obstructive sleep apnea through the measurement of 
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excessive daytime sleepiness. We will obtain a parent proxy report for children 
ages 4-6.
Quality of Life
The PedsQL Brain Tumor Module is a 24-item Likert-type scale developed to 
measure health-related quality of life in children and adolescents who are 
receiving treatment or survivors’ of pediatric brain tumors. The module contains 
six scales and includes cognitive, pain and hurt, movement and balance, 
procedural anxiety, nausea, and worry. The research participant’s forms are for 
three different age groups (5 to 7 years, 8 to 12 years, and 13 to 18 years). There 
is a parent form only for research participants between the ages of 2 and 4 years. 
There is no patient instrument for children younger than 5 years. The PedsQL 
Brain Tumor Module forms for the research participant and parents have an 
internal consistency (Cronbach’s alpha coefficients of 0.76-0.87 and 0.78-.92, 
respectively) with construct validity supported through an analysis of the inter-
correlations with the Peds QL and Fatigue Scale [239].
The Pediatric Quality of Life Inventory – PedsQL V.4 is a 23-item Likert-type 
scale developed to measure health-related quality of life in children and 
adolescents that takes about 4 to6 minutes to complete. This instrument has 
parallel forms for patient and parent report, including both acute (QOL within the 
past 7 days) and longer term (QOL within the past 30 days) forms. The patient 
forms are for three different age groups (5 to 7 years, 8 to 12 years, and 13 to 18 
years). There is a parent form only for age group 2 to 4 years. There is no patient 
instrument for children younger than 5 years. Subscales on the PedsQL V.4 
measure the patients’ physical, emotional, social, and school functioning. Both 
patient and parent forms have been found to be internally consistent (Cronbach’s 
alpha coefficients of 0.91 to 0.92, respectively), with clinical validity (i.e., able to 
distinguish between known groups of patients on and off-therapy) and beginning 
construct validity (i.e., hypotheses predicting relationships between certain 
subscales and other indicators of emotional distress, perceived competency, social 
support/functioning, and academic competence were supported) [240, 241].
6.8 
Physical Performance
Physical performance measures will be obtained at baseline, 12, 24, 36, 48 and 60 
months.  Assessment will take place in the human performance lab located at St. 
Jude Children’s Research Hospital.  The lab is staffed with two Master’s level 
Exercise Physiologists with certification as Clinical Exercise Specialists, two 
Physical Therapists and a post-doctoral student with degrees in physical therapy 
and rehabilitation science.  All personnel are certified in exercise testing and 
cardiopulmonary resuscitation.
Overall Physical Performance
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Because there is a fair amount of disagreement between self-reported and test-
based indicators of physical performance, comprehensive evaluations of mobility 
require both performance based and self-reported indicators of function [242]. In 
this protocol, we will evaluate overall physical performance with both a measured 
task sets and patient reported outcomes.  Measured task sets will include the 
Bruninks-Oseretsky Test of Motor Proficiency – Version 2 (Short Form) for those 
4-21 years old and the Physical Performance Test for those 22 years old and 
older.  The self-report instruments for will include the Pediatric Physical Function 
– Mobility Short Form 1 and the Pediatric Physical Function – Upper Extremity – 
Short Form 1 for those 4-17 years, and the Physical Functioning Short Form 1 for 
those 18 years and older.  
The Bruinicks-Oseretsky Test of Motor Proficiency Version 2 (BOT-2) is norm-
referenced and designed to test motor function in children and adolescents 4-21 
years of age.  The motor composite score describes overall motor abilities and 
comprises fine motor control, manual coordination, body coordination, strength 
and agility.  We will use the total motor composite from the BOT-2 Short Form to 
describe overall motor function.  Internal consistency reliability coefficients for 
the BOT-2 total motor composite are 0.95, 0.95 and 0.96 for 4-7, 8-11, and 12-21 
year olds, respectively.  Test-retest reliability correlation coefficients are 0.83, 
0.82, and 0.77 for the three age groups.  Inter-rater reliability is extremely high 
with an overall correlation of 0.98.  Scores on the BOT-2 consistently increase 
with increasing age and have been used to demonstrate differences between 
healthy children and children with clinical motor deficits.  Correlations between 
the BOT-2 and other tests of motor performance, like the Peabody Developmental 
Motor Scales (adj. R2=0.73) and the Test of Visual Motor Skills Revised (adj. 
R2=0.74) have been reported.  The items on the BOT-2 will be administered and 
scored according to the standardized procedures in the manual.  Standard BOT-2 
scores will be used for analysis [243].
To quantify overall physical performance in those 22 years of age and older, 
participants will be asked to complete the 7-task physical performance test (PPT) 
[244]. The PPT is reliable (Cronbach’s alpha=0.87), with excellent test-retest 
reliability (r=0.99).  It is moderately correlated with several other measures of 
health and is more sensitive than traditional self-reports in detecting functional 
loss prior to disability [245, 246]. It includes fine and gross motor components 
and takes approximately 10 minutes to administer.  The PPT was originally tested 
in the elderly in clinical, residential and institutional settings [244]. A 
modification of the PPT has been used to compare cancer survivors with normal 
controls.  Controls outperformed cancer survivors in this study by a factor of at 
least two [247]. Adults with no deficits score a 28/28 on the PPT.    
Self-reported physical performance will be evaluated using the Pediatric Physical 
Function – Mobility Short Form 1 and the Pediatric Physical Function – Upper 
Extremity – Short Form 1 for those 4-17 years, and the Physical Functioning 
Short Form1 for those 18 years and older from the Patient-Reported Outcomes 
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Measurement Information System (PROMIS) 
(http://www.nihpromis.org/default.aspx), a network of NIH-funded primary 
research sites and coordinating centers that have worked collaboratively to 
develop a series of tools to reliably and validly measure patient-reported 
outcomes (PROs). The instruments selected for our protocol are derived from 
patient responses to a set of rigorously designed questions about physical 
functioning.  Each instrument has been subjected to a multi-stage development 
and testing program to ensure that the information meets scientific standards of 
reliability.  The PROMIS instruments are free of charge to enable clinicians and 
researchers to have access to efficient, precise, valid, and responsive indicators of 
a person’s health status.  These measures are available for use across a wide 
variety of chronic diseases and conditions and in the general population.  They are 
free of charge and can be administered via paper and pencil or as computerized 
adaptive testing.
Body Composition
Anthropometric measurements, including height by wall mounted stadiometer 
(without shoes), weight by electronic scale, and waist and hip circumference, will 
be obtained. Trained clinic staff will measure waist and hip girths (cm) with a 
non-stretching anthropometric tape directly over the skin. Waist circumference 
will be measured midway between the anterior superior iliac spine, and the lower 
rib margin and hip girth will be measured at the maximum hip width. 
Measurements will be recorded to the nearest 0.5cm. Waist to hip ratio will be 
calculated by dividing waist by hip circumference. Intra- and inter-rater reliability 
coefficients are reported at 0.99 for waist and at 0.98 for hip measurements [248].  
Waist circumferential measurements have a sensitivity of 85% to correctly 
classify persons with central adiposity when compared to classifications made by 
DEXA [249]. These measurements are part of the comprehensive evaluation and 
will not be treated as individual outcomes.  Body weight and/or BMI are used to 
normalize strength values [250]. 
Flexibility (Ankle Range of Motion and Sit and Reach)
Ankle dorsiflexion active and passive range of motion will be measured with a 
goniometer. The goniometer is a reliable and valid measure of active and passive 
range of motion with standard procedures [251-253].  Normative data have been 
published by Norkin, Moseley and Baggett [254-256]. Overall flexibility will be 
measured by having the participant perform the sit and reach test.  A yardstick is 
placed on a firm flat surface and tape is placed across it at a right angle to the 15 
inch mark.  The participant sits with the yardstick between the legs, with legs 
extended at right angles to the taped line on the floor.  The heels of the feet touch 
the edge of the taped line and are 10-12 inches apart.  The participant reaches 
forward with both hands as far as possible, and the best value for three trials, in 
centimeters, at the fingertips is recorded [67, 257, 258].  Reference ranges for 
typically developing children, adolescents and young adults are available for both 
of these measures [97, 102, 255, 259]. 
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Balance
Balance will be measured by having the subject complete the sensory 
organization test (SOT) on a computerized dynamic posturography system 
(SmartEquitest, Neurocom International).  Participants will stand on dual force 
plates which are pitched up or down in an anterior-posterior direction to provoke 
ankle motion.  The participant stands in an upright position with the medial 
malleoli positioned directly over the axis of rotation of the force plates.  A colored 
visual screen surrounds the participant on three sides.  Visual and kinesthetic 
inputs are manipulated to create six different conditions, each of which is tested 
with three 20 second trials.  During testing, the device continuously records the 
participant’s center of pressure over the force plates.  A difference score is 
computed from the normal range of anterior-posterior sway (12.5 degrees) and the 
maximum range of sway of the participant on each trial; that score is expressed as 
a percentage.  The higher the score, the less the participant swayed.  A trial ending 
in a fall (injury prevented because of the safety harness) is scored at zero [260].  
Mean data from the three trials under each condition will be used to characterize 
balance. Reference data are available for typically developing children, 
adolescents and young adults from the literature and from normal population 
controls tested in our human performance laboratory [261-269]. 
Coordination  
Fine motor coordination will be measured with the composite cerebellar function 
severity score and overall coordination with the brief ataxia rating scale.  The 
composite cerebellar function severity score is based on performance on two fine 
motor tasks.  The examination quantifies finger and hand coordination. The first 
task is the nine-hole pegboard test [270, 271]. The participant is seated and holds 
nine dowels in one hand. The participant places them, one by one, with the 
opposite hand, in a board with nine holes. The time begins when the first peg is 
placed in a hole and ends when the last peg is placed. The second test is the click 
test.  It uses two mechanical counters fixed on a wooden board 39cm apart. The 
participant is seated in front of a table on which the counters are placed. S/he uses 
his/her index finger to press the buttons on the counters alternately 10 times each. 
Timing starts when the first button is depressed and stops when the second 
counter reads 10. The trial is repeated for each hand [272]. The times to complete 
each task are converted into age adjusted z-scores and log transformed.  Normal 
scores range from 0.64-0.94 log seconds. The brief ataxia rating scale (BARS) is a 
modification of the International Cooperative Ataxia Rating Scale (ICARS) 
designed to be used by neurologists and movement specialists.  It includes Gait, 
Kinetic Function- Arm, Kinetic Function-Leg, Speech, and Eye Movements.  It 
correlates with the Modified ICARS and the Scale for the Assessment and Rating 
of Ataxia [273] 0.90 and 0.92. Intra-rater and inter-rater reliability (intraclass 
correlation coefficient) are 0.91 and 0.93 respectively purposes.  Reference data 
are available for both coordination tests [270-272, 274].
Muscle Strength and Power (Knee Extension, Dorsiflexion, and Grip)
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Lower extremity strength values will be evaluated with the Biodex III.  
Participants will be seated for both tests and secured on the padded seat with 
manufacturer provided positioning straps at the chest, waist, and thigh.  Peak 
torques will be recorded during isometric [175] and isokinetic contractions (60, 
120, 180 degrees per second ages 5-12 years, and 60, 180, and 300 degrees per 
second ages 13 years or older - knee; 30, 60 degrees per second - ankle).  
Calibration will be performed before each session according to manufacturer’s 
instructions. Subjects will warm up by walking or cycling for 5 minutes prior to 
testing.  Care will be taken to align the anatomical axis of the joint with the 
mechanical axis of the dynamometer before the tests. Two to four trials will be 
performed before testing, followed by three maximal voluntary movements.  
Torque will be corrected for gravitational moments of the lower leg and the lever 
arm. A rest period of 2 minutes will be allowed between trials to minimize fatigue 
[275].  We will initially use peak torque values from knee speeds of 60 degrees 
per second and ankle speeds of 30 degrees per second for analysis as these speeds 
closely represent power for daily activities like moving sit to stand, climbing 
stairs and lifting and carrying.  Normative values and ranges for children and 
adults are available from the equipment manufacturer and from previously 
published data [68, 123, 250, 276-287].  Hand grip strength in kilograms will be 
measured using a Jamar hand held dynamometer (Sammons Preston Rolyan, 
Nottinghamshire, UK).  Participants will be seated with the shoulder at 0-10 
degrees and the elbow in 90 degrees of flexion.  The forearm will be positioned in 
neutral.  Each participant will complete three trials, the average used for analysis 
[288, 289]. Age and gender specific normative data have been published by 
Mathiowetz et al. [288-290]. 
Cardiopulmonary fitness
Resting Electrocardiogram (ECG): A resting ECG will be completed to examine 
heart rate, rhythm, hypertrophy, and ischemia to rule out any acute cardiac 
problems prior to exercise testing. A standard 12 lead electrocardiogram (the Med 
Graphics Cardio Perfect® Resting/Stress ECG system) will be collected for 15 
seconds at 25mm/s with a gain setting of 10mm/V with the patient in a recumbent 
position. 
Resting Energy Expenditure (REE): REE will be measured with indirect 
calorimetry after an overnight fast. This measurement will be conducted using 
MedgraphicsUltima Cardio O2® metabolic testing system (E.C. Certificate No. 
CE 94534). This system collects breath-by-breath measurements of flow, carbon 
dioxide and oxygen with other calculated gas exchange parameters. Flow is 
measured with the flow sensor connected to a pair of differential pressure 
transducers. Flow through the flow sensor causes a pressure differential that 
generates an electrical signal which is translated into flow and volume 
calculations. Oxygen analysis is performed via gas fuel cell method. This method 
has a range of 0 to 100% oxygen saturation; accuracy is 1% of reading across the 
range, and a response time less than 130 msec [291].  Carbon dioxide is measured 
with a non-dispersive infrared sensor and chambered gas. This method has a 
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range of 0 to 15%, accuracy is ± 0.05 %CO2 and a response time of less than 
130msec [292]. The system is capable of sampling and analysis with as little as 
0.5 L/min. Gas correlations are verified with known gas concentrations before 
each test and flow volumes are calibrated once daily with a 3 L syringe. 
Following a resting ECG recording, a 5 to 10 minute seated rest period will be 
given. After the rest period, the patient will be fitted with a neoprene mask with 
attached pneumotach and sampling lines. The patient will lie in a supine position 
on an exam table for a 5 to 10 minute “settling in” period.  Immediately followed 
by the “settling in” period, data collection will begin and will consist of 10 
minutes of steady state energy expenditure defined as a confidence interval of less 
than 10% [293]. Once breathing and heart rate are stabilized, VO2 and VCO2 will 
be recorded breath by breath for 10 minutes and averaged for analysis. 
Respiratory quotient (RQ) will be continuously monitored and averaged for 
analysis. 
Cardiopulmonary Exercise Test (CPET):  Maximal cardiopulmonary exercise 
testing with ECG and breath by breath gas exchange analysis will be completed 
on a treadmill using the Balke protocol or cycle ergometer using an incremental 
ramping protocol. During this test, ECG, and gas exchange will be monitored 
continuously by the previously described systems while blood pressure will be 
measured every 2 minutes throughout the protocol using the Tango automated 
system interfaced to the Cardioperfect program. Rating of perceived exertion will 
be monitored with each blood pressure check using the modified Borg scale with 
the faces of exertion. 
The Balke protocol will be used for the treadmill test will be completed on a 
Trackmaster 425 [294]. After a light warm up, the protocol will begin with the 
child walking at 3.5 mph on a 0% graded and increasing incline 2% every 2 
minutes until exhaustion. The participant will be instructed to use the rails for 
balance only and a spotter will be in place in the event of a fall or stumble. This 
test may be modified by adding initial incline and/or increasing speed for more fit 
participants with the goal of keeping test duration between 8 and 11 minutes.
A cycle ergometer protocol will be used in those who are unable to complete the 
treadmill test. A ramp protocol will be chosen based on the participant’s current 
fitness level. For smaller and unfit children, an initial workload of 10 W and an 
increase of 10 W/min until exhaustion will be used. For older and more fit 
children, an initial workload of 20 to 25 W and an increase of 20 to 25 W/min will 
be used [294]. The Lode Corival cycle ergometer is fully adjustable and capable 
of accommodating small children to adults. The seat height and crank length will 
be adjusted to create 160 degree knee bend at full extension. The participant will 
be instructed to maintain a pedaling cadence equal to 50 to 60 rpm. The rpm will 
be continuously displayed in direct view so the participant has constant feedback 
and can adjust cadence accordingly. 
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For both modes of CPET, ECG, gas collection, and blood pressure monitoring 
will begin 5 to 10 minutes pre test and continue until 5 to 10 minutes post test 
termination.  All exercise testing will continue until exhaustion. The CPET will be 
terminated early if the clinical information indicates that further testing would 
compromise the patient’s health, when the clinical findings are established and 
additional testing is unlikely to provide more information, and if there is any 
abnormality or malfunction of testing equipment. The following clinical signs will 
be used in addition to good clinical judgment to determine termination necessity 
(304). 

A decrease in ventricular rate with increasing workload associated with 
symptoms inadequate cardiac output 

Failure of heart rate to increase with exercise and symptoms indicating 
inadequate cardiac output 

Progressive fall in systolic blood pressure with increasing workload

Severe hypertension in excess of 250mmHg systolic or 125mmHg diastolic 

Dyspnea the participant finds intolerable

Symptomatic tachycardia the participant finds intolerable

Presence of a ≥ 3mm flat or downward sloping ST-segment depression

Increasing ventricular ectopy with increasing workload, including a > 3- beat 
run

Patient requests termination of the study 
Normative data for cardiopulmonary testing are available for children, adolescents 
and adults [102-107]. 
6.9  
Diagnostic and Investigational MR Imaging
6.9.1  General Information
Diagnostic imaging will be performed at enrollment regardless of prior surgery 
history.
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(1) Investigational imaging may be performed at enrollment or deferred until after 
planned surgery.
(2) Diagnostic imaging should be repeated when indicated after planned surgery 
and prior to radiation therapy.
(3) Repeating the investigational imaging following planned surgery is not 
required if performed at the time of enrollment; however, attempted completion of 
the investigational imaging is expected prior to radiation therapy.
6.9.2  Diagnostic MR Examination
The number of diagnostic imaging studies is similar to the follow-up of newly 
diagnosed patients. Each patient will have the diagnostic imaging study 
performed at the time of enrollment. The initial diagnostic study will serve as the 
baseline evaluation and the dataset to be used to assess for residual disease after 
surgery and for radiation therapy planning. The diagnostic imaging study will be 
repeated for those who undergo surgical intervention, when indicated. Diagnostic 
imaging performed prior to enrollment is considered part of the dataset and 
critical to this research and the evaluation and treatment of each patient.
The study time point (t=0) will be the first day of radiation therapy. Follow-up 
MRI will be performed every 3 months for the first 2 years, then 6 month 
intervals through the end of the fifth year. Optional MRI scan at 27 and 33 month 
at the discretion of the treating physician.
Diagnostic imaging performed for suspected neurotoxicity should include the 
standard protocol sequences. Diagnostic imaging performed at unscheduled time 
points because of concerns regarding toxicity, tumor progression or other reasons 
will be considered part of the protocol data set even though the methods for these 
evaluations may not correspond exactly to the protocol. It is suggested that the 
protocol imaging sequences be used in these unscheduled evaluations.
The core clinical imaging examination will be according to the prevailing St. Jude 
standard of care.  Diffusion tensor imaging and investigational MT imaging will 
be performed at each follow-up.  After the acquisition of four DTI/MT 
examinations in 15 patients, interim analysis of MT imaging data will be 
performed. The investigational MT sequence will no longer be performed after 
8/1/2020.  Perfusion MRI and susceptibility-weighted imaging [295] will be 
performed once per year.  Perfusion MRI will permit evaluation of subtle changes 
in perfusion, which may accompany microvascular damage undetectable by 
conventional MR angiographic imaging. Susceptibility-weighted imaging allows 
the detection and characterization of subtle foci of hemorrhage or mineralization 
not detectable on conventional sequences. Baseline DTI FA and ADC in 
brainstem and cerebellar peduncles will be compared to healthy children 
benchmarks. The time course of DTI FA and ADC changes in brainstem and 
cerebellar peduncles will be determined. The perfusion of motor and sensory 
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cortex and tumor will be observed, DTI of white matter tracts will be correlated 
with neurological outcome.
All clinical and research MR imaging studies will be performed on 3T MR 
systems unless contraindicated. To facilitate comparisons with magnetization 
transfer imaging and previously acquired benchmark data in healthy children, 
examinations performed at St. Jude will be preferentially performed on the 3T 
Trio system (Siemens, Erlangen Germany), and may be performed at 1.5T if 
imaging at 3T is contraindicated.
6.9.3  Positron Emission Tomography
Positron emission tomography (PET) will be performed at the time of study entry, 
12, 24, and 36 months after the start of radiation therapy. The objective of this 
study is to correlate PET findings with rate and pattern of failure. The 
interpretation will include degree of avidity (none, low, moderate, high) and 
qualitative change when reviewing follow-up studies. The following data will be 
acquired: 1) metabolic tumor volume at different SUV levels; 2) metabolic 
activity within MRI defined volumes (target volumes and solid, cystic and 
combined components); 3) minimum, maximum and mean SUV of the solid 
component, 4) SUV distributions of the metabolic tumor volume and MRI defined 
volumes at different time points; and 5) change in parameters over time.
F18-FDG PET will be obtained with the patient NPO for at least 6 hours. Images 
will be acquired in 3-D mode for 5-15 minutes, 1 hour after the administration of 
F18-FDG. Radiopharmaceutical dose will be 0.10-0.15 mCi/kg body weight 
(minimum: 2mCi per dose; maximum: 12mCi per dose). A non-contrast CT scan 
of the area of interest will be obtained immediately prior to the commencement of 
PET image acquisition.
6.9.4 MET-PET
MET-PET participants will fast for at least 4 hours prior to the study. Patients are 
then injected intravenously with 20mCi/1.7 sq m body surface area of 11C-
methionine (maximum prescribed dose 20 mCi). The administered dose will be 
+/- 20% of the prescribed dose due to the rapid decay of 11C-methionine. For 
doses outside this range, physician documentation is required. A non-contrast CT 
scan of the area of interest will be obtained immediately prior to the 
commencement of PET image acquisition. Scanning may begin immediately for 
dynamic studies using a framing rate to be determined. For non-dynamic studies, 
scanning may begin ~ 5 minutes after injection for ~15 minutes. Acquired data 
are reconstructed into multiplanar attenuation and nonattenuation images using 
standard vendor supplied software.
PET Logistics: In the event of delays which cause the available activity to fall to 
less than 25% of the prescribed dose, then the decision to proceed will be based 
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on factors such as ability to reschedule the patient in a timely manner, cyclotron 
chemistry availability, anesthesia resources, need to commence therapy, etc. The 
nature of the study allows flexibility. The study can be abbreviated and tailored so 
that the primary objective can be satisfied without sufficient activity to address 
the secondary objectives. Image analysis will be performed both qualitatively and 
semi quantitatively.
PET Analysis: Qualitative analysis will be conducted by the responsible 
investigators and will consist of visual inspection of the area suspected to contain 
tumor and comparison with uninvolved nearby tissue. The tumor will be 
compared with uninvolved brain and the uptake will be graded on a scale 
comparable to the following: 0=no detectable uptake; 1=uptake present but less 
than noninvolved background; 2= uptake approximately equal to background; 
3=uptake greater than background. Semi-quantitative analysis will be performed 
include calculation of a standardized uptake value (SUV: activity in the region of 
interest normalized to participant weight and injected dose) by drawing a region 
of interest (ROI) over the area suspected to contain tumor.
6.10
Pathology and Biological Studies 
6.10.1  Central pathology review
All tumor samples will be submitted for pathology review and biological studies 
(see below for guidance on submission of tissue to St. Jude Children's Research 
Hospital). 
The purpose of pathology review is to confirm that patients registered on the trial 
have a diagnosis of ependymoma as follows:

Classic ependymoma (WHO grade II) 

Anaplastic ependymoma (WHO grade III)
Tumors with a diagnosis of ependymoblastoma and other embryonal tumors or 
gliomas are not eligible. 
Pathology review will be undertaken on submitted unstained sections on slides 
and tissue scrolls from formalin-fixed paraffin-embedded (FFPE) tissue blocks 
used to make the initial (first surgery) diagnosis of ependymoma AND on 
submitted unstained sections on slides and tissue scrolls from FFPE tissue blocks 
used to confirm a diagnosis of recurrent ependymoma at any subsequent surgical 
resection. An additional aim of pathology review, in the event of obtaining 
peritumoral CNS tissue, is assessment of the adverse effects of prior radiation 
therapy on normal tissues, including blood vessels. 
6.10.2  Biological studies 
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IRB APPROVAL DATE: 02/01/2023

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All tumor samples will be submitted for pathology review and biological studies 
(see below for guidelines on submission of tissue). However, in a situation where 
tumor samples are limited, the priority will be an accurate pathological diagnosis. 
6.10.3  Methods
Biological studies will be undertaken on diagnostic FFPE samples with regard for 
preserving tumor in the tissue block(s). Tissue archived at initial presentation 
(first surgery) and obtained at subsequent surgical events for recurrent tumor(s) 
will be requested. 
 
6.10.4  Preparation and shipment of tissue
Where frozen samples that have been flash-frozen and stored at -80oC or in liquid 
nitrogen are available, we request 100-200mg of tissue, which should be shipped 
to the address below on dry ice separately from FFPE tissue. 
Whether frozen samples are available or not, we are requesting FFPE tissue 
blocks as described above for both pathology review and biological studies. If 
FFPE blocks are submitted, these will be processed rapidly by the SJCRH 
neuropathology research laboratory and returned to the referring pathology 
department with adequate tissue for further diagnostic or medicolegal use. FFPE 
blocks are much preferred, but if they cannot be submitted, we request the 
following materials from the referring pathology department, which will used for 
both pathology review and biological studies:

20x5µm FFPE sections from a block containing at least a 10x10mm area of 
tumor without surgical or processing artifacts placed on coated slides 
(safeguard for antigen retrieval during immunohistochemistry). If a block 
conforming to these criteria exists and also contains peritumoral CNS 
parenchyma, then this tissue is preferred. 

3x20µm FFPE tissue scrolls placed in a single Eppendorf tube. 
All samples must be submitted with patient identifiers and information, e.g., 
pathology accession number, which will identify primary, recurrent and 
metastatic tumor samples. For the purpose of pathology review, it is also 
necessary to submit copies of pathology reports from initial diagnosis (first 
surgery) and subsequent surgical events for recurrent or metastatic disease, from 
which samples are submitted. This allows confirmation of diagnosis and accurate 
identification of samples. 
For biological studies, all samples will be de-identified and receive a code that 
will render the samples (link)-anonymized for research aspects of the trial. Frozen 
tissue samples will be stored in the Tissue Resources Laboratory at SJCRH. 
St. Jude Children's Research Hospital
IRB NUMBER: Pro00004349
IRB APPROVAL DATE: 02/01/2023

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Rev. 3.2  dated:   1/19/2023                                                   IRB Approval date:  
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FFPE samples can be shipped overnight at room temperature, along with any 
venous blood samples, but separate from any frozen samples (see above for 
guidelines), to the address below. 
Tissue samples should be shipped to: 
Dr. David Ellison
Dept. of Pathology 
St. Jude Children's Research Hospital
262 Danny Thomas Place, MS# 250
Memphis TN 38105
901-595-5438 (tel.)
901-595-3100 (fax.)
It is important to ship samples by FedEx overnight to SJCRH and to avoid 
shipment dates that will avoid receipt at SJCRH on weekends or US public 
holidays. 
6.10.5   Cytokine Collection
Purpose: Collect and store patient blood for future cytokine measurement.
Procedure for Processing Blood for Cytokine Collection, Storage, and 
Documentation
1. Verify patient lab order and collection date and time.  
2. Use Universal Precautions.  Draw blood from patient (blood will be collected 
in Ambulatory Clinics:  A/T, Chili’s Center, and TTU).
3. Collect two tubes: one purple top for plasma (EDTA coated) and one red top 
tube for serum; tube size 5 cc.  Collect approximately 4 cc blood for purple top 
(plasma) and 2 cc blood for red top (serum).  Place tubes vertical in ice in 
hazardous bag. A/T clinic will page (#1223) the research nurse when blood is 
ready for pick-up. Verify patient name on tube upon pick-up. Print out extra 
labels for storage tubes. Bring blood tubes w/ labels to Danny Thomas 
Research Center Room D5031.
4. Wipe tubes with Kimwipe and place in centrifuge (equal and opposite). Spin 
samples for 20 minutes @ 4,200 rpm at 4° C. Prepare labels while tubes are 
spinning; total 6 cryogenic tubes per patient; 3 plasma and 3 serum.
5. Put on gloves. After spinning is complete, take tubes out and place on rack on 
a clean work bench. Purple tube = plasma; red top = serum. Remove plasma 
and serum by pipetting into cryogenic tubes by the following method:  
6. Process plasma (purple top) first. Total of 450 µl plasma will be collected in 
increments of 150 µl: pipette 150 µl of plasma into each tube until total of 450 
µl (pipette 150 µl into each tube x 3).
7. Repeat the process for the serum (red top) for a total of 450 µl per 3 serum 
tubes.  
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8. Note: keep volume in 150 µl increments. It may be too difficult to get the full 
450 µl in each tube: pipette 450, 300 or 150 µl. Record exact volume of each 
tube on label. To assist in identifying plasma vs. serum, mark all plasma tube 
caps (top of tube) with black sharpie marker.
9. Screw top cap on cryogenic tube. Place label on cryo tube with the following 
information: ID#, patient’s name, date collected, plasma vs. serum; quantity in 
µl, and evaluation time point.  Place tubes in order inside Revco storage box. 
In the storage box, for each patient, place the 3 plasma tubes first followed by 
the 3 serum tubes.  Place Revco box in deep freeze refrigerator set at minus 
80° C.
Document
1. Record: document on the Recording Sheet for Cytokine Collection.  This 
recording sheet contains the following: protocol number, patient’s name, 
medical record number, date collected, box number, time point collected 
(evaluation), number of tubes with quantity in each, and collector’s initial.
2. Record: document on the Revco Box Record of Samples (this identifies what is 
located inside each box).
3. Record:  place large Millie lab label with accession number and collection date 
in cytokine binder in Radiation Oncology research office.
4. Record lab collection and completion in Millie through PathNet Application 
Bar (AppBar). This will ensure and record the lab completion in Powerchart 
orders.
6.11
Patient Support
In order to pursue all-inclusive care and support for RERTEP patients, a 
consultation visit may be scheduled with Quality of Life Services and neuro-
oncology. These services will be considered standard of care and unrelated to any 
protocol testing; no data will be collected from these visits. 
Quality of Life Services
Integration of pediatric palliative care for children with relapsed or progressive 
ependymoma and their families is an integral aspect of the provision of holistic 
cancer care. Patients on RERTEP may receive consultation with the Quality of 
Life for All (QOLA) team, and the QOLA team provides longitudinal services 
and resources to the patient and family throughout their illness trajectory, 
including at the end of life. The QOLA team is comprised of physicians, nurse 
practitioners, nurses, and a specialized grief and bereavement psychologist, all of 
whom are trained in the expert provision of compassionate palliative care and 
hospice services for children with cancer. The primary goal of the QOLA team is 
to alleviate or mitigate physical, psychosocial, and spiritual distress experienced 
by the patient or family. QOLA clinicians are available 24-7 to assist with the 
management of complex or refractory symptoms, as well as to provide 
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IRB NUMBER: Pro00004349
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Protocol document date: 1/19/2023                                
anticipatory guidance with regards to expected signs and symptoms of disease 
treatment, progression, and the end of life period. Additionally, QOLA clinicians 
provide psychosocial support to patients and families during this challenging 
emotional period, and they collaborate closely with psychology, spiritual care, 
child life, and social work to optimize psychosocial services for patients and 
families. QOLA clinicians also assist with care coordination across diverse care 
locations, including coordination of community-based palliative care and hospice 
services and resources, and they remain available 24-7 to provide guidance via 
telephone to patients, families, and local palliative care teams and hospice 
agencies to ensure high-quality care at every stage of the illness experience.
Neuro-Oncology 
With permission of the patient or parent, a consultation will be scheduled with the 
neuro-oncology service to discuss treatment options in addition to re-irradiation. 
The purpose of the consultation will be provision of information and will not infer 
that systemic therapy will be provided or administered by the consulting unit. The 
goal will be to ensure that the patient or their parents understand available 
treatment options.
Table 6.0.1 
Evaluations at Baseline and Follow-up (Prior to Amendment 2.0)
Months after RT Start
Evaluations/Schedule1
0
4
8
12
16
20
24
28
32
36
42
48
54
60
Imaging
Diagnostic/Investigational MR
X
X
X
X
X
X
X
X
X
X
X
X
X
X
MR Spine4
X
X
X
X
X
X
FDG-PET6
X
X
X
X
PET-methionine6, 7
X
X
X
X
Lateral skull X-ray
X
Bone Age/Q-CT/DEXA
X
Clinical-Standard
Assessment/Triage
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Exam‡#
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Lab: CBC‡
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Lab: Chemistry‡
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Lab: Endocrine Screen‡
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Audiometry2‡
X
X
X
X
X
X
Endocrine Clinic‡
X
X
X
X
X
X
Neurology Clinic‡
X
X
X
X
X
X
Ophthalmology‡
X
X
X
X
X
X
CSF Cytology5
X
Clinical-Investigational
Endocrine/Provocative3
X
X
X
Psychology
X
X
X
X
X
X
Function Laboratory
X
X
X
X
X
X
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IRB NUMBER: Pro00004349
IRB APPROVAL DATE: 02/01/2023

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Rev. 3.2  dated:   1/19/2023                                                   IRB Approval date:  
Protocol document date: 1/19/2023                                
Sleep/Fatigue Research
Actigraphy
X
X
X
X
X
X
Questionnaires/QOL
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory-Investigational
Genomics
X
Cytokines7
X
X
X
X
X
X
*Patient of childbearing potential requires a negative pregnancy test prior to starting treatment. (‡) should be repeated if clinically 
indicated following craniotomy. 1Imaging and clinical tests should be performed prior to radiation therapy; however, logistics 
may make it difficult to complete all exams prior to treatment. The principal investigator reserves the right to accept pre-
irradiation testing within 16 weeks of the initiation of radiation therapy. PET-FDG and PET-methionine will also be done at time 
of progression or recurrence if prior to 24 months. Assessment/triage includes neck and abdomen circumference. #Edinburgh 
Handedness Inventory performed once. 2Patients who are unable to undergo standard audiometry may undergo ABR at the 
treating physician’s discretion. 3Provocative screening will not be conducted for patients when the number of days off 
corticosteroids prior to the test date is less than the number of days on corticosteroids prior to discontinuance.4MR spine may be 
performed more frequently for patients with spinal metastatic disease or at the discretion of the treating physician. 5Lumbar 
puncture for CSF cytology may be waived with PI approval based on contraindication or if adequate evaluation was performed 
within 3 weeks of enrollment.  6MET PET and FDG-PET scans not performed at 12, 24 or 36 month evaluation may be 
performed at a subsequent follow-up evaluation. All METPET studies will be whole-body regardless of the presence or absence 
of metastatic disease at the time of enrollment. 7Test will not be collected after July 1, 2020
St. Jude Children's Research Hospital
IRB NUMBER: Pro00004349
IRB APPROVAL DATE: 02/01/2023

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Rev. 3.2  dated:   1/19/2023                                                   IRB Approval date:  
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Table 6.0.2 
Evaluations at Baseline and Follow-up at St. Jude (Amendment 2.0) 
Months after RT Start
Evaluations/Schedule1
0
3
6
9
12
15
18
21
24
27**
30
33**
36
42
48
54
60
Imaging
Diagnostic/Investigational 
MR
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
MR Spine4
X
X
X
X
X
X
FDG-PET6
X
X
X
X
PET-methionine6, 9
X
X
X
X
Lateral skull X-ray
X
Bone Age/Q-CT/DEXA7
X
Clinical-Standard
Assessment/Triage
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Exam‡#
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Lab: CBC‡
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Lab: Chemistry‡
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Lab: Endocrine Screen‡
X
X
X
X
X
X
X
X
X
X
X
X
X
Audiometry2‡
X
X
X
X
X
X
Endocrine Clinic‡
X
X
X
X
X
X
Neurology Clinic‡
X
X
X
X
X
X
Ophthalmology‡
X
X
X
X
X
X
CSF Cytology5
X
Clinical-Investigational
Endocrine/Provocative3
X
X
X
Psychology
X
X
X
X
X
X
Function Laboratory
X
X
X
X
X
X
Sleep/Fatigue Research
Actigraphy
X
X
X
X
X
X
Questionnaires/QOL
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory-
Investigational
Genomics
X
Cytokines8, 9
X
X
X
X
X
X
*Patient of childbearing potential requires a negative pregnancy test prior to starting treatment. (‡) should be repeated if clinically 
indicated following craniotomy. 1Imaging and clinical tests should be performed prior to radiation therapy; however, logistics 
may make it difficult to complete all exams prior to treatment. The principal investigator reserves the right to accept pre-
irradiation testing within 16 weeks of the initiation of radiation therapy. PET-FDG and PET-methionine will also be done at time 
of progression or recurrence if prior to 24 months. Assessment/triage includes neck and abdomen circumference. #Edinburgh 
Handedness Inventory performed once. 2Patients who are unable to undergo standard audiometry may undergo ABR at the 
treating physician’s discretion. 3Provocative screening will not be conducted for patients when the number of days off 
corticosteroids prior to the test date is less than the number of days on corticosteroids prior to discontinuance.4MR spine may be 
performed more frequently for patients with spinal metastatic disease or at the discretion of the treating physician. 5Lumbar 
puncture for CSF cytology may be waived with PI approval based on contraindication or if adequate evaluation was performed 
within 3 weeks of enrollment.  6MET PET and FDG-PET scans not performed at 12, 24 or 36 month evaluation may be 
performed at a subsequent follow-up evaluation. All METPET studies will be whole-body regardless of the presence or absence 
St. Jude Children's Research Hospital
IRB NUMBER: Pro00004349
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of metastatic disease at the time of enrollment. 7Patient must be > 3 years of age. 8For patients enrolled before August 30, 2019   
9Test will not be collected after July 1, 2020 **Optional at the dicretion of the treating physician
Table 6.0.3 Evaluations during Radiation Therapy at St. Jude
Week on therapy
Evaluation
1
2
3 
4 
5 
6 
7 
Imaging 
Activation PET*
X
X
X
X
X
X
X
Clinical-Standard
Physical examination
X
X
X
X
X
X
X
CBC
X
Chemistry
X
Clinical-Investigational
QOL
X
X
Toxicity Assessment
X
X
X
X
X
X
X
Laboratory-Investigational
Cytokines1
X
X
*frequency depending on feasibility and availability
1For patients enrolled before August 30, 2019 
7.0
EVALUATION CRITERIA
In the setting of high-dose irradiation, tumor and normal tissue responses 
observed on imaging (MR and PET) may mimic tumor progression or present a 
mixed picture that might include a range of responses including tumor 
progression, tumor pseudo progression or necrosis. Key to the evaluation of 
response is timing relative to treatment, history of prior treatment(s) and toxicity, 
and the presence or absence and volume of residual disease. Disease progression 
should not be based on a single imaging examination time point, rather definitive 
evidence of unrelenting tumor progression. In the setting of high-dose irradiation, 
the specter of necrosis and the urgency associated with intervention and 
mitigating the consequences of parenchymal and vascular damage requires serial 
and multimodality imaging examinations at short intervals. The investigator has 
the option of repeating the MRI, earlier than the next scheduled follow-up, to 
confirm disease progression, necrosis or in considering surgery to document the 
same. Disease progression and response will be determined using conventional 
MR imaging sequences.
Response Criteria
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Protocol document date: 1/19/2023                                

Complete Response: the disappearance of all neuroimaging-discernable 
tumor.

Partial Response: A greater than 50% decrease in the product of the 
perpendicular diameters of the tumor measured relative to the baseline 
evaluation, without the appearance of any new areas of disease.

Stable Disease: A less than 50% decrease in the product of the perpendicular 
diameters of the tumor relative to the baseline evaluation, without the 
appearance of any new areas of disease. For patients treated following gross-
total resection, stable disease is defined as the lack of appearance of any new 
discernable tumor.

Progressive Disease: Greater than 25% increase in the product of the 
perpendicular diameters of the tumor relative to the baseline evaluation or the 
appearance of any new areas of disease. Progression of disease is 
characterized similarly with an increase noted on successive imaging 3-6 
months after the study which first demonstrated tumor area or volume 
enlargement of more than 25%. Cystic enlargement is not considered to be 
progression of disease. Investigators may elect to repeat imaging earlier that 
the next scheduled follow-up or wait until the next scheduled follow-up to 
declare progression.
Necrosis
Necrosis will be defined by enhancement of normal tissues as assessed by 
contrast-enhanced T1-weighted MR imaging, increased signal on T2 and FLAIR 
imaging, and the imaging parameters of apparent diffusion coefficient, fractional 
anisotropy, FDG-PET, and MR spectroscopy, when available. The gold standard 
to diagnose radiation necrosis has been biopsy; however, surgical intervention 
may increase morbidity, especially when considering the brainstem and 
cerebellum. Several imaging modalities have been investigated for their ability to 
diagnose necrosis and distinguish between necrosis and recurrent tumor. We will 
rely on serial changes, including increasing parenchymal enhancement on post-
contrast T1 images and increasing volume of T2-weighted MR imaging signal 
abnormality and symptoms to grade necrosis according to the CTCAE v4.0. We 
have found that resolution of necrosis can be a long process during which lesions 
can show signs of improvement followed by progression in the same or other sites 
before stabilizing. According to the CTCAE v4.0 terminology, CNS necrosis has 
five grades: (1) asymptomatic; clinical or diagnostic observations only; 
intervention not indicated, (2) moderate symptoms; corticosteroids indicated, (3) 
severe symptoms; medical intervention indicated, (4) life-threatening 
consequences; urgent intervention indicated, (5) death. We anticipate that the rate 
of CNS necrosis (CTCAE v4.0 > grade 3) will be greater than 5% and less than 
20% when estimated at one year. The lower bound of this estimate is based on our 
published data for patients treated in the primary setting [6, 137, 296]. The upper 
bound of this estimate is empiric. Asymptomatic patients with grade 1 necrosis 
referred for hyperbaric oxygen or other interventions to prevent progression of 
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imaging findings and the potential development of symptoms will be scored as 
grade 1 with supportive documentation. 
8.0
REMOVAL FROM PROTOCOL AND OFF-STUDY CRITERIA
The survival for all participants will be followed on study until their death unless 
they or their parents request that no further information be made available to this 
study group.
For participants who are treated at collaborating institutions it is recommended 
that each patient to be taken off protocol be discussed with the PI of the study and 
if needed, pertinent studies should be sent to the PI for review.
8.1
Off-Study Criteria:

Parent/Patient request

Death

PI discretion 

Lost to follow-up

Protocol compliance

Study completion

Treatment with chemotherapy during the administration of radiation therapy

Disease progression
8.2
Collaborating Sites Notification
Collaborating institutions should enter an off-study date into CRIS database, 
accompanied by emailing a copy of the clinic/progress note documenting the 
reason the participant was taken off study to RadiationOncology-
CRA@STJUDE.ORG.
9.0
SAFETY AND ADVERSE EVENT REPORTING REQUIREMENTS
9.1  
Reporting Adverse Experiences and Deaths to St. Jude IRB
9.1.1
Only “unanticipated problems involving risks to participants or others” 
referred to hereafter as “unanticipated problems” are required to be reported to the 
St. Jude IRB promptly, but in no event later than 10 working days after the 
investigator first learns of the unanticipated problem. Regardless of whether the 
event is internal or external (for example, an IND safety report by the sponsor 
pursuant to 21 CFR 312.32); only adverse events that constitute unanticipated 
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problems are reportable to the St. Jude IRB.  As further described in the definition 
of unanticipated problem, this includes any event that in the PI’s opinion was:
•
Unexpected (in terms of nature, severity, or frequency) given 1) the 
research procedures that are described in the protocol-related documents, 
such as the IRB-approved research protocol and informed consent 
document, as well as other relevant information available about the 
research; 2) the observed rate of occurrence (compared to a credible 
baseline for comparison); and 3) the characteristics of the subject 
population being studied; and
•
Related or possibly related to participation in the research; and
•
Serious; or if not serious suggests that the research places subjects or 
others at a greater risk of harm (including physical, psychological, 
economic, or social harm) than was previously known or recognized. 
Unrelated, expected deaths do not require reporting to the IRB.  Though 
death is “serious”, the event must meet the other two requirements of 
“related or possibly related” and “unexpected/unanticipated” to be 
considered reportable.
Deaths meeting reporting requirements are to be reported immediately to 
the St. Jude IRB, but in no event later than 48 hours after the investigator 
first learns of the death. 
9.1.2
The following definitions apply with respect to reporting adverse 
experiences: 
9.1.2.1 Serious Adverse Event (SAE): Any adverse event temporally associated 
with the subject’s participation in research that meets any of the following criteria:
•
results in death;
•
is life-threatening (places the subject at immediate risk of death from the 
event as it occurred);
•
requires inpatient hospitalization or prolongation of existing 
hospitalization;
•
results in a persistent or significant disability/incapacity;
•
results in a congenital anomaly/birth defect; or
•
any other adverse event that, based upon appropriate medical judgment, 
may jeopardize the subject’s health and may require medical or surgical 
intervention to prevent one of the other outcomes listed in this definition 
(examples of such events include:  any substantial disruption of the ability 
to conduct normal life functions, allergic bronchospasm requiring 
intensive treatment in the emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse), a congenital 
anomaly/birth defect, secondary or concurrent cancer, medication 
overdose, or is any medical event which requires treatment to prevent any 
of the medical outcomes previously listed.  
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For the purpose of this protocol, the following events will NOT be considered 
serious or unexpected adverse events:
•
Radiation Dermatitis, Dry skin
•
Pain due to Radiation
•
Mucositis
•
Nausea, Vomiting, Loss of appetite, Fatigue
•
Hair loss
•
New or recurrent neurological systems such as swelling of the brain 
•
Cyst enlargement
•
Stroke occurring after completion of radiation therapy
•
Secondary tumors occurring after completion of radiation therapy
•
Hormone deficiencies
•
Events relating to hypothalamic obesity, precocious puberty or diabetes 
insipidus
•
Loss of hearing, vision or neurological function and seizure
•
Death unequivocally related to disease progression; hospitalization for 
treatment of expected signs or symptoms of disease complications (shunt 
placement and revisions, cyst decompression) or progression of disease
•
Wound infection or dehiscences from surgery
•
Necrosis
9.1.2.2 Unexpected Adverse Event: 
•
Any adverse event for which the specificity or severity is not consistent 
with the protocol-related documents, including the applicable investigator 
brochure, IRB approved consent form, Investigational New Drug (IND) or 
Investigational Device Exemption (IDE) application, or other relevant 
sources of information, such as product labeling and package inserts; or if 
it does appear in such documents, an event in which the specificity, 
severity or duration is not consistent with the risk information included 
therein; or 
•
The observed rate of occurrence is a clinically significant increase in the 
expected rate (based on a credible baseline rate for comparison); or 
•
The occurrence is not consistent with the expected natural progression of 
any underlying disease, disorder, or condition of the subject(s) 
experiencing the adverse event and the subject’s predisposing risk factor 
profile for the adverse event. 
9.1.2.3 Internal Events: Events experienced by a research participant enrolled at a 
site under the jurisdiction of St. Jude IRB for either multicenter or single-center 
research projects.
9.1.2.4 External Events: Events experienced by participants enrolled at a site 
external to the jurisdiction of the St. Jude Institutional Review Board (IRB) or in a 
study for which St. Jude is not the coordinating center or the IRB of record.
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9.1.2.5 Unanticipated Problem Involving Risks to Subjects or Others: An 
unanticipated problem involving risks to subjects or others is an event which was 
not expected to occur and which increases the degree of risk posed to research 
participants.  Such events, in general, meet all of the following criteria: 
•
unexpected; 
•
related or possibly related to participation in the research; and 
•
suggests that the research places subjects or others at a greater risk of 
harm (including physical, psychological, economic, or social harm) than 
was previously known or recognized.  An unanticipated problem involving 
risk to subjects or others may exist even when actual harm does not occur 
to any participant. 
9.1.3
Consistent with FDA and OHRP guidance on reporting unanticipated 
problems and adverse events to IRBs, the St. Jude IRB does not require the 
submission of external events, for example, IND safety reports, nor is a summary 
of such events/reports required; however, if an event giving rise to an IND safety 
or other external event report constitutes an “unanticipated problem involving 
risks to subjects or others” it must be reported in accordance with this policy.  In 
general, to be reportable external events need to have implications for the conduct 
of the study (for example, requiring a significant and usually safety-related change 
in the protocol and/or informed consent form).
9.1.4
Although some adverse events will qualify as unanticipated problems 
involving risks to subjects or others, some will not; and there may be other 
unanticipated problems that go beyond the definitions of serious and/or 
unexpected adverse events.  Examples of unanticipated problems involving risks 
to subjects or others include:
•
Improperly staging a participant’s tumor resulting in the participant being 
assigned to an incorrect arm of the research study;
•
The theft of a research computer containing confidential subject 
information (breach of confidentiality); and 
•
The contamination of a study drug.  Unanticipated problems generally will 
warrant consideration of substantive changes in the research protocol or 
informed consent process/document or other corrective actions in order to 
protect the safety, welfare, or rights of subjects or others.
9.2  
Serious Adverse Events (SAE) or Adverse Events (AE) felt to be related to 
11C-methionine (IND #104987)
Participants will be carefully monitored and adverse events collected using the 
Common Terminology Criteria for Adverse Events version 4.0 (CTCAE) during 
active participation of the 11C-methionine PET scan. Active participation is 
defined as: from time of injection through one hour post injection of 11C-
methionine. Vital signs (BP, RR, HR) will be assessed prior to receiving the 
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injection and at the end of the MET PET scan. Participants will be watched 
continuously via an in-room camera during the scan.
REPORTING REQUIREMENTS: 
Office of Human Subjects’ Protection (OHSP): The non-serious adverse events 
occurring during active participation will be reported to the OHSP in the 
continuing review reports. In addition to the continuing review reports to the 
Institutional Review Board, known as the Office of Human Subjects’ Protection 
(OHSP), the principal investigator is responsible for the expeditious reporting of 
all serious, unexpected adverse events (AEs) involving research participants that 
occur during active participation. All adverse events occurring outside of active 
participation (injection to one hour post injection) will follow reporting rules set 
in Section 9.1.
Serious Adverse Events (SAEs) occurring during active participation that are 
unexpected-fatal or unexpected-life threatening are to be reported to the OHSP 
immediately, but every effort will be made to assure it is no later than 48 hours of 
notification of the event to the principal investigator or designees. All other 
unexpected (non-fatal or non-life threatening) SAEs occurring during active 
participation will be reported as soon as possible but within 10 working days of 
notification of the event.  All other SAEs occurring outside of active participation 
will be reported according to the reporting rules in 9.1.
The SAE of expected death for all on study participants will be reported to the 
OHSP as soon as possible but no later than approximately 3 working days upon 
notification of event to the principal investigator or designees. Expected, life 
threatening SAEs noted during active participation will be reported to the OHSP 
as soon as possible but no later than 10 working days of notification of the event 
to the principal investigator or designees. All other SAEs (expected and non-life 
threatening) and captured AEs occurring during active participation will be 
reported to the IRB in the continuing review reports. 
The term “life threatening” refers to any adverse experience that places the 
research participant, in the view of the investigator, at immediate risk of death 
from the reaction, as it occurred, not an event that hypothetically might have 
caused death if it occurred in a more severe form. 
U.S. Food and Drug Administration (FDA): The study will be conducted under 
IND authorization.  Any unexpected fatal or unexpected life-threatening event 
judged by the principal investigator to possibly be due to the investigational 
agent/radiopharmaceutical, will be reported to the FDA by telephone or fax as 
soon as possible but no later than 7 calendar days after notification of the event 
and followed by a written safety report as complete as possible within 8 additional 
calendar days (i.e., full report 15 calendar days total after notification of event).   
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Unexpected, non-fatal and non-life-threatening SAEs, which occur in on-study, 
participants during the time period of active participation that are considered due 
to or possibly due to the injection of the radiopharmaceutical agent, will be 
reported to the FDA by written safety report as soon as possible but no later than 
15 calendar days of the notification of the occurrence of the event. Expected 
SAEs, and unexpected fatal SAEs considered by the principal investigator to be 
unrelated to the study, will be reported to the FDA in the Annual Review Report 
along with non-serious AEs. All FDA correspondence and reporting will be 
conducted through the St. Jude Regulatory Affairs Office.
Copies of all correspondence to the St. Jude IRB, including SAE reports, are 
provided to the St. Jude Regulatory Affairs Office. All FDA related 
correspondence and reporting will be conducted through the Regulatory Affairs 
Office. 
Continuing review reports of protocol progress and summaries of adverse events 
will be filed with the St. Jude OHSP, St. Jude Clinical Protocol Scientific Review 
and Monitoring Committee (CPSRMC), and FDA at least annually.   
9.3  
Recording Adverse Events and Serious Adverse Events
Adverse events (AEs) will be evaluated and documented by the clinical staff and 
investigators and graded using the scoring system according to the NCI Common 
Toxicity Criteria v4.0. Only the radiotherapy-related adverse events will be 
collected and scored. Adverse events will be reported per institutional policy. 
Both serious and unexpected adverse events (Grade 3-5) will be reported through 
the St. Jude TRACKS (Total Research and Knowledge System) system. Toxicity 
grading will be determined by the PI, radiation oncologist or neurosurgeon 
utilizing the pertinent patient history, physical exam and imaging studies.  These 
events will be reported expeditiously to the St. Jude IRB within the timeframes as 
described above. Cumulative summary of Grade 3-5 events will be reported as 
part of the progress reports to IRB at the time of continuing review. Specific data 
entry instructions for AEs and other protocol-related data will be documented in 
protocol-specific data entry guidelines that have been developed and maintained 
by study team and clinical research informatics. CRAs are responsible for 
reviewing documentation related to AEs and entering directly into CRIS protocol-
specific database. 
9.4
Process for Reporting Adverse Events from and to Collaborative Sites
Adverse events occurring in patients enrolled by collaborating sites will also be 
reviewed by the PI and discussed in study team meetings. SAE reports from 
collaborating sites for AEs that are serious, unexpected, and at least possibly 
related to protocol treatment or interventions will be reported to the site’s IRB per 
the site’s local reporting and timeline requirements and to Dr. Merchant at St. 
Jude within the reporting requirements.
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The PI will determine if the event needs to be reported expeditiously to all 
participating sites, considering the following criteria:
• Is the AE serious, unexpected, and related or possibly related to participation in 
the research?
• Is the AE expected, but occurring at a significantly higher frequency or severity 
than expected?
• Is this an AE that is unexpected (regardless of severity that may alter the IRB’s 
analysis of the risk versus potential benefit of the research and, as a result, warrant 
consideration of substantive changes in the research protocol or informed consent 
process/document?
If the event does not require expeditious reporting to all sites, it will be included 
in the annual continuing review.
The PI will report all SAEs reported by collaborating sites to the St. Jude IRB 
using the “Reportable Event” in St. Jude TRACKS application per the timelines 
outlined in section 9.1.1 The PI will indicate if all sites should be notified to 
report to their IRBs, and if the protocol and/or consent should be amended 
(consent will be amended if event is information that should be communicated to 
currently enrolled subjects). Generally, only events that warrant an amendment to 
the protocol and/or consent will be reported expeditiously to all sites. However, any 
event may be reported expeditiously to all sites at the discretion of the PI.
 
9.4.1
Reporting Timelines:
For Collaborating Sites: Serious AND unexpected AND related events are to be 
reported to the St. Jude PI (Dr. Thomas E Merchant, DO, PhD) within five (5) 
working days of event awareness via fax or email. Unexpected deaths must be 
reported to the St. Jude PI via phone call or email within 24 hours of the event. A 
written report using the St. Jude “External Unanticipated Problem/Adverse Event 
Report” form available from the collaborative sites website must follow.  
9.5  
Radiation Safety Committee
Initial approval is not required.
10.0
DATA COLLECTION, STUDY MONITORING, AND CONFIDENTIALITY
10.1
Data Collection
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10.1.1 Electronic case report forms (eCRFs) will be completed by the SJCRH Radiation 
Oncology CRAs.  Data will be entered into a secure database (CRIS) developed 
and maintained by St. Jude Clinical Research Informatics.
10.1.2 Data Collection Instructions for Collaborative Sites
 
Collaborating sites will collect data using e-CRFs via remote electronic data entry 
using the CRIS database. Protocol-specific data and adverse events will be 
recorded by the collaborating sites’ clinical research associates ideally within 2 
weeks of completion.  
10.2  Study Monitoring
High Risk 3 (HR-3) – Phase II or Phase III Therapeutic Studies with an IND 
or IDE
The Eligibility Coordinators will verify 100% of the informed consent 
documentation on all participants and verify 100% of St. Jude participants’ 
eligibility status within 10 working days of the completion of enrollment.
The study team will meet at appropriate intervals to review case histories or 
quality summaries on participants.
The Clinical Research Monitor will assess protocol and regulatory compliance as 
well as the accuracy and completeness of all data points for the first 2 participants 
then 15% of study enrollees every 6 months. Accrual will be tracked continuously 
for studies that have strata.  All SAE reports will be monitored for type, grade, 
attribution, duration, timeliness and appropriateness on all study participants 
semi-annually.  
The monitor will also verify 100% of all data points on the first 2 participants and 
on 15% of cases thereafter.  Protocol compliance monitoring will include 
participant status, eligibility, the informed consent process, demographics, 
staging, study objectives, subgroup assignment, treatments, evaluations, 
responses, participant protocol status, off-study, and off-therapy criteria.  The 
Monitor will generate a formal report which is shared with the Principal 
Investigator (PI), study team and the Internal Monitoring Committee (IMC).
Monitoring may be conducted more frequently if deemed necessary by the 
CPDMO or the IMC.  
Continuing reviews by the IRB and CT-SRC will occur at least annually.  In 
addition, SAE reports in TRACKS are reviewed in a timely manner by the IRB/ 
OHSP.
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St. Jude collaborating study sites will be monitored on-site by a representative of 
St. Jude at intervals specified in the Data and Safety Monitoring Plan. 
International collaborators will be monitored according to the study-specific 
monitoring plan.
10.3 
Confidentiality
Source documents from the study, which identify the study participant, will be 
kept confidential in a secured area and a password-protected database.
11.0
STATISTICAL CONSIDERATIONS
The primary objective of this protocol is to prospectively estimate the PFS and 
OS distributions of children and young adults after a second course of irradiation 
and to demonstrate that many of these patients may be safely salvaged, if 
additional surgery and radiation therapy are administered. PFS and OS 
distributions will be measured from the initiation of re-irradiation. The historical 
data discussed below are retrospective and without correlative neuropsychological 
and quality of life information; thus, the data are not sufficiently convincing for 
most investigators.
To conduct this trial, we expect that a high percentage of patients will have 
received chemotherapy post progression and prior to registering on this trial. The 
primary objective will be assessed without regard to whether patients did or did 
not receive prior chemotherapy. However, the potential association of primary 
outcome with specific chemotherapy given prior to re-irradiation will be explored 
(exploratory objective 1.3.4).  
Historical Data and Analyses
These analyses should be interpreted as exploratory and p-values are to be 
interpreted descriptively and are not adjusted for multiple comparisons. Patients 
with ependymoma who experience initial failure may be characterized based on 
their pattern of failure type (POF1 = local failure, POF2 = distant or POF3 = 
combined). We analyzed 50 patients previously retreated between 2000 and 2011 
according to their retreatment strategy. Possible retreatment strategies include 
focal retreatment, which was used only for patients with local failures (RT2focal), 
and craniospinal irradiation with focal irradiation of the metastatic site(s) and 
primary site when indicated (RT2CSI). RT2CSI was used for all patients with 
combined or distant failure and selected patients with local only failure
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Table 11.0  Pattern of Failure and Treatment Strategy for Historical Cohort
The following figure and table provide Kaplan-Meier estimates of the 
distributions of Progression-Free Survival and Overall Survival for the 50 patients 
in the historical cohort. PFS and OS are measured from the date of re-irradiation 
(RT2) until failure (relapse, disease progression, second malignancy or death) or 
death, respectively. Patients who have not failed are censored at their last date of 
contact.
Figure 11.1 
Progression-free and Overall Survival Historical Cohort
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0
2
4
6
8
10
12
PFS
OS
Progression-Free Survival and Overall Survival
Years Since Iniatiation of the Second RT
Probability
Retreatment Group
Initial Pattern of Failure
Retreatment Strategy
N
A
POF1 = local
RT2focal = focal irradiation
22
B
POF1 = local
RT2CSI =  craniospinal irradiation
7
C
POF2 = distant
RT2CSI
16
D
POF3 = local + distant
RT2CSI
5
Total
50
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Table 11.1 
PFS and OS for the Historical Cohort
PFS
OS
Years Since 
Iniatiation of 
RT2
Risk
Fail
Cens
Prob
SE
Years Since 
Iniatiation of 
RT2
Risk
Fail
Cens
Prob
SE
0 
50 
0 
0 
1.000
0.000
0 
50 
0 
0 
1.000
0.000
1 
50 
13 
3 
0.729
0.064
1 
50 
1 
3 
0.979
0.021
2 
34 
5 
2 
0.621
0.072
2 
46 
9 
5 
0.778
0.064
3 
27 
5 
4 
0.500
0.081
3 
32 
3 
5 
0.704
0.077
4 
18 
3 
3 
0.402
0.086
4 
24 
3 
3 
0.607
0.087
5 
12 
0 
2 
0.402
0.094
5 
18 
1 
2 
0.569
0.093
6 
10 
0 
1 
0.402
0.098
6 
15 
2 
2 
0.493
0.101
7 
9 
2 
2 
0.301
0.103
7 
11 
2 
4 
0.395
0.125
8 
5 
0 
1 
0.301
0.113
8 
5 
0 
1 
0.395
0.137
9 
4 
0 
2 
0.301
0.145
9 
4 
0 
2 
0.395
0.177
11 
2 
0 
2 
0.301
0.252
11 
2 
0 
2 
0.395
0.307
Descriptive statistics of the duration of initial disease control measured in years from the date of 
initial irradiation (RT1) until failure is shown in the next table. 
N
Mean Std
Min 25th % Median 75th %
Max
Duration of Initial Disease 
Control
In Years
50
2.63
2.24
0.23 1.22
1.84
3.53
10.35
Kaplan-Meier estimates of the PFS after re-irradiation, by quartile of initial 
disease control, are shown in the following figure. Of the patients whose initial 
disease control was at least 3.53 years, only one has experienced disease 
progression after re-irradiation. The p-value for a log-rank comparison of the four 
groups is 0.0101.
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0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0
2
4
6
8
10
12
0<,<=1.22
1.22<,<=1.84
1.84<,<=3.53
3.53<,<=10.35
Progression-Free Survival by Duration of Initial Disease Control
Years Since Initiation of Second Course of Irradiation
Probability
 
The following Cox models also suggest that duration of initial disease control is associated with 
duration of PFS and OS after re-irradiation. 
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Cox Model of PFS for Duration of Initial Disease Control
Number of 
Patients 
(events)
Parameter
Estimate
Standar
d
Error
Pr > ChiSq
Hazard
Ratio
95% Hazard 
Ratio Confidence 
Limits
50 (28)
-0.379
0.157
0.0159
0.685
0.503
0.932
Cox Model of OS for Duration of Initial Disease Control
Number of 
Patients (events)
Parameter
Estimate
Standard
Error
Pr > ChiSq
Hazard
Ratio
95% Hazard 
Ratio Confidence 
Limits
50 (21)
-0.743
0.281
0.0081
0.476
0.275
0.825
Factors Associated with Outcome: Neuropathology at Initial Recurrence
The following table shows the distribution of neuropathology at initial recurrence, which was not 
available for 4 of the 50 patients.
Neuropathology at Recurrence
Anaplastic Ependymoma (AEP)
26
52.0%
Ependymoma (EP)
18
36.0%
Focal Anaplastic Ependymoma (FAEP)
2
4.0%
No Pathology
4
8.00%
Below are Kaplan-Meier estimates of distributions of PFS and OS by recurrent histology. The 
Cox models following the figures suggest that patients with AEP at recurrence have a worse 
outcome as measured by PFS and OS. 
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0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0
2
4
6
8
10
12
AEP
FAEP
EP
Progression-Free Survival by Recurrent Histology
Years Since Initiation of Second Course of Irradiation
Probability
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0
2
4
6
8
10
12
AEP
FAEP
EP
Overall Survival by Recurrent Histology
Years Since Iniatiation of Second Course Irradiation
Probability
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Cox Model of PFS for Recurrent Histology
Parameter
Estimate
Standard
Error
Pr > ChiSq
Hazard
Ratio
95% Hazard Ratio 
Confidence Limits
AEP vs. (FAEP+ 
EP)
1.13029
0.42714
0.0081
3.097
1.341
7.153
Cox Model of OS for Recurrent Histology
Parameter
Estimate
Standard
Error
Pr > ChiSq
Hazard
Ratio
95% Hazard Ratio 
Confidence Limits
AEP vs. 
(FAEP+EP)
1.55020
0.53783
0.0039
4.712
1.642
13.522
Factors Associated with Outcome: Extent of Surgical Resection at Initial Recurrence
The following table shows the distribution of surgical resection with a gross total resection 
achieved in 68% of patients.
Extent of Surgical Resection or Metastasectomy
Gross Total Resection (GTR)
34
68.0%
Near Total Resection (NTR)
9
18.0%
Sub Total Resection (STR)
7
14.0%
Below are Kaplan-Meier estimates of distributions of PFS and OS by extent of surgical resection 
at initial recurrence. The Cox models following the figures suggest that patients for whom a 
gross total resection was achieved have better survival. 
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0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0
2
4
6
8
10
12
GTR
NTR
STR
Progression-Free Survival by Extent of Surgical Resection
Years Since Initiation of Second Course of Irradiation
Probability
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0
2
4
6
8
10
12
GTR
NTR
STR
Overall Survival of by Extent of Surgical Resection
Years Since Iniatiation of Second Course of Irradiation
Probability
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Cox Model of PFS for Extent of Surgical Resection
Parameter
Estimate
Standard
Error
Pr > ChiSq
Hazard
Ratio
95% Hazard Ratio 
Confidence Limits
GTR vs. NTR +STR -0.91550
0.42108
0.0297
0.400
0.175
0.914
Cox Model of OS for Extent of Surgical Resection
Parameter
Estimate
Standard
Error
Pr > ChiSq
Hazard
Ratio
95% Hazard Ratio 
Confidence Limits
GTR vs.NTR+STR -1.01384
0.47177
0.0316
0.363
0.144
0.915
Factors Associated with Outcome: Age at Time of Re-Irradiation
There is no evidence of any association between age at re-irradiation and PFS (p>0.85) or OS 
(p>0.94).
Reasonable Prognostic Strata:
The association between duration of initial disease control and neuropathology at recurrence is 
shown in the following table.
Based on the above analyses of outcome, duration of initial disease control (IDC) longer than 
3.53 years identifies a subgroup of approximately 24% of patients with an excellent outcome. 
Patients who experience shorter durations of initial disease control and have anaplastic 
ependymoma (AEP) at recurrence identifies a subgroup of approximately 44% of patients with a 
poor outcome. A third subgroup (Other) of approximately 32% of patients have FAEP or EP or 
no neuropathology at recurrence and initial disease control less than 3.53 years (<3.53). These 
three strata are proposed for monitoring PFS for the current trial against the historical data. PFS 
for the historical cohort by these three strata are shown in the following figure and table. A log-
rank comparison of the three groups results in a p-value of 0.0003. 
Initial Disease Control in Years
Neuropathology
at Recurrence
≤ 1.22 
1.22< - ≤ 
1.84 
1.84< - ≤ 
3.53 
3.53< - ≤ 
10.35 
Totals
N
%
N
%
N
%
N
%
N
%
AEP
7
26.92
7
26.92
8
30.77
4
15.38
26
52.0
EP
4
22.22
2
11.11
4
22.22
8
44.44
18
36.0
FAEP
0
0
2
100.0
0
0
0
0
2
4.0
No Path
1
25.0
2
50.0
1
25.0
0
0
4
8.0
Totals
12
24.0
13
26.0
13
26.0
12
24.0
50
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0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0
2
4
6
8
10
12
>3.53
<=3.53 & AEP
Others
Progression-Free Survival by Strata 
Years Since Initiation of  Second  Course of Irradiation
Probability
>3.53
<=3.53 & AEP
Others
Years 
Since 
Initiation 
of RT2
Risk
Fail
Cens
Prob
SE
Risk
Fail
Cens
Prob
SE
Risk
Fail
Cens
Prob
SE
0 
12 
0 
0 
1.000
0.000
22 
0 
0 
1.000
0.000
16 
0 
0 
1.000
0.000
1 
12 
0 
2 
1.000
0.000
22 
11 
1 
0.476
0.104
16 
2 
0 
0.875
0.080
2 
10 
1 
1 
0.900
0.095
10 
2 
1 
0.381
0.106
14 
2 
0 
0.750
0.104
3 
8 
0 
3 
0.900
0.116
7 
4 
0 
0.163
0.075
12 
1 
1 
0.688
0.116
4 
5 
0 
2 
0.900
0.142
3 
0 
0 
0.163
0.075
10 
3 
1 
0.458
0.127
5 
3 
0 
0 
0.900
0.142
3 
0 
1 
0.163
0.086
6 
0 
1 
0.458
0.138
6 
3 
0 
0 
0.900
0.142
2 
0 
1 
0.163
0.106
5 
0 
0 
0.458
0.138
7 
3 
0 
2 
0.900
0.201
1 
0 
0 
0.163
0.106
5 
2 
0 
0.275
0.117
8 
1 
0 
0 
0.900
0.201
1 
0 
0 
0.163
0.106
3 
0 
1 
0.275
0.135
9 
1 
0 
0 
0.900
0.201
1 
0 
1 
0.163
0.149
2 
0 
1 
0.275
0.166
11 
1 
0 
1 
0.900
0.285
1 
0 
1 
0.275
0.234
Factors Associated with Outcome: Initial Pattern of Failure and Retreatment Volume
These data are presented to provide evidence for the proposed retreatment volume based on site 
of tumor recurrence.
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0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0
2
4
6
8
10
12
POF1 & RT2focal
POF2 & RT2CSI
POF3 & RT2CSI
Progression-Free Survival
Years Since Initiation of Second  Course of  Irradiation 
Probability
Log-rank test: p-value=0.2416
POF1 & RT2focal
POF2 & RT2CSI
POF3 & RT2CSI
Years 
Since 
Initiation 
of RT2
Risk
Fail
Cens
Prob
SE
Risk
Fail
Cens
Prob
SE
Risk
Fail
Cens
Prob
SE
0 
22 
0 
0 
1.000
0.000
16 
0 
0 
1.000
0.000
5 
0 
0 
1.000
0.000
1 
22 
5 
2 
0.762
0.093
16 
2 
0 
0.875
0.080
5 
3 
1 
0.250
0.153
2 
15 
2 
1 
0.660
0.107
14 
1 
1 
0.812
0.098
1 
0 
0 
0.250
0.153
3 
12 
1 
2 
0.605
0.120
12 
3 
2 
0.587
0.133
1 
0 
0 
0.250
0.153
4 
9 
2 
2 
0.432
0.133
7 
1 
0 
0.503
0.134
1 
0 
0 
0.250
0.153
5 
5 
0 
1 
0.432
0.146
6 
0 
0 
0.503
0.134
1 
0 
1 
0.250
0.217
6 
4 
0 
0 
0.432
0.146
6 
0 
1 
0.503
0.145
7 
4 
1 
1 
0.324
0.154
5 
1 
1 
0.377
0.149
8 
2 
0 
0 
0.324
0.154
3 
0 
1 
0.377
0.172
9 
2 
0 
0 
0.324
0.154
2 
0 
2 
0.377
0.298
11 
2 
0 
2 
0.324
0.267
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0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0
2
4
6
8
10
12
POF1 & RT2focal
POF2 & RT2CSI
POF3 & RT2CSI
Overall Survival
Years Since Iniatiation of Second  Course of Irradiation
Probability
Log-rank test: p-value=0.0242
POF1 & RT2focal
POF2 & RT2CSI
POF3 & RT2CSI
Years 
Since 
Iniatiation 
of RT2
Risk
Fail
Cens
Prob
SE
Risk
Fail
Cens
Prob
SE
Risk
Fail
Cens
Prob
SE
0 
22 
0 
0 
1.000
0.000
16 
0 
0 
1.000
0.000
5 
0 
0 
1.000
0.000
1 
22 
1 
2 
0.950
0.048
16 
0 
0 
1.000
0.000
5 
0 
1 
1.000
0.000
2 
19 
2 
3 
0.841
0.087
16 
2 
1 
0.875
0.083
4 
3 
0 
0.250
0.153
3 
14 
1 
2 
0.781
0.106
13 
1 
3 
0.802
0.113
1 
0 
0 
0.250
0.153
4 
11 
3 
2 
0.533
0.138
9 
0 
0 
0.802
0.113
1 
0 
0 
0.250
0.153
5 
6 
0 
1 
0.533
0.149
9 
0 
0 
0.802
0.113
1 
0 
1 
0.250
0.217
6 
5 
0 
0 
0.533
0.149
9 
2 
1 
0.624
0.145
7 
5 
1 
2 
0.426
0.186
6 
1 
2 
0.499
0.177
8 
2 
0 
0 
0.426
0.186
3 
0 
1 
0.499
0.204
9 
2 
0 
0 
0.426
0.186
2 
0 
2 
0.499
0.353
11 
2 
0 
2 
0.426
0.323
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11.1 
Statistical Analysis of Primary Objective 1.1
The primary objective is to estimate the distributions of PFS and OS post re-
irradiation at initial failure for patients with ependymoma. In addition, we will 
monitor PFS as compared with the retrospective historical data discussed in 
section 11.0 to ensure that the current approach is not inferior to the retrospective 
historical experience.
Based on the work of Korn and Freidlin (2006) [297] we will estimate the sample 
size required to monitor that the prospective results are not inferior to the 
retrospective results, as if a prospective randomized trial were to be conducted. 
The historical PFS data were used to estimate the hazard rate during the first 4 
years of 0.233 and for the hazard rate for the period greater than 4 years of 0.056. 
The following figure shows that a piece-wise exponential distribution with these 
two hazard rates is an outstanding fit to the historical PFS distribution.
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0
2
4
6
8
10
12
PFS
Piece-wise Exponential
Progression-Free Survival
Years Since Iniatiation of the Second RT
Probability
The calculations for the monitoring design assume piece-wise exponential 
distributions. The design will have 80% power to detect an unacceptable decrease 
in the 3-year PFS rate from 50% to 35% (α=0.10: one-sided test). East© (version 
5) was used to calculate that with one interim analysis and approximately 64% of 
patients assigned to the new treatment, a total of 140 patients would need to be 
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randomized over 9 years of accrual. Thus, we will need to accrue 90 patients to 
our new regimen over approximately 9 years. The final analyses will be 
conducted 2 years after initiation of irradiation for the last patient.
The one interim analysis, based on the work by Xiong et al, [298] will be 
conducted when 50% of the expected number of failures (67) for the 90 patients 
to be treated prospectively (assuming the alternative hypothesis) has been 
observed (~34 patients have failed). The planned interim analysis will occur at 
approximately 68% of the expected total “transformed information time,” 
assuming the alternative hypothesis. Accrual will be suspended until all available 
information has been considered, if the observed nominal p-value is ≤0.0582. At 
the final analysis, one would conclude that the prospective results are inferior to 
the retrospective results if the p-value is ≤0.10. The log-rank comparisons will be 
stratified by three strata define above and the power should be retained [299]. 
With this design the actual significance level is 0.1089; the power is 0.7915 and 
the maximum probability of an interim decision being discordant with a decision 
that would be made by a final analysis is 0.05 (5%).
While the expected accrual to this trial is considerably greater than our historical 
experience, we expect that accruing 12 patients per year is realistic. Our current 
case review for re-irradiation includes approximately two chart review 
consultations per month. Patients treated to date include those previously 
irradiated in department or from our region. Based on institutional policy, patients 
cannot be accepted for treatment at St. Jude in the absence of a clinical protocol. 
Thus when this trial opens, we will begin to actively recruit patients for the trial. 
Furthermore, we have offers from a number of centers to collaborate in this effort. 
If accrual is not meeting expectations by the end of year 2, we will contact these 
centers to participate. 
At the time of amendment #2, the study had been open for 4 years and we accured 
53 patients. The accrual rate was approximately 10 patients/year and less than the 
15 patients per year target (initial). We extended the accrual time by 3 years to 
reach the accrual goal and added a collaborative site.  
Stopping Rule for Necrosis:
Necrosis will be monitored throughout the trial and accrual to the trial suspended 
at any time the following stopping criteria are met. Necrosis will be graded 
according to the CTCAE v4.0 terminology. If evidence develops that more than 
20% of patients are expected to develop necrosis (CTCAE v4.0 > grade 3) the 
treatment will be considered unacceptable. The number of patients who 
experience necrosis is based upon the number of enrolled patients. The stopping 
criteria shown in the following table are based on exact lower 95% Blyth-Still-
Casella confidence bounds.
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11.2
Statistical Analysis of Secondary Objective 1.2.1 Neurological, Endocrine 
and Cognitive
Objective: To explore potential associations of clinical and treatment factors with 
the incidence and severity of neurological, endocrine and cognitive deficits in 
children and young adults with ependymoma treated with a second course of 
irradiation.
To assess the side effects of radiation therapy in neurology, ophthalmology, 
audiology, endocrinology, and cognitive state, the data will be collected in a 
longitudinal setting. The time schedule for data collection is presented in Table 
6.0.1 (Evaluations at baseline and follow-up). Since patients treated by focal or 
craniospinal radiation will be not at random, to compare the treatment effect, we 
need to adjust other clinical factors to limit the confound effects in the regression 
models as discuss below. In addition to the analysis plan below, once we have 15 
patients in each stratum (a total of at least 45 patients) followed for 1 year, 
descriptive statistical analyses and regression analyses as discussed below will be 
conducted. The results of these interim analyses will be submitted for presentation 
at an appropriate national scientific meeting, as well as to the CT-SRC. There are 
not expectations that the findings of these interim analyses would raise concerns 
for the current trial.
Neurology: The neurologic signs and symptoms such as seizures, headache, 
motor sensation, ataxia, cranial nerve deficits and others will be collected. 
Neurological data will be obtained from the neurological protocol exam form. 
Grade 3-5 toxicity data as determined by the NCI CTCAE v 4.0 will be reported. 
The distribution of ordinal outcomes and percentages will be estimated. Mixed-
effects Proportional Odds Regression [300] will be performed to estimate their 
changes over time, and compare severity in the two treatment arms adjusted by 
confound factors.
Ophthalmology: Vision status of a patient will be dichotomized into None and 
Impaired, according to clinical meanings, as described in Section 6.3.  We will 
Number of Patients
Experiencing Necrosis
Number of Eligible
Patients
Exact 95% Lower
Confidence Bounds
7
≤ 20
≥ 0.201
10
≤ 30
≥ 0.193
13
≤ 40
≥ 0.204
16
≤ 50
≥ 0.211
18
≤ 60
≥ 0.204
20
≤ 70
≥ 0.202
23
≤ 80
≥ 0.211
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also use the information recorded in the clinical neurology form (see appendix) 
and NCI CTCAE v4.0 when relevant. The percentages for both statuses will be 
estimated.  Generalized Estimating Equations (GEE) with logistic link will be 
employed to estimate the change of vision over time, and compare severity of 
vision in the two treatment groups adjusted by confound factors.  
Audiology: To assess hearing loss in patients, hearing will be dichotomized as 
normal if all thresholds are within 0-20 DB HL and otherwise abnormal. GEE 
with logistic link will be modeled to explore the trend over time and investigate 
impacts of specific clinical and treatment factors on hearing loss. In the presence 
of missing data, Weighted GEE will be employed to address missingness. In 
addition, the cumulative incidence of hearing loss will be estimated with death as 
a competing risk. Chang Ototoxicity Grading Scale (COGS) will also be used to 
evaluate the hearing loss. The ordinal COGS will be analyzed similarly as 
Neurology grade.
Endocrine: Endocrine data as a continuous variable will be collected. Descriptive 
statistical analysis will be performed.  Diabetes Insipidus (DI) is a hormone 
deficiency that results only from direct damage to the hypothalamus and pituitary 
axis (mainly pituitary stalk) by tumor or surgery. This longitudinal binary variable 
(coded as “yes” or “no”) will be compared between the surgery and radiation 
groups using GEE adjusted by other confounding factors. Hormone Deficiency, 
such as Growth Hormone Deficiency (GHD), will be compared between the 
surgery and radiation groups. Growth hormone will be dichotomized with 
GHD=1 for <7ng/ml and GHD=0, otherwise. We define GHD=1 as event. Since 
the treatment of other hormone deficiency could be a compete risk for this event, 
cumulative incidence regression analysis using Fine and Gary method will be 
employed [301]. Specific clinical and treatment group factors will be included as 
covariates to investigate the treatment group difference. Other Hormone 
Deficiency, including Thyroid Hormone Deficiency (central hypothyroidism), 
Adrenal Insufficiency, Gonadotropin Deficiency or Precocious Puberty, Diabetes 
Insipidus, Hypothalamic Obesity (not a specific endocrine deficiency but an 
endocrine problem nonetheless), will be analyzed similarly. Some of these 
measures are graded in the NCI CTCAE v4.0.
Neurocognitive: Neurocognitive measures are continuous. GEE will be 
employed to estimate treatment group difference with specific clinical factors and 
time also included as covariates. For some neurocognitive measures, children and 
young adults (adolescents) will have different forms.  When we pool data together 
to perform the analysis, we will take these differences into account in the GEE 
model to control for variations. Neurocognitive measures will also be 
dichotomized into normal and abnormal groups based on cut-off values (average 
range vs. outside of the average range for a given test instrument) at specific time 
points after therapy. GEE with logistic link will be used to investigate the 
treatment group effect. Frequency and percentage of dichotomized cognitive 
measures will be calculated.  
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11.3 
Statistical Analysis of Secondary Objective 1.2.2 Sleep, Fatigue and Quality 
of Life
Objective: Using specific measures of sleep quality, excessive daytime sleepiness, 
daytime activity, fatigue, symptom distress, and quality of life, explore 
associations of sleep, fatigue and quality of life with other measures of CNS 
effects, clinical and treatment factors in children and young adults with 
ependymoma treated with a second course of irradiation.
Stratified by treatment arms (focal vs. craniospinal radiation), descriptive 
statistics of the longitudinal assessments of sleep, fatigue and quality of life will 
be described. Specifically, on a yearly basis starting from the pre-treatment time 
point to year 5 post treatment initiation, quality of life in patients ≥ 2 years of age 
as measured by the PedsQoL brain tumor module will be reported; daytime 
activity and up to 20 sleep measurements as measured by wrist actigraphy along 
with sleep diary-patient/parent will be reported. On a more frequent basis (every 3 
months for the first 2 years, every 6 month to month 60), sleep complaints in 
patients ≥ 8 years of age as measured by Symptom Distress Scale (SDS) and 
Epworth Sleepiness Scale will be reported and fatigue in patients ≥ 2 years of age 
as measured by The Peds QL Multidimensional Fatigue scale will be reported, 
along with PedsQoL brain tumor module. The Acute version of the 
Multidimensional Fatigue scale and Peds brain tumor module will be 
administered weekly during radiation therapy.
As an exploratory analysis, each of above mentioned measurements will be 
compared between two treatment arms by longitudinal data analysis. Generalized 
Estimating Equation (GEE) will be employed to compare outcome changes over 
time between two treatment arms by using time and treatment as covariates of the 
model. The interaction term between treatment arm and time will be added if two 
arms show different change rate. The other covariates of interest will be selected 
by Bayesian information criterion (BIC). However, any response with <3 
assessments would not be included in the list. To analyze sleep measurements 
which will be examined annually, the other measurements used in the model will 
only include their data points measured at the same time as sleep measurements. 
Multidimensional Fatigue scale and Peds brain tumor module will be measured 
each week for 4 weeks at the first year. We will analyze them in two ways. First, 
we will only use the first 4 weeks data to fit the GEE. Second, it will also be fitted 
in a large time picture but only the first week data of these 4 weeks will be used. 
In addition, Epworth Sleepiness Scale score will also be dichotomized by 10 and 
then fitted using GEE with a logistic link. 
Similarly, the same modeling approach will be used to explore associations 
between each of above mentioned outcome and patient characteristics/clinical 
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factors that are of interest. The independent effect of resultant significant factors 
will be explored further in multiple regression models.  
Based on the number of tests performed to address this secondary objective, 
adjustments for multiple comparisons will be made to mitigate over interpreting 
exploratory findings.
11.4 
Statistical Analysis of Secondary Objective 1.2.3 Physical Performance
Objective: To describe physical performance and movement in children, 
adolescents and young adults with ependymoma treated with a second course of 
radiation.
Physical performance measures will be obtained at baseline, 12, 24, 36, 48 and 60 
months. We will provide descriptive statistics of the following outcomes at each 
time point, and also provide the plots of individual profiles and mean profiles of 
the outcomes across time. The descriptive statistical analysis will be stratified by 
gender, age at diagnosis and total dose of brain radiation. 
To model the outcomes’ pattern and change over time, we will use generalized 
estimating equation (GEE) methodology with time as the main independent 
variable while adjusting for gender, age at diagnosis and total dose of brain 
radiation, including an interaction term if indicated. The assigned distribution and 
link function in each model will depend on the characteristic of the specific 
outcome as listed in next paragraph(s). The continuous measures will be modeled 
using normal distribution and identity link whereas the binary outcomes will be 
modeled using binomial distribution and logit link.
These analyses will be conducted at the conclusion of the trial and at an interim 
time point at which we have 15 patients in each stratum (a total of at least 45 
patients) followed for 1 year. The results of the interim analyses will be submitted 
for presentation at an appropriate national scientific meeting, as well as to the CT-
SRC. 
List of outcomes:
1.
Overall physical performance: Two sets. 
(a)
Measured task sets: BOT2 (4-21 years old) and PPT (≥22 years 
old). 
•
BOT2 outcome: total motor composite, a standardized 
score range from 20 to 80, with a mean of 50 and a 
standard deviation of 10.
•
PPT (7-item questionnaire) outcome: a score range from 0 
to 28. The normative data is available from the human 
performance lab.
We will standardize the two above scores into z-scores for data analysis. 
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(b)
Self-reported instruments (PROMIS): Three questionnaires.
•
Pediatric Physical Function – Mobility – SF1: 8-item 
questionnaire with the score range from 0 to 32. 
•
Pediatric Physical Function – Upper Extremity – SF1: same 
as above.
•
Physical Function – SF1: 10-item questionnaire with the 
score range from 0 to 50. 
We will standardize the above scores into T-scores for data analysis based on the 
normative data from PROMIS.
2.
Body Composition: BMI (kg/m2) and waist/hip ratio (cm/cm).
3.
Flexibility 
(a)
Ankle dorsiflexion active and passive range of motion: measured 
by goniometer, and recorded as an angle (degree).
(b)
Overall flexibility: measured by sit and reach test, and recorded as 
a length (cm).
4.
Balance
Measured by sensory organization test (SOT), and the result from the test is the 
equilibrium score, a percentage range from 0% to 100%, with the higher 
percentage, the better balance. The outcome is a binary variable with a cutoff 
score of < 70% indicates future risk for a fall.  
5.
Coordination 
(a)
Fine motor coordination (finger and hand coordination).
Measured by Composite Cerebellar Functional Severity Score 
(CCFS), and the outcome is an age-adjusted z-score and log 
transformed. 
(b)
Overall coordination
Measure by brief ataxia rating scale (five-item questionnaire). The 
outcome is a total scale range from 0 to 22.
6.
Muscle strength and power 
(a)
Lower extremity strength: measured by BiodexIII, and the 
outcomes are peak torque value/body weight ratios at different 
speeds of motion.
(b)
Hand grip strength: measured by a Jamar hand held dynamometer 
and recorded in kilograms (kg).
We will standardize the above scores into z-scores for data analysis based on 
normative data. 
7.
Cardiopulmonary fitness  
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(a)
Resting Energy Expenditure: measured with indirect calorimetry 
after an overnight fast and recorded as REE (kcal/day). 
(b)
Cardiopulmonary Exercise test (CPET): the test will be completed 
on a treadmill using the Balke protocol or cycle ergometer using an 
incremental ramping protocol. The outcome is recorded as 
VO2max (ml/kg/min). 
We will standardize the above scores into z-scores for data analysis based on 
normative data. 
11.5 
Statistical Analysis of Secondary Objective 1.2.4 Neuroimaging
Objective: Estimate and compare the response of residual tumor and the incidence 
and severity of structural, functional and vascular effects of normal brain in 
children and young adults with ependymoma after treatment with a second course 
of irradiation using specific methods of diffusion, contrast-enhancement, vascular 
and functional neuroimaging, and explore the association between these and other 
measures of CNS effects and clinical and treatment factors. Determine the time 
course of white matter tract injury and recovery post irradiation and the 
association between imaging metrics derived from serial quantitative neural 
imaging and radiation dosimetry as well as neuro-cognitive outcomes.
Mixed effect models will be used to estimate and compare the structural, 
functional and vascular effects over time of normal brain and residual tumor in 
children and young adults with ependymoma after treatment with a second course 
of irradiation based on comprehensive imaging from MTR, DTI, DSC and SWI 
etc.  Associations of those changes in the brain with other measures of CNS 
effects and clinical and treatment factors will be investigated using mixed effects 
models as well.  The time course of white matter tract injury and recovery post 
irradiation by MTR and DTI will be described graphically and fitted by mixed 
effect models.  The association between those quantitative neural imaging 
measurements change and radiation dosimetry/neuro-cognitive outcomes will be 
explored by mixed effect models.
Based on the number of tests performed to address this secondary objective, 
adjustments for multiple comparisons will be made to mitigate over interpreting 
exploratory findings. After the acquisition of four DTI/MT examinations in 15 
patients in each stratum (a total of at least 45 examinations), interim analysis of 
MT imaging data will be performed and reported at an appropriate scientific 
meeting, as well as to the CT-SRC. The investigational MT sequence will no 
longer be performed after 8/1/2020.
11.6 
Statistical Analysis of Exploratory Objective 1.3.1 Avidity to FDG and C-
MET
Objective: Estimate the avidity of ependymoma to 18F-fluorodeoxyglucose (FDG) 
and 11C-methionine positron emission tomography (IND # 104987) prior to 
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radiation therapy and correlate change in avidity 12, 24 and 36 months after a 
second course of irradiation with tumor progression. Estimate the avidity of FDG-
PET and MET-PET at baseline and compare those two by t test or Wilcoxon rank 
sum test based on the distribution of the variables.  The association between 
tumor progression and avidity to FDG and to MET will be explored by Cox 
regression model by using PFS as response variable and avidity measurements as 
time dependent covariates, where clinical and demographics variables of interest 
may also be included in these models, if the number of events is sufficient to 
support such a multivariable analysis.  The association between PFS and baseline 
avidity will be also investigated. In these survival models, nine events per 
covariate are required. We will describe necrosis based on MET/FDG 
descriptively and graphically. The association between necrosis findings based on 
MET/FDG and necrosis findings based on MRI will be explored by mixed effect 
model. 
Based on the number of tests performed to address this secondary objective, 
adjustments for multiple comparisons will be made to mitigate over interpreting 
exploratory findings.
11.7 
Statistical Analysis of Exploratory Objective 1.3.2 Growth Factor and 
Cytokine Responses
Objective: Measure growth factor and cytokine responses in children and young 
adults with recurrent ependymoma after treatment with a second course of 
irradiation, and explore associations between these and other measures of CNS 
effects and clinical and treatment factors. 
Growth factor and cytokine responses in serum will be measured longitudinally 
before, during and post radiation therapy in consenting patients. Hence the 
planned exploratory analyses based on this data will mainly utilize longitudinal 
models. We will study possible associations between cytokine levels and 
demographic and clinical variables, response to treatment as measured by PFS as 
well as between cytokine levels and various side effects. We will investigate 
possible associations between the change in cytokine levels and factors such as 
radiation dose and irradiated volume, tumor volume, tumor response, surgical and 
host factors, etc.  We will also evaluate presence of associations between cytokine 
responses and measures of sleep, fatigue and function as well as associations 
between cytokine responses and neurological, endocrine and cognitive/quality of 
life parameters. Additionally, we will examine whether an association exists 
between dose distribution and cytokine response. Considering the large number of 
exploratory analyses planned for these data, the multiplicity issues that will arise 
will be addressed by reporting false discovery rate estimates.
11.8 
Statistical Analysis of Exploratory Objective 1.3.3 Radiogenomics
Objective: Conduct a variety of exploratory genetic analyses on tumor samples 
(and blood where a germline control is required), including but not limited to 
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broad (genome-wide/array based) or focused (gene-specific) analyses at the DNA, 
RNA, or protein level and next generation sequencing in an effort to better 
understand the biology of ependymoma. Explore associations between molecular 
findings and treatment response and various side effects including vasculopathy, 
hearing loss, cognitive deficits, and growth hormone deficiency and other 
measures as appropriate. 
This objective carries a general goal of exploring the genetic basis of 
ependymoma in an effort to identify genetic variations which may associate with 
tumor formation, treatment responses and toxicity. We will use statistical 
association tests, as appropriate, to investigate the association between genotypes 
and these phenotypes of interest. We will compare sequence/genetic variations 
from germline, untreated tumor and treated tumor samples to pinpoint the genetic 
events occurring during tumor initiation and development. Considering the large 
number of exploratory analyses planned for these data, the multiplicity issues that 
will arise will be addressed by reporting false discovery rate estimates.
A important goal of this analysis is to identify genetic variations in germline that 
predict for side effects from RT with the long-term aim of screening susceptible 
patients prior to irradiation and to study the biology of late effect. We will 
investigate genetic variants associated with side effects related phenotypes: 
vasculopathy, hearing loss, cognitive deficiencies, and hormone deficiencies by 
genome-wide association studies and candidate gene analyses. The currently 
known candidate genes and gene mutations for the phenotypes of interest are 
described below. However, since these data won’t be available for several years 
from the initiation of enrollment and in some cases later if longer term follow-up 
is needed, the list of candidate genes may change substantially by the time we are 
ready to perform these analyses.  Hence, the analysis plan below merely reflects 
the current state of knowledge and is subject to change.
Genetic Abnormalities Associated with Vasculopathy: The candidate genes based 
on current knowledge include: 1) gene HgS, IL4R, TNF, ADRB, VCAM-1 and 
LDLR which were associated with stroke risk in sickle cell disease (SCD) 
patients; 2) gene Factor II, Factor V, MTHFR and PAI-1 and promoter region of 
GPx-3 gene which were associated with venous sinus thrombosis and arterial 
ischemic stroke; 3) gene ELNINT20/INT23, COL1A2 and TNFRSF13B which 
were associated with intracranial aneurysm (IA) risk; 4) inositol 1,4,5-
triphosphate 3-kinase C (ITPKC) gene which were associated with Kawasaki 
disease susceptibility and formation of coronary artery aneurisms; 5) HLA-
AW24, -BW46, and -BW54 serotypes which are associated with Moya-moya 
syndrome, defined as bilateral severe stenosis or occlusion of the internal carotid 
arteries with collateral formation. 
Genetic Abnormalities Associated with Hearing Loss: The candidate gene 
mutations under our investigation include: 1) mutations of the GJB2 gene which 
was associated with recessive and sporadic deafness; 2) mutations in the 
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mitochondrial 12S ribosomal RNA gene which were associated with ototoxicity 
for patients taken Aminoglycoside antibiotics; 3) GSTP1 gene and megalin 
mutations which were associated with cisplatin-induced ototoxicity.
Genetic Abnormalities Associated with Cognitive Deficiencies: The candidate 
genes under our investigation include: 1) GDI1, oligophrenin, PAK3, FMR2, 
IL1RAPL, TM4SF2, VCX-A, ARHGEF6, GPC3, GPC4 and HTR2A which were 
associated with nonsyndromic mental retardation (NSMR); 2) SNAP-25 gene and 
APOE gene which were associated with cognitive function; 3) 894TT genotype of 
NOS3 gene which was associated with cognitive decline following radiation 
therapy; 4) COMT genotype which was associated with white matter performance 
and resiliency against late effects of irradiation.
Genetic Abnormalities Associated with Hormone Deficiencies: The candidate 
genes under our investigation include: genetic aberrations in GST (GSTM1, 
GSTP1, GSTT1) which have been associated with the risk of relapse of certain 
cancers and modulate response to therapy; GSTM1 gene was associated with 
susceptibility to growth hormone deficiency.
11.9
Statistical Analyses of Exploratory Objective 1.3.4: Association of prior 
chemotherapy with PFS and OS distributions. 
Cox proportional hazard models will be used to explore possible association of 
chemotherapy given prior to re-irradiation with outcome. Due to the expected 
limited sample sizes for any chemotherapy agent, the results of these exploratory 
analyses will be considered as descriptive.
11.10 Statistical Analyses of Exploratory Objective 1.3.5: To compare the 
progression-free and overall survival distributions for children (age > 3 
years) and young adults with recurrent ependymoma and 1q gain treated 
with a second course of irradiation (focal or craniospinal) while monitoring 
for excessive central nervous system necrosis.
Of the 117 patients in RT1 cohort, total of 20 had a “distant or combined” pattern 
of failure, 8 did and 12 did not have 1q gain.  Total of 22 patients had a “local” 
pattern of failure, 4 did and 18 did not have 1q gain. A total of 75 patients did not 
experience treatment failure (tumor progression), 4 did and 71 did not have 1q 
gain. The detailed frequency is shown in Table 1. There is association between 
type of failure with 1q gain status (p=0.0003, Chi-square test). 
Table 1. Pattern of failure by 1q gain status
Pattern of Failure
1q gain
No
Yes
Total
Distant or Combined
12
8
20
Local Only
18
4
22
None
71
4
75
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Total
101
16
117
Cumulative incidence of Distant or combined failure by 1q gain status
The cumulative incidence of distant or combined failure analysis with competing 
risks was assessed. The distant or combined failure was considered as event and 
other events (local failure and death) were considered as competing risks. Patients 
with no events were considered as censored. The cumulative incidence with 
competing risks is shown in Table 2 and plotted in Figure 1. The cumulative 
incidence of distant or combined failure after 14 years of follow-up was 0.1256 ± 
0.0346 (Table 2) for patients without 1q gain, considering the competing risk 
factors. The cumulative incidence of distant or combined failure after 12 years of 
follow-up was 0.5000 ± 0.1328 for patients with 1q gain, considering the 
competing risk factors. The Chi-square test had P value of <0.0001 (Table 2), 
indicating that there was statistically significant difference for the cumulative 
incidence of distant or combined failure among patients with the presence of 1q 
gain vs. absence of 1q gain. 
Table 2. Cumulative incidence of distant or combined failure for infratentorial ependymoma 
patients with competing risks Chi-square = 15.8814, df = 1, p = 0.0000674383
no_Gain_1q 
Gain_1q
Years since 
start of RT
Risk
Fail
Fail 
other
Cens
CI
SE
Years since 
start of RT
Risk
Fail
Fail 
other
Cens
CI
SE
0 
101 
0 
0 
0 
0.0000
0.0000
0 
16 
0 
0 
0 
0.0000
0.0000
1 
101 
3 
3 
0 
0.0297
0.0170
1 
16 
4 
1 
0 
0.2500
0.1123
2 
95 
3 
6 
0 
0.0594
0.0236
2 
11 
2 
2 
0 
0.3750
0.1267
3 
86 
4 
7 
2 
0.0991
0.0299
3 
7 
2 
0 
0 
0.5000
0.1328
4 
73 
0 
2 
2 
0.0991
0.0299
4 
5 
0 
0 
0 
0.5000
0.1328
5 
69 
0 
0 
8 
0.0991
0.0299
5 
5 
0 
0 
1 
0.5000
0.1328
6 
61 
1 
1 
4 
0.1114
0.0320
6 
4 
0 
0 
1 
0.5000
0.1328
7 
55 
1 
1 
8 
0.1259
0.0346
7 
3 
0 
1 
0 
0.5000
0.1328
8 
45 
0 
0 
7 
0.1259
0.0346
8 
2 
0 
0 
0 
0.5000
0.1328
9 
38 
0 
2 
6 
0.1259
0.0346
9 
2 
0 
0 
0 
0.5000
0.1328
10 
30 
0 
1 
5 
0.1259
0.0346
10 
2 
0 
0 
1 
0.5000
0.1328
11 
24 
0 
0 
11 
0.1259
0.0346
11 
1 
0 
0 
0 
0.5000
0.1328
12 
13 
0 
0 
6 
0.1259
0.0346
12 
1 
0 
0 
1 
0.5000
0.1328
13 
7 
0 
0 
6 
0.1259
0.0346
14 
1 
0 
0 
1 
0.1259
0.0346
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Figure 1: Cumulative Incidence of Distant or Combined Failure for RT1 Patients with Competing Risks
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0
2
4
6
8
10
12
14
16
1q gain (-)
1q gain (+)
Years from Enrollment
CI
So, the 1q gain status is important factor to consider when plan treatment of 
cranial spinal irradiation vs. focal irradiation by historic data.  We will offer 
patients the optional second course of cranial spinal irradiation treatment when 
they have 1q gain in this procol. We will compare PFS and OS of patients with 1q 
gain status who receive cranial spinal irradiation vs. focal irradiation by log rank 
test if sample size is reasonable big. Due to the expected limited sample sizes, the 
results of these exploratory analyses will be considered as descriptive.
11.11 Monitoring Outcomes for the Retrospective Cohort
The primary objective of this study is to estimate the distributions of PFS and OS 
after re-irradiation for patients with ependymoma and comparing them to 
retrospective historical data. Because of the clinicopathologic factors that predict 
for disease control and functional outcomes and clinical and treatment factors 
associated with complications evolve over time and will affect the analyses 
performed for patients enrolled on this study, we will periodically update 
outcomes from our retrospective cohort to be published and used for comparative 
analysis. This means that RERTEP will include a retrospective assessment of 
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disease control and functional outcomes for re-irradiated ependymoma patients 
treated prior to the activation of this study or those not enrolled. The retrospective 
review will include an update of the PFS and OS analyses used to develop the 
statistical design for this study, limited functional outcome and complication 
assessments used to design the secondary and exploratory aims, incorporate and 
updating clinicopathologic assessments routinely performed for patients with 
ependymoma, and other clinical and treatment factors and measures of CNS 
effects. The list of patients to whom this retrospective research applies will be 
available through protocol documents in TRACKS.
12.0
OBTAINING INFORMED CONSENT
12.1
Consent/Assent at Enrollment
The process of obtaining informed consent will follow institutional guidelines. 
Informed consent will be obtained by the attending physician or their designee 
after the diagnosis of recurrent ependymoma is confirmed and the research 
participant is deemed eligible. We will seek consent from parents or guardians if 
the research participant is less than 18 year old and from the research participant 
if he/she is 18 years of age or older. Verbal assent will be obtained from research 
participants 7 to 14 years of age and written assent from research participants 14 
to less than 18 years of age. A copy of the signed document will be given to the 
person who has signed the form. 
12.2 
Consent at Age of Majority
When a participant who was enrolled in the study with parental or guardian 
permission subsequently reaches the age of majority (18 years of age), the 
participant must go through an informed consent process in order to continue 
participation in the study.
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13.0
REFERENCES
  
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isokinetic muscle strength measurements in children 7 to 12 years of age. Acta Paediatr. 
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dorsiflexor strength measurements in healthy young men and women. Scand J Rehabil Med. 
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relationships. Arch Phys Med Rehabil. 1983;64:77-80.
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dynamometry useful for the measurement of quadriceps strength in older people? A comparison 
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children. J Orthop Sports Phys Ther. 1995;22:73-6.
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concentric knee isokinetic strength and power in nonathletic men and women from 20 to 80 
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peak torque in children six through thirteen years old. Pediatr Phys Ther. 2006;18:3-18.
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the knee joint. Yonsei Med J. 1991;32:33-43.
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strength: normative data for adults. Arch Phys Med Rehabil. 1985;66:69-74.
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year-olds. Am J Occup Ther. 1986;40:705-11.
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[291] Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. 
Standardisation of spirometry. Eur Respir J. 2005;26:319-38.
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Standardisation of the single-breath determination of carbon monoxide uptake in the lung. Eur 
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[294] Paridon SM, Alpert BS, Boas SR, Cabrera ME, Caldarera LL, Daniels SR, et al. Clinical 
stress testing in the pediatric age group: a statement from the American Heart Association 
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and Obesity in Youth. Circulation. 2006;113:1905-20.
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factors and irreversible complications. Pediatr Neurosurg. 1999;31:131-6.
[296] Murphy ES, Merchant TE, Wu S, Xiong X, Lukose R, Wright KD, et al. Necrosis after 
craniospinal irradiation: Results from a prospective series of children with CNS embryonal 
tumors. Int J Radiat Oncol Biol Phys. 2012;In Press.
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controls. Stat Med. 2006;25:2922-31.
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[299] Schoenfeld D. Sample-Size Formula for the Proportional-Hazards Regression Model. 
Biometrics. 1983;39:499-503.
[300] Hedeker D, Demirtas H, Mermelstein RJ. A mixed ordinal location scale model for 
analysis of Ecological Momentary Assessment (EMA) data. Stat Interface. 2009;2:391-401.
[301] Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a competing 
risk. J Am Stat Assoc. 1999:496-509.
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APPENDICES
Appendix I:    Evaluation Schedules
Table 6.0.1 Evaluations at Baseline and Follow-up (Prior to Amendment 2.0)
Months after RT Start
Evaluations/Schedule1
0
4
8
12
16
20
24
28
32
36
42
48
54
60
Imaging
Diagnostic/Investigational 
MR
X
X
X
X
X
X
X
X
X
X
X
X
X
X
MR Spine4
X
X
X
X
X
X
FDG PET6
X
X
X
X
PET-methionine6, 7
X
X
X
X
Lateral skull X-ray
X
Bone Age/Q-CT/DEXA
X
Clinical-Standard
Assessment/Triage
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Exam‡#
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Lab: CBC‡
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Lab: Chemistry‡
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Lab: Endocrine Screen‡
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Audiometry2‡
X
X
X
X
X
X
Endocrine Clinic‡
X
X
X
X
X
X
Neurology Clinic‡
X
X
X
X
X
X
Ophthalmology‡
X
X
X
X
X
X
CSF Cytology (Spinal tap)5
X
Clinical-Investigational
Endocrine/Provocative3
X
X
X
Psychology
X
X
X
X
X
X
Function Laboratory
X
X
X
X
X
X
Sleep/Fatigue Research
Actigraphy
X
X
X
X
X
X
Questionnaires/QOL
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory-
Investigational
Genomics
X
Cytokines7
X
X
X
X
X
X
*Patient of childbearing potential requires a negative pregnancy test prior to starting treatment. (‡) should be repeated if clinically 
indicated following craniotomy. 1Imaging and clinical tests should be performed prior to radiation therapy; however, logistics 
may make it difficult to complete all exams prior to treatment. The principal investigator reserves the right to accept pre-
irradiation testing within 16 weeks of the initiation of radiation therapy. PET-FDG and PET-methionine will also be done at time 
of progression or recurrence if prior to 24 months. Assessment/triage includes neck and abdomen circumference. #Edinburgh 
Handedness Inventory performed once. 2Patients who are unable to undergo standard audiometry may undergo ABR at the 
treating physician’s discretion. 3Provocative screening will not be conducted for patients when the number of days off 
corticosteroids prior to the test date is less than the number of days on corticosteroids prior to discontinuance.4MR spine may be 
performed more frequently for patients with spinal metastatic disease or at the discretion of the treating physician. 5Lumbar 
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puncture for CSF cytology may be waived with PI approval based on contraindication or if adequate evaluation was performed 
within 3 weeks of enrollment. 6METPET and FDG-PET scans not performed at 12, 24 or 36 month evaluation may be performed 
at a subsequent follow-up evaluation. All METPET studies will be whole-body regardless of the presence or absence of 
metastatic disease at the time of enrollment.  7Test will not be collected after July 1, 2020  
Table 6.0.2 
Evaluations at Baseline and Follow-up at St. Jude (Amendment 2.0) 
Months after RT Start
Evaluations/Schedule1
0
3
6
9
12
15
18
21
24
27**
30
33**
36
42
48
54
60
Imaging
Diagnostic/Investigational 
MR
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
MR Spine4
X
X
X
X
X
X
FDG-PET6
X
X
X
X
PET-methionine6, 9
X
X
X
X
Lateral skull X-ray
X
Bone Age/Q-CT/DEXA7
X
Clinical-Standard
Assessment/Triage
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Exam‡#
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Lab: CBC‡
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Lab: Chemistry‡
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Lab: Endocrine Screen‡
X
X
X
X
X
X
X
X
X
X
X
X
X
Audiometry2‡
X
X
X
X
X
X
Endocrine Clinic‡
X
X
X
X
X
X
Neurology Clinic‡
X
X
X
X
X
X
Ophthalmology‡
X
X
X
X
X
X
CSF Cytology5
X
Clinical-Investigational
Endocrine/Provocative3
X
X
X
Psychology
X
X
X
X
X
X
Function Laboratory
X
X
X
X
X
X
Sleep/Fatigue Research
Actigraphy
X
X
X
X
X
X
Questionnaires/QOL
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory-
Investigational
Genomics
X
Cytokines8. 9
X
X
X
X
X
X
*Patient of childbearing potential requires a negative pregnancy test prior to starting treatment. (‡) should be repeated if clinically 
indicated following craniotomy. 1Imaging and clinical tests should be performed prior to radiation therapy; however, logistics 
may make it difficult to complete all exams prior to treatment. The principal investigator reserves the right to accept pre-
irradiation testing within 16 weeks of the initiation of radiation therapy. PET-FDG and PET-methionine will also be done at time 
of progression or recurrence if prior to 24 months. Assessment/triage includes neck and abdomen circumference. #Edinburgh 
Handedness Inventory performed once. 2Patients who are unable to undergo standard audiometry may undergo ABR at the 
treating physician’s discretion. 3Provocative screening will not be conducted for patients when the number of days off 
corticosteroids prior to the test date is less than the number of days on corticosteroids prior to discontinuance.4MR spine may be 
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performed more frequently for patients with spinal metastatic disease or at the discretion of the treating physician. 5Lumbar 
puncture for CSF cytology may be waived with PI approval based on contraindication or if adequate evaluation was performed 
within 3 weeks of enrollment.  6MET PET and FDG-PET scans not performed at 12, 24 or 36 month evaluation may be 
performed at a subsequent follow-up evaluation. All METPET studies will be whole-body regardless of the presence or absence 
of metastatic disease at the time of enrollment. 7Patient must be > 3 years of age.  8For patients enrolled before August 30, 2019 
9Test will not be collected after July 1, 2020  **Optional at the dicretion of the treating physician
Appendix II:   Evaluations During Radiation Therapy at St. Jude
TABLE 6.0.3 EVALUATIONS DURING RADIATION THERAPY
Week on therapy
Evaluation
1
2
3 
4 
5 
6 
7 
Imaging 
Activation PET*
X
X
X
X
X
X
X
Clinical-Standard
Physical examination
X
X
X
X
X
X
X
CBC
X
Chemistry
X
Clinical-Investigational
QOL
X
X
Toxicity Assessment
X
X
X
X
X
X
X
Laboratory-Investigational
Cytokines1
X
X
*frequency depending on feasibility and availability
1For patients enrolled before August 30, 2019
Appendix III:  Research Tests
Prior to Amendment 2.0
Research Test
Time Acquisition
MRI of Brain
Baseline and  4, 8, 12, 16, 20, 24, 28, 32, 36, 42,  
48, 54, 60 months
Sleep Fatigue and Quality of Life 
Questionnaires
Baseline, each week during treatment and  4, 8, 12, 
16, 20, 24, 28, 32, 36, 42, 48, 54, 60 months
Serum Cytokine 
Baseline, week 3 & 6 during treatment and 12, 24, 
36, 48, 60 months
MET PET & FDG PET
Baseline and 12, 24, 36 month
Genomics
Baseline
Neuropsychological Testing
12, 24, 48, 60 months
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Human Performance Laboratory
Baseline and 12, 24, 36, 48, 60 months
Actigraphy
Baseline and 12, 24, 36, 48, 60 months
Provocative Endocrine Testing
Baseline 
Lateral skull X-ray
Baseline
Amendment 2.0
Research Test
Time Acquisition
MRI of Brain (research portion)
Baseline and  3, 6, 9, 12, 15, 18, 21, 24, 27 & 33 
(optional), 30, 36, 42, 48, 54, 60 months
Sleep Fatigue and Quality of Life 
Questionnaires1
Baseline, each week during treatment and  3, 6, 9, 
12, 15, 18, 21, 24, 30, 36, 42, 48, 54, 60 months
Serum Cytokine1 
Baseline, week 3 & 6 during treatment and 12, 24, 
36, 48, 60 months
MET PET1 & FDG PET1
Baseline and 12, 24, 36 month
Genomics1
Baseline
Neuropsychological Testing
12, 24, 48, 60 months
Human Performance Laboratory1
Baseline and 12, 24, 36, 48, 60 months
Actigraphy1
Baseline and 12, 24, 36, 48, 60 months
Provocative Endocrine Testing1
Baseline 
Lateral skull X-ray
Baseline
PET Activation1
 Depending on feasibility and availability
1Performed only at St. Jude Children’s Research Hospital. Collaborating sites will not participate
 in these tests.
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Appendix IV:  RERTEP Ophthalmology Form
Patient Name:                                        MRN:                         Exam date:
Contrast Sensitivity
OD (Right Eye)
OS (Left Eye)
Circle 
one/eye
1    2     3     4     5
1    2     3     4     5
Legend
1=1.25%, 2=2.5%, 3=5%, 4=10%, 5=25%
Visual Acuity
OD (Right Eye)
OS (Left Eye)
Distance Vision with Glasses
Distance Vision without Glasses
Near Vision With Glasses
Near Vision without Glasses
APD
+  /   -
+  /   -
Strabismus
OD (Right Eye)
OS (Left Eye)
XT
+  /   -
+  /   -
ET
+  /   -
+  /   -
HT
+  /   -
+  /   -
Visual Fields
Method:  
 Sitafast 24-2      
Goldmann         
Confrontation
Grade
Achievement
OD (Right Eye)
OS (Left Eye)
Descriptive
8
Monocular Full
+  /   -
+  /   -
7
Monocular Quadrantic
+  /   -
+  /   -
6
Binocular Quadrantic
+  /   -
+  /   -
5
Monocular Hemianopic
+  /   -
+  /   -
4
Binocular Hemianopic
+  /   -
+  /   -
3
Monocular Hemi and 
Quadrantic
+  /   -
+  /   -
2
Binocular Hemi and 
Quadrantic
+  /   -
+  /   -
1
Total Loss
+  /   -
+  /   -
Color Vision
Method:  
 Ishihara’s      
Farnsworth
Grade
Colors Matched
OD (Right Eye)
OS (Left Eye)
8
Match 13-16 colors
7
Match 11-12 colors
6
Match 9-10 colors
5
Match 7-8 colors
4
Match 5-6 colors
3
Match 3-4 colors
2
Match 1-2 colors
1
0 color matched
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Fundoscopy
OD (Right Eye)
OS (Left Eye)
Optic Atrophy
Papilledema
Other:_________________________________________________________________________________
                                                                                                      ____________________________
                                                                Signature
St. Jude Children's Research Hospital
IRB NUMBER: Pro00004349
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