Efficacy of Carboplatin Administered Concomitantly With Radiation and Isotretinoin as a Pro-Apoptotic Agent in Other Than Average Risk Medulloblastoma/PNET Patients
Phase: PHASE3
Conditions: Anaplastic Medulloblastoma, Medulloblastoma
Sponsor: Children's Oncology Group

 
 
ACNS0332 
 
Activated: 
March 26, 2007 
Version Date: 
4/11/18 
Closed: 
September 7, 2018 
Amendment #: 
6 
 
 
 
CHILDREN’S ONCOLOGY GROUP 
 
ACNS0332 
 
Efficacy of Carboplatin Administered Concomitantly With Radiation and Isotretinoin as a 
Pro-Apoptotic Agent in Other Than Average Risk Medulloblastoma/PNET Patients 
 
A Groupwide Phase III Study 
 
CTEP ID / SKION Participating Institution 
  
Investigator ID 
51075  /  Dutch Childhood Oncology Group 
 
43656 
 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, AND SHOULD NOT BE COPIED, REDISTRIBUTED OR USED FOR 
ANY OTHER PURPOSE. MEDICAL AND SCIENTIFIC INFORMATION CONTAINED WITHIN THIS PROTOCOL IS NOT 
INCLUDED TO AUTHORIZE OR FACILITATE THE PRACTICE OF MEDICINE BY ANY PERSON OR ENTITY.  RESEARCH 
MEANS A SYSTEMATIC INVESTIGATION, INCLUDING RESEARCH DEVELOPMENT, TESTING AND EVALUATION, 
DESIGNED TO DEVELOP OR CONTRIBUTE TO GENERALIZABLE KNOWLEDGE.  THIS PROTOCOL IS THE RESEARCH 
PLAN DEVELOPED BY THE CHILDREN’S ONCOLOGY GROUP TO INVESTIGATE A PARTICULAR STUDY QUESTION OR 
SET OF STUDY QUESTIONS AND SHOULD NOT BE USED TO DIRECT THE PRACTICE OF MEDICINE BY ANY PERSON OR 
TO PROVIDE INDIVIDUALIZED MEDICAL CARE, TREATMENT, OR ADVICE TO ANY PATIENT OR STUDY SUBJECT.  THE 
PROCEDURES IN THIS PROTOCOL ARE INTENDED ONLY FOR USE BY CLINICAL ONCOLOGISTS IN CAREFULLY 
STRUCTURED SETTINGS, AND MAY NOT PROVE TO BE MORE EFFECTIVE THAN STANDARD TREATMENT.  ANY PERSON 
WHO REQUIRES MEDICAL CARE IS URGED TO CONSULT WITH HIS OR HER PERSONAL PHYSICIAN OR TREATING PHYSICIAN 
OR VISIT THE NEAREST LOCAL HOSPITAL OR HEALTHCARE INSTITUTION. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For Statistics and Data Center Contact Person see: http://members.childrensoncologygroup.org 
 

 
Version Date: 4/11/18 
 
2 
 
 
CONTACT INFORMATION 
 
To 
submit 
site 
registration 
documents: 
For patient enrollments: 
Submit study data 
Regulatory documentation must 
be submitted to the CTSU via the 
Regulatory Submission Portal. 
Regulatory Submission Portal: 
(Sign 
in 
at 
www.ctsu.org,  
and 
select 
the 
Regulatory 
Submission sub-tab under the 
Regulatory tab.)  
 
Institutions with patients waiting 
that are unable to use the Portal 
should alert the CTSU Regulatory 
Office immediately at 1-866-651-
2878 to receive further instruction 
and support. 
 
Contact the CTSU Regulatory 
Help Desk at 1-866-651-2878 for 
regulatory assistance. 
Please refer to the patient enrollment 
section of the protocol for instructions 
on using the Enrollment application in 
the eRDE system. If you have problems 
with enrollment, refer to online help in 
the Applications area of the COG 
website. 
 
Data collection for this study will 
be done exclusively through 
eRDE system. Please see the 
Data Submission Schedule in the 
CRF 
packet 
for 
further 
instructions.  
 
 
The most current version of the study protocol and all supporting documents must be downloaded from the 
protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org. Access to the CTSU 
members’ website is managed through the Cancer Therapy and Evaluation Program - Identity and Access 
Management (CTEP-IAM) registration system and requires user log on with CTEP-IAM username and password. 
Permission to view and download this protocol and its supporting documents is restricted and is based on person 
and site roster assignment housed in the CTSU RSS.  
For clinical questions (i.e. patient eligibility or treatment-related) contact the Study PI of the Lead Protocol 
Organization. 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data submission) contact 
the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and correspondence 
will be triaged to the appropriate CTSU representative.  
The CTSU Website is located at https://www.ctsu.org. 
 
 
 
 
 
 
 
 

 
 
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3 
 
ACNS0332 
TABLE OF CONTENTS 
 
SECTION 
PAGE 
STUDY COMMITTEE 
6 
ABSTRACT 
10 
EXPERIMENTAL DESIGN SCHEMA 
11 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
12 
1.1 
Primary Objectives 
12 
1.2 
Correlative Science Objectives 
12 
2.0 
BACKGROUND 
12 
2.1 
Rationale for Selected Approach and Trial Design 
12 
2.2 
Rationale for Concurrent Carboplatin and Radiation Therapy 
12 
2.3 
Rationale for Concurrent Isotretinoin and Adjuvent Chemotherapy 
13 
2.4 
Rationale for Continued Enrollment of Medulloblastoma Patients and Discontinued 
Enrollment of PNET Patients 
16 
2.5 
Rationale for Biology Studies 
16 
2.6 
Gender and Race Differences 
17 
2.7 
Rationale for Continued Enrollment of Medulloblastoma Patients on Carboplatin 
Randomization and Discontinue Isotretinoin radomization 
17 
3.0 
STUDY ENROLLMENT AND PATIENT ELIGIBILITY 
17 
3.1 
Study Enrollment 
17 
3.2 
Patient Criteria 
19 
4.0 
TREATMENT PLAN 
23 
4.1 
Regimen A Administration Schedule for Radiation Therapy 
23 
4.2 
Regimen B Administration Schedule for Radiation Therapy 
27 
4.3 
Regimen A or Regimen B Maintenance 
30 
5.0 
DOSE MODIFICATIONS FOR TOXICITIES 
33 
5.1 
Dose Modifications During Radiation Therapy 
33 
5.2 
Dose Modifications during Maintenance Chemotherapy 
33 
6.0 
DRUG INFORMATION 
35 
7.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
36 
7.1 
Required Observations, Pre-Treatment and During Radiation Therapy for Regimen A 36 
7.2 
Required Observations, Pre-Treatment and During Radiation Therapy for Regimen B 
(With Carboplatin) 
37 
7.3 
Required Observations During Maintenance Chemotherapy for Regimens A and B 
38 
7.4 
Required Observations Following Therapy 
39 
7.5 
Optional Studies 
40 
8.0 
SUPPORTIVE CARE GUIDELINES 
40 
8.1 
Venous Access 
40 
8.2 
Antiemetics 
40 
8.3 
Fever and Neutropenia 
40 
8.4 
Prophylactic Antibiotics 
40 
8.5 
Azole Anti-fungal Agents 
41 
8.6 
Blood Products 
41 
8.7 
Nutritional Support 
41 

 
 
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ACNS0332 
9.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA 
42 
9.1 
Criteria for Removal from Protocol Therapy 
42 
9.2 
Off Study Criteria 
42 
10.0 
STATISTICAL CONSIDERATIONS 
42 
10.1 
Design Considerations 
43 
10.2 
Patient Accrual 
43 
10.3 
Study Duration 
44 
10.4 
Study Endpoints for Analysis of Treatment Efficacy 
44 
10.5 
Statistical Analysis of Difference in Long-Term EFS Rate 
44 
10.6 
Interim Monitoring 
45 
10.7 
Statistical Analysis of the Post-RT Response 
48 
10.8 
Stratification 
48 
10.9 
Neuropsychological and Quality of Life 
48 
10.10 Gender and Ethnicity Considerations 
49 
11.0 
EVALUATION CRITERIA 
50 
11.1 
Common Terminology Criteria for Adverse Events v4.0 (CTCAE) 
50 
11.2 
Methodology to Determine Tumor Measurement 
50 
11.3 
Selection of Target and Non-Target Lesions 
53 
11.4 
Response Criteria for Target Lesions 
53 
11.5 
Response Criteria for Non-target Lesions 
54 
12.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
54 
12.1 
Purpose 
54 
12.2 
Determination of Reporting Requirements 
54 
12.3 
Reporting of Adverse Events for Commercial Agents – via CTEP-AERS 
55 
12.4 
Routine Adverse Event Reporting 
55 
13.0 
RECORDS AND REPORTING 
56 
13.1 
Categories of Research Records 
56 
13.2 
CDUS 
56 
14.0 
SURGICAL GUIDELINES 
56 
14.1 
Neurosurgical Procedure 
56 
14.2 
Shunts 
57 
14.3 
Assessment of Residual Tumor 
57 
14.4 
Extent of Tumor Resection 
58 
14.5 
Imaging Confirmation of Extent of Resection 
58 
14.6 
Peri-operative Corticosteroids 
58 
15.0 
PATHOLOGY GUIDELINES AND SPECIMEN REQUIREMENTS 
59 
15.1 
Neuropathology Goals 
59 
15.2 
Requirements for Handling Biopsy or Surgical Resection Tissue 
59 
15.3 
Pathology Review Materials 
59 
15.4 
Central Review Process 
60 
16.0 
SPECIMEN REQUIREMENTS FOR BIOLOGY STUDIES 
60 
16.1 
Optional Biology Studies 
60 
16.2 
Specific Aims 
63 
16.3 
Aim 1. To determine the molecular subtype of each medulloblastoma patient. 
64 
16.4 
Aim 2. To describe the genomic profiles of sPNET patients in the context of >800 
reference samples from pediatric brain tumor patients 
64 

 
 
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ACNS0332 
16.5 
Aim 3. To confirm prognostic indicators of therapy failure in high-risk 
medulloblastomas 
65 
16.6  
Aim 4: To identify candidate prognostic indicators of therapy failure in high-risk 
medulloblastomas 
65 
16.7 
Aim 5: To generate patient-derived resources that help prioritize targeted therapies for 
future clinical trials 
66 
16.8 
Aim 6. Tissue Banking 
66 
17.0 
IMAGING STUDIES REQUIRED AND GUIDELINES FOR OBTAINING 
66 
17.1 
Whole Brain MRI With and Without Contrast 
67 
17.2 
MR Spine With and Without Contrast 
67 
17.3 
Central Review 
68 
18.0 
RADIATION THERAPY GUIDELINES 
69 
18.1 
Timing of Radiation Therapy 
70 
18.2 
Equipment 
70 
18.3 
3-D Target Volume and Organ At Risk Definitions 
71 
18.4 
Dosimetry 
74 
18.5 
Treatment Technique 
76 
18.6 
Normal Tissue Sparing 
78 
18.7 
Dose Calculations and Reporting 
78 
18.8 
Quality Assurance Documentation 
79 
18.9 
Definitions of Deviation in Protocol Performance 
81 
19.0 
QUALITY OF LIFE AND NEUROPSYCHOMETRIC GUIDELINES 
82 
APPENDIX I: PERFORMANCE STATUS SCALES/SCORES 
83 
APPENDIX II: M-STAGING SYSTEM FOR POSTERIOR FOSSA AND NON POSTERIOR FOSSA 
PNET 
84 
APPENDIX III: YOUTH INFORMATION SHEETS 
85 
APPENDIX IV:  CTEP AND CTSU REGISTRATION PROCEDURES 
89 
REFERENCES 
91 

 
 
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STUDY COMMITTEE 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
  
  
  
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
   
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 

 
 
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COMMITTEE MEMBERS 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
AGENT  
 
 
 
NSC#  
 
Carboplatin (Paraplatin®)   
 
241240 
 
CISPLATIN  
 
 
 
119875 
 
CYCLOHOSPHAMIDE  
 
 
026271 
 
Filgrastim (G-CSF)  
 
 
 614629 
 
Isotretinoin (13-cis Retinoic Acid)   
329481 
 
Vincristine  
  067574 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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The Children's Oncology Group has received a Certificate of Confidentiality from the federal government, 
which will help us protect the privacy of our research subjects. The Certificate protects against the 
involuntary release of information about subjects collected during the course of our covered studies. The 
researchers involved in the studies cannot be forced to disclose the identity or any information collected in 
the study in any legal proceedings at the federal, state, or local level, regardless of whether they are criminal, 
administrative, or legislative proceedings. However, the subject or the researcher may choose to voluntarily 
disclose the protected information under certain circumstances. For example, if the subject or his/her 
guardian requests the release of information in writing, the Certificate does not protect against that 
voluntary disclosure. Furthermore, federal agencies may review our records under limited circumstances, 
such as a DHHS request for information for an audit or program evaluation or an FDA request under the 
Food, Drug and Cosmetics Act.  
 
The Certificate of Confidentiality will not protect against mandatory disclosure by the researchers of 
information on suspected child abuse, reportable communicable diseases, and/or possible threat of harm to 
self or others. 
 
 
 
ABSTRACT 
 
Medulloblastoma is the most common malignant childhood brain cancer. The goal of this study is to 
determine whether radiosensitization with carboplatin improves cure rates for children with other than 
average risk medulloblastoma. All patients will receive standard therapy consisting of surgery, radiation 
therapy and chemotherapy. Subsets of patients will be randomly assigned to receive carboplatin 
radiosensitization. Carboplatin has activity as a single agent against medulloblastoma and it has been shown 
to enhance radiation-induced tumor cell kill. A previous study, CCG-99701, demonstrated that it was 
feasible and safe to administer carboplatin on a daily basis during radiation therapy. Correlative biology 
studies are incorporated into the research design. ACNS0332 previously included a second randomization 
to assess whether the addition of Isotretinoin improved suvival. This randomization has been closed because 
the question has been answered. ACNS0332 previously included supratentorial primative neuroectodermal 
tumor (PNET) patients in addition to medulloblastoma patients. The PNET component of the trial has 
concluded. 
 
Note: Enrollment to Regimen C and D on ACNS0332 has been suspended effective January 27, 2015:  
 
Following review of the ACNS0332 study data during the COG Fall 2014 meeting, the DSMC requested a 
yearly futility analysis to be performed. Based on the most recent analysis and recommendations from the 
DSMC, it was concluded that treatment of patients with medulloblastoma with isotretinoin as performed in 
the context of this study will not lead to a significant event free survival advantage. The Study Committee 
and Group Chair have therefore decided to stop further randomization of patients to isotretinoin (Regimen 
C and D). The Study Committee recommends that subjects currently receiving protocol therapy on Regimen 
C or D discontinue administration of isotretinoin.  
 
A futility analysis was also conducted for the carboplatin randomization; the DSMC determined that no 
changes be made to the carboplatin component of this trial. Therefore, Regimens A and B will remain open 
for accrual to address this important question. Enrollment of newly diagnosed patients with high-risk 
medulloblastoma onto this study continues to be strongly encouraged. 
 
 
 

 
 
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EXPERIMENTAL DESIGN SCHEMA 
 
  
 
SURGERY 
ON STUDY 
RANDOMIZATION 
REGIMEN A 
RT  
WITH 
VINCRISTINE  
REGIMEN B 
RT  
WITH 
VINCRISTINE 
AND  
CARBOPLATIN 
REGIMEN C 
RT  
WITH 
VINCRISTINE 
REGIMEN D 
RT  
WITH 
VINCRISTINE 
AND 
CARBOPLATIN 
MAINTENANCE 
MAINTENANCE 
MAINTENANCE 
WITH 
ISOTRETINOIN 
CONTINUATION  
THERAPY WITH  
ISOTRETINOIN 
CONTINUATION  
THERAPY WITH  
ISOTRETINOIN 
MAINTENANCE 
WITH 
ISOTRETINOIN 
Randomization to arms C and D stopped as of 1/27/15 

 
 
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1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
 
1.1 
Primary Objectives 
1.1.1 
To determine whether carboplatin radiosensitization increases long term event-free 
survival for high risk medulloblastoma/PNET patients. 
 
1.1.2 
To determine whether Isotretinoin increases long term event-free survival for high risk 
medulloblastoma/PNET patients. 
 
1.2 
Correlative Science Objectives 
1.2.1 
To compare residual disease response to radiation alone versus radiation plus carboplatin. 
 
1.2.2 
To identify molecular prognostic indicators suitable for patient stratification in future trials. 
 
1.2.3 
To evaluate the HRQOL during phases of active treatment specific to treatment modalities. 
 
1.2.4 
To describe the neuropsychological functioning of the study population and to evaluate the 
relationship between neuropsychological status and health related quality of life. 
 
 
2.0 
BACKGROUND  
 
2.1 
Rationale for Selected Approach and Trial Design  
Advances in surgical technique, radiation therapy and chemotherapy have improved the 
outcome for children with medulloblastoma and other PNETs. Unfortunately, the rate of 
recurrence, death, and treatment-related morbidity remain unacceptable. 1-4 Therapeutic 
approaches that improve efficacy with minimal added toxicity are needed. 
 
This study will be conducted in parallel with the ACNS0331 study for standard risk 
medulloblastoma, thereby completing the therapeutic platform for these tumors. Because 
the results in patients with high-risk medulloblastoma have historically been substantially 
inferior to those in patients with standard risk disease, the current study differs from 
ACNS0331 by maintaining the use of "standard" radiation doses and seeks to test the 
efficacy of adding radiosensitization and retinoid therapy to the backbone of radiotherapy 
and moderate intensity adjuvant chemotherapy as a way to improve survival in these high 
risk patients. In parallel with the ACNS0331 study, the current study will also evaluate the 
utility of biological parameters as predictors of treatment response and the impact of 
therapy on quality of life and neuropsychiatric measures. Such approaches, if validated, 
would then be incorporated in subsequent studies for these tumors. 
 
2.2 
Rationale for Concurrent Carboplatin and Radiation Therapy 
Carboplatin as a single agent is effective for medulloblastoma/PNET patients, with 
complete or partial responses observed in 7 out of 15 recurrent disease patients receiving 
100-210 mg/m2/week. 5-7 Most of these patients received 175/mg/m2/week as a single dose. 

 
 
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In the proposed study, patients will receive 175/mg/m2/week divided into five daily 35 
mg/m2/day doses. Based on the efficacy data in relapsed patients, co-administration of 
carboplatin and radiation in the post-surgical period would be justified even in the absence 
of laboratory studies showing positive interaction between the two modalities. In addition, 
multiple laboratory and clinical studies show that cancer cell response is greater in the 
presence of carboplatin and radiation than either modality alone. 8-14 
Early laboratory studies reporting enhancement of radiation effects by platinum agents 
have been reviewed. 8 The enhancement of radiation-induced cell kill may involve multiple 
mechanisms including free radical-mediated radiosensitization, inhibition of recovery from 
potentially lethal or sublethal damage, and direct chemotherapy effects augmented by 
radiation-mediated enhanced cellular uptake of platinum agents. 8-14  
Concurrent administration of carboplatin and radiation has been well tolerated by adults 
and elderly patients in clinical trials and has led to improved response rates compared to 
radiation alone. In patients with advanced head and neck cancer, concurrent administration 
of carboplatin at AUC of 0.4 per week, docetaxel at 10 mg/m2 and 64-82 Gy radiotherapy 
resulted in 81% complete response and 19% partial response rates. 15 Elderly patients with 
small cell lung cancer were treated with daily carboplatin (30 mg/m2/day x 4 weeks) and 
50-60 Gy radiotherapy and achieved a 50% response rate (1 CR, 18 PR, 38 patients total). 
16  A phase III trial of 283 patients with unresectable stage III lung cancer showed an 18% 
CR rate in patients that received carboplatin (100 mg/m2/week) plus 60 Gy radiation versus 
10% in the radiation only arm (P = 0.1). 17  
Concurrent administration of carboplatin (35 mg/m2/day x 30 doses) and radiation therapy 
in high risk medulloblastoma/PNET patients has been shown to be safe in protocol CCG 
99701. In that study, carboplatin, rather than cisplatin was selected for reduced toxicities 
in addition to radiosensitization based primarily on pharmacokinetic properties, as both 
have been reported to have similar radiosensitizing activity. 18 Because carboplatin binds 
to plasma proteins more slowly than cisplatin, more free drug is available to cross the blood 
brain barrier. 19,20 Following intravenous administration of comparable doses in a primate 
model cerebrospinal AUC levels were 10-fold higher for carboplatin compared to cisplatin. 
21 Brain tumor levels of carboplatin sufficient for radiosensitization can be obtained with 
doses of carboplatin as low as 20 mg/m2. 22-24  
 
2.3 
Rationale for Concurrent Isotretinoin and Adjuvent Chemotherapy 
Pre-clinical studies showed that Isotretinoin and ATRA induced programmed cell death in 
medulloblastoma cells through a mechanism that involves induction of bone 
morphogenetic protein 2 (BMP2)-mediated phosphorylation of p38 MAP kinase. 25 
Independent studies by Drs Reddy and Phillips at the Children’s Hospital of Philadelphia 
confirmed the pro-apoptotic activity of retinoids in medulloblastoma and demonstrated 
caspase activation. 26 Fenretinide has also been tested and caused significantly less 
apoptosis in medulloblastoma cell lines than Isotretinoin or ATRA despite pro-apoptotic 
effects of fenretinide in other types of cancer (Hallahan and Olson, unpublished data).  
 
Cultured medulloblastoma cells undergo apoptosis as the predominant response to 
retinoids. In two medulloblastoma cell lines, D283 and D341, Isotretinoin and all-trans 
retinoic acid (ATRA) induced apoptosis in a dose- and time-dependent fashion at 
concentrations that are readily achievable in the central nervous system. Efficacy was 
observed at concentrations ranging from 10 nM to 1 µM. 25 The response increased with 
duration of treatment so that by 6-8 days, 79% +/- 4% of D283s and 67% +/- 4% of D341s 
were apoptotic. 25 Because cultured tumor cells do not always faithfully represent primary 

 
 
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tumors, patient-derived medulloblastoma specimens were placed in tissue culture media 
within 20 minutes of resection from their blood supply, mechanically triturated into near 
single-cell 
suspensions 
and 
then 
treated 
with 
RA. 
Eight 
of 
10 
primary 
medulloblastoma/primitive neuroectodermal tumor specimens tested showed significantly 
increased cell death in response to these retinoids. Only 32 ± 5.2% of cells remained viable 
after 48 hours of ATRA exposure compared to 70 ± 5.5% of vehicle-treated cells (P < 
0.0006). In both established cultures and patient-derived specimens, cell cycle arrest and 
neuronal differentiation was observed in a subset of the cells that failed to apoptose. 
Importantly, little or no retinoid-induced apoptosis was observed in neuroblastoma or 
glioma cells indicating that retinoids interfere with a pathway that is uniquely critical for 
medulloblastoma cell survival. This would suggest that retinoids might have even more 
efficacy in medulloblastoma patients than has been observed with neuroblastoma patients.  
To determine whether the therapeutic window for retinoids was suitable for in vivo 
medulloblastoma treatment, studies were conducted in athymic mice bearing D283 
medulloblastoma xenografts. ATRA or Isotretinoin sharply limited tumor growth. The 
average volume of treated animals was less than 1/3 that of untreated animals (p < 0.01, n 
= 24 controls, 12 ATRA-treated, 12 Isotretinoin-treated). 25 
 
A subsequent study also showed that a putative medulloblastoma oncogene is negatively 
regulated by ATRA. In this study, ATRA repressed OTX2 and induced apoptosis in 
medulloblastoma cell lines that overexpress OTX2. 27 In contrast to the ex vivo data above, 
these studies indicate that retinoids will be beneficial for treatment of medulloblastomas 
with anaplastic features. The conflicting preliminary data will be directly addressed as part 
of the biology correlative studies described in Section 16. 
 
Isotretinoin rather than ATRA was selected for this study because of superior 
pharmacokinetic properties and comparatively reduced incidence of headaches and 
pseudotumor cerebri. Isotretinoin crosses the blood brain barrier and achieves parenchymal 
concentrations that show efficacy in pre-clinical studies. In a phase II clinical trial that 
measured pharmacokinetic data in 30 children treated with Isotretinoin, the mean serum 
level ranged from 4.9-8.9 µmol/l at doses of 100-200 mg/m2/day. 28 The area under the 
curve was maintained through multiple courses of therapy and clearance of Isotretinoin did 
not increase during therapy. In this study, the half-life was 5.1 ± 3.2 hours. A study of 
adults with melanoma similarly showed that serum concentrations greater than 2 µmol/l 
were achieved with doses much lower than proposed in this study (40 mg every other day). 
29 In this study, the plasma half-life averaged 33 hours. Studies of Isotretinoin levels in 
brain gray and white matter in rats showed that brain concentrations are approximately 30-
50% those of serum. 30 Thus, mean serum levels of 4.9-8.9 µmol/l in pediatric patients are 
expected to provide levels in brain greater than the highest concentration used in pre-
clinical studies (1 µmol/l) and over 100 times higher than the minimally effective 
concentration in pre-clinical studies (10 nmol/l). In the event of disrupted blood brain 
barrier, the concentration of retinoids in the brain may be even higher.  
There is no clinical trial data demonstrating efficacy of retinoids in medulloblastoma, 
however, Isotretinoin is safe and effective in patients with neuroblastoma. Isotretinoin was 
tested in a phase III clinical trial of pediatric patients with high risk neuroblastoma. In the 
cohort that completed the retinoid phase of therapy, 3 year event free survival was 
increased from 29% to 45% by a six month course of Isotretinoin. 31 Complete responses 
were also observed in 3 patients with bone marrow metastases as the only site of detectable 
neuroblastoma in a phase I study. 32 These studies demonstrated that retinoids were 

 
 
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effective and that the dose and schedule proposed for the current study was well tolerated 
in pediatric patients. 
The most compelling reason for providing Isotretinoin concurrently with adjuvant 
chemotherapy is that medulloblastoma cell apoptosis is significantly higher in the presence 
of cisplatin and Isotretinoin than either agent alone as described in more detail in the next 
paragraph. In addition, approximately 29% of medulloblastoma/PNET recurrences occur 
prior to the completion of adjuvant therapy. If Isotretinoin administration began after 
adjuvant chemotherapy was complete, there would be no opportunity to improve outcome 
for this group of patients.  
 
Isotretinoin acts synergistically with cisplatin in cultured medulloblastoma cells. Cisplatin 
serves as a key agent in medulloblastoma therapy because of its demonstrated efficacy 
against medulloblastoma cells and because of improved outcomes in clinical trials that 
utilized platinum-based chemotherapy regimens. Preliminary studies show that Isotretinoin 
acts synergistically with cisplatin both in vitro and in vivo, increasing apoptosis of D283 
cells by as much as three fold compared to either agent alone (Hallahan and Olson, 
unpublished). In an earlier study, the combination of 1 µg/ml cisplatin and 10 µM/l 
Isotretinoin led to complete cessation of growth of Med-3 medulloblastoma cells. 33 In 
other studies, retinoid agonists increased the efficacy of cisplatin against skin squamous 
cell carcinoma cell lines, oral squamous cell carcinoma xenografts, ovarian 
adenocarcinoma cells, ovarian caracinoma xenografts, and squamous head and neck cancer 
cells. 34-37 In addition, durable responses were observed when retinoid agonists and 
cisplatin were co-administered in patients with recurrent or advanced squamous cell 
carcinoma of the head and neck, advanced squamous cell carcinoma of the skin, advanced 
non-small-cell lung cancer. 34,38 
 
Cisplatin and Isotretinoin have largely non-overlapping toxicities. Prevalent cisplatin 
toxicities include hearing loss, renal dysfunction, nausea and marrow suppression. 
Isotretinoin has been safely administered in pediatric neuroblastoma patients. The most 
common untoward effects of Isotretinoin included dry skin, xerostomatitis, and headache, 
though the frequency of headache is much lower than seen with other retinoids such as 
ATRA. In a study of 43 adults treated with Isotretinoin for glioma, there were no instances 
of headache or pseudotumor cerebri.39 Because cisplatin and Isotretinoin act 
synergistically, they have been combined in multiple clinical trials that involved adult 
patients. In one study, that involved administration of ATRA at 150 mg/m2 on an every 
day basis without breaks, ATRA was poorly tolerated and discontinued by some patients. 
In three other trials that utilized breaks in the Isotretinoin dosing regimen, the combination 
was well tolerated establishing that the drugs can be safely co-administered.34,38 The current 
study follows a two weeks on, two weeks off schedule for Isotretinoin, similar to the 
schedule that has been well tolerated in children with neuroblastoma. 
 
Following review of the ACNS0332 study data during the COG Fall 2014 meeting, the 
DSMC requested a yearly futility analysis be performed. Based on the most recent analysis 
and recommendations from the DSMC, it was concluded that treatment of patients with 
medulloblastoma with isotretinoin as performed in the context of this study will not lead 
to a significant event free survival advantage. The Study Committee and Group Chair have 
therefore decided to stop further randomization of patients to isotretinoin (Regimen C and 
D) effective 1/27/15. The Study Committee recommends that subjects currently receiving 
protocol therapy on Regimen C or D discontinue administration of isotretinoin. 
 

 
 
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A futility analysis was also conducted for the carboplatin randomization; the DSMC 
determined that no changes be made to the carboplatin component of this trial. Therefore, 
Regimens A and B will remain open for accrual to address this important question. 
Enrollment of newly diagnosed patients with high-risk medulloblastoma onto this study 
continues to be strongly encouraged. 
 
2.4 
Rationale for Continued Enrollment of Medulloblastoma Patients and Discontinued 
Enrollment of PNET Patients 
As of Amendment #2, the ACNS0332 protocol has been amended to discontinue 
enrollment of PNET patients and to extend enrollment of medulloblastoma patients to 300 
eligible and evaluable patients. 300 patients have been enrolled on the study. Four (4) of 
these patients were deemed to be ineligible for the protocol, leaving 296 eligible patients. 
211 of the 296 patients had medulloblastoma and the other 85 were diagnosed with SPNET. 
The SPENT patients enrolled on the trial will be replaced. 
 
Randomization to this study was stratified on dissemination and tumor location 
(supratentorial PNET vs. medulloblastoma). The study was powered to detect treatment 
effects among all patients (PNET and medulloblastoma) combined. New data on biological 
differences between supratentorial PNET and medulloblastoma have become available, 
raising concern that heterogeneity of treatment effect across tumor type may reduce power. 
Therefore, the study has been re-powered to detect treatment effects among 
medulloblastoma patients alone. Accrual of supratentorial PNET patients will be 
discontinued since power to detect treatment effects in this group, which accounts for less 
than 30% of enrolled patients, will not be attainable within a reasonable time-frame.  
 
As of June 2014, treatment is complete for all supratentorial PNET patients enrolled on 
ACNS0332.  The diagnoses were made with the best available pathologic tools at the time 
of diagnosis and it is now clear that these tumors are biologically different than 
medulloblastomas.  PNET patient data will be reported separately from medulloblastoma 
patient data and each will state the statistical power that accompanies the studies.  The 
genomic studies that will commence on ACNS0332 patient samples will be retrospective 
and non-CLIA certified.  It is being done to advance molecular pathology diagnoses for 
future patients rather than to alter treatment decisions.  
 
Analyses will be performed separately for medulloblastoma and PNET patients. Statistical 
power for detecting treatment effects will be unchanged from that reported in the original 
protocol among medulloblastoma patients. Achieving the same statistical power among 
PNET patients however, would require more than 10 years of additional accrual, which is 
not feasible. Therefore outcomes for PNET patients will be reported with a statement 
regarding the current power.  
 
The study duration is expected to be about 11 years, including the suspension for the 
amendment, additional 3 years of accrual, and 1 year of follow-up at the end. 
 
2.5 
Rationale for Biology Studies 
Since the activation of ACNS0332, four molecular subtypes of medulloblastoma have been 
defined, namely Wnt, Sonic Hedgehog (Shh), Group 3 and Group 4. Within these 
molecular subtypes, additional prognostic indicators are emerging and some previous 
inidcators have been disproven as reliable biomarkers of outcome 
 

 
 
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As of Amendment #2, the biology studies included in Section 16.0 will permit the biology 
group within the Study Committee to assign each patient to one of the four molecular 
subclasses of medulloblastoma using fixed tissue, which is available for nearly all patients.  
 
Likewise the PNET patient profiles will be compared to over 800 pediatric patient 
specimens to help determine the correct molecular subclasses of this disease. While this 
will not affect the statistical analysis of the study, it will enable the investigators to report 
patient outcomes in the context of molecular subtypes. 
 
2.6 
Gender and Race Differences 
There is no reported evidence to suggest that there are differences in outcome by gender or 
race when otherwise identical patients receive the same treatment. 
 
2.7 
Rationale for Continued Enrollment of Medulloblastoma Patients on Carboplatin 
Randomization and Discontinue Isotretinoin radomization 
Amendment #3 incorporates the DSMC request to incorporate interim futility monitoring 
for both randomizations. We use conditional power as a guide for futility monitoring which 
is planned to coincide with annual DSMC reports. Prior to the activation of this amendment 
and in line with a request from the DSMC we conducted an interim futility analysis using 
the conditional power approach for Isotretinoin randomization based on data frozen as of 
June 30, 2014. This interim analysis led to the decision that continuing the randomization 
for Isotretinoin until the end of the trial had a very small chance of leading to a significant 
difference between the two arms and thus the DSMC recommended closure of the 
Isotretinoin randomization. At the same time we also conducted a similar interim analysis 
for the Carboplatin randomization which led to the conclusion that the randomization 
should continue.  
 
 
3.0 
STUDY ENROLLMENT AND PATIENT ELIGIBILITY 
 
3.1 
Study Enrollment  
 
3.1.1 
IRB Approval 
Sites must obtain IRB/REB approval for this protocol and submit the supporting 
documentation to the CTSU Regulatory Office prior to patient enrollment. Allow 
3 business days for processing. The submission must include a fax coversheet (or 
optional CTSU IRB Transmittal Sheet) and the IRB approval document(s).  The 
CTSU IRB Certification Form may be submitted in lieu of the signed IRB approval 
letter.  All CTSU forms can be located at on the CTSU web page 
(https://www.ctsu.org). Any other regulatory documents needed for access to the 
study enrollment screens will be listed for the study on the CTSU Member’s 
Website under the RSS Tab.   
 
IRB/REB approval documents may be faxed (1-215-569-0206), Emailed 
(CTSURegulatory@ctsu.coccg.org) or mailed to the CTSU Regulatory office.   
 
When a site has a pending patient enrollment within the next 24 hours, this is 
considered a “Time of Need” registration.  For Time of Need registrations, (1) 
mark your submissions as ‘URGENT,’ (2) fax the regulatory documents, and (3) 
call the CTSU Regulatory Helpdesk at: 1-866-651-CTSU. For general (non-
regulatory) questions call the CTSU General Helpdesk at: 1-888-823-5923. 

 
 
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Sites can check the status of their registration packets by querying the Regulatory 
Support System (RSS) site registration status page of the CTSU members’ web 
site by entering credentials at https://www.ctsu.org. For sites under the CIRB 
initiative, IRB data will automatically load to RSS. 
 
Note: Sites participating on the NCI CIRB initiative and accepting CIRB 
approval for the study are not required to submit separate IRB approval 
documentation to the CTSU Regulatory Office for initial, continuing or 
amendment review. However, these sites must submit a Study Specific 
Worksheet for Local Context (SSW) to the CIRB (via IRB Manager) to indicate 
their intention to open the study locally. The CIRB’s approval of the SSW is then 
communicated to the CTSU Regulatory Office for compliance in the RSS.  
Signatory site may be contacted by the CTSU Regulatory Office or asked to 
complete information verifying the participating institutions on the study. Other 
site registration requirements (e.g., laboratory certifications, protocol-specific 
training certifications, or modality credentialing) must be submitted to the CTSU 
Regulatory Office or compliance communicated per protocol instructions. 
 
3.1.2 
Patient Registration 
Prior to enrollment on this study, patients must be assigned a COG patient ID 
number. This number is obtained via Patient Registry module in OPEN once 
authorization for the release of protected health information (PHI) has been 
obtained. The COG patient ID number is used to identify the patient in all future 
interactions with COG. If you have problems with the registration, please refer to 
the online help. For additional help or information, please contact the CTSU Help 
Desk at 1-888-823-5923 or ctsucontact@westat.com. 
 
In order for an institution to maintain COG membership requirements, every newly 
diagnosed patient needs to be offered participation in ACCRN07, Protocol for the 
Enrollment on the Official COG Registry, The Childhood Cancer Research Network 
(CCRN) or APEC14B1, Project:EveryChild A Registry, Eligibility Screening, 
Biology and Outcome Study. 
  
A Biopathology Center (BPC) number will be assigned as part of the registration 
process. Each patient will be assigned only one BPC number per COG Patient ID. 
For additional information about the labeling of specimens, please refer to the 
Pathology and/or Biology Guidelines in this protocol. 
 
 
Please see Appendix IV for detailed CTEP Registration Procedures for Investigators 
and Associates, and Cancer Trials Support Unit (CTSU) Registration Procedures 
including: how to download site registration documents; requirements for site 
registration, submission of regulatory documents and how to check your site’s 
registration status. 
 
3.1.3 
Study Enrollment 
Patients may be enrolled on the study once all eligibility requirements for the study 
have been met. Study enrollment is accomplished by going to the Enrollment 
application in the eRDE system. If you have problems with enrollment, refer to 
online help in the Applications area of the COG website. 
 

 
 
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3.1.4 
Neurocognitive Testing 
Enrollment onto ALTE07C1 is strongly encouraged. 
 
3.1.5 
Timing 
Patients must be enrolled before treatment begins. The date protocol therapy is 
projected to start must be no later than 10 calendar days after the date of study 
enrollment. In the event that Day 10 falls on a Saturday, Sunday or Holiday, 
therapy must begin the following business day. 
 
All patients must begin therapy within 31 days of diagnostic surgery. In the event 
that Day 31 falls on a Saturday, Sunday or Holiday, therapy must begin the 
following business day. 
 
3.1.6 
Bilingual Services  
To allow non-English speaking patients to participate in the study, bilingual health 
care services will be provided in the appropriate language. 
 
3.1.7 
Randomization 
Randomization will take place at the time a patient is entered On Study via RDE. 
Patients will be assigned to either: Regimen A (RT without Carboplatin), Regimen 
B (RT with Carboplatin). Randomization will be stratified on the basis of location 
and dissemination. Six strata will be defined: (1) M0 Medulloblastoma with >1.5 
cm2 residual; (2) M+ Medulloblastoma; (3) M0 Supratentorial PNET with <1.5 
cm2 residual; (4) M0 SPNET with >1.5 cm2 residual; (5) M+ SPNET, (6) M0 
Diffusely Anaplastic Medulloblastoma.  
 
As of Amendment #2, because the accrual of sPNET will be discontinued, only the 
three strata of medulloblatoma will be defined: (1) M0 Medulloblastoma with >1.5 
cm2 residual; (2) M+ Medulloblastoma; (3) M0 Diffusely Anaplastic 
Medulloblastoma. 
 
As of Amendment #3, only one randomization will take place to Regimen A or B. 
 
3.1.8 
Mandatory Submission of Tissue for Central Pathology Review (See Section 15.0) 
All patients must have tissue submitted for central pathology review. Pathology 
slides from the time of diagnosis must be sent to the COG Biopathology Center 
within 10 days of study enrollment. See Section 15.0 for information regarding 
specimen submission.  
 
3.2 
Patient Criteria 
Important note: The eligibility criteria listed below are interpreted literally and cannot 
be waived (per COG policy posted 5/11/01). All clinical and laboratory data required for 
determining eligibility of a patient enrolled on this trial must be available in the patient's 
medical/research record which will serve as the source document for verification at the 
time of audit.  
 
All clinical and laboratory studies to determine eligibility must be performed within 
7 days prior to enrollment unless otherwise indicated. Laboratory values used to 
assess eligibility must be no older than seven (7) days at the start of therapy. 
Laboratory tests need not be repeated if therapy starts within seven (7) days of 
obtaining labs to assess eligibility. If a post-enrollment lab value is outside the limits 

 
 
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of eligibility, or laboratory values are > 7 days old, then the following laboratory 
evaluations must be re-checked within 48 hours prior to initiating therapy: CBC with 
differential, bilirubin, ALT (SGPT) and serum creatinine. If the recheck is outside 
the limits of eligibility, the patient may not receive protocol therapy and will be 
considered off protocol therapy.  
 
3.2.1 
Age 
Age greater than or equal to 3 and less than 22 years at the time of diagnosis.  
 
3.2.2 
Diagnosis  
Newly diagnosed, previously untreated: (1) M0 Medulloblastoma with >1.5 cm2 
residual; 
(2) 
M+ 
Medulloblastoma. 
Patients 
with 
diffusely 
anaplastic 
medulloblastoma are eligible regardless of M-stage or residual tumor. See Appendix 
II for M-Staging. 
 
As of Amendment #2, enrollment of patients with supratentorial PNET has 
been discontinued. 
 
All patients with M4 disease are not eligible.  
 
 
3.2.3 
Cranial and Spinal MRI 
A pre-operative MRI scan of the brain with and without contrast is required. 
NOTE: CT scans are NOT sufficient for study eligibility since radiation 
therapy planning and response will be based on MRI scans only. 
 
Post-operative head MRI scan with and without contrast (preferably within 72 
hours post-surgery). For patients who undergo stereotactic biopsy only, either a 
pre or post-operative MRI is sufficient. For patients with M2 and M3 disease, a 
post-op MRI is strongly encouraged, but not mandatory. 
 
Spinal MRI imaging with and without gadolinium is required within 10 days of 
surgery if done pre-operatively or within 28 days of surgery if done post-
operatively. For posterior fossa tumors, pre-operative MRI scans are preferred 
because surgically-induced inflammation/blood can be difficult to distinguish from 
tumor. 
 
3.2.4 
Evaluation of Lumbar CSF Cytology 
Lumbar CSF cytology examination must be obtained pre-operatively or within 31 
days following surgery. The optimal time for obtaining CSF is prior to surgery or 
1-3 weeks following surgery. Ventricular CSF (either pre- or post-op) may be used 
only if a post-operative spinal tap is contraindicated. If a spinal tap is 
contraindicated and there is no ventricular CSF available, then CSF cytology can 
be waived for patients with supratentorial tumors or if there is documentation of 
spinal subarachnoid metastases (M3). Patients who are categorized as M1 must 
have either an intra-operative positive CSF (via lumbar puncture at the end of the 
procedure) or a positive lumbar CSF obtained > 7 days post-operatively (to rule 
out surgically induced false positives). 
 

 
 
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3.2.5 
Performance Level (See Appendix I) 
Patients must have a Karnofsky performance level of ≥ 30 for patients > 16 years of 
age or a Lansky performance scale of ≥ 30 for patients ≤ 16 years of age and life 
expectancy > 8 weeks. 
 
3.2.6 
Prior Therapy 
No previous chemotherapy or radiation therapy.  
 
3.2.7 
Concomitant Medications Restrictions 
 
3.2.7.1 
Corticosteroids should not be used during chemotherapy administration as an 
antiemetic because of their effect on the blood-brain barrier.  
 
3.2.7.2 
Clinically significant drug interactions have been reported when using vincristine 
with strong CYP450 3A4 inhibitors and inducers. Selected strong inhibitors of 
cytochrome P450 3A4 include azole antifungals, such as fluconazole, 
voriconazole, itraconazole, ketoconazole, and strong inducers include drugs such 
as rifampin, phenytoin, phenobarbitol, carbamazepine, and St. John’s wort. The 
use of these drugs should be avoided with vincristine.  
 
3.2.7.3 
The clinical outcome and significance of CYP450 interactions with 
cyclophosphamide are less clear. CYP450 3A4 stimulators or inhibitors should be 
avoided or used with great caution. Aprepitant also interacts with CYP3A4 and 
should be used with caution with etoposide or vincristine chemotherapy.  
 
Additional inducers or inhibitors of CYP450 enzymes can be found at 
 http://medicine.iupui.edu/clinpharm/ddis/.  
 
3.2.7.4  
Cisplatin should be used with caution with nephrotoxic drug. Aminoglycoside 
should be avoided or used with caution during or shortly after cisplatin 
administration and concomitant use with amphotericin B should probably also be 
avoided. Patients receiving Cisplatin and other potentially ototoxic drugs such as 
aminoglycoside or loop diuretics concomitantly should be closely monitored for 
signs of ototoxicity. 
 
In patients receiving cisplatin and phenytoin or fosphenytoin, serum 
concentrations of phenytoin may decrease. Carbamazepine concentration may also 
decrease with concomitant use. Plasma levels of anticonvulsant agents should be 
monitored and doses adjusted during therapy with Cisplatin. 
 
3.2.7.5 
No other experimental therapy is permitted while on study.  
 
 

 
 
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3.2.8 
Organ Function Requirements:  
 
3.2.8.1 Adequate renal function defined as: 
- Creatinine clearance or radioisotope GFR ≥ 70mL/min/1.73m2 OR 
- A serum creatinine based on age/gender as follows: 
 
Age 
Maximum Serum 
Creatinine (mg/dL) 
 
Male 
Female 
2 to < 6 years 
0.8 
0.8 
6 to < 10 years 
1 
1 
10 to < 13 years 
1.2 
1.2 
13 to < 16 years 
1.5 
1.4 
≥ 16 years 
1.7 
1.4 
The threshold creatinine values in this Table were derived from the Schwartz formula for 
estimating GFR (Schwartz et al. J. Peds, 106:522, 1985) utilizing child length and stature 
data published by the CDC. 
 
3.2.8.2 
Adequate liver function defined as: 
- 
Total bilirubin < 1.5 x upper limit of normal (ULN) for age, and 
- 
SGOT (AST) or SGPT (ALT) < 2.5 x upper limit of normal (ULN) for 
age. 
- 
For patients on anti-seizure medications, SGOT (AST) or SGPT (ALT) 
must be < 5 x ULN. 
 
3.2.8.3 
Adequate bone marrow function defined as: 
- 
ANC > 1,000/µL 
- 
Platelets > 100,000/µL (untransfused) 
- 
Hemoglobin > 8 g/dL (may be transfused) 
 
3.2.9 
Pregnancy 
There is information indicating a risk of fetal or teratogenic toxicity with this 
treatment.  
 
Female patients who are post-menarchal must have a negative pregnancy test. 
Lactating female patients must agree not to breast-feed while on this trial. Males 
or females of reproductive potential may not participate unless they have agreed 
to use an effective contraceptive method.  
 
3.2.10 Regulatory 
 
3.2.10.1 
All patients and/or their parents or legal guardians must sign a written informed 
consent. 
 
3.2.10.2 
All institutional, FDA, and NCI requirements for human studies must be met. 
 

 
 
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4.0 
TREATMENT PLAN 
 
 
 
 
 
 
 
 
 
Overview of Treatment Plan 
Following neurosurgical procedure and staging, patients will be randomized to receive either 36 
Gy craniospinal irradiation with appropriate boost to the tumor bed or the same radiation regimen 
with addition of carboplatin as a radiosensitizing agent. All patients must begin therapy within 31 
days of surgery. The dose of carboplatin will be 35 mg/m2/day for 30 doses over 6 ½ weeks based 
on the dose finding phase of COG 99701. All patients will receive vincristine 1.5 mg/m2 once per 
week during radiation therapy for a total of 6 doses. 
 
Following radiation and a 6 week rest period, patients will then undergo Maintenance 
chemotherapy with cisplatin, vincristine, and cyclophosphamide in 28 day cycles for a total of 6 
cycles (according to COG 99701, Regimen B). Note: Maintenance may be delayed up to 8 weeks 
based on experience from 99701. Approximately 10% of patients will drop counts between 4-6 
weeks after completing radiation therapy and Maintenance should not be initated until counts 
recover. 
 
Radiation Therapy  
All patients will receive craniospinal radiation therapy (CSRT) to doses of: 
36 Gy CSRT 
55.8 Gy Posterior fossa (cumulative dose) 
 
See Section 18.0 for details regarding technique and doses to the brain, spine and boosts to known 
sites of metastases depending on disease stage and tumor response. 
 
ALL PATIENTS WILL REQUIRE REVIEW OF THEIR RADIATION THERAPY 
TREATMENT 
PLAN. 
THE 
RADIATION 
TREATMENT 
PLAN 
FOR 
THE 
CRANIOSPINAL FIELDS MUST BE SUBMITTED TO IROC RI (QARC) FOR QA 
REVIEW WITHIN 3 DAYS OF INITIATION OF RADIATION THERAPY (SECTION 
18.9). THE TREATMENT PLAN FOR THE BOOST VOLUME MUST BE SUBMITTED 
BEFORE THE START OF THE BOOST TREATMENT. 
 
4.1 
Regimen A Administration Schedule for Radiation Therapy 
 
All patients must begin therapy within 31 days of diagnostic surgery. In the event that Day 
31 falls on a Saturday, Sunday or Holiday, therapy must begin the following business day. 
 
VinCRIStine: IV push over 1 minute (or infusion via minibag as per institution policy) 
1.5 mg/m2/day (maximum single dose 2 mg) once weekly Weeks 1-6 during radiation for 
a total of 6 doses. Vincristine should be started within the first week of starting radiation 
Timing of protocol therapy administration, response assessment studies, and surgical interventions are 
based on schedules derived from the experimental design or on established standards of care. Minor 
unavoidable departures (up to 72 hours) from protocol directed therapy and/or disease evaluations (and 
up to 1 week for surgery) for valid clinical, patient and family logistical, or facility, procedure and/or 
anesthesia scheduling issues are acceptable per COG Administrative Policy 5.14 (except where 
explicitly prohibited within the protocol).  

 
 
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therapy and given weekly thereafter. The absolute dose of vincristine should be rounded 
down to the nearest 0.1 mg.  
Avoid extravasation; the use of a central line is suggested. 
 
Special precautions: FOR INTRAVENOUS USE ONLY.   
The container or the syringe containing vinCRIStine must be enclosed in an overwrap 
bearing the statement “Do not remove covering until moment of injection. For intravenous 
use only - Fatal if given by other routes.” 
 
Medication errors have occurred due to confusion between vinCRIStine and 
vinBLAStine.  VinCRIStine is available in a liposomal formulation (vinCRIStine sulfate 
liposomal injection, VSLI, Marqibo®).  Use conventional vincristine only; the 
conventional and liposomal formulations are NOT interchangeable. 
 
Myeloid Growth Factor: Subcutaneous (preferred) or IV 
Filgrastim or biosimilar 5 micrograms/kg/day OR sargramostim 250 micrograms/m2/day 
to be administered during Radiation Therapy as needed. CBCs will be obtained weekly. If 
ANC ≥ 1500/µL, no myeloid growth factor is needed and weekly CBCs will continue. If 
ANC ≤1500/µL at any point, then the following regimen should replace weekly CBCs. If 
ANC ≤1500/µL on any Friday, myeloid growth factor will be administered subcutaneously 
or IV on Friday, Saturday, and Sunday. Myeloid growth factor should not be given until 
after the radiation treatment on Friday has been delivered. If the ANC >1500/µL, no 
myeloid growth factor will be administered that weekend. On any Monday or Wednesday, 
if the ANC <1000/µL, myeloid growth factor will be administered on that day and the 
following day after the radiation treatment. If the ANC ≥1000/µL on Monday or 
Wednesday, myeloid growth factor will not be administered (see Table below). Family 
members should be taught to administer myeloid growth factor. Myeloid growth factor 
guidelines are tabulated below: 
 
Guidelines for Myeloid Growth Factor Administration During Radiotherapy 
DAY 
CBC with diff, plts 
ANC 1000-1500 
ANC < 1000 
Friday 
x 
Filgrastim or biosimilar 5 
micrograms/kg/day OR 
sargramostim 250 
micrograms/m2/day Fri., 
Sat., Sun. 
Filgrastim or biosimilar 5 
micrograms/kg/day OR 
sargramostim 250 
micrograms/m2/day Fri., Sat., 
Sun. 
Monday 
x 
No myeloid growth factor  
 Filgrastim or biosimilar 5 
micrograms/kg/day OR 
sargramostim 250 
micrograms/m2/day Mon., 
Tues. 
Wednesday 
x 
No myeloid growth factor  
 Filgrastim or biosimilar 5 
micrograms/kg/day OR 
sargramostim 250 
micrograms/m2/day Wed., 
Thur.. 
There is to be no dose escalation of myeloid growth factor for neutropenia alone. In the 
event of a potentially life-threatening infection with neutropenia, filgrastim or 
biosimilar may be increased to 10 micrograms/kg/day. There will be no dose 
escalations of sargramostim. 

 
 
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Significant myelosuppression is likely to occur, particularly during the last two-three 
weeks of radiation. However, radiation should not be withheld for myelosuppression 
alone. Radiation should be continued even if the patient is hospitalized with fever and 
neutropenia as long as the patient is clinically stable. Administration of the boost 
should not be substituted for craniospinal radiation in the face of low counts.  
 
Myeloid growth factor following the completion of radiotherapy (Week 7-12) should only 
be used in the setting of fever and/or infection with neutropenia (i.e. not prophylactically) 
but should be stopped 24 hours prior to starting Maintenance. 
 

 
 
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4.1.1 ACNS0332: Regimen A Radiation Therapy 
Six weeks of radiation therapy (Weeks 1-6) and 6 weeks of rest (Weeks 7-12) will constitute one reporting period. 
 
_________________________ 
________________ 
    Patient name or initials 
 
DOB  
Radiation Therapy (See Section 18.0) must begin within 31 days of diagnostic surgery. Week 7 to 12 is a rest period (6 Week Rest Period), then proceed to Maintenance. The Therapy Delivery Map 
is on one page. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine 
(VCR)  
IV Push over  
1 minute or 
infusion via 
minibag as 
per 
institutional 
policy 
1.5 mg/m2 
 (maximum dose 2 mg)  
Administer once 
weekly Weeks 
1-6 during 
radiation for a 
total of 6 doses 
Vincristine should be started 
within the first week of starting 
radiation 
therapy 
and 
given 
weekly thereafter and can be 
administered any day during the 
week. The absolute dose of 
vincristine should be rounded 
down to the nearest 0.1 mg. 
a. Physical and Neurologic Exam, Weight 
b. MRI of Brain with and without Gadolinium 
c. MRI of Spine with Gadolinium 
d. Lumbar CSF Cytology* 
e. Audiogram  
f. CBC, Differential, Platelets  
 
*- If a spinal tap is contraindicated and there is no ventricular CSF available, then 
CSF cytology can be waived for patients with supratentorial tumors or if there is 
documentation of spinal subarachnoid metastases (M3). 
 
See Section 7.1 for a complete list of observations. 
OBTAIN OTHER STUDIES AS REQUIRED FOR GOOD PATIENT CARE 
Myeloid 
Growth Factor 
SubQ or IV 
(SubQ 
preferred) 
 Filgrastim or biosimilar 
5 micrograms/kg/day 
OR sargramostim 250 
micrograms/m2/day 
See 
Administration 
Guidelines 
(Section 4.1) 
Should be administered during 
Radiation Therapy as needed. See 
Administration Guidelines 
(Section 4.1).  
 
Regimen______ 
Ht_______cm 
 
Wt_______kg 
 
BSA_______m2 
Date  
Due 
Date 
Given  
Week 
Day 
VCR 
____mg 
Myeloid Growth 
Factor Used 
______ 
_____mcg 
Studies 
Comments (Include any held doses, or dose modifications) 
Indicate days myeloid growth factor given on each week 
 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
1 
1 
____mg# 
____mcg$ 
a ,f 
 
 
 
2 
8 
____mg# 
 
a ,f 
 
 
 
3 
15 
____mg# 
 
a ,f 
 
 
 
4 
22 
____mg# 
 
a ,f 
 
 
 
5 
29 
____mg# 
 
a ,f 
 
 
 
6 
36 
____mg# 
 
a ,f 
 
 
 
7 
43 
 
 
a,f 
 
 
 
8 
 
 
 
a,f 
 
 
 
9 
 
 
 
a,f 
 
 
 
10 
 
 
 
b%,c%,d%,e%, 
 
 
 
11 
 
 
 
 
 
 
 
12 
 
 
 
 
Indicate last day of myeloid growth factor dose _____ 
 
 
 
 
To begin Maintenance, the ANC must be ≥ 750/µL, platelets ≥ 75,000/µL and the patient must have been off myeloid growth factor for at least 24 hours. If ANC 
< 750/µL or platelets < 75,000/µL then repeat CBC and differential at least twice a week until criteria are met. 
# - Vincristine can be administered any day during the week. 
 
$ - Administer myeloid growth factor as needed and according to table in Section 4.1. 
% - Obtain during Weeks 10-12. Obtain Spinal MRI and cytology only if initially positive. 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE SECTION 8.0 FOR SUPPORTIVE CARE
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4.2 
Regimen B Administration Schedule for Radiation Therapy 
All patients must begin therapy within 31 days of diagnostic surgery. In the event that Day 
31 falls on a Saturday, Sunday or Holiday, therapy must begin the following business day. 
 
VinCRIStine: IV push over 1 minute (or infusion via minibag as per institution policy) 
1.5 mg/m2/day (maximum single dose 2 mg) once weekly Weeks 1-6 during radiation for 
a total of 6 doses. Vincristine should be started within the first week of starting radiation 
therapy and given weekly thereafter. Administer prior to CARBOplatin. The absolute dose 
of vincristine should be rounded down to the nearest 0.1 mg.  
Avoid extravasation; the use of a central line is suggested. 
 
Special precautions: FOR INTRAVENOUS USE ONLY.   
The container or the syringe containing vinCRIStine must be enclosed in an overwrap 
bearing the statement “Do not remove covering until moment of injection. For intravenous 
use only - Fatal if given by other routes.” 
 
Medication errors have occurred due to confusion between vinCRIStine and 
vinBLAStine.  VinCRIStine is available in a liposomal formulation (vinCRIStine sulfate 
liposomal injection, VSLI, Marqibo®).  Use conventional vincristine only; the 
conventional and liposomal formulations are NOT interchangeable. 
 
CARBOplatin: IV over 15 minutes 
35 mg/m2/day given daily during radiation therapy for a total of 30 doses. The first dose of 
CARBOplatin should be administered on the first day of radiation therapy. CARBOplatin 
will be over 15 minutes 1-4 hours prior to radiation therapy. This should be sufficient time 
for patients who may require sedation or who travel to another facility. If a radiation 
treatment is not given, CARBOplatin should be held as well. If a dose of 
CARBOplatin is given and radiation therapy is NOT administered due to sedation or 
technical issues, the CARBOplatin dose should not be made up (i.e. no more than 30 
doses of CARBOplatin should be given). Since there are 31 fractions of radiation, the 
last radiation treatment will not be preceded by a dose of CARBOplatin. 
 
Avoid use of aluminum containing needles or administration sets. 
Medication errors have occurred due to confusion between CISplatin (Platinol®) and 
CARBOplatin (PARAplatin®). 
 
Myeloid Growth Factor: Subcutaneous (preferred) or IV 
Filgrastim or biosimilar 5 micrograms/kg/day OR sargramostim 250 micrograms/m2/day 5 
micrograms/kg/day to be administered during Radiation Therapy as needed. CBCs will be 
obtained every Monday, Wednesday, and Friday. If ANC ≤1500/µL on any Friday, 
myeloid growth factor will be administered subcutaneously or IV on Friday, Saturday, and 
Sunday. Myeloid growth factor should not be given until after the radiation treatment on 
Friday has been delivered. If the ANC > 1500/µL, no myeloid growth factor will be 
administered that weekend. On any Monday or Wednesday, if the ANC <1000/µL, 
myeloid growth factor will be administered on that day and the following day after the 
radiation treatment. If the ANC ≥1000/µL on Monday or Wednesday, myeloid growth 
factor will not be administered (see Table below). Family members should be taught to 
administer myeloid growth factor. Myeloid growth factor guidelines are tabulated below: 
 
 

 
 
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Guidelines for Myeloid Growth Factor Administration During Radiotherapy 
DAY 
CBC with diff, plts 
ANC 1000-1500 
ANC < 1000 
Friday 
x 
Filgrastim or 
biosimilar 
5 micrograms/kg/day 
OR sargramostim 250 
micrograms/m2/day 
Fri., Sat., Sun. 
Filgrastim or biosimilar 
5 micrograms/kg/day 
OR sargramostim 250 
micrograms/m2/day 
Fri., Sat., Sun. 
Monday 
x 
No myeloid growth 
factor  
 Filgrastim or 
biosimilar 
5 micrograms/kg/day 
OR sargramostim 250 
micrograms/m2/day 
Mon., Tues 
Wednesday 
x 
No myeloid growth 
factor  
 Filgrastim or 
biosimilar 
5 micrograms/kg/day 
OR sargramostim 250 
micrograms/m2/day 
Wed., Thur. 
There is to be no dose escalation of myeloid growth factor for neutropenia alone. In the 
event of a potentially life-threatening infection with neutropenia, filgrastim or 
biosimilar may be increased to 10 micrograms/kg/day. There will be no dose 
escalations of sargramostim. 
 
Significant myelosuppression is likely to occur, particularly during the last two-three 
weeks of radiation. However, radiation should not be withheld for myelosuppression 
alone. Radiation should be continued even if the patient is hospitalized with fever and 
neutropenia as long as the patient is clinically stable. Administration of the boost 
should not be substituted for craniospinal radiation in the face of low counts.  
 
Filgrastim following the completion of radiotherapy (Week 7-12) should only be used in 
the setting of fever and/or infection with neutropenia (i.e. not prophylactically). 
 
 
 
 

 
 
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4.2.1 ACNS0332: Regimen B Radiation Therapy 
Six weeks of radiation therapy (Weeks 1-6) and 6 weeks of rest (Weeks 7-12) will 
constitute one reporting period. 
 
_________________________ 
________________ 
    Patient name or initials 
 
DOB  
Radiation Therapy (See Section 18.0) must begin within 31 days of diagnostic surgery. Week 7 to 12 is a rest period (6 Week Rest Period), then 
proceed to Maintenance. The Therapy Delivery Map is on one page. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine 
(VCR)  
IV Push over  
1 minute or 
infusion via 
minibag as per 
institutional 
policy 
1.5 mg/m2 
 (maximum dose 2 mg)  
Administer once 
weekly Weeks 
1-6 during 
radiation prior to 
CARBOplatin 
dose that day for 
a total of 6 doses 
VinCRIStine should be started within 
the first week of starting radiation 
therapy and given weekly thereafter 
and can be administered any day 
during the week. The absolute dose of 
vinCRIStine should be rounded down 
to the nearest 0.1 mg. 
a. Physical and Neurologic Exam, Weight 
b. MRI of Brain with and without Gadolinium 
c. MRI of Spine with Gadolinium 
d. Lumbar CSF Cytology* 
e. Audiogram  
f. CBC, Differential, Platelets  
g.  Electrolytes, Ca, Magnesium, Creatinine, BUN, Phosphorus 
*- If a spinal tap is contraindicated and there is no ventricular 
CSF available, then CSF cytology can be waived for patients 
with supratentorial tumors or if there is documentation of spinal 
subarachnoid metastases (M3). 
 
See Section 7.2 for a complete list of observations. 
OBTAIN OTHER STUDIES AS REQUIRED FOR GOOD 
PATIENT CARE 
CARBOplatin 
(CARBO) 
IV 
over 
15 
minutes 
35 mg/m2/day  
Daily during RT 
for a Total of 30 
Doses 
CARBOplatin and VinCRIStine will 
be given 1-4 hours prior to RT. See 
Adminitration Guidelines (Section 
4.2). 
Myeloid 
Growth Factor  
SubQ or IV 
(SubQ 
prefered) 
 Filgrastim or biosimilar 
5 micrograms/kg/day 
OR sargramostim 250 
micrograms/m2/day 
 
Should 
be 
administered 
during 
Radiation Therapy as needed. See 
Administration Guidelines (Section 
4.2).  
 
Regimen______ 
Ht_______cm 
 
Wt_______kg 
 
BSA_______m2 
Date 
Date 
Week 
Day 
Time 
CARBO 
Finished 
Time 
XRT 
Started 
CARBO 
____mg 
VCR 
____mg 
Myeloid Growth 
Factor Used 
______ 
_____mcg 
Studies 
Comments 
(Include any held doses, or dose modifications) 
Indicate days myeloid growth factor given on each 
week 
 
 
 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
1 
1 
 
 
____mg 
____mg# 
____mcg$ 
a ,f, g 
 
 
 
 
2 
 
 
____mg 
 
 
 
 
 
 
 
3 
 
 
____mg 
 
 
f 
 
 
 
 
4 
 
 
____mg 
 
 
 
 
 
 
 
5 
 
 
____mg 
 
 
f 
 
 
 
2 
8 
 
 
____mg 
____mg# 
 
a,f 
 
 
 
 
9 
 
 
____mg 
 
 
 
 
 
 
 
10 
 
 
____mg 
 
 
f 
 
 
 
 
11 
 
 
____mg 
 
 
 
 
 
 
 
12 
 
 
____mg 
 
 
f 
 
 
 
3 
15 
 
 
____mg 
____mg# 
 
a ,f, g 
 
 
 
 
16 
 
 
____mg 
 
 
 
 
 
 
 
17 
 
 
____mg 
 
 
f 
 
 
 
 
18 
 
 
____mg 
 
 
 
 
 
 
 
19 
 
 
____mg 
 
 
f 
 
 
 
4 
22 
 
 
____mg 
____mg# 
 
a,f 
 
 
 
 
23 
 
 
____mg 
 
 
 
 
 
 
 
24 
 
 
____mg 
 
 
f 
 
 
 
 
25 
 
 
____mg 
 
 
 
 
 
 
 
26 
 
 
____mg 
 
 
f 
 
 
 
5 
29 
 
 
____mg 
____mg# 
 
a,f, g 
 
 
 
 
30 
 
 
____mg 
 
 
 
 
 
 
 
31 
 
 
____mg 
 
 
f 
 
 
 
 
32 
 
 
____mg 
 
 
 
 
 
 
 
33 
 
 
____mg 
 
 
f 
 
 
 
6 
36 
 
 
____mg 
____mg# 
 
a,f 
 
 
 
 
37 
 
 
____mg 
 
 
 
 
 
 
 
38 
 
 
____mg 
 
 
f 
 
 
 
 
39 
 
 
____mg 
 
 
 
 
 
 
 
40 
 
 
____mg 
 
 
f 
 
 
 
7 
 
 
 
 
 
 
f&, g 
 
 
 
8 
 
 
 
 
 
 
f& 
 
 
 
9 
 
 
 
 
 
 
f& 
 
 
 
10 
 
 
 
 
 
 
b%,c%,d%,e%,f& 
 
 
 
11 
 
 
 
 
 
 
f 
 
 
 
12 
 
 
 
 
 
 
f 
Indicate last day of myeloid growth factor  dose 
_____ 
 
 
 
 
To begin Maintenance, the ANC must be ≥ 750/µL, platelets ≥75,000/µL and the patient must have been off myeloid growth factor for at 
least 24 hours. If ANC < 750/µL or platelets < 75,000/µL then repeat CBC and differential at least twice a week until criteria are met. 
# - Vincristine can be administered any day during the week. 
 
$ - Administer myeloid growth factor as needed and according to table in Section 4.2. 
% - Obtain during Weeks 10-12. Obtain Spinal MRI and cytology only if initially positive. 
& - If counts are low, CBC should be performed twice weekly. 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE SECTION 8.0 FOR SUPPORTIVE CARE 
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4.3 
Regimen A or Regimen B Maintenance  
Begin each cycle of Maintenance on Day 29 and when ANC ≥ 750/µL, platelets 
≥ 75,000/µL and the patient must have been off myeloid growth factor for at least 24 hours 
for a total of 6 Cycles. 
 
CISplatin: IV over 6 hours  
75 mg/m2 on Day 1  
 
 
Suggested hydration and supportive care: Prehydration should begin at least 2 hours prior 
to CISplatin infusion with normal saline and mannitol (7.5 g/L) at 125 mL/m2/hr. After the 
completion of the CISplatin infusion, begin D5NS and mannitol (7.5 g/L) and 8 mEq 
Magnesium sulfate/L at 125 mL/m2/hr x 8 hours. IV fluids should then be changed to D5 
1/2 NS + 20 mEq KCl/l + 8 mEq Magnesium sulfate/L at 125 mL/m2/hr to complete 24 
hours of hydration (until first dose of cyclophosphamide). Urine output of at least 3 
mL/kg/hr should be achieved prior to CISplatin infusion and maintained for at least 8 hours 
following completion of the infusion. Mannitol 0.5 g/kg may be used to maintain urine 
output. If a mannitol bolus fails to increase urine output over the ensuing hour, then 
furosemide 1 mg/kg IV should be given as a bolus. Four hour input and output totals should 
be maintained within 20% of each other. 
 
Oral magnesium supplementation following CISplatin administration may be necessary. 
Electrolytes (i.e., Mg, Ca, PO4, K) should be followed closely thereafter. 
 
Avoid use of aluminum containing needles or administration sets. The infusion solution 
should include at least 0.2% sodium chloride. CISplatin solutions should not be refrigerated 
to avoid precipitation. CISplatin is incompatible with sodium bicarbonate and alkaline 
solutions. Accidental extravasation with solutions that are > 0.5 mg/mL may result in 
significant tissue toxicity.  
 
Medication errors have occurred due to confusion between CISplatin (Platinol®) and 
CARBOplatin (PARAplatin®). 
 
 
VinCRIStine: IV push over 1 minute (or infusion via minibag as per institution policy) 
1.5 mg/m2/day (maximum single dose 2 mg) on Days 1 and 8. The absolute doses of 
vincristine to be delivered are a function of body surface area, rounded down to the nearest 
0.1 mg. 
 
Avoid extravasation; the use of a central line is suggested. 
 
Special precautions: FOR INTRAVENOUS USE ONLY.   
The container or the syringe containing vinCRIStine must be enclosed in an overwrap 
bearing the statement “Do not remove covering until moment of injection. For intravenous 
use only - Fatal if given by other routes.” 
 
Medication errors have occurred due to confusion between vinCRIStine and 
vinBLAStine.  VinCRIStine is available in a liposomal formulation (vinCRIStine sulfate 
liposomal injection, VSLI, Marqibo®).  Use conventional vincristine only; the 
conventional and liposomal formulations are NOT interchangeable. 

 
 
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Cyclophosphamide: IV over 1 hour  
1000 mg/m2 on Day 2 and Day 3. On Day 2, cyclophosphamide should be given at least 24 
hours after CISplatin.  
 
Suggested hydration and supportive care: Urine output should be maintained at a minimum 
of 3 ml/kg/hr. Hydration is continued with D5 1/2NS plus 20 mEq/L KCl at 100 mL/m2 
per hour. After second dose of cyclophosphamide, hydration should be continued for a 
minimum of 8 hours and until patient maintains normal PO intake. Note: nausea and 
vomiting are likely and prolonged IV fluids may be necessary to prevent dehydration and 
maintain electrolyte balance. 
 
Myeloid Growth Factor: Subcutaneous (preferred) or IV 
Filgrastim or biosimilar 5 micrograms/kg/day OR sargramostim 250 micrograms/m2/day 
daily starting on Day 4 and continue for at least 10 days until post-nadir ANC > 1500µL. 
Myeloid Growth Factor must be discontinued for a minimum of 24 hours prior to next 
chemotherapy cycle if counts have recovered. 
 
Do not start the next cycle of chemotherapy until at least 24 hours after myeloid growth 
factor has been stopped. Myeloid growth factor may be given concomitantly with 
vincristine. 

 
 
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4.3.1 ACNS0332: Regimen A and Regimen B Maintenance  
Four consecutive weeks (28 days) will constitute one cycle. Use one copy of the TDM 
for each cycle (please note cycle number). 
 
_______________________ 
________________ 
    Patient name or initials 
 
DOB  
 
Begin each subsequent cycle of Maintenance on Day 29 and when count criteria are met. The Therapy Delivery Map is on one page. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT 
NOTES 
OBSERVATIONS 
CISplatin (CDDP) 
IV over 6 
hours 
75 mg/m2 
Day 1 
See 
Administration 
Guidelines (Section 4.3) 
a. 
Physical and Neurologic Exam, Weight 
b. MRI of Brain with and without Gadolinium 
c. 
MRI of Spine with Gadolinium 
d. Lumbar CSF Cytology* 
e. 
Audiogram  
f. 
CBC, Differential, Platelets  
g. Electrolytes, Ca, Magnesium, Creatinine, 
BUN, Phosphorus  
h. SGOT, SGPT, Alkaline Phosphate, Bilirubin 
i. 
Creatinine Clearance or GFR 
j. 
Urinalysis 
k. Thyroid Function  
*- If a spinal tap is contraindicated and there is no 
ventricular CSF available, then CSF cytology can 
be waived for patients with supratentorial tumors 
or if there is documentation of spinal subarachnoid 
metastases (M3).  
 
See Section 7.3 for a complete list of observations. 
OBTAIN OTHER STUDIES AS REQUIRED 
FOR GOOD PATIENT CARE 
VinCRIStine 
(VCR)  
IV Push over  
1 minute or 
infusion via 
minibag as 
per 
institutional 
policy 
1.5 mg/m2 
 (maximum 
dose 2 mg)  
Days 1 and 8 
The absolute doses of 
vincristine 
to 
be 
delivered are a function 
of body seruface area, 
rounded down to the 
nearest 0.1 mg. 
Cyclophosphamide 
(CPM) 
IV over 1 hour 
1000 mg/m2 
Days 2 and 3 
See 
Adminitration 
Guidelines (Section 4.3) 
Myeloid 
Growth 
Factor 
SubQ or IV 
(SubQ 
preferred) 
 Filgrastim or 
biosimilar 
5 microgram/
kg/day 
OR 
sargramostim 
250 
micrograms/
m2/day 
Start on Day 4 
and 
continue 
for at least 10 
days until post-
nadir 
ANC 
> 1500µL.  
Do not start the next 
cycle of chemotherapy 
until at least 24 hours 
after myeloid growth 
factor has been stopped. 
Myeloid growth factor 
may 
be 
given 
concomitantly 
with 
vincristine. 
 
Regimen______   Cycle ______  Ht_______cm  
Wt_______kg 
 
BSA_______m2 
Date 
Due 
Date 
Given 
Week 
Day 
CDDP 
____mg 
VCR 
____mg 
CPM 
____mg 
Myeloid 
Growth 
Factor Used 
_____ 
_____mcg 
Studies 
Comments 
(Include any held doses, or dose 
modifications) 
 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
1 
1 
____mg 
____mg 
 
 
a, e, f, g, h, i%, j 
(b, c@, d#)##, 
  
 
 
 
2 
 
 
____mg 
 
 
 
 
 
 
3 
 
 
____mg 
 
 
 
 
 
 
4 
 
 
 
____mcg 
 
 
 
 
2 
8 
 
____mg 
 
 
f+,g 
 
 
 
3 
15 
 
 
 
 
f+,g 
 
 
 
4 
22 
 
 
 
 
f+,g 
Indicate last day of  Myeloid Growth 
Factor dose_____ 
 
 
 
28 
 
 
 
 
f+,g (a, b, c@, d#, 
e, f, g, h, k )& 
 
 
 
 
29 
 
To begin next cycle of Maintenance, the ANC must be ≥ 750/µL, platelets ≥ 75,000/µL and the patient 
must have been off myeloid growth factor for at least 24 hours. If ANC < 750/µL or platelets < 75,000/µL 
then repeat CBC and differential at least twice a week until criteria are met. See Section 5.2.2.1 
+ 
If counts are low and while on myeloid growth factor, it is recommended that CBCs be performed twice weekly.  
@ 
Spinal imaging is only necessary for patients with M1 – M3 disease. 
# 
Required only for patients who are positive at diagnosis. 
% 
Obtain if creatinine is greater than normal for age (see Section 3.2.8.1) 
& 
Obtain within 1 month of completing Maintenance. 
## Obtain prior to Cycle 4. 
 
 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE SECTION 8.0 FOR SUPPORTIVE CARE 
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5.0 
DOSE MODIFICATIONS FOR TOXICITIES 
 
5.1 
Dose Modifications During Radiation Therapy 
 
5.1.1 
Vincristine 
5.1.1.1 Neurotoxicity  
For Grade 3/4: foot drop, severe paresis, disabling paresthesias, ileus or 
cranial neuropathy hold vincristine and resume at 1 mg/m2 (1.5 mg 
maximum) when symptoms resolve. 
 
5.1.1.2 Jaw Pain 
Treat with analgesics (not salicylates). Do not hold or reduce vincristine. 
 
5.1.1.3 Hepatotoxicity 
If total bilirubin is greater than 1.9 mg/dL, hold vincristine dose. If total 
bilirubin is 1.5 - 1.9 mg/dL, administer vincristine at 1 mg/m2 (1.5 mg 
maximum). 
 
5.1.2 
Carboplatin (Regimen B) 
 
5.1.2.1 Hematologic Toxicity 
It is likely that patients will develop myelosuppression during the last two-
three weeks of radiation therapy. See Section 4.2 for myeloid growth factor 
guidelines during radiation. Red cell and platelet transfusions should be used 
to 
maintain 
the 
Hct 
>30% 
and 
platelets 
>30,000/µL 
during 
chemoradiotherapy. No dose modifications of Carboplatin will be made. 
 
5.1.2.2 Nephrotoxicity 
If the serum creatinine increases to greater than twice the baseline value, a 
creatinine clearance or GFR should be done. If the creatinine clearance or 
GFR falls below 60 ml/min/1.73m2, reduce carboplatin dose by 25% to 
26 mg/m2. A serum creatinine should be checked three times a week 
thereafter. If the creatinine returns to less than twice the baseline value and 
the creatinine clearance or GFR to > 60 ml/min/1.73m2, return to full dosage.  
 
5.2 
Dose Modifications during Maintenance Chemotherapy 
 
5.2.1 
Vincristine 
 
5.2.1.1 Neurotoxicity 
For Grade 3/4: foot drop, severe paresis, disabling paresthesias, ileus or 
cranial neuropathy hold vincristine and resume at 1 mg/m2 (1.5 mg 
maximum) when symptoms resolve. 
 
5.2.1.2 Jaw Pain 
Treat with analgesics (not salicylates). Do not hold or reduce vincristine. 
 
5.2.1.3 Hepatotoxicity 

 
 
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If total bilirubin is greater than 1.9 mg/dL, hold vincristine dose. If total 
bilirubin is 1.5 - 1.9 mg/dL, administer vincristine at 1 mg/m2 (1.5 mg 
maximum). 
 
5.2.2 
Cyclophosphamide 
 
5.2.2.1 Hematological Toxicity 
If chemotherapy is due and the absolute neutrophil count is below 750/µL or 
the platelet count is less than 75,000/µL, the next cycle of chemotherapy 
should be delayed. Repeat CBC and platelet count twice-weekly. The next 
cycle of therapy should be administered when the ANC >750 and the platelet 
count >75,000, but the dose of cyclophosphamide should be reduced by 25% 
to 750 mg/m2/dose (i.e. each daily dose should be reduced by 25%). 
 
If the ANC is above 750/µL but below 1,000/µL or the platelet count is > 
75,000/µL but below 100,000/µL, the next cycle of therapy should be 
administered, but the dose of cyclophosphamide should be reduced by 25% 
to 750 mg/m2/dose (i.e. each daily dose should be reduced by 25%). 
 
Subsequent cycles should be given at full dose as long as counts recover on 
time. 
 
5.2.2.2 Bladder Injury 
If microscopic (> 10 RBC/hpf on at least 2 urine analyses) or gross hematuria 
occurs (hemorrhagic cystitis), give hydration to 3000 mL/m²/day (3500 to 
4000 mL/m²/day for gross hematuria) using fluid containing at least 0.45% 
NaCl. Achieve urine specific gravity <1.010 prior to start of 
cyclophosphamide. May use diuretics (like furosemide) to increase urine 
output. For microscopic hematuria, give mesna 360 mg/m2 with the 
cyclophosphamide and administer mesna for 24 hours after each 
cyclophosphamide dose at 120 mg/m2/hr by continuous infusion. For gross 
hematuria give mesna at 100% of the cyclophosphamide dose by continuos 
infusion. If gross hematuria persists or recurs, delete subsequent 
cyclophosphamide doses. 
 
5.2.2.3 Renal Dysfunction 
If estimated creatinine clearance (by Schwartz formula for children or 
radioisotope GFR) is < 10 ml/min/1.73 m2, reduce the dose of 
cyclophosphamide by 25% to 750 mg/m2/dose (i.e. administer 75% of the 
full dose.) 
 
5.2.3 
Cisplatin 
 
5.2.3.1 Nephrotoxicity 
If the creatinine clearance or GFR is < 60 ml/min/1.73 m2, then the cisplatin 
should not be given. If the creatinine clearance or GFR improves to 
>60 ml/min/1.73 
m2, 
cisplatin 
should 
be 
reinstituted 
at 
50% 
(37.5mg/m2/dose) dosage for the next two cycles of chemotherapy. After two 
cycles of therapy with stable creatinine clearance (>60 ml/min/1.73 m2), 
cisplatin should be given at full doses. 

 
 
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5.2.4 
Ototoxicity 
PLEASE SEE TOXICITY SCALE BELOW. NOTE: THIS IS A DIFFERENT 
TOXICITY SCALE THAN USED IN PREVIOUS COG STUDIES 
 
 
GRADE 1 
 
> 25 db loss at > 4 KHz, Asymptomatic 
 
GRADE 2 
 
> 25 db loss at 4 KHz, tinnitus 
 
GRADE 3 
 
≥ 25 db loss at ≥ 2 KHz 
 
GRADE 4 
 
≥ 40 db loss at ≥ 2 KHz 
 
 
If there is a disparity between ears, the grading should reflect the better ear. For Grade 
0 ototoxicity, no dose modification should be made. For Grade 1 ototoxicity (defined 
as a > 25 db loss at > 4 KHz, asymptomatic) a 25% reduction to 56 mg/m2/dose 
should be made in cisplatin dosage. For Grade 2 ototoxicity (defined as a > 25 db 
loss at 4 KHz, tinnitus) an additional 25% reduction (to 42 mg/m2/dose) in cisplatin 
should be made if previously reduced or a 50% reduction (to 37.5 mg/m2/dose) in 
cisplatin dose should be made. For Grade 3 and 4 ototoxicity (defined as a > 25 db 
loss at ≥2 KHz and ≥ 40 db loss at ≥ 2 KHz) cisplatin should be deleted and not 
restarted. 
 
5.2.5 
Hypomagnesemia 
As a consequence of renal tubular wastage of magnesium caused by cisplatin, 
hypomagnesemia can develop. It may become symptomatic manifested by 
paresthesias, muscle cramps, weakness and occasionally disorientation or seizures. 
If hypomagnesemia develops, magnesium should be given orally or intravenously.  
 
 
6.0 
DRUG INFORMATION 
 
See the consent document for toxicities. All other information is available on the COG website in the manual 
titled “Drug Information for Commercial Agents used by the  
Children’s Oncology Group” at: 
https://members.childrensoncologygroup.org/prot/reference_materials.asp under Standard Sections for 
Protocols. 
 
 
 
 

 
 
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7.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
All baseline studies must be performed prior to starting protocol therapy unless otherwise noted 
below.  
 
 
 
 
 
 
 
 
 
 
 
 
7.1 
Required Observations, Pre-Treatment and During Radiation Therapy for Regimen A  
 
Evaluation 
Pre-Study  Weeks 1-6 Weeks 10-12 
(After XRT) 
CBC with diff, platelets 
X 
Weekly 
 
 
Physical/Neuro exam, weight 
X 
Weekly 
 
Electrolytes, Ca, Creatinine, BUN, magnesium, 
phosphorus, SGOT (or SGPT), bilirubin 
X 
 
 
Serum Creatinine, Creatinine Clearance or GFR 
X 
 
 
Audiogram (See Section 5.2.4 for Grading 
Scale) 
X 
 
X 
MRI of the Head (T2-weighted imaging and T1-
weighted imaging pre- and post-contrast) and 
Spine with and without Contrast 
X# 
 
X+ 
 
Lumbar CSF cytology 
X@ 
 
X+ 
Pregnancy Test (For Females who are Post-
Menarchal) 
X 
 
 
Central Pathology Review (Section 15.0) 
X 
 
 
Optional Biology Studies (Section 16.0) 
X 
 
 
 
+ 
Spine MRI and cytology to be done only if initially positive 
# 
Post-op MRI should be done within 72 hours of surgery. For patients who undergo stereotactic biopsy only, post-
op MRI is not required. For patients with M2 and M3 disease, a post-op MRIis encouraged, but not mandatory. 
Spinal MRI is required within 28 days of surgery if done post-operatively and within 10 days of surgery if done 
pre-op. (If MRI scan is performed within 10 days prior to surgery, then only a post-contrast examination is 
required). A pre-operative spinal MRI scan is preferable for patients with posterior fossa tumors because 
surgically-induced inflammation/blood can be difficult to distinguish from tumor. 
@ 
Ventricular CSF (either pre-or post-op) may be used only if a post-operative spinal tap is contraindicated. If 
a spinal tap is contraindicated and there is no ventricular CSF available, then CSF cytology can be waived 
for patients with supratentorial tumors or if there is documentation of spinal subarachnoid metastases (M3).  
 
 
Timing of protocol therapy administration, response assessment studies, and surgical interventions 
are based on schedules derived from the experimental design or on established standards of care. 
Minor unavoidable departures (up to 72 hours) from protocol directed therapy and/or disease 
evaluations (and up to 1 week for surgery) for valid clinical, patient and family logistical, or 
facility, procedure and/or anesthesia scheduling issues are acceptable per COG Administrative 
Policy 5.14 (except where explicitly prohibited within the protocol).  

 
 
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7.2 
Required Observations, Pre-Treatment and During Radiation Therapy for Regimen B 
(With Carboplatin) 
 
Evaluation 
Pre-Study  
Weeks 1-6 
Weeks 7-9 
(After XRT) 
Weeks 10-12 
(After XRT) 
CBC with diff, platelets 
X 
 
3x/Week 
Weekly% 
Weekly 
Physical/Neuro exam, weight 
X 
Weekly 
 
 
Electrolytes, Creatinine, BUN, 
Ca, magnesium, phosphorus 
X 
 
q o week 
Week 7 
 
Serum Creatinine, Creatinine 
Clearance or GFR 
X 
 
 
 
Audiogram (See Section 5.2.4 
for Grading Scale) 
X 
 
 
X 
MRI of the Head (T2-weighted 
imaging 
and 
T1-weighted 
imaging pre- and post-contrast) 
and Spine with and without 
Contrast 
X# 
 
 
X+ 
 
Lumbar CSF cytology 
X@ 
 
 
X+ 
Pregnancy Test (For Females 
who are Post-Menarchal) 
X 
 
 
 
Central 
Pathology 
Review 
(Section 15) 
X 
 
 
 
Optional 
Biology 
Studies 
(Section 16) 
X 
 
 
 
 
+ 
Spine MRI and cytology to be done only if initially positive 
# 
Post-op MRI should be done within 72 hours of surgery. For patients who undergo stereotactic 
biopsy only, post-op MRI is not required. For patients with M2 and M3 disease, a post-op MRIis 
encouraged, but not mandatory. Spinal MRI is required within 28 days of surgery if done post-
operatively and within 10 days of surgery if done pre-op. (If MRI scan is performed within 10 days 
prior to surgery, then only a post-contrast examination is required). A pre-operative spinal MRI 
scan is preferable for patients with posterior fossa tumors because surgically-induced 
inflammation/blood can be difficult to distinguish from tumor. 
% 
If counts are low, CBC should be performed twice weekly. 
@ 
Ventricular CSF (either pre-or post-op) may be used only if a post-operative spinal tap is 
contraindicated. If a spinal tap is contraindicated and there is no ventricular CSF available, then 
CSF cytology can be waived for patients with supratentorial tumors or if there is documentation of 
spinal subarachnoid metastases (M3).  
 
 
 
 
 
 
 

 
 
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7.3 
Required Observations During Maintenance Chemotherapy for Regimens A and B 
 
Evaluation 
Prior to 
Each Cycle 
During 
Each 
Cycle 
Prior to 
Cycle 4 
1 Month 
After 
Cycle 6 
Relapse/Disease 
Progression 
Physical 
(Ht, 
Wt, 
BSA)/Neurologic exam 
X 
 
 
X 
X 
CBC with Diff, Platelets, 
X 
Weekly+ 
 
X 
X 
Electrolytes, 
Ca, 
Magnesium, 
Creatinine, 
BUN, Phosphorus 
X 
Weekly 
 
X 
 
SGOT, SGPT, Alkaline 
Phosphate, Bilirubin 
X 
 
 
X 
 
Creatinine Clearance or 
GFR 
X## 
 
 
 
 
Urinalysis 
X  
 
 
 
 
Audiogram (See Section 
5.2.4 for Grading Scale) 
X 
 
 
X 
 
MRI of the head (T2-
weighted imagining and 
TI-weighted 
imagining 
pre-and post- contrast) and 
spine with contrast 
 
 
X* 
X* 
X 
CSF cytology 
 
 
X # 
X # 
X 
Thyroid 
Function 
Evaluation (Free T4 and 
TSH) 
 
 
 
X 
 
 
* 
Spinal imaging is only necessary for patients with M1 – M3 disease. 
# 
Required only for patients who are positive at diagnosis. 
+ 
If counts are low and while on Filgrastim, it is recommended that CBCs be performed twice weekly. 
## 
Obtain if creatinine is > normal for age see Section 3.2.8.1. 
 

 
 
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7.4 
Required Observations Following Therapy 
 
 
Evaluation 
 
3 
mos 
 
6 
mos 
 
9 
mos 
 
12  
mos 
 
15 
 mos 
 
18  
mos 
 
21  
mos 
 
2.0  
yrs 
 
2.5  
yrs 
 
3.0  
yrs 
 
3.5  
yrs 
 
4.0  
yrs 
 
Annually 
At Relapse 
Disease 
Progression 
History, 
Physical 
with 
Neurologic Exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Liver 
Function, 
BUN, 
Creatinine, 
Electrolytes 
(Ca, Mg), CBC 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
MRI of head (with contrast) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Spinal MRI (with contrast)* 
X$ 
X$ 
X$ 
X$ 
X$ 
X$ 
X$ 
X$ 
X$ 
X$ 
X$ 
X$ 
X$ 
X 
Lumbar CSF Cytology# 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Audiogram 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
Thyroid 
Function 
Evaluation (Free T4 and 
TSH) 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
X 
 
LH, 
FSH, 
estradiol 
or 
testosterone 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
X 
 
Serial 
Measurment 
of 
Height (Stature)% 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
X 
 
* 
Spinal MRI should include complete spine (cervical, thoracic, lumbar and sacral) 
% Refer to endocrinologist if a growth below the 3rd percentile, drop in height percentile on growth grid, growth velocity <4-5cm/yr in childhood 
or lack of pubertal growth spurt 
$ 
Obtain if initially positive. Patients with M1-M3 disease require the more frequent scans. 
# 
Obtain per institutional standard of care. 
 
 

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7.5 
Optional Studies 
 
7.5.1 
Neuropsychologic Evaluations 
Patients who consent to participate on ALTE07C1 will be assessed at three times 
points: at 9 months (± 3 months) post cancer diagnosis; at 30 months (± 3 months) 
post diagnosis, and again at 60 months (± 3 months) post diagnosis. Age 
appropriate tests will be used and will include measures of broad cognitive 
functioning (IQ) and specific areas of neuropsychological functioning, emotional-
behavioral functioning, and quality of life. Total testing time should be 
approximately 1 hour at each assessment point.  
 
 
 
8.0 
SUPPORTIVE CARE GUIDELINES 
 
These are provided for institutional consideration. Investigator discretion should be used, and 
individual considerations made for specific patient situations and institutional practices. Patients 
may receive supportive care as clinically indicated. Supportive care for any reason, including care 
of complications arising from the cancer, adverse reactions, or other underlying diseases, must be 
recorded through resolution of the event. The Study Chair may be called with any questions or 
problems. Please also see the COG Supportive Care Guidelines at: 
 https://members.childrensoncologygroup.org/prot/reference_materials.asp and the Supportive Care 
of Children with Cancer, 2004 ed., Arthur R. Altman, M.D. 
 
8.1 
Venous Access 
Patients are required to have an indwelling central venous access catheter.  
 
8.2 
Antiemetics 
Antiemetics and use of serotonin antagonists should be used according to institutional 
guidelines. Corticosteroids should not be used during chemotherapy administration 
as an antiemetic because of their effect on the blood-brain barrier. 
 
Dexamethasone may be used for delayed nausea and vomiting.  
 
8.3 
Fever and Neutropenia 
Patients who develop a fever greater than 38.5°C should be evaluated for neutropenia and 
infection. Blood cultures should be drawn and antibiotics should be administered per 
institutional policy. Aminoglycosides should be avoided if possible to decrease the chance 
of ototoxicity. 
 
Significant myelosuppression is likely to occur, particularly during the last two-three 
weeks of radiation. However, radiation should not be withheld for myelosuppression 
alone. Radiation should be continued even if the patient is hospitalized with fever and 
neutropenia as long as the patient is clinically stable. Administration of the boost 
should not be substituted for craniospinal radiation in the face of low counts.  
 
8.4 
Prophylactic Antibiotics 
Patients who receive chemotherapy should be started on trimethoprim/sulfamethoxazole 
(TMP/SMZ) at trimethoprim 2.5mg/kg/dose twice daily on 2 or 3 sequential days per week 
or per primary care institution’s protocol for Pneumocystis carinii prophylaxis. TMP/SMZ 

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can be discontinued 3 months after chemotherapy has been discontinued. Patients with 
TMP/SMZ allergy should be treated with dapsone or pentamidine. Additional treatments 
and information can be found in the COG Supportive Care Guidelines (see above). 
 
8.5 
Azole Anti-fungal Agents 
Avoid co-administration of vincristine and azole anti-fungal agrents such as fluconazole, 
itraconazole and voriconazole whenever possible. The risk of vinca alkaloid toxicity (eg 
constipation, myalgia, neutropenia) may be increased. If co-administration is necessary and 
vinca alkaloid toxicity increases, it may be necessary to alter vincristine dosing as 
described in sections 5.1.1 and 5.2.1. 
 
 
8.6 
Blood Products 
 
8.6.1 
Irradiation 
Blood products should be irradiated following the current FDA guidelines found at: 
http://www.fda.gov/cber/gdlns/gamma.htm  
 
Investigators in Canadian institutions need to follow the CSA standards for Blood and 
Blood Components CAN/CSA-Z902-04 issued in March 2004 and available at 
http://www.shopcsa.ca. 
 
8.6.2 
Platelets 
Patients will be transfused as necessary with platelets. It is suggested that the platelet count be 
maintained > 30,000/µL. All blood products will be irradiated to prevent graft-versus-host 
disease. Filters to remove leukocytes should be used to prevent WBC sensitization. CMV 
seronegative patients should receive CMV negative blood products. 
 
8.6.3 
Red Blood Cells 
Therapy-induced anemia and reticulocytopenia are expected with this protocol. Patients 
will be transfused as necessary with irradiated packed red blood cells to maintain a 
hematocrit > 20-25%. Blood products will be irradiated to prevent graft-versus-host 
disease. Filters should be used to prevent WBC sensitization. 
 
8.7 
Nutritional Support 
Any patient with greater than 10% weight loss should begin megestrol (Megace) at 5 
mg/kg/dose twice daily or nutritional support either enterally or via a central venous 
catheter with parenteral hyperalimentation. Patients should have their magnesium checked 
frequently and be supported with magnesium supplementation if necessary. 
 
 

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9.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA 
 
9.1 
Criteria for Removal from Protocol Therapy 
 
a) 
Progressive disease. 
b) 
Refusal of further protocol therapy by patient/parent/guardian. 
c) 
Completion of planned therapy. 
d) 
Physician determines it is in patient’s best interest. 
e) 
Development of a second malignant neoplasm (SMN) 
f) 
Repeated eligibility studies outlined in the protocol are outside the parameters 
required for eligibility. 
 
 
Patients who are off protocol therapy are to be followed until they meet the criteria for Off 
Study (see below). Follow-up data will be required unless consent was withdrawn. 
 
9.2 
Off Study Criteria 
 
a) Death. 
b) Lost to follow-up. 
c) Patient enrollment onto another COG study with tumor therapeutic intent (e.g. at 
recurrence) 
d) Withdrawal of consent for any further data submission. 
e) The tenth anniversary of the date the patient was enrolled on this study. 
 
 
10.0 
STATISTICAL CONSIDERATIONS 
 
This is a randomized, phase III, factorial-designed study comparing induction radiation therapy 
(XRT) alone to XRT + carboplatin (XRT+CBCDA) both followed with maintenance therapy ± 
Isotretinoin, for the treatment of supratentorial PNET or disseminated infratentorial PNET 
(medulloblastoma). The primary objective of the statistical analysis will be to test whether the 
addition of CBDCA to XRT or the addition of Isotretinoin to maintenance therapy results in an 
increase in the proportion of patients who are long-term event-free survivors.  
 
Prior to Amendment 2, randomization to this study was stratified on dissemination and tumor 
location (supratentorial PNET vs. medulloblastoma). The study was initially powered to detect 
treatment effects among all patients (PNET and medulloblastoma) combined. However emergence 
of new data on biological differences between supratentorial PNET and medulloblastoma raised 
the concern that heterogeneity of treatment effect across tumor types may reduce power. Therefore, 
as of Amendment 2, the accrual goals of the study were adjusted to detect treatment effects among 
medulloblastoma patients alone. Accrual of supratentorial PNET patients was discontinued since 
power to detect treatment effects in this group, which accounts for less than 30% of enrolled 
patients, would not be attainable within a reasonable time-frame. At the conclusion of the study the 
analyses will be performed separately for medulloblastoma and PNET patients.  
As of Amendment 3, the isotretinoin randomization was closed effective 1/27/15 following a 
futility analysis. As noted in the original study design, detailed below, since a factorial design 
approach was used to power the study, closure of one of the randomizations does not affect the 
power considerations for the remaining randomization, based on the original design assumptions. 

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10.1 
Design Considerations 
Since the administration of CBDCA as a radiation sensitizer and Isotretinoin as a pro-
apoptotic agent occur at different times during therapy, it is considered extremely unlikely 
that the addition of CBDCA to XRT in induction will qualitatively change the effect on 
efficacy of Isotretinoin in maintenance, or similarly, that the addition of Isotretinoin in 
maintenance will qualitatively change the effect on efficacy of the addition of CBDCA 
during XRT. Hence, the study is not designed with, nor is it considered necessary to 
provide, high power to detect these unlikely qualitative interactions. 
 
This trial consists of factorial randomization: one addressing a carboplatin question and the 
other addressing an Isotretinoin question. If one of the two randomizations is closed 
(whether due to efficacy, toxicity or other considerations), then the trial will continue 
accrual and randomization to the other randomization during the time that an amendment 
is being prepared and processed to modify the protocol. Continuing accrual until the 
amendment is prepared is appropriate because the two clinical questions being tested 
through these randomizations are independent of each other, and because the study design 
remains valid if one of the randomizations is stopped. 
 
If this circumstance arises, the following procedure will be used for consenting patients 
until the new protocol and consent form is available. Patients will sign the exiting consent 
form, and may be enrolled provided that the enrolling physician documents in the medical 
record that: (1) the randomization to one of the randomization factors has been closed, but 
the other randomization remains open per the protocol; (2) since the randomizations and 
study questions are independent as stated in the protocol, the patient can be enrolled on the 
study as the official amendment to change the study is being processed; and (3) this has 
been explained to the patient and he/she understands the changes in the study and agrees 
to enter the study. When the amended consent form is approved, the patient will be re-
consented to complete the record. 
 
As of Amendment 3, the isotretinoin randomization was closed following a futility 
analysis. As noted in the original study design, detailed below, since a factorial design 
approach was used to power the study, closure of one of the randomizations does not affect 
the power considerations for the remaining randomization, based on the original design 
assumptions. 
 
  
10.2 
Patient Accrual 
 
 
Accrual of eligible, supratentorial PNET or disseminated infratentorial PNET 
(medulloblastoma) patients to the pilot study CCG-99701 has averaged approximately 25 
patients per year (after accounting for temporary suspensions). Given that this study targetted 
75% of patients in former CCG institutions, and that during the COG A9961 study in 
medulloblastoma, former POG institutions enrolled approximately 77% of the total number 
of patients enrolled by CCG institutions, the projected COG accrual of these patients is 
expected to be 60 per year. A similar estimate results from the older CCG-9931 study, which 
enrolled supratentorial PNET and disseminated MBL patients at a rate of 39 per year. This is 
considered an underestimate, since CCG-9931 was open only to patients with measurable 
residual disease. Adjusting for groupwide participation, this results in an estimated accrual of 
66 per year in COG. Hence, it is reasonable to expect that accrual rate of at least 60 per year 
will be observed, with higher rates possible.  
 

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As of Amendment #2, it is estimated that about 35 medulloblastoma patients could be enrolled 
every year according to the accrual history of the study. 
 
10.3 
Study Duration 
 
 
The planned study duration will be 5 years of accrual and 1 year of follow-up. This study will 
accrue for 5 years provided that total number of eligible, correctly randomized and followed 
patients is projected to be at least 300. If annual accrual is slower than the required 60 patients 
per year, accrual will be extended until a minimum of 300 patients has been accrued, with 
final analysis one year after the end of accrual. If annual accrual is greater than 60 per year, 
the accrual can continue for the full 5 years of accrual, depending on the need for patients in 
successor studies at this time, and at the discretion of the disease committee, in order to 
increase precision and power. Much of the remaining discussion will refer the minimum 
nominal accrual goal of 300 patients accrued over 5 years and followed for 1 year.  
 
The accrual rate of eligible, correctly randomized and followed patients will be evaluated 
at month 18 of the study using the average accrual rate achieved between months 7 and 18. 
Accrual rates of 50/year or less at this time will be of concern. 
 
As of Amendment #2, 300 patients have been enrolled on the study. Four (4) of these 
patients were deemed to be ineligible for the protocol, leaving 296 eligible patients. 211 of 
the 296 patients had medulloblastoma and the other 85 were diagnosed with SPNET. The 
SPENT patients enrolled on the trial will be replaced. Patients who do not have metastatic 
disease or residual disease >1.5 cm2 by central neuroradioloty review, patients with 
localized medulloblastoma and < 1.5 cm2 residual disease who were enrolled because of 
diffuse large cell anaplasia, but were found not to have this diagnosis, and patients who are 
found to have a histologic diagnosis other than medulloblastoma (e.g., ATRT) by central 
pathology review will be excluded from the final data set used to address the primary 
objectives. We expect approximately 10% of the patients falling in this category. 
Therefore, the study will accrue additional 100 medulloblastoma patients to ensure about 
280 ((211+100)*0.9) eligible and evaluable patients for the analysis of primary objectives. 
Due to the extended accrual time and longer follow-up for the patients who have been 
enrolled, similar power can be obtained with this target number of eligible and evaluable 
patients.  
 
With these changes the maximum accrual becomes 400 (300+100) targeting 280 eligible 
and evaluable medulloblastoma patients for the primary objectives of the study. The study 
duration is expected to be about 11 years, including the suspension for the amendment, 
additional 3 years of accrual, and 1 year of follow-up at the end. 
 
10.4 
Study Endpoints for Analysis of Treatment Efficacy 
The primary endpoint for the evaluation of treatment efficacy will be time to an event, 
which will be used to compute the event-free survival (EFS) percentage. An event 
comprises disease progression or recurrence, occurrence of a second malignant neoplasm, 
or death from any cause. Secondary endpoints in this analysis will be tumor response to 
radiation therapy ± carboplatin, and time to death, from which the survival (S) percentage 
will be computed.  
 
10.5 
Statistical Analysis of Difference in Long-Term EFS Rate  
The main study analysis will be based a stratified logrank test, 40 with stratification on all 
randomization stratifiers (below) as well as on the factorial treatment group not the subject 

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of the analysis. Good approximation to the power of these test are obtained using the 
methods of Sposto and Sather. 41  
 
It is expected that 300 eligible medulloblatoma patients are accrued over eight years with 
one year additional follow-up, with an annual 1% censoring rate. The reference group 
(XRT alone, no Isotretinoin) is best represented by a PCM with long-term EFS (cure) rate 
of 56%, and two-year EFS of 61%, based on the most recently available COG data in a 
similar cohort of patients (R Sposto, personal communication). Based on a one-sided test 
with 5% Type I error, the test of the CBDCA effect, under the assumption that Isotretinoin 
has no effect, will have at least 80% power to detect a 15% increase in long-term EFS (56% 
to 71%, RFR=0.591), and at least 90% power to detect a 17% increase (56% to 73%, 
RFR=0.543). Under the assumption that Isotretinoin results in a halving of the failure rate, 
the test of the CBDCA effect will have at least 80% power to detect a 14% increase in 
long-term EFS (65% to 79%, RFR=0.547), and at least 90% power to detect a 16% increase 
(65% to 81%, RFR=0.489). The problem is symmetrical, so that these figures apply to the 
test of the Isotretinoin effect. No adjustment for multiple comparison will be made in this 
comparison. The figure below illustrates the power under these two scenarios. 
 
10.6 
Interim Monitoring 
Monitoring for differences in long-term EFS will be based on the same one-sided 
likelihood ratio test as described above. Interim monitoring rules will be devised according 
to the methods of Lan-Demets. 42 To detect substantial increases in efficacy due to the 
addition of either CBDCA or Isotretinoin, the 5% Type I error will be spent at a rate of αt2, 
where t is the appropriate information-time scale. To detect substantial decreases in 
efficacy due to either of these additions, a 20% Type I error rate will be used, with error 
spent at a rate of αt.   
 
Initially interim monitoring analyses were planned at least after 2, 3, 4, and 5 years of the 
study. Monitoring after 5 years was not planned, because all patients on the trial were 
expected to have completed treatment. As of Amendment #2, interim monitoring analyses 
were to be conducted yearly until the accrual of the study is completed. 
 
-
0.10
0.20
0.30
0.40
0.50
0.60
0.70
0.80
0.90
1.00
0%
5%
10%
15%
20%
Improvement in EFS in CBDCA Group
Power of one-sided test
Power with CisRA effect
Power without CisRA Effect

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Amendment #3 is in response to the DSMC comments following the Fall 2014 COG 
Meeting. In their comments the DSMC requested that the protocol be amended to reflect 
interim monitoring of the results for medulloblastoma patients only, as a result of the fact 
that the primary cohort of the study was limited to medulloblastoma patients as of the last 
amendment of the study. The DSMC also requested that futility monitoring is added for 
the two randomizations.  
 
Revised monitoring rule for efficacy for medullablastoma patients only (inactive 
as of Amendment #4): 
The number of events observed to date in medulloblastoma cohort is different from the 
combined Medulloblastoma+PNET cohort and it is clear that the interim monitoring rule 
for the medulloblastoma cohort needs to take this difference in the number of events into 
account. We propose to do this by following the second approach in Anderson (2014, 
unpublished manuscript) which accounts for the alpha-spending that has already occurred 
in planning future interim analyses. Not surprisingly the number of events in the combined 
Medulloblastoma/PNET cohort is larger than the number of events in the Medulloblastoma 
only cohort hence the alpha already spent in the previous analyses is larger than what would 
be suggested by the information present in the Medulloblastoma cohort. Anderson (2014, 
unpublished manuscript) suggests accounting for this by skipping one or more of the 
planned interim analyses until the accumulated information can catch up to the alpha 
already spent based on the previous design parameters. Based on the data available as of 
Amendment 3, this approach suggests that the first interim analysis we can perform for the 
medulloblastoma cohort will be in Fall 2017, which is expected to be very close to the end 
of accrual. We will then perform what will likely be the final analysis in Fall 2018.  
 
Updated monitoring rule for efficacy for medullablastoma patients only (Amendment 
#4)): 
In response to DSMC comments following Fall 2015 COG meeting, the monitoring rule 
for efficacy for medulloblastoma patients only was further updated. Consistent with the 
discussions and the consensus that followed between the DSMC and CTEP statisticians, 
we propose to use the number of events, which was calculated based on the original study 
design for the combined medulloblastoma/sPNET cohort, as the full information for the 
medulloblastoma cohort as well since the assumptions in the original design are reasonable 
and valid for medulloblastoma cohort as well. The following points were agreed upon and 
will be used in all future analyses of the data from the medulloblastoma cohort: 
• 
The full information will be defined as 110 events, which was calculated based on the 
original design parameters in the protocol. 
• 
The alpha already spent in the previous interim analyses of the trial will be calculated 
based on the data from medullablastoma cohort alone. Furture interim analyses will 
be conducted based on the leftover alpha following this approach. 
• 
The final analysis for the trial will be conducted once 280 eligible and evaluable 
medulloblastoma patients have been enrolled and all have been followed for at least 1 
year as specified in Amendment #2, regardless of the number of events observed at 
that time.  
 
The last interim analysis was conducted in Fall 2014. No interim analysis was conducted 
in Fall 2015 per the analysis plan specified in Amendment #3A. Following the above 
described approach, we will implement interim analyses to correspond with the Fall 2016 
and Fall 2017 DSMC reports. Based on the observed number of events at these scheduled 
interim analyses, we will calculate the % of information, interim monitoring boundary for 

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efficacy and overall alpha expended according to the methods of Lan and Demets.  The 5% 
type I error will be spent at a rate of αt2, where t is the % of information. The 100% 
information is defined as the 110 events. The same approach will be implemented to find 
the boundary for efficacy for the final analysis which is expected to be conducted in Fall 
2018.   
 
Updated monitoring rule for efficacy for medullablastoma patients only (Amendment 
#5): 
 
• 
The final analysis for the trial will be conducted once 280 eligible and evaluable 
medulloblastoma patients have been enrolled and all have been followed for at least 1 
year as specified in Amendment #2. The interim analysis as described as in 
Amendment #4 will be implemented annually until the final analysis point is reached 
as described above.  
 
 
Interim futility monitoring for Carboplatin randomization 
We will use conditional power as a guide for futility monitoring at interim monitoring time 
points. The following outlines the steps we will follow to conduct the interim futility 
monitoring: First, the design is mimicked in East 6.4. Consistent with the original design 
this design assumes that the 2-year EFS rate is 61% and long-term EFS rate is 56% in the 
control group. Based on a sample size of 300 patients and a one sided log-rank test with 
5% type I error, the test of the Carboplatin effect was estimated to have at least 80% power 
to detect a 15% increase in long-term EFS (56% for control vs. 71% for carboplatin). 
Second, the test-statistic for one-sided stratified log rank test is calculated to compare the 
two treatment groups based on most recently frozen data. Thrid, this test statistic is used as 
the basis for calculating conditional power for interim monitoring via East 6.4. Fourth, the 
conditional power estimate would then be communicated to the DSMC at each interim 
analysis point with our recommendations on the futility of continuing this randomization. 
Though it is difficult to come up with a strict cut-off, we will consider recommending 
stopping the carboplatin randomization if the conditional power estimate falls below 10%. 
 
Interim futility monitoring for Isotretinoin randomization 
A similar approach to the one described above was used to assess futility based on data 
frozen on June 30, 2014 which led to the conclusion that the likelihood of reaching a 
statistically significant result at the end of the study for the Isotretinoin randomization was 
very small. Thus this randomization was suspended as of Amendment 3.  
 
Interim Monitoring for Ototoxicity: 
Previous studies that utilized full dose craniospinal irradiation followed by cisplatin-based 
maintenance therapy showed approximately 25% to 30% grade 3 and 10% grade 4 
ototoxicity (personal communication with Dr. Roger Packer). The occurrence of excessive 
grade 4 ototoxicity rates at any time during therapy will constitute a primary endpoint for 
safety monitoring. A grade 4 ototoxicity rate that exceeds p0=15% will be considered 
unacceptable. A Bayesian monitoring rule with prior density Beta (2,12) on the probability 
p of ototoxicity rate will be used as a trigger for careful assessment of excess hearing loss. 
The prior has median p=0.125 and mean p=0.14, with approximately 95% of support less 
than p=0.32. A posterior probability P (p> p0|data)>85% will satisfy the monitoring 
criterion. This represents 85% certainty that the ototoxicity rate exceeds p0 given the data 
and the assumed prior density. Ototoxicity rates will be monitored separately in each of the 
two chemotherapy induction groups. Operationally, the monitoring criterion will be 

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satisfied if 4 patients develop Grade 4 ototoxicity in the first 10 patients, or ≥6/20, ≥8/30, 
etc. If the monitoring criterion is satisfied, an immediate clinical review of the cause and 
timing of the hearing loss will be undertaken. In frequentist viewpoint, this criterion will 
be satisfied 9% of time if p=11% and 94% of time if p=20% assuming we have n=150 
patients. 
 
10.7 
Statistical Analysis of the Post-RT Response 
 
 
In CCG-99701, 50/146 patients (34%) had residual tumor measuring at least 1.5 cm2. These 
are the patients who will be evaluable for post-RT response assessment. Hence, approximately 
100 patients in the current study, 50 each receiving XRT alone or XRT+CBDCA, will be 
evaluable for this endpoint. Using a two-sided test of proportions with Type I error 5%, this 
sample size will provide at least 80% power to detect a 30% difference in post-RT response 
rate between the two treatment groups. There will be no interim monitoring based on this 
endpoint. 
 
10.8 
Stratification 
 
 
Randomization will be stratified on the basis of location and dissemination. Six strata will be 
defined: (1) M0 Medulloblastoma with >1.5 cm2 residual; (2) M+ Medulloblastoma; (3) M0 
Supratentorial PNET with <1.5 cm2 residual; (4) M0 SPNET with >1.5 cm2 residual; (5) M+ 
SPNET, (6) M0 Diffusely Anaplastic Medulloblastoma.  
 
As of Amendment #2, because the accrual of sPNET will be discontinued, only the 
three strata of medulloblatoma will be defined: (1) M0 Medulloblastoma with >1.5 cm2 
residual; (2) M+ Medulloblastoma; (3) M0 Diffusely Anaplastic Medulloblastoma. 
 
10.9 
Neuropsychological and Quality of Life 
The primary objective of this part of the study is to assess the quality of life (QOL) and 
neuropsychological (NP) outcome of the study population.  
 
Descriptive statistics, including means, standard errors, medians, inter-quartile ranges, 
proportions, will be used to characterize the overall QOL and NP outcome for patients. 
Descriptions at baseline will estimate the acute effects of the tumor before the onset of 
treatment effects, and descriptions at follow up periods will estimate the long-term effects 
of the tumor and its treatment. The raw scores obtained in this study population, for 
example, the Processing Speed Indices from the WISC-IV or WAIS-III, will be compared 
with established population test norms provided in the scoring tables of the manuals. Test 
variables of the instruments, for example, nonverbal skills and processing speed, will be 
compared on the basis of intercorrelations. Using two-sample t tests for continuous 
variables and Pearson’s χ  test for categorical variables, the intervention and the control 
arms will be compared in terms of clinical characteristics at the time of randomization, and 
in terms of baseline QOL and NP scores. Data-reduction strategy, such as factor analysis 
can be used to reduce the overall number of statistical comparisons and thus minimize 
inferential errors associated with multiple univariate tests of dependent variables.  
 
For patients who have baseline and at least two follow up evaluations, a growth curve 
model, which is a particular variant of random-effects models, will be utilized. This 
approach treats data from different patients as statistically independent and data from the 
same patient as correlated. Growth curve models emphasize the explanation of within-
person variation over time by a natural developmental process. The growth curve model 
allows an estimation of the average rate of change (or slope) over time for patients within 

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the total group, as well as an estimation of the differences in the slopes between subgroups. 
Growth curves for patients will be averaged, and comparisons will be made between those 
who receive intervention and those who do not, controlling for variables such as age at 
diagnosis, sex, race/ethnicity and treatment related factors. 
 
10.9.1 Sample Size Calculation 
The primary interest of this study is on long-term effects of treatment on QOL and 
NP outcomes, so that the sample size calculation will be based on a comparison of 
the two-year QOL and NP assessment between the treatment groups, the 
Isotretinoin vs. the standard chemotherapy arms. The calculation also applies to 
detecting significant CBDCA effect. It is assumed that 300 patients will be accrued 
over five years with two-additional follow-up. Of the approximately 61% of 
patients who are alive and free from progression at three years, we will assume 
that at minimum 80% (73 patients per treatment arm) will have QOL and NP 
assessments at three years. Using a two-sided two-sample t-test with Type I error 
0.05, we have 80% power to detect a 0.46 standard deviation (SD) difference in 
the mean change between the two treatment groups. We assume that a difference 
in mean QOL and NP scores between different treatment groups as small as one-
half of one standard deviation will be considered to be clinically significant.  
 
10.9.2 Subject Attrition and Missing Data 
 
We want to plan the study in a manner that avoids missing data. It is proposed that 
each participating institution will be asked to identify one person (i.e. nurse, CRA, 
psychologist) who will be responsible for monitoring the data collection/submission. 
This individual will serve as the institution’s “contact person” regarding this portion 
of the protocol. If the above procedure is carried out, we can anticipate that the loss 
to follow-up in this study will be minimal. We will collect covariates that explain 
variability in the outcome and missing data patterns. We will document the reasons 
for missing data. These missing values are expected to be missing at random and not 
associated with any outcome of the study. When there is any suspicion that the 
missing data will be related to events or outcomes that will affect QOL, appropriate 
models such as selection models, and mixture models will be utilized in longitudinal 
data analyses to deal with such issues.  
 
10.10 Gender and Ethnicity Considerations 
 
Review of outcome data from previous CCG medulloblastoma studies indicates that treatment 
effects are consistent within gender and ethnicity. That is, no one treatment examined has 
proven superior for one gender or ethnic group. Because of this, the study size will not be 
adjusted to ensure high power to detect differences in outcome in groups defined by ethnicity 
or gender. 
 
 

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Expected Accrual by Sex and Race/Ethnicity for the Additional 100 
Medulloblastoma Patients  
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
18 
25 
43 
Not Hispanic or Latino 
138 
217 
355 
Unknown 
1 
1 
2 
Ethnic Category: Total of all subjects 
157 
243 
400 
Racial Category 
 
American Indian or Alaskan Native 
2 
2 
4 
Asian 
5 
7 
12 
Black or African American 
9 
17 
26 
Native Hawaiian or other Pacific Islander 
1 
2 
3 
White 
137 
209 
346 
Other 
2 
4 
6 
Not Reported 
1 
2 
3 
Racial Category: Total of all subjects 
157 
243 
400 
 
 
 
11.0 
EVALUATION CRITERIA  
 
11.1 
Common Terminology Criteria for Adverse Events v4.0 (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting 
beginning January 1st, 2011. All appropriate treatment areas should have access to a 
copy of the CTCAE version 4.0, and a copy can be downloaded from the CTEP web 
site (http://ctep.cancer.gov). Additionally, toxicities are to be reported on the appropriate 
data collection forms. 
 
11.2 
Methodology to Determine Tumor Measurement  
In order to completely document the assessment of response, the three-dimensional tumor 
measurements for all target lesions upon which the assessments of tumor response are 
based should be explicitly noted in the radiology report for the baseline and all subsequent 
follow-up exams.  Reports for the follow-up exams should reiterate the measurements 
obtained at baseline for each target lesion.  Non-target lesions or newly occurring lesions 
should also be enumerated in these reports, and changes in non-target lesions should be 
described. 
  
Tumor response criteria are determined by changes in size using all 3 dimensional 
measurements: width (W), transverse (T), and length (L) measurements. Thus for all 
tumors these 3 measurements need to be recorded, using either T1 or T2 weighted images 
(which ever gives the best estimate of tumor size). The following section describes the 
methodology. 

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(See drawing below for illustration) 
1. Longest diameter of target lesion(s) should be selected in the axial plane only for CT. 
For MRI imaging, the longest diameter can be measured from the axial plane or the 
plane in which the tumor is best seen or measured, provided the same plane is used in 
follow ups. 
2. The longest measurement of the tumor (or width, W) should be determined.  
3. The 2 perpendicular measurements should be determined (transverse (T) 
measurement-perpendicular to the width in the selected plane, and the length (L) – 
tumor extent in the plane perpendicular to the selected plane) 
 
 
 
Figure 11.1: COG Guidelines for Measurement of Tumor Size 
 
 
Z
AXIS
W
T
A
B
C
D
E
COG GUIDELINE: TUMOR SIZE
MEASUREMENT BASED ON
CROSS-SECTIONAL IMAGING
• A, B, C, D, & E are contiguous
parallel slices in the X-Y plane
(usually axial) showing the tumor
• W and T are the maximal
perpendicular diameters on the slice
(C in this example) showing the
largest surface area
• Tumor length in the Z-axis (L)
(perpendicular to X-Y plane) can be
obtained either by the [a] (difference
in table position of the first and last
slices showing the tumor + one slice
thickness), or [b] the product of (slice
thickness + gap) and the number of
slices showing the tumor
X-Y
PLANE
L

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Table 11.1: RELATIONSHIP BETWEEN CHANGE IN SINGLE DIAMETER (RECIST), 
PRODUCT OF TWO DIAMETERS (WHO), AND THREE PERPENDICULAR 
DIAMETERS (“VOLUME”) 
(Modified from Appendix II, Table 2, JNCI 92:213, 2000) 
 
 
 
 
 
Diameter, 2R 
       Product, (2R)2 
Volume, 4/3pR3 
Response 
 
Decrease 
       Decrease 
    
Decrease 
 
 
    
30% 
          
 
50% 
     
 65% 
 
 
    
50% 
        
 
75%         
 87% 
Disease Progression 
  Increase 
       Increase 
   
Increase 
 
 
    
 12% 
         
 
25%       
 40% 
 
 
    
20% 
         
 
44%           
 73% 
 
 
    
 25% 
         
 
56%         
95% 
 
 
    
 30% 
         
 
69% 
     
120% 
 
4. Therefore only the solid component of cystic/necrotic tumors should be measured. If 
cysts/necrosis compose the majority of the lesion, the lesion may not be “measurable”.  
 
Options: 
 
• if the cyst/necrosis is eccentric, the W, T and L of the solid portion should be 
measured, the cyst/necrosis excluded from measurement 
• if the cyst/necrosis is central but represents a small portion of the tumor (<25%), 
disregard and measure the whole lesion 
• if the cyst/necrosis is central but represents a large portion of the tumor, identify 
a solid aspect of the mass that can be reproducibly measured 
5. Leptomeningeal tumor spread is usually not a target lesion, and usually cannot be 
measured accurately. Presence and location of leptomeningeal tumor spread should be 
noted, change in extent/thickness assessed on follow up studies. 
6. Overall Response Assessment 
The overall response assessment takes into account response in both target and non-
target lesion, and the appearance of new lesions, where applicable, according to the 
criteria described in the table below. The overall response assessment is shown in the 
last column, and depends on the assessments of target, non-target, and new lesions in 
the preceding columns. 
 
Table 11.2 Overall Response Assessment 
 
Target Lesions 
 
Non-target Lesions 
 
New Lesions 
 
Overall Response 
CR 
CR 
No 
CR 
CR 
IR/SD 
No 
PR  
PR 
 CR, IR/SD 
No 
PR 
SD  
 CR, IR/SD 
No 
SD  
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
CR – Complete Response 
 
PD – Progressive Disease 
PR – Partial Response 
 
IR – Incomplete Response 
SD – Stable Disease 
 
The sections that follow discuss the selection and evaluation of each of these types of 
lesions. 

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11.3 
Selection of Target and Non-Target Lesions 
1. For most CNS tumors, only one lesion/mass is present and therefore is considered a 
“target” for measurement/follow up to assess for tumor progression/response.  
2. If multiple measurable lesions are present, up to 5 should be selected as “target” 
lesions. Target lesions should be selected on the basis of size and suitability for 
accurate repeated measurements. All other lesions will be followed as non-target 
lesions (including CSF positive for tumor cells).  
3. The lower size limit of the target lesion(s) should be at least twice the thickness of the 
slices showing the tumor to decrease the partial volume effect (e.g. 8 mm lesion for a 
4 mm slice). 
4. Any change in size of non-target lesions should be noted, though does not need to be 
measured. 
 
11.4 
Response Criteria for Target Lesions 
1. Response criteria are assessed in 3 dimensions – the product of LxWxT. An elliptical 
model volume (=0.5LxWxT) is used. 
2. To assess response/progression, the ratio is calculated: 
 
 
LxWxT (current scan)  
 
 
LxWxT (reference scan) 
 
3. Development of new disease or progression in any established lesions is considered 
progressive disease, regardless of response in other lesions – e.g. when multiple lesions 
show opposite responses, the progressive disease takes precedence. 
 
4. Response Criteria for target lesions: 
 
Complete Response (CR): Disappearance of all target lesions.  
Partial response (PR): ≥65% decrease in the sum of the products of the three 
perpendicular diameters of all target lesions (up to 5), taking as reference the initial baseline 
measurements. 
Stable Disease (SD): Neither sufficient decrease in the sum of the products of the three 
perpendicular diameters of all target lesions to qualify for PR (taking as reference the initial 
baseline measurements), nor sufficient increase in a single target lesion to qualify for PD, 
(taking as reference the smallest disease measurement since the treatment started). 
Progressive Disease (PD): 40% or more increase in the product of perpendicular diameters 
of ANY target lesion, taking as reference the smallest product observed since the start of 
treatment, or the appearance of one or more new lesions.  
 
In the rare circumstance that the length of a lesion cannot be determined, then comparison 
of 2 dimensional measurements, TxW (product of the longest diameter and its longest 
perpendicular diameter) can be used. 
 
Complete Response (CR): Disappearance of all target lesions.  
Partial response (PR): ≥50% decrease in the sum of the products of the two perpendicular 
diameters of all target lesions (up to 5), taking as reference the initial baseline 
measurements 
Stable Disease (SD): Neither sufficient decrease in the sum of the products of the two 
perpendicular diameters of all target lesions to qualify for PR (taking as reference the initial 
baseline measurements), nor sufficient increase in a single target lesion to qualify for PD, 
(taking as reference the smallest disease measurement since the treatment started). 

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Progressive Disease (PD): 25% or more increase in the product of perpendicular diameters 
of ANY target lesion, taking as reference the smallest product observed since the start of 
treatment, or the appearance of one or more new lesions.  
 
11.5 
Response Criteria for Non-target Lesions 
Complete Response (CR): Disappearance of all non-target lesions.  
Incomplete Response/Stable Disease (IR/SD): The persistence of one or more non-target 
lesions.  
Progressive Disease (PD): The appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  
 
 
12.0 
ADVERSE EVENT REPORTING REQUIREMENTS  
 
12.1 
Purpose 
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of patients enrolled in the studies as well as those who 
will enroll in future studies using similar agents.  
 
12.2 
Determination of Reporting Requirements 
Reporting requirements may include the following considerations: 1) the characteristics of 
the adverse event including the grade (severity); 2) the relationship to the study therapy 
(attribution); and 3) the prior experience (expectedness) of the adverse event. 
  
Commercial agents are those agents not provided under an IND but obtained instead from 
a commercial source. In some cases an agent obtained commercially may be used for 
indications not included in the package label. In addition, NCI may on some occasions 
distribute commercial supplies for a trial. Even in these cases, the agent is still considered 
to be a commercial agent and the procedures described below should be followed. 
 
 
Determine the prior experience Expected events are those that have been previously 
identified as resulting from administration of the agent. An adverse event is considered 
unexpected, for reporting purposes only, when either the type of event or the severity of 
the event is not listed in:  
 
• 
The current known toxicities for each commercial agent as provided in the Drug 
Information for Commercial Agents Used by the Children’s Oncology Group 
posted on the COG website; or  
• 
the drug package insert  
 
Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous 
malignancy (eg, treatment with investigational agent/intervention, radiation or 
chemotherapy). A metastasis of the initial neoplasm is not considered a secondary 
malignancy.  
 
All secondary malignancies that occur following treatment need to be reported via 
CTEP-AERS. Three options are available to describe the event:  
• Leukemia secondary to oncology chemotherapy  
• Myelodysplastic syndrome  

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• Treatment related secondary malignancy 
 
12.3 
Reporting of Adverse Events for Commercial Agents – via CTEP-AERS  
Expedited AE reporting must use CTEP-AERS (Adverse Event Expedited 
Reporting System), accessed via https://eapps-ctep.nci.nih.gov/ctepaers 
 
Commercial reporting requirements are provided in Table B. The commercial agent(s) used 
in this study are listed in the in the front of this protocol immediately following the Study 
Committee roster.  
.  
• 
COG requires the CTEP-AERS report to be submitted within 7 calendar days of 
learning of the event.  
• 
Use the NCI protocol number and the protocol-specific patient ID provided during trial 
registration on all reports.  
 
CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 can be downloaded 
from the CTEP website at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
Table B 
Reporting requirements for adverse events experienced by patients on study who 
have NOT received any doses of an investigational agent on this study. 
 
CTEP-AERS Reporting Requirements for Adverse Events That Occur During 
Therapy With a Commercial Agent or Within 30 Days1 
 
Attribution 
Grade 4 
Grade 5 
 
Unexpected 
Expected 
 
Unrelated 
or 
Unlikely 
 
 
CTEP-AERS 
Possible, 
Probable, 
Definite 
CTEP-AERS 
 
CTEP-AERS 
1This includes all deaths within 30 days of the last dose of treatment with a 
commercial agent, regardless of attribution. Any death that occurs more than 
30 days after the last dose of treatment with a commercial agent which can 
be attributed (possibly, probably, or definitely) to the agent and is not due to 
cancer recurrence must be reported via CTEP-AERS. 
 
12.4 
Routine Adverse Event Reporting 
Note: The guidelines below are for routine reporting of study specific adverse events on 
the COG case report forms and do not affect the requirements for CTEP-AERS reporting. 
 
The NCI defines both routine and expedited AE reporting.  Routine reporting is 
accomplished via the Adverse Event (AE) Case Report Form (CRF) within the study 
database.  For this study, routine reporting will include all Grade 3 and higher Adverse 
Events. 

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13.0 
RECORDS AND REPORTING 
 
13.1 
Categories of Research Records 
 
Research records for this study can be divided into three categories: 
 
1. 
Non-computerized Information: Pathology Narrative Reports and Surgical 
Reports. These forms are submitted through the Imaging Document System in the 
eRDES. 
 
2. 
Reference Labs’ required reports, and IROC RI (QARC) data: These data 
accompany submissions to these centers, which forward their review data 
electronically to the COG Statistics and Data Center. 
 
3. 
Computerized Information Electronically Submitted: All other computerized data 
will be entered in the COG Remote Data Entry System with the aid of schedules 
and worksheets (essentially paper copies of the RDE screens) provided in the data 
form packet. 
 
See separate Data Form Packet posted on the COG web site, which includes submission 
schedule. 
 
13.2 
CDUS 
This study will be monitored by the Clinical Data Update System (CDUS). Cumulative 
CDUS data will be submitted quarterly to CTEP by electronic means. Reports are due 
January 31, April 30, July 31 and October 31. This is not a responsibility of institutions 
participating in this trial. 
 
 
14.0 
SURGICAL GUIDELINES 
 
Evaluation of disease stage and sites of tumor involvement should reflect a synthesis, by the 
primary treating physician, of neuroradiological, neurosurgical, neuropathological, and clinical 
opinions available after all required pre-treatment studies have been completed. 
 
14.1 
Neurosurgical Procedure 
The goal of surgery is to re-establish CSF flow and to obtain a histologic diagnosis, to 
accurately state size, location, and extent of metastatic deposits, and to remove as much 
tumor as possible without causing further neurologic deficits. 
 
14.1.1 Types of Surgery 
A craniotomy is necessary to remove the bulk of the tumor, to re-establish CSF 
flow through the fourth ventricle, and to establish a tissue diagnosis. When 
feasible, an attempt will be made to perform a gross total tumor removal; if not 
feasible, an attempt will be made to remove as much tumor as possible without 
jeopardizing the patient. Eligible patients are strongly encouraged to undergo 
resection of residual tumor prior to radiation therapy. Biopsies alone, with no 
attempt at resection, may be associated with statistically worse survival and should 
not be done. No patient will be eligible for this study without a pathologic 

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diagnosis. The surgical procedure may be carried out in any position in which the 
neurosurgeon feels comfortable; i.e. sitting, prone, or park bench. 
 
14.1.2 Opening the Dura 
A wide dural opening should be made to allow for adequate exposure of the 
underlying brain. After opening the dura, the brain should be carefully inspected and 
the extent of tumor and any seeding noted and subsequently recorded. 
 
14.1.3 Leptomeningeal Examination 
The neurosurgeon should examine the regional leptomeninges to determine 
whether metastatic nodules are present in the arachnoid or whether the entire 
leptomeningeal surface is infiltrated with tumor. 
 
14.1.4 Hemostatic Agents in the Intra-operative Field 
Metallic clips should not be used for hemostasis, since these can cause MRI scan 
artifacts. Vanadium clips are preferable. 
 
Placement of gelfoam or oxidized cotton, etc., for maintenance of hemostasis 
should be noted, since these agents can also appear radio-dense in the postoperative 
scan. An attempt should be made to remove all foreign bodies from the operative 
site prior to closure. 
 
14.1.5 Pathology Studies 
As much tumor as possible should be sent for pathology and biology studies. Tissue 
should go directly to the institutional pathologist in saline for histologic diagnosis (see 
Neuropathology Guidelines, Section 15.0). 
 
14.1.6 Biology Studies 
Please note that the biology studies in this protocol request approximately 2 grams (2 
cc) of tissue, divided into fixed, snap frozen, and fresh tissue shipped in tissue culture 
media. Because the fresh tissue must remain sterile, please coordinate tissue handling 
with the pathology service and refer to tissue submission guidelines in Section 16.1. 
In many institutions, the responsibility for obtaining consent for biology studies will 
be the responsibility of the surgeons because it is necessary to obtain consent prior to 
surgery. 
 
14.1.7 Ancillary Neurosurgical Procedures 
Surgical procedures not directly involving tumor removal also will be reported. These 
include ventricular shunt placement, removal of subdural or intracerebral hematoma, 
or cyst aspiration. 
 
14.2 
Shunts 
Children whose preoperative MRI scans indicate the possibility of a medullo-
blastoma/PNET may need precraniotomy external CSF shunts (external ventricular drain 
(EVDs)), if they are primarily symptomatic because of tumor induced hydrocephalus. A 
third ventriculostomy can be used as an alternative to a shunt. 
 
14.3 
Assessment of Residual Tumor 
The assessment of presence or absence of residual tumor will be based primarily on 
post-surgical MRI, with due consideration to the neurosurgeon's assessment of residual tumor 

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from visual inspection of the tumor bed. Tumor unequivocally detectable on MRI or by 
surgical impression is considered residual tumor. 
 
14.3.1 Size of Post-Surgical Residual Tumor 
The size of residual tumor present after surgery will be based on post-surgical MRI as 
dileneated in Section 11, with due consideration to the neurosurgeon's assessment of residual 
tumor based upon visual inspection of the tumor bed.  
 
Measurements should include solid residual tumor or tumor cysts with enhancing walls only. 
Tumor cysts without enhancement in the wall should not be included in the measurements of 
residual.  
 
14.4 
Extent of Tumor Resection 
The extent of tumor resection will be based primarily on post-surgical MRI, with due 
consideration to the neurosurgeon's assessment of residual tumor from visual inspection of the 
tumor bed. Extent of tumor resection will be categorized as follows: 
 
Biopsy: An open surgical removal or closed (e.g., needle) removal of tissue for the purpose of 
establishing a pathological diagnosis, with tumor removal less than 10% of the total tumor 
mass. 
 
Partial: Removal of 10 - 49% of the tumor mass. 
 
Subtotal Resection: Removal of 50 - 95% of the tumor mass.  
 
Radical Subtotal Resection (Near Total): Removal of > 95% but less than 100% of the tumor 
mass. 
 
Gross Total Resection: No visible tumor is left at the time of surgery and this is confirmed by 
postoperative CT or MRI. 
 
14.5 
Imaging Confirmation of Extent of Resection 
All patients will have confirmation of the neurosurgical staging of the extent of resection with 
a postoperative MRI scan, with and without contrast. This scan should be carried out after 
surgery, preferably within 72 hours post surgery. 
 
14.6 
Peri-operative Corticosteroids 
Some patients with large tumors may require initiation of corticosteroid therapy preopera-
tively to reduce associated cerebral edema. If possible, this should not be started until after the 
initial MRI scan, since corticosteroids may affect tumor contrast enhancement. 
 
Usual corticosteroid dosage is 0.25 to 1 mg/kg/day of Decadron, in divided doses, every 
4-6 hours. 
 
Corticosteroids may be continued during the peri-operative period. Every attempt should 
be made to taper and discontinue corticosteroid therapy as soon as clinically feasible. 
 
 
 

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15.0 
PATHOLOGY GUIDELINES AND SPECIMEN REQUIREMENTS 
 
15.1 
Neuropathology Goals 
Precise histopathological diagnosis of tumors of primitive neuroepithelium. 
 
15.2 
Requirements for Handling Biopsy or Surgical Resection Tissue 
 
15.2.1 Light Microscopy  
A portion of tumor tissue should be fixed and processed in the usual manner.  
 
15.2.2 Biology Studies 
Two grams (2 cc) of tissue should be requested from the operating room for biology 
studied in addition to the tissue needed for pathologic diagnosis. Instructions for 
sending fixed and frozen tissue to the Biopathology Center and fresh tissue to Dr. 
Martine Roussel’s laboratory are provided in Section 16.0. 
 
15.2.3 Autopsy Tissue 
If necropsy tissue becomes available it should be submitted on APEC14B1.  
 
A complete autopsy report along with representative sections of residual tumor and/or 
metastases should be sent to the primary review pathologist. If available, snap frozen 
and fixed specimens of non-neoplastic cerebellum, cerebral cortex (frontal, parietal, 
occipital), basal ganglia, and pons should be sent to the Biopathology Center using 
guidelines in APEC14B1. These tissues are valuable controls for biology studies 
 
15.3 
Pathology Review Materials 
All patients must be centrally reviewed and the diagnosis consistent with Medulloblastoma 
or CNS PNET. Slides and pathology reports must be sent to the Biopathology Center for 
Pathology Review within 10 days of study enrollment. 
 
The neuropathologist at each participating institution at the completion of review of each 
case originating at his/her institution, should submit the following to the COG 
Biopathology Center for confirmation of the diagnosis by central pathology review.  
 
Required materials for continued inclusion in this study:  
Paraffin Blocks*: Submit representative paraffin embedded tissue blocks. Please label blocks 
or slides with the institutional surgical pathology number, block number and the patient's 
COG Patient ID Number. If blocks are unavailable, send all of the following slides of tumor: 
- Two (2) H&E stained slide of each representative lesion 
- Four (4) unstained slides from one representative tumor block 
 
Pathology Reports or Forms: Write the patient's COG patient identification number on all 
reports submitted to the BPC. 
- Institutional pathology report 
- Operative report 
- Electron Microscopy Report, if available. 
- Photographs of representative gross lesions, if available 
- Specimen transmittal form (with each shipment). 
 

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*Paraffin blocks will be retained at the Biopathology Center unless the institution requests 
their return. For cases requiring urgent return of paraffin blocks to the primary institution, 
the referring institution should contact the Biopathology Center to request that initiation of 
the review process be expedited or blocks be returned immediately after completion of 
central review. 
 
15.4 
Central Review Process 
The primary review pathologist, will be the reviewer of record. For any questions regarding 
review submission, contact the Biopathology Center at 614-722-2894. 
 
Shipping  
Send all materials for pathology review by regular mail or using the institution’s courier 
account to: 
COG Biopathology Center 
Nationwide Children's Hospital 
700 Children's Drive, WA1340* 
Columbus, Ohio 43205 
Phone: (614) 722-2865 
Fax: (614) 722-2897 
Email:BPCParaffinTeam@nationwidechildrens.org 
 
 
*Be sure to include the room number. Packages received without a room number may be 
returned to sender.  
 
 
 
 
16.0 
SPECIMEN REQUIREMENTS FOR BIOLOGY STUDIES 
 
16.1 
Optional Biology Studies 
Institutions are encouraged to enroll and submit specimens for APEC14B1.  
 
Fixed and snap frozen tissue is to be sent to the Biopathology Center and fresh tissue is to 
be sent directly to Dr.Roussel’s laboratory. 
 
16.1.1 Materials for Submission: 
The following materials must be sent to the Biopathology Center at the time of 
diagnosis for consenting patients: 
 
Snap Frozen Tissue: Submit as many 100-mg pieces of tumor tissue as possible. 
Wrap each piece of tissue in sterile foil and snap freeze in vapor phase liquid 
nitrogen (do not submerge the tissue in liquid nitrogen) within 10 minutes of 
removal. A minimum of > 0.5 cm2 is preferred. Label with the COG Patient ID 
Number, collection date and specimen type. 
 
Peripheral Blood: 5 cc of peripheral blood in a green top tube (sodium heparin) 
and 5 cc of blood in a purple top tube (EDTA) should be sent at room temperature 
any time before the initiation of therapy. Do not send if the patient has had a whole 
blood transfusion. Label blood with COG Patient number, collection date and 
specimen type. 
 

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Formalin Fixed Tissue: Submit 10 tissue sections fixed in 10% buffered formalin; 
two of which should be on positively charged slides for possible 
immunohistochemistry. Label with the Patient ID Number, surgical pathology ID 
number, block number, collection date and specimen type. 
 
Pathology Reports and Transmittal Forms. Send the institutional pathology report 
and include a specimen transmittal form with each shipment. Write the patient's COG 
Patient ID Number on all reports submitted 
 
The following materials must be sent to Dr. Roussel’s laboratory at the time of 
diagnosis: 
 
Fresh surgical tissue: Submit at least 0.5 grams (0.5 cc) sterile fresh tissue in 
tissue transport media packed on ice packs by overnight “First a.m.” delivery as 
described in 16.1.3. 
 
16.1.2 Shipment Of Fixed and Frozen Specimens 
Biological specimens (other than fresh tissue which is sent to Dr. Roussel) can be 
shipped to the BPC in a Specimen Procurement Kit. Specimen Procurement Kits 
must be shipped to the BPC, Monday through Thursday for delivery Tuesday 
through Friday since Saturday delivery is only available for fresh blood or bone 
marrow. The specimen procurement kit is constructed to allow shipment of frozen 
(on dry ice) and ambient temperature tissues in the same container. Dry ice may be 
placed in either compartment of the kit, but should not be put in both. This kit 
contains most of the supplies necessary for shipping specimens to the BPC. To 
request a specimen procurement kit, go to the BPC Kit Management link 
(https://ricapps.nationwidechildrens.org/KitManagement). 
 
Before specimens are placed into the Specimen Procurement Kit, they need to be 
placed in several layers of packaging. Package the frozen and room temperature 
specimens separately so that they can be placed into separate compartments of the 
kit for shipping. First place specimens into a biohazard envelope with absorbent 
material. Next, place the secondary biohazard envelope into the white Tyvek 
envelope. Expel as much air as possible before sealing each envelope 
 
Snap frozen tissue is shipped in one of the kit compartments filled with 
approximately 4 lbs. of dry ice. Layer dry ice on the bottom of the compartment until 
the compartment is about half full. Place the frozen tissue on top of the dry ice. Cover 
the tissue with more dry ice until the compartment is almost completely full. Set the 
foam lid on top of the kit compartment to secure specimens during shipment. 
 
Formalin fixed tissue and blood are shipped at room temperature in the second 
compartment of the kit. Place the specimens (already packaged in the biohazard and 
Tyvek envelopes) into the kit compartment. Insert the transmittal form, pathology 
report and any other required documents. Place the foam insert on top to secure 
specimens during shipment.  
 
Close the outer lid of the Specimen Procurement Kit and secure it with filament or 
other durable sealing tape. Print shipping label via the BPC Kit Management system 

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and attach to the top of the kit. Complete the dry ice label (UN 1845). Place the dry 
ice and Exempt Human Specimen labels to the side of the kit. 
 
Arrange for Federal Express pick-up through your usual institutional procedure or 
by calling 1-800-238-5355.  
 
 
Send the Specimens to: 
 
Biopathology Center 
Nationwide Children’s Hospital 
700 Children’s Drive, Room WA1340* 
Columbus, OH 43205 
Phone: (614) 722-2865 
FAX: (614) 722-2897  
Email: BPCBank@nationwidechildrens.org 
 
*The room number is required. Packages not listing the room number will 
be denied and returned to the sender. 
 
16.1.3 Shipment Of Fresh Specimens 
Complete the Specimen Transmittal Form on the RDE and print a copy to send 
with the specimen. Label specimens with COG patient identification and the BPC 
Number (if available). Fax a copy of the transmittal form to Dr. Marine Roussel at 
(901) 595-2381. Transport of fresh primary brain tumors should abide by the 
following guidelines to maximize the viability after transport. First, all fresh 
tumors should be sent ON ICE OR ICE PACKS. Also, while RPMI media is 
acceptable, DMEM-F12 with 10% FBS and Antibiotics and Antimycotics is far 
preferable. Please contact the Roussel Lab at martine.roussel@stjude.org to obtain 
frozen 
aliquots 
of 
this 
media. 
Also, 
please 
notify 
the 
lab 
(martine.roussel@stjude.org, li.lu@stjude.org, barbara.rhodes@stjude.org) 
as soon as possible that a tumor is resected or ready for shipment; this allows 
time to make the necessary preparations for specimen processing. Any further 
questions should be addressed to martine.roussel@stjude.org .  
 
Ship specimens ON ICE PACKS, PRIORITY OVERNIGHT for first a.m. 
delivery. Specimens may be sent 7 days a week to the address below: 
 
 

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Martine F Roussel, PhD 
Member 
Endowed Chair in Molecular Oncogenesis 
Co-Leader of the Cancer Genetics, Biochemistry and Cell Biology Cancer Center 
Program 
Department of Tumor Cell Biology, MS# 350  
Danny Thomas Research Center, D-5006C St Jude Children's Research Hospital  
262, Danny Thomas Place Memphis, TN, 38105 
Phone: (901) 595-3481 
Fax: (901) 595-2381 
E-mail: martine.roussel@stjude.org 
 
 
Arrange for Federal Express pick-up through your usual institutional procedure or 
by calling 1-800-238-5355.  
 
16.2 
Specific Aims 
Biology studies are critical to the development of more effective and less toxic 
therapies and for the purpose of stratifying patients to the most appropriate 
treatment regimens. In the period since this clinical trial was first proposed, extensive 
collaboration between members of the ACNS0332 biology group and colleagues has 
clearly defined four consensus molecular subtypes of medulloblastoma, namely Wnt-
driven, Sonic Hedgehog (Shh)-driven, Group 3 and Group 4. Within these molecular 
subtypes, additional candidate prognostic indicators are emerging and some previous 
candidates have been disproven as reliable biomarkers of outcome.  
 
Genomic analyses have also shown that sPNETs are clearly different than 
medulloblastomas. Approximately 1/3 of sPNETs are genomically aligned with high grade 
gliomas raising the possibility that in the future, some sPNET patients should perhaps no 
longer be treated per protocols that have been optimized for medulloblastoma patients. In 
other instances, sPNET patients were shown to have genomic profiles consistent with 
various medulloblastoma molecular subclasses, atypical teratoid rhabdoid tumors 
(ATRTs), or low grade astrocytomas. In several of these instances, re-analysis of tissue 
from the patient in question revealed pathognomonic mutations (e.g, INI1/hSNF5 gene in 
ATRT).  
 
The specific aims of the biology studies are: 
1. To determine the molecular subtype of each medulloblastoma patient. 
2. To describe the genomic profiles of sPNET patients in the context of >800 reference 
samples from pediatric brain tumor patients  
3. To confirm prognostic indicators of therapy failure in high-risk medulloblastomas 
4. To identify prognostic indicators of therapy failure in high-risk medulloblastomas 
5. To generate patient-derived resources that help prioritize targeted therapies for 
future clinical trials 
6. Tissue banking 
Tissue utilization will be prioritized in order of the Specific Aims. 
 
 

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16.3 
Aim 1. To determine the molecular subtype of each medulloblastoma patient. 
 
At the 2013 Global Summit on Pediatric Brain Tumors, an interdisciplinary internationally 
renowned group of experts reached consensus that 1) the next WHO guidelines should 
reflect the four established molecular subclasses of medulloblastoma as primary criteria 
for diagnosis, 2) that the concordance between subgroup classification by 850K Illumina 
analyses or Nanostring platform was superior to immunohistochemistry and on par with or 
superior to gene expression profiling, 3) that 850K Illumina analyses were least susceptible 
to batch effects and were more robust than competing platforms when performed on 
formalin fixed paraffin-embedded (PPFE) tissue. Since snap frozen tissue has been 
submitted on about 1/3 of patients enrolled in ACNS0332 and PPFE tissue was submitted 
on nearly 100%, the ACNS0332 biology group recommended using PPFE unstained slides 
as the source of DNA for evaluation on the 850K Illumina platform as the primary means 
for molecular subclassification. This will be performed first on a test batch, then on tissue 
from 3-4 unstained slides for all ACNS0332 patients. In rare instances, where tissue was 
not submitted in any form, attempts will be made to retrieve tissue from the institutions 
involved in patient enrollment. 
 
For this aim, the 850K data set from each patient will be compared to a reference set of 
hundreds of pediatric brain tumor specimens. Those cases that clearly fall within one of 
the four established medulloblastoma subclasses will be designated as such. Outliers will 
be identified and best efforts will be made using remaining tissue samples to clearly define 
the correct molecular subclass of medulloblastoma, or if indicated, an alternative diagnosis. 
In such cases, the final determination will be made by the biology group in consultation 
with study neuropathologists. The final designations will be the basis for reporting 
molecular subclass results. In the event that the neuropathologists and biologists conclude 
that a patient has a disease that is not eligible for ACNS0332, appropriate eligibility actions 
will be taken by the study chair. 
 
The biology committee will meet and review all cases in the context of molecular subclass, 
age, 850K data and other available information to determine whether additional molecular 
studies are required for proper molecular diagnoses prior to tissue being released for other 
biology studies described below. 
 
16.4 
Aim 2. To describe the genomic profiles of sPNET patients in the context of >800 
reference samples from pediatric brain tumor patients  
 
In the 1980s, the World Health Organization adopted a diagnostic classification system 
that “lumped” all primitive neuroectodermal tumors of the central nervous system. Using 
genome wide analyses, two competing hypotheses have recently emerged. The first, 
advanced by Dr. Annie Huang, suggests that about 1/3 of sPNETs are molecularly similar 
to high grade gliomas and very distinct from medulloblastomas. The remaining 2/3 of 
patients classify into 4 molecular subtypes by cluster analyses. In unpublished data, Stefan 
Pfister analyzed over 50 cases diagnosed as sPNETs in the context of approximately 800 
pediatric brain tumor specimens. Like Dr. Huang, Dr. Pfister’s group observed that about 
1/3 of these cases cluster with high grade gliomas. The remaining cases, however, do not 
cluster together but rather cluster individually or in small groups with various molecular 
subclasses of medulloblastoma, ATRTs, low grade gliomas, or other central nervous 
system malignancies. Dr. Pfister has raised the question of whether an entity of sPNET 
exists. 
 

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Neuropathologists frequently experience difficulty in distinguishing sPNET from high 
grade glioma at the time of diagnosis – and often tumors diagnosed as one of these recur 
with predominant features of the other. We hypothesize that a subclass of tumors exist that 
have both glioma and PNET features, that respond poorly to either glioma- or sPNET-
therapy, and may represent a biphenotypic or stem-cell origin. We further wish to 
distinguish between the two hypotheses stated above for the remaining cases – and 
entertain a third possibility in which some of the sPNET cases share genomic signatures 
with medulloblastoma or other pediatric brain tumors and there are also distinct subset(s) 
of sPNET tumors. To accomplish this, we will generate a reference data set from 
approximately 100 sPNET cases submitted to ACNS0332 using the 850K Illumuna 
platform as described in Aim 1. These data, data from approcximately 200 
medulloblastoma cases from ACNS0332 and approximately 800 reference pediatric brain 
tumor cases analyzed by Dr. Pfister’s group will be made available to 3 groups of scientists 
skilled in genomic analyses of pediatric brain tumors (Pomeroy/Cho; Taylor/Huang; and 
Pfister). The ACNS0332 biology committee will meet with these investigators to review 
analysis methods, findings, similarities, and discrepancies. The consensus will be the basis 
for subgroup analyses of patient outcomes for those patients enrolled as sPNET patients in 
ACNS0332.  
 
16.5 
Aim 3. To confirm prognostic indicators of therapy failure in high-risk 
medulloblastomas 
We hypothesize that certain children can be prospectively identified as patients who will 
likely fail therapy even with 36 Gy craniospinal irradiation, combination chemotherapy, 
and augmentations such as carboplatin radiosensitization or isotretinoin. If this hypothesis 
is correct, children with a very high risk of death due to medulloblastoma may be 
considered for therapeutic options other than typical high risk therapeutic protocols in the 
future. 
 
Certain gene amplifications or deletions, particularly in the context of molecular subclass 
designation, are evolving as candidate prognostic indicators based on very large genomic 
studies of previously treated patients. Likewise, mutations in certain genes may confer 
prognostic information. Amplifications, deletions and sequence mutations can all be 
determined by multiple different methods, can be determined on FFPE tissue, and are not 
subject to “batch effect” variation.  
 
In some cases, prognostic indicators have been validated in large “test sets” after being 
identified in large “training sets”. Unfortunately, none of these studies were prospective 
and most involved “community” patient populations, meaning that treatment and data 
collection were not standardized. Even so, it is difficult to find survivors with some of these 
mutations across multiple data sets and raises the possibility that we will be able to identify 
children who are at high risk of failing therapeutic regimens such as those used in 
ANCS0332. We will use a combination of gene expression analyses, exome sequencing, 
targeted candidate sequencing, 850K methylation analyses, immunohistochemistry, and 
other methods to screen for and validate potential prognostic indicators and potential 
variants from existing medulloblastoma molecular classifiers. 
 
 
16.6  
Aim 4: To identify candidate prognostic indicators of therapy failure in high-risk 
medulloblastomas 
It is possible that additional important DNA- or RNA-based prognostic markers will be 
identified in this study. Because of statistical considerations of multiple comparisons and 

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small genetically defined prognostic subgroups, the only candidate prognostic indicators 
that will be tested prospectively are those listed in section 16.5. Once Aims 1-3 are 
completed to the ANCS0332 biology group’s satisfaction, then data sets and remaining 
unstudied tissue will be provided to researchers for the purpose of identifying additional 
candidate prognostic indicators or other biologic features that provide insight into 
medulloblastoma genesis or behavior. 
 
16.7 
Aim 5: To generate patient-derived resources that help prioritize targeted therapies 
for future clinical trials 
Approximately 20 genetically engineered mouse models of medulloblastoma have been 
generated worldwide to date. Unfortunately, nearly all of these represent Shh-driven 
medulloblastomas and there are few models that represent other types of medulloblastoma 
and none that represent sPNET. Due to medulloblastoma incidence rates, it is possible for 
COG to run a major Phase III study about once every 6-9 years. For this reason, it is critical 
to prioritize candidate therapeutics in the best available mouse models before initiating 
human clinical trials. Through ACNS0332, ACNS02B1 and related studies, over 50 
malignant pediatric brain tumors have been orthotopically transplanted into the brains of 
immunocompromised mice. Approximately half of these have generated tumors in mice 
that survive serial transplantation and are suitable for non-clinical in vivo pharmacology 
studies. Though far less successful, attempts to generate stable cultures of these cells under 
serum free conditions has yielded a small number of cell lines that are suitable for in vitro 
studies. All of these patient derived resources are currently being genomically analyzed 
and compared to the initial specimen from the patient of origin.  
 
Generation of these resources will continue under ACNS0332 with the ultimate goal of 
generating multiple mouse models that represent each of the major medulloblastoma 
molecular subtypes to the extent that each grows under these conditions. All patient-
derived resources are made available to researchers world-wide in a manner consistent with 
informed consent. Investigators using the models or cell lines are encouraged to share data 
with the COG Central Nervous System and New Agents committees as early as reasonable 
to enable the data to be considered in clinical trial strategy. 
 
16.8 
Aim 6. Tissue Banking 
Snap frozen and fixed tissue specimens that are not used for the experiments described 
above will be banked through the COG Biopathology Center as described in protocol 
ACNS02B3. In addition, primary cultures of enriched medulloblastoma cells derived from 
patients in this study will be cryopreserved and stored for future use.  
 
 
17.0 
IMAGING STUDIES REQUIRED AND GUIDELINES FOR OBTAINING 
 
 
 
 
 
 
 
 
Timing of protocol therapy administration, response assessment studies, and surgical 
interventions are based on schedules derived from the experimental design or on established 
standards of care. Minor unavoidable departures (up to 72 hours) from protocol directed therapy 
and/or disease evaluations (and up to 1 week for surgery) for valid clinical, patient and family 
logistical, or facility, procedure and/or anesthesia scheduling issues are acceptable per COG 
Administrative Policy 5.14 (except where explicitly prohibited within the protocol).  

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17.1 
Whole Brain MRI With and Without Contrast  
A pre-operative MRI scan of the brain with and without contrast is required. NOTE: CT 
scans are NOT sufficient for study eligibility since radiation therapy planning and 
response will be based on MRI scans only. 
 
To document the degree of residual tumor postoperative cranial MRI with and without 
contrast must be done. Post-operative head MRI scan with and without contrast (should be 
done within 72 hours post-surgery). For patients who undergo stereotactic biopsy only, a 
post-operative MRI is not required. For patients with M2 and M3 disease, a post-op MRI 
is strongly encouraged, but not mandatory. Patient eligibility by imaging criteria requires 
demonstration of residual tumor > 1.5 cm2 or metastatic disease. 
 
 (Note: all quoted slice/skip thicknesses are maximal; thinner slices/skip are encouraged, 
[and may be necessary if the lesion imaged is very small] allowing for signal to noise and 
cross talk limitations depending on the particular platform employed)  
 
Required sequences: 
1. Sagittal T1 localizer; 4 mm skip 0.4 mm 
2. Axial FSE T2; 4 mm, skip 0.4 mm 
3. Axial T2 FLAIR; 4 mm skip 0.4 
4. Axial diffusion; 4-5 mm skip 0 (single shot, matrix 128 x 128 or 128 x 192, 
B=1000) 
5. Axial T1; 4 mm skip 0.4 mm  
6. Axial T1 with contrast; 4 mm skip 0.4 mm  
7. Sagittal T1 with contrast; 4 mm skip 0.4 mm  
8. Axial T2 FLAIR with contrast; 4 mm skip 0.4 
 
Optional sequences  
Precontrast : 
1. Axial susceptibility weighted imaging (SWI) or 
gradient echo (susceptibility sequence); 4-5 mm skip 1-2 mm. TE=20, flip angle =20. 
2. Sagittal or coronal FSET2; 4 mm skip 0.4 mm, depending on tumor 
configuration/orientation 
3. Axial T2 FLAIR; 4 mm skip 0.4 
4. Diffusion Tension Imaging (DTI) sequence: 12 – 30 direction (depending upon scanner) 
2.5-5 
mm skip 0, b=1000 
Post contrast : 
1. Coronal T1 : 4mm skip 0.4 
2. T1-weighted gradient echo volume sequence (SPGR or equivalent) 
 
Notes: 
1. DO NOT INTERLEAVE T1 weighted sequences 
2. Flow compensation should not be used (or al least not on all T1 enhanced sequences) 
3. Fat Saturation not necessary 
 
17.2 
MR Spine With and Without Contrast 
Spinal MRI (T-1 weighted imaging with and without gadolinium) is required within 28 
days of surgery if done post-operatively and within 10 days of surgery if done pre-
operatively. If an MRI scan is performed within 10 days prior to surgery, than only a post-

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contrast examination is necessary. For posterior fossa tumors, pre-operative MRI scans are 
preferred because surgically-induced inflammation/blood can be difficult to distinguish 
from tumor.  
 
If there is significant motion artifact and/or hemorrhage, then the scan is not evaluable and 
must be repeated or the patient is not eligible for study.  
1. Whole spine sagittal T1; 3 mm skip 0 – 0.3 mm. 
Technical notes: 
- Phase direction AP, frequency direction SI 
- Acquire 2 separate acquisitions (one cervical and upper thoracic, the second lower 
thoracic and lumbosacral) to optimize placement of presaturation pulse. 
- Place anterior saturation pulse close to the anterior margin of the spinal column - to 
minimize motion artifacts from chest/abdomen. 
- Pixel size 1 mm2 or less (example: for 26 cm FOV, use 256 x 256 matrix) 
- Keep TE to minimum (<15 msecs) 
- Do not use fat saturation 
2. Axial T1 images through the entire spine; 4-5 mm thick, skip 1-2mm. 
Technical notes: 
- Phase direction RL, frequency direction AP 
- Keep TE to minimum (< 15 msecs) 
- DO NOT INTERLEAVE 
 
For primary tumors of the spinal cord, add: 
1. Whole spine sagittal T2; 3 mm skip 0 mm. 
Technical notes: 
- Can keep Phase direction AP, frequency direction SI, with anterior saturation pulses; or 
switch phase direction SI, frequency direction AP, with inferior and superior 
saturation pulses if that produces better images (less CSF pulsation artefacts) 
- Pixel size 1 mm2 or less (example: for 26 cm FOV, use 256 x 256 matrix) 
2. Axial FSE T2, 4-5mm skip 0-1 mm, through tumor 
NOTE: 
In the routine evaluation for subarachnoid metastatic dissemination from brain tumors to 
the spine: 
1. High quality T1 images are essential - without artifacts from physiologic motion 
(cardiac, 
respiratory) or from CSF pulsation. 
2. T2 weighted sequences (sagittal or axial) are not needed. They are optional. 
 
17.3 
Central Review 
All patients will have central neuroradiological review. Submit the following studies with their 
corresponding radiology reports to the address below.  
 
Pre-operative Cranial MRI with and without contrast  
 
Post-operative Cranial MRI with and without contrast  
 
Pre OR Post-operative Spinal MRI with contrast  
 
Cranial and Spinal MRI with and without contrast at the end of Radiation Therapy 
(Week 10 Prior to Start of Maintenance) 
 
Cranial and Spinal MRI with and without contrast 4 weeks following the end of 
Maintenance or best response if relapse during therapy 
 
Cranial MRI at progression (relapse) with and without contrast 
 
Spinal MRI at progression (relapse) with contrast 
 
Copies of all Operative Reports  

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Submission of Diagnostic Imaging data in digital format is required. Digital files must be 
in DICOM format. These files can be submitted via sFTP. Information for obtaining an 
sFTP account and submission instructions can be found at www.QARC.org. Follow the 
link labeled digital data. Alternatively, if sFTP is not feasible, the imaging may be burned 
to a CD and mailed to IROC RI (QARC) at the address below. Multiple studies for the 
same patient may be submitted on one CD; however, please submit only one patient per 
CD. Sites using Dicommunicator may submit imaging via that application. Contact IROC 
RI (QARC) with questions or for additional information. 
 
Imaging studies submitted on CD should be sent to:  
IROC RI (QARC) 
Building B, Suite 201 
640 George Washington Highway,  
Lincoln, RI  02865-4207 
Phone: (401) 753-7600 
Fax: (401) 753-7601 
 
 
18.0 
RADIATION THERAPY GUIDELINES 
 
 
 
 
 
 
 
 
 
18.0.1 General Guidelines 
Radiation therapy for patients on COG protocols can only be delivered at approved COG RT 
facilities (see COG’s Policies and Procedures). Contact IROC RI (QARC) for questions or 
further information. 
 
Three-dimensional image-based radiation therapy treatment planning and computer-controlled 
delivery systems (conformal radiation therapy) should improve disease control and functional 
outcome for infants with brain tumors. The tools necessary to perform conformal radiation therapy 
have become widely available, thus sufficient experience has been gained to develop guidelines for 
use by investigators who treat these patients. The allowed treatment methods are restricted to 
conformal or intensity-modulated radiation therapy using photons or proton beam therapy and 
electronic data submission is required. 
 
For treatment planning and delivery all collaborating investigators should have general anesthesia 
and/or deep-sedation capabilities as needed, and customized immobilization that provides for 
treatment that is both reproducible and safe. 
 
18.0.2 Credentialing Requirements 
Radiation therapy will be administered using protons or photons. Required photon methods include 
3D-conformal radiation therapy (3D-CRT), intensity modulated radiation therapy (IMRT) and 
craniospinal radiation therapy. Centers participating in this protocol using 3D-CRT are required to 
complete the 3D benchmark; those using IMRT and not previously credentialed for use of IMRT 
Timing of protocol therapy administration, response assessment studies, and surgical interventions 
are based on schedules derived from the experimental design or on established standards of care. 
Minor unavoidable departures (up to 72 hours) from protocol directed therapy and/or disease 
evaluations (and up to 1 week for surgery) for valid clinical, patient and family logistical, or 
facility, procedure and/or anesthesia scheduling issues are acceptable per COG Administrative 
Policy 5.14 (except where explicitly prohibited within the protocol).  

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in COG trials must successfully irradiate IROC Houston’s IMRT head and neck phantom and must 
update their Facility Questionnaire on IROC Houston’s website. All centers must have completed 
the IROC craniospinal radiation therapy benchmark. All centers participating in this protocol must 
complete the IROC CT/MR image fusion benchmark. Benchmark materials may be obtained from 
IROC RI (QARC) (www.irocri.qarc.org) and must be submitted and approved before case reviews 
can be finalized. Use of both scanned and scattered proton techniques are allowed, but each proton 
beam line used to treat patients on this study must be credentialed prior to clinical trial use by IROC 
Houston. For information regarding the IMRT phantoms and proton credentialing, please contact 
IROC Houston (http://rpc.mdanderson.org/rpc). 
 
18.0.3 Guidelines and Requirements for the Use of IMRT 
Investigators using IMRT will be required to comply with the guidelines developed for the use of 
IMRT in National Cancer Institute sponsored cooperative group trials. These guidelines are 
available through www.qarc.org. These guidelines require that the protocol explicitly state their 
requirements and methods for localization and immobilization; the use of volumetric imaging; 
target and organ motion management; nomenclature, definitions and rationale for targets and 
organs at risk; target volume coverage and normal tissue dose constraints; effects of heterogeneity 
in tissues; and quality assurance. 
 
18.0.4 Guidelines and Requirements for the Use of Proton Beam Therapy 
Investigators using proton beam therapy will be required to comply with current guidelines for the 
use of protons in National Cancer Institute sponsored clinical group trials. These guidelines are 
available through www.qarc.org.  
 
18.1 
Timing of Radiation Therapy 
All patients shall receive irradiation to the craniospinal axis followed by a boost to the 
posterior fossa. All patients shall begin radiation treatments after registration on study and 
within 31 days of definitive surgery.  
 
18.2 
Equipment 
Use of either photons or protons is allowed on this study. If IMRT is used, photon energy 
should be no greater than 10 MV. 
Equipment/Method 
Photons 
(any energy) 
IMRT 
(4-10MV) 
Protons 
Linear Accelerator 
X 
X 
 
Proton Beam  
 
 
X 
 
18.2.1 Modality 
X-rays with a nominal energy ≥ 4 MV. Craniospinal axis irradiation is best done 
with x-rays between 4-6 MV. The boost volume may be treated with a nominal 
energy ≥ 4 MV, as long as dosimetric constraints are accomplished. Electron 
beams of suitable energy to treat the spinal cord may be allowed if prior 
documentation has been reviewed and approved by IROC RI (QARC). Proton 
beams may be used by credentialed centers and will require digital submission of 
treatment planning data to IROC RI for QA review. 
 
18.2.2 Calibration 
The calibration of therapy machines used in this protocol shall be verified by IROC 
Houston (formerly the RPC). 
  

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18.2.3 Equipment 
Patients enrolled on this study must be treated using conformal radiation therapy 
treatment planning and delivery techniques at a minimum for the primary. IMRT 
or Proton Therapy will be allowed if appropriate credentialing requirements have 
been met.. All patients must be treated on isocentric machines. All machines must 
have a minimum source-to-axis distance (SAD) of 80 cm. Treatments may be 
given with fixed SSD techniques. If proton beams are used, prior approval from 
the study radiation therapy coordinator is necessary. For treatment to be conformal 
the following criteria must be met:  
 
• 
Three-dimensional imaging data (CT or MR) are acquired with the patient 
in the treatment position. Three dimensional treatment planning software 
must be used in this trial. Allowable treatment techniques are 3D 
conformal, IMRT, and proton therapy provided that all credentialing 
requirements have been met for the technique in use. 
• 
Image data are used to delineate and reconstruct a gross target volume, 
clinical target volume, planning target volume, and normal or critical 
structures in 3-dimensions. 
• 
Radiation beams can be freely oriented in 3-dimensions for both the 
planning and delivery process, and structures traversed by the beam can 
be visualized with the eye of the beam. 
• 
The distribution of dose relative to the target volume or any structure is 
computable on a point-by-point basis in 3-dimensional space. 
• 
Institutions not equipped to perform conformal radiation therapy 
according to these guidelines should refer the patient to a participating 
COG institution with proven capabilities to comply with the outlined 
parameters. 
 
18.3 
3-D Target Volume and Organ At Risk Definitions 
The definitions for the target volumes and treatment dosimetry will adhere as closely as 
possible to the ICRU Report 62 definitions whenever possible. 
 
RT volumes for this study will be determined by the collective information that delineates 
the extent of disease at the time of diagnosis and prior to radiation therapy. These guidelines 
are meant to be comprehensive and include all anticipated treatment scenarios. If for any 
reason the following guidelines do not match the characteristics of a given patient, the 
treating physicians are asked to contact the radiotherapy coordinator(s).  
 
18.3.1 Gross Tumor Volume (GTV) 
The GTV includes all gross residual tumor and/or the walls of the resection cavity 
at the primary site based on the initial imaging examination that defines the tissues 
initially involved with disease anatomically and the post-operative and pre-
irradiation neuroimaging examinations that identify residual disease and the tumor 
bed. 
 
In accordance with ICRU-50, the Gross Tumor Volume (GTV) is defined as the 
contrast-enhanced tumor in the Brain and the Spine, unless the preoperative tumor 
is predominantly non-enhancing, in which case this represents the preoperative 
tumor extent as defined by the most informative MR imaging sequence.  

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18.3.2 Clinical and Photon Planning Target Volumes (CTV and PTV) 
The CTV includes the GTV with an added margin that is meant to treat subclinical 
microscopic disease and is anatomically confined (i.e., the CTV is limited to the 
confines of the bony calvarium and tentorium where applicable). For this study, 
multiple CTVs will be treated.  
 
The Clinical Target Volume1 (CTV1) is the entire craniospinal axis. The 
craniospinal axis Planning Target Volume (PTV1) is institution-defined according 
to immobilization techniques and their inherent setup uncertainties. The margin 
defining the PTV may range from 0.3 cm to 1.0 cm. For the Craniospinal volume, 
a larger PTV1 margin should be considered due to inexactness of repositioning for 
the spinal fields.  
 
Although conventional simulation will be allowed for the craniospinal axis PTV1 
treatments, it should be noted that CT based or 3D treatment planning for 
craniospinal axis irradiation may offer advantages over conventional simulation 
methods. (Reference Mah Int J Radiat Oncol Biol Phys 2000). A better 
appreciation of the cribriform plate and middle cranial fossa can be gained with a 
CT simulation. In most circumstances, the same CT simulation data used for 
planning the craniospinal axis RT can be used to plan the 3-D conformal boost. 
 
If conventional simulation and treatment planning are used to treat the craniospinal 
axis, the cranial dosimetry from that part of the treatment course shall be included 
in the 3-D conformal plan for the target volume boost, including the DVHs. 
 
Whole Brain (CTV1): The whole-brain field shall extend anteriorly to include the 
entire frontal lobe and cribriform plate region. Coverage of the CTV takes 
precedence over protection of the lenses or eyes. Inferiorly, the CTV1 shall be at 
least 0.5 cm below the base of the skull at the foramen magnum. PTV1 should be 
defined to account for setup error. The radiation fields to cover this target volume 
should follow established guidelines for cranial irradiation in medulloblastoma. 
There will be a junction with the spinal field.  
 
Spine (CTV1): The spinal target volume will be the entire thecal sac. The field to 
cover this volume should extend laterally on both sides to cover the recesses of the 
entire vertebral bodies, with at least a 1 cm margin on either side. The superior 
border will be the junction with the whole brain field. The inferior border of the 
treatment volume will be placed after review of the spinal MRI. The border will 
be 2 cm below the termination of the subdural space. This will extend at least to 
the inferior border of the second sacral segment (S2-S3 interspace), but may be as 
low as the inferior border of S4. If this cannot be accomplished in a single field, 
there will be a junction between the two spinal fields. PTV1 should be defined to 
account for setup error.  
 
For proton therapy, the spinal target volume will include the vertebral bodies for 
skeletally immature patients to minimize the risk of unequal vertebral 
growth.  Skeletal maturity can be estimated with a wrist x-ray to determine bone 
age.  Dose to the thyroid gland can be attenuated by allowing incomplete coverage 
of the lower cervical vertebra.  The spinal target volume in skeletally mature 

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patients will include the spinal subarachnoid space with a margin of 3-5 mm into 
the vertebral body to allow for inter-fraction set up variation. 
 
The dose prescription for the brain and spine will be daily fractions of 1.80 Gy. 
See Table 18.4 for doses required by initial disease stage and early RT response. 
 
Posterior Fossa Boost (CTVPF): This volume refers to patients with posterior fossa 
primaries. 3D-based treatment planning is mandatory for these volumes. IMRT is 
allowed for the PTVPF. The CTVpf should encompass the entire posterior fossa. 
The posterior fossa must be defined on the planning CT scan. It is strongly 
recommended that a sagittal and or coronal MRI be used to assist in identification 
of the position of the tentorium. The CTVPF extends inferiorly from C1 vertebral 
canal through the foramen magnum, laterally to the bony walls of the occiput and 
temporal bones and superiorly to the tentorium cerebelli. Generally, the sigmoid 
sinuses define the lateral-superior extent of the bony confines of the posterior fossa 
that attach contiguously to the tentorium above. The folia of the cerebellum and 
the anterior border of the brainstem and midbrain bound the CNS contents of the 
posterior fossa. The Planning Target Volume (PTVPF) is a 0.3cm to 0.5cm margin 
around the CTV to account for day-to-day setup variation. The PTVPF should not 
extend beyond the external bony confines of the skull except at the foramen 
magnum to C1-C2. The PTVPF should extend anteriorly to the posterior clinoids 
(the pituitary is not included) and inferiorly to the C1-C2 junction. In treatment 
planning, shielding of critical structures should be attempted. At least 95% of the 
prescription study dose of 55.8 Gy must encompass at least 95% of the PTVPF (the 
posterior fossa) as shown by DVH. No part of the PTVPF should receive less than 
50 Gy. Treatment techniques for the PTVPF may include parallel opposed laterals 
or other 3D CRT methods to limit dose to the supratentorial brain, hypothalamus, 
pituitary or middle ear. 
 
Metastasis Site Boost (CTVM):  
Patients with M1 disease will receive no additional boost. 
Patients with M2 disease (intracranial subarachnoid disease) will receive boosts to 
areas of supratentorial or posterior fossa metastatic disease.  
Patients with M3 disease (spinal deposits of disease) are subdivided into those with 
diffuse disease and those with focal disease.  
Diffuse spinal disease is defined as radiographically visible multiple sites of 
disease in each of at least 3 out of 4 spinal regions (i.e., cervical, thoracic, lumbar 
or sacral). If there is diffuse involvement of the spine, the entire spine will be 
treated in the boost volume.  
The CTVm margin for boosting metastatic deposits will be 0.5 to 1.0 cm 
encompassing the lesion within the anatomic compartment. Another 0.3 to 0.5 cm 
margin will be added for the PTVM. Field shaping may be conformal and 
consideration may be given for normal organ sparing and abutment of other high 
dose or boost sites. 
18.3.2.1 
Proton Definitions for GTV, CTV and PTV 
• 
GTV is the same for protons and photons. 
• 
CTV is the same for protons and photons. 

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• 
PTV is the same as photons and will be used to select the 
appropriate beam size and beam arrangements to achieve lateral 
coverage of the targeted volume and to minimize heterogeneity. The 
PTV will not be used to determine the distal range for the individual 
proton beams but will be used to report dose according to ICRU 
Report-78. The proton distal target margin will be determined per beam 
using the guidelines in Section 18.4.5. 
 
18.3.3 Organs at Risk (OAR) 
The following organs must be defined for 3-D conformal radiation therapy or 
IMRT planning:  
• 
Supratentorial brain (left and right)  
• 
Cochlea (left and right)  
• 
Hypothalamus/pituitary  
• 
Eyes (left and right)  
• 
Optic nerves (left and right) 
• 
Optic chiasm 
• 
Cervical spinal cord (foramen magnum to C2) 
• 
Skin (non-specified tissues)  
 
A Web based atlas with normal organ contours is available at www.QARC.org 
under Resources. 
  
18.4 
Dosimetry 
 
18.4.1 Prescription Point 
The prescription point for the neuroaxis (PTV1, whole brain and spine) is at or near 
the center of the targets. For the brain this may be a point other than the central 
axis. Consideration should be made to using a point midway of the biparietal 
diameter. The spinal axis dose should be prescribed to the anterior aspect of the 
spinal canal. In many cases, the depth of the anterior spinal canal will vary by 
vertebral level. An average depth may be used that keeps the dose uniformity 
within the constraints defined below. For the posterior fossa and limited target 
boost volumes, the doses shall be prescribed in order to have at least 95% of the 
55.8 Gy isodose covers at least 95% of the respective planning target volumes. The 
minimum dose to the PTVPF, PTVST or PTVboost shall not be < 50 Gy. 
 
18.4.2 Dose Definition 
Dose is to be specified in Gray (Gy)-to-muscle. For proton beam, the absorbed dose 
shall be specified in CGE, which is the same as ICRU 78 DRBE using a standard 
RBE of 1.10 with respect to water. 
 
18.4.3 Prescribed Dose and Fractionation 
36.0 Gy CSRT (PTV1) 
55.8 Gy Posterior fossa boost, cumulative dose (PTVPF or PTVST) 
Patients with M1 disease will receive no additional boost. 
Patients with M2 disease (intracranial subarachnoid disease) will receive boosts to 
areas of supratentorial or posterior fossa metastatic disease. (Table 18.4) 

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Patients with M3 disease (spinal deposits of disease) are subdivided into those with 
diffuse disease and those with focal disease. Patients with diffuse disease will have 
their entire spine boosted to 39.6 Gy. (Table 18.4) 
 
Table (18.4) Radiation Dose for Craniospinal Axis Radiation Therapy 
 
M-Stage 
at 
Diagnosis 
CSRT 
Dose 
Metastasis location 
Dose 
to 
PTVM 
Total 
Dose 
to PTVM 
Dose 
to 
PTVPF/ 
PTVST 
Total 
Dose 
to 
PTVPF 
/PTVST 
M0, M1 
36 Gy 
None 
NA 
NA 
19.8 Gy 
55.8 Gy 
M2  
36 Gy 
Intracranial 
19.8 Gy 
55.8 Gy 
19.8 Gy 
55.8 Gy 
M3 
36 Gy 
Diffuse 
3.6 Gy 
39.6 Gy 
19.8 Gy 
55.8 Gy 
Focal, above terminus 
of spinal cord 
9 Gy 
45 Gy 
19.8 Gy 
55.8 Gy 
Focal, below terminus 
of spinal cord 
14.4 Gy 
50.4 Gy 
*note: if M3 and has intracranial metastatic disease, follow schema for M2 cranial dosage 
as well 
 
18.4.4 Dose Fractionation 
Patients will receive one fraction of 1.8 Gy per day, five days per week. 
 
18.4.5 Dose Uniformity 
The dose variations in each target volume shall be within +10%, -5% of the 
prescription-point dose. This applies to all photon modalities. 
 
At least 95% of the PTVPF, PTVST or PTVboost should be encompassed within 95% 
of the 55.8 Gy isodose surface and no more than 5% of the PTV should receive 
greater than 110% of the prescription dose as evaluated by DVH. These targets 
should not receive less than 50 Gy. Treatment should be planned to spare the spinal 
cord, brainstem, optic chiasm and optic nerves from the highest doses resulting 
from dose inhomogeneity. An effort to should be made to spare the cochlea and 
middle ear contents. 
 
18.4.5.1 Proton Dose Uniformity 
For protons, 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. The PTV; however, will be only be used to select the 
appropriate beam size and beam arrangements to achieve lateral coverage of the 
targeted volume and to minimize heterogeneity. The lateral margin for proton 
beam therapy should be 3 to 5mm. 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 Range † = CTV(d) + Square root ((Range Uncertainty)2 + 
(Set-up Margin)2 + (Internal Margin)2) 
• 
CTV(d) = the distal aspect of the CTV 

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• 
Range Uncertainty = 1.5% of the water-equivalent range of the CTV 
 at max depth 
o > 1mm 
• 
Set-up Margin = set-up, mechanical and dosimetric uncertainties 
o Protons are relatively unaffected by set-up uncertainty in axis of 
beam 
o Uncertainty in hardware and software – no assigned value 
available 
• 
Internal margin = compensates for all variations in site, size and shape of 
the tissues contained in or adjacent to the CTV 
o > 1mm 
 
Proton Proximal Target Range † = CTV(p) - Square root ((Range Uncertainty)2 + 
(Set-up Margin)2 + (Internal Margin)2) 
• 
CTV(p) = the proximal aspect of the CTV 
• 
Range Uncertainty = 1.5% of the water-equivalent range of the 
CTV at max depth 
o > 1mm 
• 
Set-up Margin = set-up, mechanical and dosimetric uncertainties 
o Protons are relatively unaffected by set-up uncertainty in 
axis of beam 
o Uncertainty in hardware and software – no assigned value 
available 
• 
Internal margin = compensates for all variations in site, size and 
shape of the tissues contained in or adjacent to the CTV 
o > 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 4mm. 
 
18.4.6 Treatment Interruptions 
Treatment will not be interrupted for anemia, leukopenia, or thrombocytopenia 
unless life threatening. Blood product support should be instituted according to 
institutional/protocol guidelines. For interruptions of more that 2 treatment days, 
please notify Dr. Jeff Michalski. 
 
18.5 
Treatment Technique 
 
18.5.1 Craniospinal Axis Irradiation 
 
18.5.1.1 
Patient Position 
For cranio-spinal irradiation the patient may be treated prone or supine. The neck 
should be extended sufficiently to keep the mandible out of the exit beam of the 
spinal field but not so much as to exceed the dose uniformity specifications of the 
spinal field. Reproducible setups are critical. Immobilization devices such as head 
holders or custom molds are highly recommended. Deep sedation or general 
anesthesia is strongly encouraged for young children. For the posterior fossa boost 
the patient may be in either the prone or supine position.  
 

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18.5.1.2 
Whole Brain Irradiation 
Conformal treatment planning (or CT simulation) is encouraged but not required 
for this initial aspect of the protocol treatment. Regardless, dose from this 
component of the radiation therapy shall be included in the 3D CRT plan of the 
limited boost volume, including DVHs of the targets and adjacent organs at risk. 
 
Parallel opposed fields may be used. Alternatively, the field center can be placed 
near the match line with the spinal field and an independent jaw or half-beam block 
technique utilized. This method decreases overlap at the match line. The 
collimation of the brain field should be rotated to match the divergence of the 
spinal field.  
 
If symmetric collimator jaws are used: 
 
The angle = tan-1 Error! Bookmark not defined. spine length/2 
               SAD 
 
If asymmetric collimator jaws are used:  
 
The angle = tan-1 Error! Bookmark not defined. upperspine length 
             SAD 
 
The lateral fields may be angled posteriorly to spare the collateral lens, but, if this 
is done, great care must be taken to assure adequate coverage of the cribriform 
plate. Custom divergent blocking of at least 5 HVL should be used to shape the 
brain field at the base of the skull and around the eyes. The brain field should 
extend to at least 1 cm beyond the periphery of the scalp.  
 
18.5.1.3 
Spine Irradiation 
Preferably, the spinal volume should be treated with a single posterior field. An 
extended SSD is preferable to the use of adjacent ports. If adjacent ports are 
necessary, the 50% decrement should cross at the posterior margins of the vertebral 
body. It is preferable that the match line be placed inferior to the spinal cord (below 
L2) and should be moved every 900 cGy. Custom blocking may be required at the 
inferior border of the spine.  
 
18.5.1.4 
Abutting Fields 
With the use of collimator rotation and an independent jaw technique, the cranial 
and spinal fields may be directly abutted (light fields). Many radiation oncologists, 
though, are more comfortable with a gap between the cranial and spinal light fields. 
A gap of 0.5 cm is allowed on this protocol. The match line should be moved at 
least twice during treatment of the cranio-spinal axis (e.g. after each 9Gy). Also, a 
penumbra broadening “match line wedge” or a dynamic wedge may be used. The 
match line should never overlap the posterior fossa boost. Therefore, it is 
recommended that the first match line lie just above the shoulder, and the last 2 cm 
higher. Alternatively, the first match point could begin at the superior point and 
end at the inferior point.  
 
18.5.1.5 
Conformal Boost Treatment 
Conformal (three-dimensional) planning is required for this study. Beam 
arrangements and treatment techniques should be used that minimize the dose to 

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the auditory apparatus (cochlea), hypothalamic-pituitary unit and supratentorial 
brain providing that they do not compromise treatment of the intended PTV.  
 
18.5.1.6 
Selection of Proton Beam Arrangements 
Proton beams have two uncertainties at the distal edge of the beam that affect 
planning. The first is the physical uncertainty of the exact location of the stopping 
edge. This is accounted for in Sect. 18.4.5. The second is the biologic uncertainty 
of the distal range of the proton beam in which the RBE may be greater than 1.1; 
therefore, single proton beam plans which stop in a critical organ will not be 
allowed. Individual proton beams which are a component of a multi-field proton 
beam and which stop within such an organ will be allowed but are not encouraged. 
It is preferable to stop the proton beam beyond the critical organ.  
 
18.5.1.7 
Field Shaping 
Field-shaping is required. Shielding shall be at least 5 HVL thick. Multi-leaf 
collimation may be used. The field shaping for protons will be done with either 
brass apertures or proton-specific multileaf collimation. 
 
18.5.1.8 
Example Cases 
http://www.qarc.org/cog/protocol%20resources/ACNS0331Atlas.pdf 
 
18.5.1.9 
Imaging 
CT (3 mm - 5 mm section thickness from the thoracic inlet to the base of the skull, 
3 mm for the entire skull) should be performed for treatment planning. 
Preoperative and postoperative MR is used primarily (co-registered with CT 
planning data) or adjunctively in the treatment planning process. Surgical 
guidelines encourage postoperative imaging within 72 hours post-operatively. 
 
18.6 
Normal Tissue Sparing 
 
Normal tissue dose recommendations are the same for photons and protons (proton dose 
measured in CGE). 
 
18.6.1 Spinal Cord 
No more than 50% of the cervical spinal cord between C-1 and C-2 should receive 
more than 54 Gy. A DVH of this volume shall be submitted. 
 
18.6.2 
Fields should be specifically designed to minimize dose to Organs At Risk such as 
the optic nerves, optic chiasm, cochlea, hypothalamic-pituitary unit and 
supratentorial brain. Maximum doses to these Organs At Risk should not exceed 
the PTVpf prescription dose. 
 
18.7 
Dose Calculations and Reporting 
Institutions using conventional 3D treatment planning must have an approved 3D 
Conformal Benchmark on file with IROC. If IMRT or Protons are to be used, 
credentialing requirements specific to those modalities must be satisfied. See Section 
18.0.2 for details regarding credentialing requirements.  
 
 

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18.7.1 Prescribed Dose 
The dose prescription and fractionation shall be reported on the RT-1 Dosimetry 
Summary Form or Proton Reporting Form. If IMRT is used, the monitor units 
generated by the IMRT planning system must be independently checked prior to 
the first treatment. Measurements in a QA phantom can suffice for a check as long 
as the patient’s plan can be directly applied to a phantom geometry. The total dose 
shall be reported on the RT-2 Radiotherapy Total Dose Record form.  
 
18.7.2 Dose Volume Histograms 
Dose volume histograms will be calculated and submitted for organs at risk 
(Section 18.3.3) including right and left optic nerves, optic chiasm, right and left 
cochlea, pituitary/hypothalamus, supratentorial brain, and spinal cord (foramen 
magnum to C2). Dose volume histograms will be calculated and submitted for the 
GTV, CTV and PTV of each volume treated. Dose volume histograms will be 
calculated and submitted in composite form whenever possible. If IMRT is used, 
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. 
 
18.8 
Quality Assurance Documentation  
All patients will undergo an on-treatment review of the CSI portion of their radiation 
therapy and a pre-treatment review of the boost, irrespective of institutional exempt status. 
All required imaging and RT data for the CSI must be submitted within three days of the 
start of radiotherapy. The required data for the boost volume must be submitted before the 
start of the boost. It is recommended that planning data for the boost volume be submitted 
at the time of the CSI on-treatment review.  
 
Digital Submission: 
 
Submission of treatment plans in digital format as DICOM RT is required. Digital data 
must include CT scans, structures, plan, and dose files. Submission may be by either sFTP 
or CD. Instructions for data submission are on the IROC RI (QARC) web site at 
www.qarc.org under "Digital Data." Any items on the list below that are not part of the 
digital submission may be included with the transmission of the digital RT data via sFTP 
or submitted separately. Screen captures are preferred to hard copy for items that are not 
part of the digital plan. 
  
 
 

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Data to be Submitted: 
 
External beam Treatment Planning System  
• 
Digitally reconstructed radiographs (DRR) each treatment field and orthogonal 
(anterior/posterior and lateral) images for isocenter localization for each group of 
concurrently treated beams. DRR’s are not required for IMRT. 
• 
RT treatment plan including CT, structures, dose, and plan files. These items are 
included in the digital plan  
• 
Dose volume histograms (DVH) for the composite treatment plan for all target volumes 
and required organs at risk. A DVH shall be submitted for the organs at risk specified 
in Section 18.3.3. When using IMRT, a DVH shall be submitted for a category of tissue 
called “unspecified tissue.” This is defined as tissue contained within the skin, but 
which is not otherwise identified by containment within any other structure. DVH's are 
included in the digital plan. 
• 
Treatment planning system summary report that includes the monitor unit calculations, 
beam parameters, calculation algorithm, and volume of interest dose statistics.  
 
Supportive Data 
• Copies of all diagnostic materials and surgical reports used in defining the target 
volume including (i) preoperative MRI and postoperative cranial MRI with and 
without contrast; (ii) pre or postoperative spinal MRI with and without contrast; 
sagittal imaging should be included for both brain and spine; (iii) copies of the all op 
reports, pathology reports, and copies of the results for the Lumbar CSF cytology 
examination must also be submitted. DICOM format is required for all imaging 
• Portal images for the craniospinal fields 
• Prescription Sheet for Entire Treatment  
• For protons, a description of the rationale for the PTV margins.  
• If the recommended doses to the organs at risk are exceeded, an explanation should 
be included for review by the IROC RI (QARC) and the radiation oncology 
reviewers. 
 
Forms 
• 
RT-1 Dosimetry Summary Form. 
• 
Proton Reporting Form (if applicable). 
 
Within 1 week of the completion of radiotherapy, the following data shall be 
submitted for all patients: 
 
• 
The RT-2 Radiotherapy Total Dose Record form. 
• 
A copy of the patient’s radiotherapy record including prescription, and the daily and 
cumulative doses to all required areas, critical organ and reference points 
• 
Documentation listed above showing any modifications from original submission. 
 

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The data should be sent to:  
IROC RI (QARC) 
Building B, Suite 201 
640 George Washington Highway  
Lincoln, RI  02865-4207 
Telephone: 
(401) 753-7600 
FAX:  
(401) 753-7601 
 
Questions regarding the dose calculations or documentation should be directed to:  
COG Protocol Dosimetrist 
IROC RI (QARC) 
Building B, Suite 201 
640 George Washington Highway, Suite 201 
Lincoln, RI  02865-4207 
Telephone: 
(401) 753-7600 
FAX:  
(401) 753-7601 
 
18.9 
Definitions of Deviation in Protocol Performance 
 
18.9.1 Prescription Dose 
 
Minor Deviation 
Brain and spine fields: The dose to the prescription point differs from the protocol 
specified dose by more than 5% but less than 10%. 
Boost field: Less than 95% of the study prescribed dose covers at least 95% of the 
PTV and/or < 50 Gy covers 100% of the PTV. 
 
Major Deviation 
Brain and spine fields: The dose to the prescription point differs from the protocol 
specified dose by more than 10%. 
 
Boost field: Less than 90% of the study prescribed dose covers at least 95% of the 
PTV and/or < 48 Gy covers 100% of the PTV. 
 
18.9.2 Dose Uniformity 
 
Minor Deviation 
The variation of dose in one of the target volumes exceeds + 10%, - 5%, but is 
within ± 15%. 
 
Major Deviation 
The variation of dose in one of the target volumes exceeds ± 15%.  
 
18.9.3 Volume 
 
Minor Deviation 
Margins less than specified, or field(s) excessively large. Major incorrect 
definition of Organs At Risk volumes. 
 
 

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Major Deviation 
Transecting tumor or potentially tumor-bearing area(s). Major incorrect definition 
of Organs At Risk volumes. 
 
 
 
19.0 
QUALITY OF LIFE AND NEUROPSYCHOMETRIC GUIDELINES 
 
Enrollment onto the neuropsychological function study ALTE07C1, Neuropsychological, Social, 
Emotional, and Behavioral Outcomes in Children with Cancer, is strongly encouraged. If the 
family agrees to participate in ALTE07C1, a separate informed consent for ALTE07C1 must be 
signed. Please refer to the ALTE07C1 protocol for eligibility requirements. 
 
 

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APPENDIX I: PERFORMANCE STATUS SCALES/SCORES 
 
Performance Status Criteria 
Karnofsky and Lansky performance scores are intended to be multiples of 10 
ECOG (Zubrod) 
Karnofsky 
Lansky* 
Score 
Description 
Score 
Description 
Score 
Description 
0 
Fully active, able to carry on all 
pre-disease 
performance 
without restriction. 
100 
Normal, no complaints, no 
evidence of disease 
100 
Fully active, normal. 
90 
Able to carry on normal 
activity, 
minor 
signs 
or 
symptoms of disease. 
90 
Minor restrictions in physically 
strenuous activity. 
1 
Restricted 
in 
physically 
strenuous 
activity 
but 
ambulatory and able to carry out 
work of a light or sedentary 
nature, e.g., light housework, 
office work. 
80 
Normal activity with effort; 
some signs or symptoms of 
disease. 
80 
Active, but tires more quickly 
70 
Cares for self, unable to carry 
on normal activity or do active 
work. 
70 
Both greater restriction of and less 
time spent in play activity. 
2 
Ambulatory and capable of all 
self-care but unable to carry out 
any work activities. Up and 
about more than 50% of waking 
hours 
60 
Required occasional assistance 
but is able to care for most of 
his/her needs. 
60 
Up and around, but minimal active 
play; keeps busy with quieter 
activities. 
50 
Requires 
considerable 
assistance and frequent medical 
care. 
50 
Gets dressed, but lies around much 
of the day; no active play, able to 
participate in all quiet play and 
activities. 
3 
Capable of only limited self-
care, confined to bed or chair 
more than 50% of waking hours.  
40 
Disabled, requires special care 
and assistance. 
40 
Mostly in bed; participates in quiet 
activities. 
30 
Severely 
disabled, 
hospitalization indicated. Death 
not imminent. 
30 
In bed; needs assistance even for 
quiet play. 
4 
Completely disabled. Cannot 
carry on any self-care. Totally 
confined to bed or chair. 
20 
Very 
sick, 
hospitalization 
indicated. Death not imminent. 
20 
Often sleeping; 
play 
entirely 
limited to very passive activities. 
10 
Moribund, 
fatal 
processes 
progressing rapidly. 
10 
No play; does not get out of bed. 
 
*The conversion of the Lansky to ECOG scales is intended for NCI reporting purposes only. 
 
 

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APPENDIX II: M-STAGING SYSTEM FOR POSTERIOR FOSSA AND NON POSTERIOR 
FOSSA PNET 
 
 
STAGE 
DEFINITION 
 
METASTASES 
M0 
No evidence of subarachnoid or hematogenous metastasis. 
M1 
Microscopic tumor cells found in CSF. 
M2 
Gross nodular seeding demonstrated in the intracranial subarachnoid space or ventricular 
system distant from the primary site. 
M3a 
Gross nodular seeding in the spinal subarachnoid space without evidence of intracranial 
seeding. 
M3b 
Gross nodular seeding in the spinal subarachnoid space as well as intracranial seeding. 
M4 
Extraneural metastasis 
 

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APPENDIX III: YOUTH INFORMATION SHEETS 
 
INFORMATION SHEET REGARDING RESEARCH STUDY – ACNS0332 
(for children from 7 through 12 years of age) 
 
A Trial to Compare Two Ways of Treating Patients with High Risk Medulloblastoma/PNET  
1. We have been talking with you about your medulloblastoma. Medulloblastoma is a type of cancer that 
grows in the brain. Sometimes cancer is called “high risk” because it is more likely to come back after 
treatment. High risk cancer is treated with stronger medicine to make it less likely to return. After doing 
tests, we have found that you have high risk medulloblastoma.  
2. We are asking you to take part in a research study because you have a type of brain cancer called high 
risk medulloblastoma. A research study is when doctors work together to try out new ways to help people 
who are sick. In this study, we are trying to learn more about how to treat the type of brain cancer that 
you have. We want to find out if adding 1 drug to the usual therapy can improve the treatment for the 
type of brain cancer that you have. The drug we are testing is carboplatin (the ‘C’ drug). We will do this 
by comparing 2 ways to treat the cancer. We don’t know which way is better. That is why we are doing 
this study.  
3. Children who are part of this study will be treated with radiation therapy and chemotherapy. Radiation 
therapy is the use of high-energy x-rays to kill cancer cells. Chemotherapy is medicine that destroys 
cancer cells. When a chemotherapy drug is given along with radiation therapy this is called 
chemoradiotherapy.  
4. On this study, everyone will be given the usual treatment for your type of cancer. But some patients will 
have 1 drug added to that therapy. This means that you will be treated in 1 of 2 ways:  
* The usual therapy.  
* The usual therapy plus the ‘C’ drug.  
5. Sometimes good things can happen to people when they are in a research study. These good things are 
called “benefits.” We hope that a benefit to you of being part of this study is that if you are given the ‘C’ 
drug this will improve the treatment and your cancer will be less likely to return. But we don’t know for 
sure if there is any benefit of being part of this study.  
6. Sometimes bad things can happen to people when they are in a research study. These bad things are 
called “risks.” The risks to you from this study are that if you are given the ‘C’ drug then you may have 
more side effects than you would on the usual therapy. Other things may happen to you that we don’t 
yet know about.  
7. Your family can choose to be part of this study or not. Your family can also decide to stop being in this 
study at any time once you start. There may be other treatments for your illness that your doctor can tell 
you about. Make sure to ask your doctors any questions that you have.  
8. We would also like to do research to see if there are ways to tell how the cancer will respond to treatment. 
We hope to find that out by doing tests on samples of tumor tissue. You have already had surgery. We 

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would use a sample of the tumor that was removed during that surgery for tests. No extra procedures 
will be done to remove tissue for these research tests. You can choose to be on the study but not to allow 
us to use extra tumor cells for research.  
 
 

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INFORMATION SHEET REGARDING RESEARCH STUDY – ACNS0332 
(for teens from 13 through 17 years of age) 
A Trial Using Chemotherapy and Radiation Therapy to Compare Two Ways of Treating Patients 
with High Risk Medulloblastoma/PNET  
1. We have been talking with you about your medulloblastoma. Medulloblastoma is a type of cancer that 
grows in the brain. Sometimes cancer is called “high risk” because it is more likely to come back after 
treatment. High risk cancer is treated with stronger medicine to make it less likely to return. After doing 
tests, we have found that you have high risk medulloblastoma.  
2. We are asking you to take part in a research study because you have high risk medulloblastoma. A 
research study is when doctors work together to try out new ways to help people who are sick. In this 
study, we are trying to find out if adding 1 chemotherapy drug to the standard therapy will improve the 
treatment for young people with high risk medulloblastoma.  
Standard therapy for medulloblastoma includes surgery, radiation therapy and chemotherapy. Radiation 
therapy is the use of high-energy x-rays to kill cancer cells. Chemotherapy is medicine that destroys 
cancer cells. When a chemotherapy drug is given along with radiation therapy this is called 
chemoradiotherapy.  
This study deals with treatment after surgery. The standard treatment for high risk medulloblastoma after 
surgery is chemoradiotherapy followed by “Maintenance” chemotherapy. In this study, we want to find 
out if adding a drug called carboplatin to the chemoradiotherapy can improve the outcome of patients.  
3. Children and teens who are part of this study will all be treated with the standard therapy for high risk 
medulloblastoma but some patients will have 1 drug added to that therapy. This means that you will be 
treated in 1 of 2 ways:  
* Standard therapy (chemoradiotherapy followed by Maintenance chemotherapy)  
* Standard therapy with the addition of carboplatin during chemoradiotherapy  
4. Sometimes good things can happen to people when they are in a research study. These good things are 
called “benefits.” We hope that a benefit to you of being part of this study is that if you receive 
carboplatin this will improve the treatment and your cancer will be less likely to return. But we don’t 
know for sure if there is any benefit of being part of this study.  
5. Sometimes bad things can happen to people when they are in a research study. These bad things are 
called “risks.” The risks to you from this study are that if you receive carboplatin then you may have 
more side effects than you would on standard therapy. Other things may happen to you that we don’t yet 
know about.  
6. Your family can choose to be part of this study or not. Your family can also decide to stop being in this 
study at any time once you start. There may be other treatments for your illness that your doctor can tell 
you about. Make sure to ask your doctors any questions that you have.  
7. Another part of the study is to see if there are ways to tell how the cancer will respond to treatment. We 
hope to find that out by doing tests on samples of tumor tissue. You have already had surgery. We would 

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use a sample of the tumor that was removed during that surgery for tests. No extra procedures will be 
done to remove tissue for these research tests. If there are any leftover samples from these tests, we 
would like your permission to store them for use in future research. This is called banking. This part of 
the study is optional.  
8. You can still be treated for your tumor if you decide not to be on this study. You can also decide to be 
on the study but not to allow us to use extra tumor cells for research.  
 
 
 

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APPENDIX IV:  CTEP AND CTSU REGISTRATION PROCEDURES 
 
CTEP INVESTIGATOR REGISTRATION PROCEDURES 
 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy 
require all investigators participating in any NCI-sponsored clinical trial to register and to renew 
their registration annually. 
 
Registration requires the submission of: 
 
• 
a completed Statement of Investigator Form (FDA Form 1572) with an original 
signature 
• 
a current Curriculum Vitae (CV) 
• 
a completed and signed Supplemental Investigator Data Form (IDF) 
• 
a completed Financial Disclosure Form (FDF) with an original signature 
 
Fillable PDF forms and additional information can be found on the CTEP website at 
<http://ctep.cancer.gov/investigatorResources/investigator_registration.htm>. For questions, please 
contact 
the 
CTEP 
Investigator 
Registration 
Help 
Desk 
by 
email 
at 
<pmbregpend@ctep.nci.nih.gov>. 
 
CTEP Associate Registration Procedures / CTEP-IAM Account 
 
The Cancer Therapy Evaluation Program (CTEP) Identity and Access Management (IAM) 
application is a web-based application intended for use by both Investigators (i.e., all physicians 
involved in the conduct of NCI-sponsored clinical trials) and Associates (i.e., all staff involved in 
the conduct of NCI-sponsored clinical trials). 
 
Associates will use the CTEP-IAM application to register (both initial registration and annual re-
registration) with CTEP and to obtain a user account. 
 
Investigators will use the CTEP-IAM application to obtain a user account only. (See CTEP 
Investigator Registration Procedures above for information on registering with CTEP as an 
Investigator, which must be completed before a CTEP-IAM account can be requested.) 
 
An active CTEP-IAM user account will be needed to access all CTEP and CTSU (Cancer Trials 
Support Unit) websites and applications, including the CTSU members’ website. 
 
Additional 
information 
can 
be 
found 
on 
the 
CTEP 
website 
at 
<http://ctep.cancer.gov/branches/pmb/associate_registration.htm>. For questions, please contact 
the CTEP Associate Registration Help Desk by email at <ctepreghelp@ctep.nci.nih.gov>. 
 
 
CTSU REGISTRATION PROCEDURES 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU).  
 
 

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Downloading Site Registration Documents: 
 
Site registration forms may be downloaded from the ACNS0332 protocol page located on the 
CTSU members’ website. Permission to view and download this protocol and its supporting 
documents is restricted and is based on person and site roster assignment housed in the CTSU RSS. 
 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
 
Click on the Protocols tab in the upper left of your screen 
 
Click on the COG link to expand, then select trial protocol ACNS0332 
 
Click on the Site Registration Documents link 
 
Requirements for ACNS0332 Site Registration: 
 
• 
CTSU IRB Certification (for sites not participating via the CIRB) 
• 
CTSU IRB/Regulatory Approval Transmittal Sheet (for sites not participating via the NCI 
CIRB)  
• 
CTSU RT Facilities Inventory Form  
NOTE: Per NCI policy all institutions that participate on protocols with a radiation therapy 
component must participate in the IROQ Houston monitoring program. If this form has 
been previously submitted to CTSU it does not need to be resubmitted unless updates have 
occurred at the RT facility. 
 
 
Submitting Regulatory Documents: 
 
Submit completed forms along with a copy of your IRB Approval to the CTSU Regulatory Office, 
where they will be entered and tracked in the CTSU RSS.  
ONLINE: www.ctsu.org  (members’ section)  Regulatory Submission Portal 
EMAIL: CTSURegulatory@ctsu.coccg.org (for regulatory document submission only) 
FAX: 215-569-0206 
MAIL: CTSU Regulatory Office 
      1818 Market Street, Suite 1100 
      Philadelphia, PA 19103 
 
Checking Your Site’s Registration Status: 
 
Check the status of your site’s registration packets by querying the RSS site registration status page 
of the members’ section of the CTSU website. (Note: Sites will not receive formal notification of 
regulatory approval from the CTSU Regulatory Office.) 
 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
 
Click on the Regulatory tab at the top of your screen 
 
Click on the Site Registration tab 
 
Enter your 5-character CTEP Institution Code and click on Go 
 

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

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Some drugs, food, and supplements may interact with cyclophosphamide. Examples 
include: 
 
Drugs that may interact with cyclophosphamide* 
• 
Allopurinol 
• 
Chloramphenicol 
• 
Cyclosporine 
• 
Digoxin  
• 
Etanercept  
• 
Hydrochlorothiazide 
• 
Indomethacin 
• 
Nevirapine 
• 
Pentostatin  
• 
Warfarin  
 
Food and supplements that may interact with cyclophosphamide** 
• 
St. John’s Wort 
• 
Drinks, food, supplements, or vitamins containing “flavonoids” or other “antioxidants” 
 
*Sometimes these drugs are used with cyclophosphamide on purpose. Discuss all drugs with 
your doctor. 
 
**Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, 
pills, or dried herbs. All forms should be avoided.  
 
 
 
Some drugs, food, and supplements may interact with vincristine. Examples include: 
 
Drugs that may interact with vincristine* 
• Antibiotics  
• Clarithromycin, erythromycin, nafcillin, rifabutin, rifampin, telithromycin 
• Antidepressants and antipsychotics  
• Aripiprazole, nefazodone, trazodone 
• Antifungals  
• Fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole 
• Arthritis medications  
• Leflunomide, tocilizumab, tofacitinib 
• Anti-rejection medications 
• Cyclosporine, tacrolimus 
• Antiretrovirals and antivirals  
• Atazanavir, boceprevir, darunavir, delaviridine, efavirenz, etravirine, 
fosamprenavir, indinavir, lopinavir, nelfinavir, nevirapine, ritonavir, saquinavir, 
Stribild, telaprevir, tenofovir, tipranavir 
• Anti-seizure medications  

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• Carbamazepine, oxcarbazepine, phenobarbital, phenytoin, primidone 
• Heart medications  
• Amiodarone, digoxin, dronedenarone, propranolol, verapamil 
• Some chemotherapy (be sure to talk to your doctor about this) 
• Many other drugs, including the following: 
• Aprepitant, deferasirox, ivacaftor, lomitapide, mifepristone, natalizumab, pimozide, 
warfarin  
 
Food and supplements that may interact with vincristine** 
• Echinacea 
• St. John’s Wort 
• Grapefruit, grapefruit juice, Seville oranges, star fruit 
 
*Sometimes these drugs are used with vincristine on purpose. Discuss all drugs with your 
doctor. 
**Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, 
capsules, pills, or dried herbs. All forms should be avoided.  
 
 

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REFERENCES 
1. 
Geyer J, et al: Survival of infants with primitive neuroectodermal tumors or malignant 
ependymomas of the CNS treated with eight drugs in 1 day: a report from the Children's Cancer 
Group. J. Clin. Oncol 12:1607-1615, 1994 
2. 
Duffner PK, Horowitz ME, Krischer JP, et al: Postoperative chemotherapy and delayed radiation 
in children less than three years of age with malignant brain tumors. NEJM 328(24):1725-31, 1993 
3. 
Zeltzer M, Boyett JM, Finlay JL, et al: Metastasis stage, adjuvant treatment, and residual tumor are 
prognostic factors for medulloblastoma in children: conclusions from the Children's Cancer Group 
921 randomized phase III study. J Clin Oncol 17:832-845, 1999 
4. 
Ris MD, Packer R, Goldwein J, et al: Intellectual outcome after reduced-dose radiation therapy 
plus adjuvant chemotherapy for medulloblastoma: a Children's Cancer Group study. Journal of 
Clinical Oncology 19:3470-6, 2001 
5. 
Allen JC, Walker R, Luks E, et al: Carboplatin and recurrent childhood brain tumors. J Clin Oncol 
5:459-463, 1987 
6. 
Mastrangelo R, Lasorella A, Riccardi R, et al: Carboplatin in childhood medulloblastoma/PNET: 
Feasibility of an in-vivo sensitivity test in an "up-front" study. Med Ped Oncol 24:188-196, 1995 
7. 
Gaynon PS, Ettinger LJ, Baum ES, et al: Carboplatin in childhood brain tumors. Cancer 66:2465-
2469, 1990 
8. 
Douple EB, Richmond RC, O’Hara JA, et al: Carboplatin as a potentiator of radiation therapy. 
Cancer Treat Rev 12:A111-24, 1985 
9. 
O’Hara JA, Douple EB, Richmond RC: Enhancement of radiation-induced cell kill by platinum 
complexes (carboplatin and iproplatin) in V79 cells. Int J Radiat Oncolo Biol Phys 12:1419-22, 
1986 
10. 
Yang LX, Douple EB, O’Hara JA, et al: Production of DNA double-stranded breaks by interactions 
between carboplatin and radiation: a potential mechanism for radiopotentiation. Radiat Res 
143:309-15, 1995 
11. 
Begg AC, van der Kolk PJ, Emont J, et al: Radiosensitization in vitro by cis-diammine (1,1-
cyclobutanedicarboxylato) 
platinum 
(II) 
(carboplatin, 
JM8) 
and 
ethylenediammine-
malonatoplatinum (II) (JM40). Radiother Oncol 9:157-65, 1987 
12. 
Yang LX, Douple EB, Wang HJ: Irradiation enhances cellular uptake of carboplatin. Int J Radiat 
Oncol Biol Phys 33:641-6, 1995 
13. 
Caffo O: Radiosensitization with chemotherapeutic agents. Lung Cancer 34:S81-90, 2001 
14. 
Geldof AA, Slotman BJ: Radiosensitizing effect of cisplatin in prostrate cancer cell lines. Cancer 
Lett 101:233-9, 1996 
15. 
Karasawa K, Shinoda H, Katsui K, et al: Radiotherapy with concurrent docetaxel and carboplatin 
for head and neck cancer. Anticancer Res 22:3785-8, 2002 
16. 
Atagi S, Kawahara M, Ogawara M, et al: Phase II trial of daily low-dose carboplatin and thoracic 
radiotherapy in elderly patients with locally advanced non-small cell lung cancer. Jpn J Clin Oncol 
30:59-64, 2000 
17. 
Clamon G, Herndon J, Cooper R, et al: Radiosentization with carboplatin for patients with 
unresectable stage III non small-cell lung cancer: a phase III trial of the Cancer and Leukemia 
Group and the Eastern Cooperative Oncology Group. J Clin Oncol 17:4-11, 1999 
18. 
Skov K, MacPhail S: Interaction of platinum drugs with clinically relevant x-ray doses in 
mammalian cells: a comparison of cisplatin, carboplatin, iproplatin and tetraplatin. Int J Radiat 
Oncol Biol Phys 20:221-225, 1991 
19. 
Patton TF, Himmelstein KJ, Belt R, et al: Plasma levels and urinary excretion of filterable platinum 
species following bolus injection and IV infusion of cis-diachlorodiammineplatinum in man. 
Cancer Treat Rep 62:1359, 1978 
20. 
Alberts DS, Mason-Liddil N: Carboplatin in the treatment of ovarian cancer. Semin Oncol 16:19-
26, 1989 

THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY  
ACNS0332 
 
Version Date: 4/11/18 
 
95 
 
21. 
Patel M, Godwin K, McCully C, et al: Plasma and cerebrospinal fluid pharmacokinetics of 
carboplatin and cisplatin. ProcAACR 37:403-404, 1996 
22. 
Alverez MV, Cobreros G, Heras A, et al: Studies of cisdichlorodiammineplatinum (II) as a 
radiosensitizer. Br J Cancer 3 (S3):68-72, 1978 
23. 
Dritschilo A, Piro AJ, Kelman AD: The effect of cis-platinum on the repair of radiation damage in 
plateau phase Chinese hamster cells. Int J Radiat Oncol Biol Phys 5:1345-1349, 1979 
24. 
Stewart DJ, Leavens M, Maor M, et al: Human central nervous system distribution of 
cisdiamminedichloroplatinum and use as a radiosensitizer in malignant brain tumors. Can Res 
42:2474-2479, 1982 
25. 
Hallahan AR, Pritchard JI, Chandraratna RA, et al: BMP-2 mediates retinoid-induced apoptosis in 
medulloblastoma cells through a paracrine effect. Nat Med 9(8):1033-8, 2003 
26. 
Gumireddy K, et al: All-trans-retinoic acid-induced apoptosis in human medulloblastoma: 
activation of caspase-3/poly(ADP-ribose) polymerase 1 pathway. Clin Cancer Res 9(11):4052-9, 
2003 
27. 
Di C LS, Adamson DC, Parrett TJ, et al: Identification of OTX2 as a Medulloblastoma Oncogene 
Whose Product can be Targeted by All-Trans Retinoic Acid. Cancer Res 65(3):919-24, 2005 
28. 
Khan AA, Villablanca JG, Reynolds CP, et al: Pharmacokinetic studies of 13-cis-retinoic acid in 
pediatric patients with neuroblastoma following bone marrow transplantation. Cancer Chemother 
Pharmacol 39(1-2):34-41, 1996 
29. 
Formelli F, Cavadini E, Mascheroni L, et al: Pharmacokinetics and effects on plasma retinal 
concentrations of 13-cis-retinoic acid in melanoma patients. Br J Cancer 76:1655-60, 1997 
30. 
LeDoze F, Debruyne D, Albessard F, et al: Pharmacokinetics of all-trans retinoic acid, 13-cis-
retinoic acid, and fenretinide in plasma and brain of Rat. Drug Metab Dispos 28:205-208, 2000 
31. 
Matthay KK, Villablanca JG, Seeger RC, et al: Treatment of high-risk neuroblastoma with 
intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic 
acid. Children's Cancer Group. N Engl J Med 341:1165-1173, 1999 
32. 
Villablanca JG, Khan AA, Avramis VI, et al: Phase I trial of 13-cis-retinoic acid following bone 
marrow transplantation. J Clin Oncol 13:894-901, 1995 
33. 
Liu J, Guo L, Luo Y, et al: All trans-retinoic acid suppresses in vitro growth and down-regulates 
LIF gene expression as well as telomerase activity of human medulloblastoma cells. Anticancer 
Res 20:2659-2664, 2000 
34. 
Shin DM, et al: Phase II and biologic study of interferon alpha, retinoic acid, and cisplatin in 
advanced squamous skin cancer. J. Clin. Oncol. 20 (2):364-370, 2002 
35. 
Shalinsky DR, et al: Enhanced antitumor efficacy of cisplatin in combination with ALRT1057 (9-
cis retinoic acid) in human oral squamous carcinoma xenografts in nude mice. Clin Cancer Res 
2:511-520, 1996 
36. 
Aebi S, et al: all-trans retinoic acid enhances cisplatin-induced apoptosis in human ovarian 
adenocarcinoma and in squamous head and neck cancer cells, Clin. Cancer Res. 3:2033-2038, 1997 
37. 
Formelli F, Cleris L: Therapeutic effects of the combination of fenretinide and all-trans-retinoic 
acid and of the two retinoids with cisplatin in a human ovarian carcinoma xenograft and in a 
cisplatin-resistant subline . 2000 
38. 
Recchia F, Lalli A, Lombardo M, et al: Ifosfamide, cisplatin, and 13-Cis retinoic acid for patients 
with advanced or recurrent squamous cell carcinoma of the head and neck: a phase I-II study. 
Cancer 92:814-21, 2001 
39. 
Yung WK, Kyritsis P, Gleason MJ, et al: Treatment of recurrent malignant Gliomas with High 
Dose 13-cis Retinoic Acid. Clin Cancer Res 2:1931-35, 1996 
40. 
Kalbfleisch JD, Prentice RL: The Statistical Analysis of Failure Time Data, 2nd Edition. New York: 
Wiley. 36:2411-2419, 2002 
41. 
Sposto R, Sather HN: Determining the duration of comparative clinical trials while allowing for 
cure. Journal of Chronic Diseases 38(8):683-90, 1985 

THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY  
ACNS0332 
 
Version Date: 4/11/18 
 
96 
 
42. 
DeMets DL, Lan KKG: "Interim analysis: The alpha spending function approach". Statistics in 
Medicine 13:1341-1352, 1994