Clinical trial NCT01602666
Conditions: Central Nervous System Nongerminomatous Germ Cell Tumor Childhood Central Nervous System Germinoma
Sponsor: Children's Oncology Group
Start date: 2012-06-27; Completion date: 2024-09-30
Enrollment: 262 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well chemotherapy followed by radiation therapy work in treating younger patients with newly diagnosed central nervous system germ cell tumors that have not spread to other parts of the brain, spinal canal, or body (localized). Drugs used as chemotherapy, such as carboplatin, etoposide, and ifosfamide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high-energy x rays to kill tumor cells. Giving chemotherapy followed by radiation therapy may kill more tumor cells.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine, as measured by the 3-year progression-free survival (PFS) rate and patterns of failure, whether dose and volume of irradiation can be safely reduced to 30.6 Gy whole ventricular-field irradiation (WVI) plus 23.4 Gy primary site boost instead of 36 Gy craniospinal irradiation (CSI) plus primary site boost in the subgroup of children and young adults (ages 3 to =\< 21 years) with localized nongerminomatous germ cell tumor (NGGCT) who have a magnetic resonance imaging (MRI) and tumor marker criteria (cerebrospinal fluid \[CSF\] and serum) for confirmed complete response (CR) or partial response (PR) to induction chemotherapy and negative serum and cerebrospinal fluid (CSF) tumor markers OR in patients who have less than a PR after induction chemotherapy with negative tumor markers who undergo a second-look surgery and are found to have only mature teratoma, residual scar or fibrosis and fit the definition of CR/PR after second-look surgery.

II. To determine, as measured by the 3-year PFS rate and patterns of failure, whether simplified chemotherapy followed by dose-reduced radiation therapy is effective for treating children and young adults (ages 3 to =\< 21 years) with localized primary central nervous system (CNS) germinoma who present with serum and/or CSF human chorionic gonadotropin-beta (hCGbeta) =\< 50 mIU/mL.

III. To prospectively evaluate and longitudinally model the cognitive, social, and behavioral functioning of children and young adults who are treated with reduced radiation dose and volume of irradiation in Stratum 1 (NGGCT) and with dose-reduced radiation therapy in Stratum 2 (germinoma) using the ALTE07C1 protocol.

SECONDARY OBJECTIVES:

I. To estimate the PFS and overall survival (OS) distributions of patients with NGGCT treated with 30.6 Gy WVI and involved-field radiation therapy (IFR) focal boost to 54 Gy.

II. To estimate the PFS and OS distributions of localized germinoma patients who present with a) serum and/or CSF hCGbeta =\< 50 mIU/mL and b) serum and/or CSF hCGbeta \> 50 mIU/mL and =\< 100 mIU/mL.

OUTLINE:

STRATUM I (NGGCT): Patients receive induction therapy comprising carboplatin intravenously (IV) over 15-60 minutes on day 1 and etoposide IV over 60-120 minutes on days 1-3 of courses 1, 3, and 5. Patients also receive ifosfamide IV over 60 minutes and etoposide over 60-120 minutes on days 1-5 of courses 2, 4, and 6. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients achieving CR or PR undergo 3-dimensional conformal radiation therapy (3DRT) or intensity modulated radiation therapy (IMRT) once daily (QD) 5 days a week for 6 weeks. Patients with normalization of markers who fail to achieve CR or PR are strongly recommended to undergo second-look surgery. Patients who achieve CR or PR after second-look surgery undergo 3DRT or IMRT QD 5 days a week for 6 weeks.

STRATUM II (GERMINOMA): Patients receive induction therapy comprising carboplatin IV over 15-60 minutes on day 1 and etoposide IV over 60-120 minutes on days 1-3. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients with CR or continued CR (CCR) undergo 3DRT or IMRT QD 5 days a week for 4 weeks. Patients with normalization of markers who fail to achieve CR or PR are strongly recommended to undergo second-look surgery. Patients found to have fibrosis, scar, mature teratoma, or non-viable tumor undergo 3DRT or IMRT QD 5 days a week for 4 weeks. Patients with stable disease (SD) or PR with \> 0.5 cm (suprasellar) or \> 1 cm (pineal) but =\< 1.5 cm residual disease do not undergo second-look surgery and undergo 3DRT or IMRT QD 5 days a week for 4 weeks.

After completion of study treatment, patients are followed up at 3, 6, and 9 months, every 4 months for 24 months, 30 months, 36 months, and then annually for up to 60 months.

Arms: arm 1: See Detailed Description
Interventions: intervention 1: 3-Dimensional Conformal Radiation Therapy intervention 2: Carboplatin intervention 3: Etoposide intervention 4: Ifosfamide intervention 5: Intensity-Modulated Radiation Therapy
Intervention descriptions: intervention 1: Undergo 3D-CRT intervention 2: Given IV intervention 3: Given IV intervention 4: Given IV intervention 5: Undergo IMRT

Protocol documents:
Prot_SAP_000.pdf: 
ACNS1123 
Page 1 
Activated: 
May 29, 2012 
Version Date: 
6/1/15 
Closed: 
October 26, 2018 
Amendment #: 
1A 
CHILDREN'S ONCOLOGY GROUP 
ACNS1123 
Phase 2 Trial of Response-Based Radiation Therapy for Patients with Localized 
Central Nervous System Germ Cell Tumors (CNS GCT) 
A Groupwide Phase II Study 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, AND SHOULD NOT BE COPIED, REDISTRIBUTED OR USED FOR ANY 
OTHER PURPOSE.  MEDICAL AND SCIENTIFIC INFORMATION CONTAINED WITHIN THIS PROTOCOL IS NOT INCLUDED TO 
AUTHORIZE OR FACILITATE THE PRACTICE OF MEDICINE BY ANY PERSON OR ENTITY.  RESEARCH MEANS A SYSTEMATIC 
INVESTIGATION, INCLUDING RESEARCH DEVELOPMENT, TESTING AND EVALUATION, DESIGNED TO DEVELOP OR 
CONTRIBUTE TO GENERALIZABLE KNOWLEDGE.  THIS PROTOCOL IS THE RESEARCH PLAN DEVELOPED BY THE 
CHILDREN’S ONCOLOGY GROUP TO INVESTIGATE A PARTICULAR STUDY QUESTION OR SET OF STUDY QUESTIONS AND 
SHOULD NOT BE USED TO DIRECT THE PRACTICE OF MEDICINE BY ANY PERSON OR TO PROVIDE INDIVIDUALIZED 
MEDICAL CARE, TREATMENT, OR ADVICE TO ANY PATIENT OR STUDY SUBJECT.  THE PROCEDURES IN THIS PROTOCOL ARE 
INTENDED ONLY FOR USE BY CLINICAL ONCOLOGISTS IN CAREFULLY STRUCTURED SETTINGS, AND MAY NOT PROVE TO 
BE MORE EFFECTIVE THAN STANDARD TREATMENT.  ANY PERSON WHO REQUIRES MEDICAL CARE IS URGED TO CONSULT
WITH HIS OR HER PERSONAL PHYSICIAN OR TREATING PHYSICIAN OR VISIT THE NEAREST LOCAL HOSPITAL OR HEALTHCARE 
INSTITUTION. 
STUDY CO-CHAIRS 
  
 
 
 
 
 
 
For Statistics and Data Center Contact Person see:  http://members.childrensoncologygroup.org 


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TABLE OF CONTENTS 
 
SECTION 
PAGE 
TABLE OF CONTENTS 
2 
STUDY COMMITTEE 
4 
ABSTRACT 
7 
EXPERIMENTAL DESIGN SCHEMA 
9 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
11 
1.1 
Primary Objectives 
11 
1.2 
Secondary Objectives 
11 
2.0 
BACKGROUND 
12 
2.1 
Stratum 1: Localized Non-Germinomatous Germ Cell Tumors (NGGCT) 
12 
2.2 
Stratum 2: Localized Germinoma 
14 
3.0 
STUDY ENROLLMENT PROCEDURES AND PATIENT ELIGIBILITY 
17 
3.1 
Study Enrollment 
17 
3.2 
Patient Eligibility Criteria 
19 
4.0 
TREATMENT PROGRAM 
23 
4.1 
Overview of Treatment Plan 
23 
4.2 
Concomitant Therapy Restrictions 
26 
4.3 
Stratum 1 (NGGCT) Administration Guidelines for Induction 
26 
4.4 
Stratum 2 (Germinoma) Administration Guidelines for Induction 
32 
5.0 
DOSE MODIFICATIONS FOR TOXICITIES 
34 
5.1 
Carboplatin 
34 
5.2 
Etoposide 
35 
5.3 
 Ifosfamide 
36 
6.0 
DRUG INFORMATION 
37 
7.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
37 
7.1 
Required Clinical, Laboratory and Disease Evaluations During Protocol Therapy 
38 
7.2 
Required Observations Following Completion of Protocol Therapy 
39 
8.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA40 
8.1 
Criteria for Removal from Protocol Therapy 
40 
8.2 
Off Study Criteria 
40 
9.0 
STATISTICAL CONSIDERATIONS 
41 
9.1 
Study Design 
41 
9.2 
Sample Size and Study Duration 
42 
9.3 
Methods of Analysis 
43 
9.4 
Gender and Minority Accrual Estimates 
47 
10.0 
EVALUATION CRITERIA 
47 
10.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
47 
10.2 
General Methodology for Determining Tumor Measurements 
47 
10.3 
Selection of Target Lesions 
49 
 
 
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10.4 
Response Criteria for Target Lesions 
49 
10.5 
Retrospective Response Review 
51 
11.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
51 
11.1 
Purpose 
51 
11.2 
Determination of Reporting Requirements 
51 
11.3 
Reporting of Adverse Events for Commercial Agents –via  CTEP-AERS 
52 
11.4 
Routine Adverse Event Reporting 
52 
12.0 
STUDY REPORTING AND MONITORING 
53 
12.1 
CDUS 
53 
12.2 
Data and Safety Monitoring Committee 
53 
13.0 
SURGICAL GUIDELINES 
53 
13.1 
Pre-operative Considerations 
54 
13.2 
Operative Management 
55 
13.3 
Management of Complications 
56 
13.4 
Second-Look Surgery 
56 
14.0 
IMAGING STUDIES REQUIRED AND GUIDELINES FOR OBTAINING 
57 
14.1 
Timing of MRIs 
57 
14.2 
MRI Guidelines for Brain/Spine Tumors 
57 
14.3 
Tumor Response Assessment 
58 
14.4 
Retrospective Central Review 
58 
15.0 
RADIATION THERAPY GUIDELINES 
59 
15.0  
General Guidelines 
59 
15.1 
Indications for Radiation Therapy 
60 
15.2 
Timing 
61 
15.3 
Emergency Irradiation 
62 
15.4 
Equipment and Methods of Delivery and Verification 
62 
15.5 
Target Volumes 
62 
15.6 
Target Dose 
66 
15.7 
Treatment Technique 
68 
15.8 
Organs at Risk 
70 
15.9 
Dose Calculations and Reporting 
71 
15.10 Quality Assurance Documentation 
73 
15.11 Definitions of Deviations in Protocol Performance 
75 
15.12 Patterns of Failure Evaluation 
76 
16.0 
NEUROPSYCHOLOGICAL FUNCTION STUDY 
77 
APPENDIX I:  CTEP AND CTSU REGISTRATION PROCEDURES 
78 
APPENDIX II:  POSSIBLE DRUG INTERACTIONS 
80 
APPENDIX III:  YOUTH INFORMATION SHEETS 
83 
REFERENCES 
87 
 
 
 
 
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AGENT                                NSC#         IND #  
 
Carboplatin                          241240         Exempt 
 
Etoposide                             141540         Exempt 
 
Ifosfamide                            109724        Exempt 
 
Filgrastim (G-CSF)              614629        Exempt 
 
Mesna                                   113891        Exempt   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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The Children's Oncology Group has received a Certificate of Confidentiality from the federal 
government, which will help us protect the privacy of our research subjects.  The Certificate 
protects against the involuntary release of information about your subjects collected during the 
course of our covered studies.  The researchers involved in the studies cannot be forced to disclose 
the identity or any information collected in the study in any legal proceedings at the federal, state, 
or local level, regardless of whether they are criminal, administrative, or legislative proceedings.  
However, the subject or the researcher may choose to voluntarily disclose the protected 
information under certain circumstances.  For example, if the subject or his/her guardian requests 
the release of information in writing, the Certificate does not protect against that voluntary 
disclosure.  Furthermore, federal agencies may review our records under limited circumstances, 
such as a DHHS request for information for an audit or program evaluation or an FDA request 
under the Food, Drug and Cosmetics Act. 
 
The Certificate of Confidentiality will not protect against mandatory disclosure by the researchers 
of information on suspected child abuse, reportable communicable diseases, and/or possible threat 
of harm to self or others 
 
 
ABSTRACT 
Primary intracranial germ cell tumors (GCTs) represent 3-5% of all central nervous system 
(CNS) tumors and occur most commonly in the pineal and suprasellar region with a male 
preponderance. Germinomas account for approximately two-thirds of intracranial GCTs and the 
remaining third are non-germinomatous germ cell tumors (NGGCTs). 1-4 NGGCTs include 
endodermal sinus tumor or yolk sac tumor (YST), choriocarcinoma (CC), embryonal carcinoma 
(EC) and more commonly mixed malignant germ cell tumors. GCTs may secrete measurable 
proteins into the blood and/or cerebro-spinal fluid (CSF). Human chorionic gonadotropin-beta 
(hCGβ) and alpha-fetoprotein (AFP) are internationally used for diagnostic purposes. 1,5-7 
Moderate elevation of hCGβ only in serum and/or CSF with characteristic neuroimaging features 
is considered diagnostic for bifocal germinoma and a biopsy is generally not mandated.  
Abnormal AFP levels and/or hCGβ levels in the serum or CSF >50 mIU/mL are generally 
considered to be consistent with NGGCTs and a biopsy is not required for diagnosis. However, 
biopsied germinomas have been reported to secrete hCGβ levels of up to 200 mIU/mL with no 
adverse impact upon survival. 8,9 Surgery/tissue biopsy is required for diagnosis in the absence of 
tumor marker elevation. 
 
The late effects of craniospinal radiation (CSI) have long been recognized, particularly in 
children.  Long-term sequelae include auditory and visual impairment, endocrine and 
neurocognitive dysfunction and secondary malignancies. 23-25, 10-14 
 
This protocol aims to reduce treatment burden in select groups of CNS GCTs, that is, localized 
NGGCT and germinoma. Localized disease as defined by this study includes tumors involving 
the suprasellar region, pineal region, both (bifocal), or elsewhere within the ventricles.  
 
The objective of this study is to investigate whether pre-radiation therapy followed by response 
based radiation therapy (RT) will yield a high progression free survival (PFS) while reducing the 
 
 
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risk of long term neurocognitive sequelae and maintaining quality of life (QoL). Cognitive, 
social, emotional and behavioral functioning will be evaluated and longitudinally modeled for all 
patients (on both strata) using the ALTE07C1 protocol. 
 
This study consists of 2 treatment strata:  Stratum 1 for patients with localized NGGCTs and 
Stratum 2 for patients with localized germinomas. Treatment for NGGCTs (Stratum 1) will 
determine, as measured by the 3-year progression-free survival (PFS) rate, whether dose and 
volume of irradiation can be safely reduced to 30.6 Gy whole ventricular field irradiation (WVI) 
and 23.4 Gy primary site boost in the subgroup of children and young adults (ages 3-21 yrs) with 
localized NGGCT who have a magnetic resonance imaging (MRI) confirmed complete response 
(CR) or partial response (PR) in response to induction chemotherapy and negative serum and 
cerebrospinal fluid (CSF) tumor markers or in patients who have less than a PR after induction 
therapy with negative tumor markers who undergo second-look surgery and are found to have 
only mature teratoma, residual scar or fibrosis and meet the criteria for CR or PR.   
 
Treatment for germinoma (Stratum 2) will determine, as measured by the 3-year PFS rate, 
whether simplified chemotherapy prior to dose-reduced radiation therapy is effective for treating 
children and young adults (ages 3-21 yrs) with localized germinoma who present with serum and 
CSF hCGβ ≤ 50 mIU/ml. PFS and survival distributions of localized germinoma patients who 
present with serum and/or CSF hCGβ > 50 mIU/ml and ≤ 100 mIU/ml will be estimated.  
 
 
 
 
 
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PR/SD/PD 
Normalization of 
Markers 
Positive 
Markers 
  Off 
Protocol     
Therapy*** 
Second-Look* 
Surgery** 
CR/PR** 
< PR 
CR/PR  
Normalization of Markers 
RADIATION THERAPY 
30.6 Gy Whole Ventricular 
Irradiation (WVI) + 23.4 Gy 
Boost to the Primary Site 
INDUCTION (6 CYCLES) 
Carboplatin/Etoposide (Cycle A) 
alternating with 
Ifosfamide/Etoposide (Cycle B) 
ENROLLMENT ON ALTE07C1 
STUDY ENROLLMENT 
PD with Increasing 
Markers: Off 
Protocol Therapy 
 
EXPERIMENTAL DESIGN SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
          RESPONSE EVALUATION 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*Second-look surgery is strongly recommended but not required. Patients with increasing mass and normalization of 
markers should also proceed to second surgery. If a mature teratoma and/or fibrosis are removed, the patient remains on 
protocol therapy and response should be assessed according to the radiographic response criteria listed in Section 10. If  
patient has viable tumor after second–look surgery or second-look surgery is not performed and patients do NOT meet 
criteria for CR or PR, they will be off protocol therapy. 
**Patients with mature teratoma/scar/fibrosis only on 2nd look surgery and who fit definitions of CR/PR will be eligible for 
reduced dose/volume XRT. 
 
CR: Complete response. See Section 10 for specific radiographic and tumor marker definitions of complete response. 
PR: Partial response. See Section 10 for specific radiographic and tumor marker definitions of partial response. 
 
Schema 1: NGGCT Stratum 1 
 
 
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Schema 2: Germinoma Stratum 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
           RESPONSE EVALUATION 
 
 
 
 
 
 
 
                     
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
INDUCTION CHEMOTHERAPY 
Carboplatin/Etoposide (Cycle A)  
x 4 CYCLES 
PR or SD or PD* 
Normalization of Markers 
Second-Look  
Surgery* 
CR/CCR  
Normalization 
of Markers 
RADIATION THERAPY 
18 Gy WVI + 12 Gy 
Boost to the Primary 
Site 
ENROLLMENT ON ALTE07C1 
STUDY ENROLLMENT 
RADIATION 
THERAPY 
24 Gy WVI + 12 Gy 
Boost to the Primary 
Site 
CR: 
Complete Response    
CCR:     Continued Complete Response    
PR:        Partial Response  
SD:  
Stable Disease 
PD:  
Progressive Disease 
See Section 10 for specific radiographic and tumor marker definitions of CR, CCR, PR, SD and PD.  
 
* Germinoma patients with PR, SD with > 1.5 cm residual and PD with normalization of hCGβ should be considered for 
second-look surgery. If histology confirms fibrosis, scar, mature teratoma or non-viable tumor, WVI to 18 Gy followed by 
local boost of 12 Gy to a total dose of 30 Gy will be delivered. Patients with > 0.5 cm (suprasellar) or > 1 cm (pineal) but 
≤ 1.5 cm residual who do not undergo second-look surgery will be treated with WVI to 24 Gy followed by local boost of 
12 Gy to a total dose of  36 Gy. If second-look surgery is not performed or patients do not meet criteria for at least PR 
with ≤ 1.5 cm residual disease or findings following second–look surgery indicate residual viable tumor, patients will be 
removed from protocol therapy. 
 
 PD with Increasing  
Markers or No 
Second-Look 
Surgery with <PR  
Off Protocol 
Therapy 
PD with Increasing 
Markers: Off Protocol 
Therapy 
Mature 
Teratoma or 
Non-Viable 
Tumor 
PR or SD  ≤ 1.5 cm residual * 
But > 0.5 cm Suprasellar or > 
1 cm Pineal 
Normalization of Markers 
No Second-Look Surgery 
Viable Tumor 
 
 
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1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
1.1 
Primary Objectives 
 
1.1.1 
To determine, as measured by the 3-year progression-free survival (PFS) rate and 
patterns of failure, whether dose and volume of irradiation can be safely reduced 
to 30.6 Gy whole ventricular field irradiation (WVI) plus 23.4 Gy primary site 
boost instead of 36 Gy craniospinal irradiation (CSI) plus primary site boost in 
the subgroup of children and young adults (ages 3 to ≤ 21 years) with localized 
non-germinomatous germ cell tumor (NGGCT) who have a magnetic resonance 
imaging (MRI) and tumor marker criteria (CSF and serum) for confirmed 
complete response (CR) or partial response (PR) to induction chemotherapy and 
negative serum and cerebrospinal fluid (CSF) tumor markers OR in patients who 
have less than a PR after induction chemotherapy with negative tumor markers 
who undergo a second-look surgery and are found to have only mature teratoma, 
residual scar or fibrosis and fit the definition of CR/PR after second-look surgery.  
 
1.1.2 
To determine, as measured by the 3-year PFS rate and patterns of failure, 
whether simplified chemotherapy followed by dose-reduced radiation therapy is 
effective for treating children and young adults (ages 3 to ≤ 21 years) with 
localized primary central nervous system (CNS) germinoma who present with 
serum and/or CSF human chorionic gonadotropin-beta (hCGβ) ≤ 50 mIU/ml. 
 
1.1.3 
To prospectively evaluate and longitudinally model the cognitive, social, and 
behavioral functioning of children and young adults who are treated with reduced 
radiation dose and volume of irradiation in Stratum 1 (NGGCT) and with dose-
reduced radiation therapy in Stratum 2 (Germinoma) using the ALTE07C1 
protocol. This objective will be assessed independently for the two strata. 
 
1.2 
Secondary Objectives 
 
1.2.1 
To estimate the PFS and overall survival (OS) distributions of patients with 
NGGCT treated with 30.6Gy WVI and involved field focal (IFR) boost to 54Gy.  
 
1.2.2 
To estimate the PFS and OS distributions of localized germinoma patients who 
present with a) serum and/or CSF hCGβ ≤ 50mIU/ml and b) serum and/or CSF 
hCGβ > 50mIU/ml and ≤ 100mIU/ml. 
 
 
 
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2.0 
BACKGROUND 
2.1 
Stratum 1: Localized Non-Germinomatous Germ Cell Tumors (NGGCT) 
 
2.1.1 
Role of Chemotherapy 
Chemotherapy regimens utilizing cisplatin, etoposide and either ifosfamide or 
cyclophosphamide have greatly improved the outcomes of patients with GCTs 
over the last few decades. 15-17  In the Second International CNS GCT Study 
Group Protocol, 16 of 17 assessable patients achieved a CR or PR after two 
courses of chemotherapy. 18 In a study by Robertson et al, 9 of 12 patients 
demonstrated objective responses to 4 cycles of platinum-based chemotherapy. 19 
Carboplatin regimens have shown similar efficacies as compared to cisplatin 
regimens with the added benefit of easier out-patient administration and less 
toxicity. 5,19-21 Chemotherapy only strategies, however, despite resulting in high 
response rates, did not provide an acceptable PFS in NGGCT patients. 20-24  The 
most recent and completed Children’s Oncology Group (COG) ACNS0122 trial 
for NGGCT patients used a combination of carboplatin/etoposide alternating 
with ifosfamide/etoposide for a total of 6 induction cycles.  Due to the safety and 
efficacy of this chemotherapy regimen and in an attempt to maintain a relevant 
comparison group, the current protocol’s NGGCT stratum will use the same 
chemotherapeutic agents as ACNS0122.   
 
2.1.2 
Role of Chemoradiotherapy 
Radiation therapy (RT) plays an important role in the treatment of NGGCT; 
however, regimens that use RT alone have only achieved 5-year OS rates of 
20%-40%, and most patients relapse within 18 months of diagnosis. 2,25-27  
Combined modality therapy including chemotherapy and RT is considered the 
current standard of care. Since CSI and whole brain irradiation (WBI) are 
associated with significant late effects, minimizing exposure to RT by stratifying 
patients according to risk of disease progression after combined modality therapy 
has been the hallmark of recent international clinical trial designs. 10-12  COG 
Study ACNS0122 utilized 36 Gy CSI with IFR to 54 Gy following 6 cycles of 
induction chemotherapy, and this resulted in a 2-year PFS and OS of 84.4 +/- 4% 
and 93 +/- 3%, respectively. 28-31 In the Société Internationale d’Oncologie 
Pédiatrique (SIOP) CNS GCT-96 trial (n=172), those patients with localized 
disease (n=135) received 4 courses of chemotherapy (cisplatin, ifosfamide and 
etoposide) followed by IFR to 54 Gy. At a median follow-up of 39 months, the 
reported PFS for the patients with localized disease was 69 + 5%. There were 33 
relapses in this group including 18 that were local, 3 that were distant and 12 that 
were combined relapses.  This data supports the use of a more localized field of 
radiation as the failures were predominantly local and distant spinal relapse were 
quite rare. 32 The Japanese GCT study group treated “intermediate prognosis” 
patients with 5 cycles of carboplatin and etoposide followed by WVI to 30.6 Gy 
and IFR to 50 Gy and showed a 10-year PFS and OS rates of 81.5% and 89.3%, 
respectively. 8,9 Patients with predominantly malignant germ cell tumor elements 
formed the Japanese “poor prognosis group” and were treated with 3 cycles of 
ifosfamide, cisplatin, etoposide and CSI. They received an additional 5 cycles of 
the same chemotherapy after CSI. The 10-year PFS and OS rates were 58.8% and 
62.7%, respectively. 8,9  
 
 
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Given the excellent results reported from the Japanese cooperative group, the 
SIOP CNS GCT-96 and COG ACNS0122 trial, the combination of induction 
chemotherapy followed by WVI with IFR to the primary site appears to be a very 
promising approach for a select group of NGGCT patients.  
 
2.1.3 
Rationale for Choosing Patients with CNS NGGCT who achieve a Complete or 
Partial Response to Induction Chemotherapy as a Subgroup for Reducing 
Radiation Dose and Volume  
The international experience of stratifying CNS NGGCT patients based upon 
different risk groups such as tumor histology, serum and/or CSF tumor markers 
(AFP and hCGβ) and responses to neoadjuvant chemotherapy gives insight into 
what subgroups are most appropriate for reduced radiation. Response to 
induction chemotherapy has most consistently proven prognostic in previous 
clinical trials and seems most appropriate for stratification of patients. Of the 34 
patients in the SIOP CNS GCT ’96 trial with residual disease at the end of 
radiotherapy, almost half (47%) relapsed and had a much worse PFS (37 + 10%) 
compared to those patients in CR post-chemoradiotherapy (86 + 4%). 33 In the 
Japanese cooperative group study, for “intermediate-risk” group patients, only 1 
of 13 patients relapsed who achieved a CR after receiving between 5 to 8 cycles 
of chemotherapy compared to 2 out of 10 patients who achieved less than 
complete response. 8,9   
 
In the First International Germ Cell Tumor Study, 26 NGGCT patients received 
four cycles of carboplatin, etoposide and bleomycin. Patients with less than CR 
received two additional cycles intensified by cyclophosphamide. All 5 patients 
with less than CR died of disease progression compared to 15 out of 21 (71.4%) 
patients with CR who were alive without disease at two years from diagnosis. 20 
In the Second International CNS Germ Cell Study Group Protocol, 20 NGGCT 
patients were treated with two to five courses of cisplatin, etoposide, 
cyclophosphamide and bleomycin. Of the 17 assessable patients for response, 11 
achieved CR after two courses and five achieved PR. The median PFS and OS in 
CR group were 62 and 75 months, respectively, compared to 23 and 41 months in 
the PR group. 18 Although the complete response rates to chemotherapy in these 
studies were very promising (65 to 76%), survival data in the PR group were less 
so, as a result of a chemotherapy only strategy.  
 
The data released documenting the outcomes of patients enrolled on COG 
ACNS0122 are very promising for patients who achieved a CR (complete 
radiographic and tumor marker response) and PR (>65% reduction in measurable 
disease radiographically and normalization of tumor markers) after induction 
chemotherapy.  Of the 104 patients enrolled on ACNS0122, 79 were determined 
to have localized tumors. Twenty five of 79 patients (31.65%) achieved a CR and 
17 of 79 (21.5%) achieved a PR at the end of induction. Of the 18 patients who 
underwent second-look surgery after induction therapy, 8 were found to have had 
only a mature teratoma, residual scar or fibrosis on pathology. The median 
follow-up time for the 64 patients without an event is 3.5 years (range: 73 days to 
6 years).  Three-year EFS were 92%, 94.1% and 85.7% for these three groups, 
respectively, without a statistical difference in outcomes among the three groups. 
Hence, based on these excellent outcomes in these three groups in ACNS0122, 
 
 
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we hypothesize that those patients with a CR or PR to induction chemotherapy 
(see Section 10 for response definition) and patients whose second-look surgery 
confirms mature teratoma or scar/fibrosis would be the appropriate group to 
safely reduce dose and volume of irradiation.   
 
2.1.4 
Growing Teratoma Syndrome and Role of Second-Look Surgery 
Often times, residual masses post-therapy can be necrosis and fibrosis devoid of 
tumor or even mature growing teratoma, a phenomenon known as growing 
teratoma syndrome. 34 It is important to distinguish this entity from residual 
active or progressive malignancy.  On the COG ACNS0122 study, there have 
been 21 second-look surgeries on 19 patients.  The pathology on these surgeries 
included 13 teratomas (4 growing teratoma syndrome), 4 fibrosis devoid of tumor 
and 4 NGGCT. 31  
 
2.2 
Stratum 2: Localized Germinoma 
Historically, CSI followed by a boost to the primary tumor area has been regarded as the 
standard treatment for intracranial germinoma. 35-37 However the role of CSI in the 
treatment of localized germinoma has been called into question due to its late effects and 
the low incidence of spinal relapses in series that have omitted spinal irradiation. 38-43 
These data support the view that it may not be necessary to utilize CSI for patients with 
non-metastatic germinoma. Excellent responses have been achieved with whole brain 
irradiation (WBI) or WVI followed by a boost to the primary tumor(s). 41,44,45 Systemic 
chemotherapy followed by IFR has been tested as a means of reducing radiation doses 
and/or volume while maintaining high cure rates. 46,47 The finding of relapses within the 
ventricles (but outside the local radiation field) in multiple studies has induced the SIOP, 
French Society of Pediatric Oncology (SFOP), and Japanese Brain Tumor clinical trial 
groups to change from IFR to WVI following chemotherapy for non-metastatic CNS 
germinoma. 7,48,49  
 
Local control rates within the irradiated whole ventricular volume remain over 90%.  In 
addition, most relapsing patients are successfully salvaged with chemotherapy and/or RT. 
50-53  This encourages exploration of further reduction in CSI and WVI radiation doses in 
an effort to reduce neurocognitive adverse late effects while maintaining excellent 
disease control.   
 
A variety of chemotherapy regimens have produced similar response and survival rates. 
Therefore, the main issue in the management of these patients relates to the short term 
and long term safety of the chemotherapy used. The use of carboplatin in extracranial 
NGGCTs has raised concerns, following the results of two randomized studies that 
demonstrated the superiority of cisplatin over carboplatin.  However, in CNS 
germinoma, carboplatin regimens have shown similar efficacy when compared with 
cisplatin regimens. 20,54  An institutional review of patients treated either with cisplatin 
and/or ifosfamide based chemotherapy revealed major risks for patients suffering from 
diabetes insipidus (DI). Despite vigilant monitoring of electrolytes and hormone 
(DDAVP) substitution adjustments significant variations in sodium levels and 
unexpected episodes of hyponatremia with consecutive complications and prolongation 
of hospital admissions were documented. 55,56 Therefore an ifosfamide-sparing regimen 
as successfully documented by the Japanese GCT study group.7,57 and Children’s 
Hospital Los Angeles experience should be adopted. 58-60  These data strongly suggest 
 
 
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that chemotherapy in germinoma can be safely simplified using a combination of 
carboplatin and etoposide with the advantage of easier out-patient administration when 
appropriate and reduced risk of hyperhydration-associated metabolic complications while 
still maintaining high cure rates with a potentially lower risk of late effects. 
 
2.2.1 
Human Chorionic Gonadotropin (hCG & hCGβ) and Need for Tissue Diagnosis 
There are conflicting data regarding the maximum level of hCGβ in germinoma 
and its prognostic significance. Sawamura et al reported that 14 of 74 germinoma 
patients had elevated hCG serum levels between 5-200 mIU/ml. The 10-year OS 
for patients with germinoma with normal serum hCG was 90%, which was 
significantly higher than the 60% for patients with hCGβ-secreting germinomas. 
61 However, in a retrospective review of germinoma patients with (n=39) and 
without (n=131) hCGβ elevation, no statistical difference in response to 
chemotherapy, clinical outcome or rate of recurrence was found. 62 This finding 
is supported by other studies, underscoring the fact that elevated hCGβ does not 
affect outcome. 40,63 The Japanese GCT Study Group used an intensified protocol 
for patients with germinoma and hCGβ secretion with higher doses of radiation 
therapy and 5 courses of post-irradiation chemotherapy. In an interim report of 
the current Japanese protocol, Matsutani et al reported no statistical difference in 
serum hCG or hCGβ between recurrent and non-recurrent patients. Following 
these results the Japanese CNS-GCT study group currently treats all localized 
germinoma patients (regardless of the level of hCGβ secretion) with the same 
regimen consisting of 3 cycles of carboplatin and etoposide followed by WVI at 
a dose of 24 Gy.7 
 
Based on these data and intensive review within the CNS study committee, the 
present study’s Stratum 2 (Germinoma) will include patients with elevations of 
serum or CSF hCGβ levels up to 100 mIU/ml provided AFP levels are in the 
normal range.  
 
2.2.2 
Subclinical Ventricular Metastases and Bifocal Germinoma 
Chemotherapy serves two roles defined by the irradiated volume: chemotherapy 
may eradicate neuraxis and extra-CNS metastatic disease outside of the volume 
of irradiation and it may reduce the tumor burden or increase the sensitivity of 
tumor cells to irradiation within the irradiated volume. The burden of metastatic 
disease that may be eradicated using chemotherapy and volume of residual 
tumor or magnitude of the response to chemotherapy that allows lower doses of 
irradiation to be utilized are unknown. That ventricular irradiation is critical to 
the success of combined modality regimens suggests that subclinical ventricular 
metastatic disease is present at the time of diagnosis in a significant proportion 
of patients and that current chemotherapy regimens are inadequate to eradicate 
this subclinical disease. In keeping with past protocols and series that have 
obtained excellent results, metastatic disease will be defined as neuroimaging 
evidence of intracranial or spinal metastatic disease or CSF involvement based 
on cytological evaluation of fluid obtained from a lumbar puncture. Therefore, 
intraoperative or endoscopic observed studding of ventricles alone (without 
evidence of seeding on MRI or CSF) will NOT be used to classify patients as 
having metastatic disease. Similarly, patients with bifocal lesions (pineal and 
suprasellar lesions) fare as well as those with unifocal lesions when treated with 
chemotherapy and ventricular irradiation. 49,64,65 These patients will be eligible 
 
 
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for study participation and, in accordance with the SFOP and SIOP approach, a 
biopsy will NOT be required if the clinical presentation (evidence of DI in 
particular) and imaging characteristics are typical in patients who present with 
serum and CSF hCGβ ≤ 50mIU/ml. Germinoma located within a ventricle with 
unifocal parenchymal extension will also be treated as localized germinoma. 
 
2.2.3 
Neurocognitive Outcomes and QOL  
The late effects of CSI have long been recognized, particularly in children.  Long 
term sequelae include auditory and visual impairment, endocrine and 
neurocognitive dysfunction and secondary malignancies. 10-14 Neurocognitive 
sequelae associated with CSI has garnered increased attention in the past two 
decades, with the resulting research consistently demonstrating treatment-related 
deficits in core neurocognitive processes such as attention, working memory, 
executive functioning, and processing speed. 68,69  These deficits interfere with 
age-appropriate acquisition of knowledge so that overtime declines may emerge 
in IQ and academic achievement scores. 70-71 Additionally, neurocognitive late 
effects are often accompanied with impairments in social and behavioral 
functioning, and may adversely impact functional capacity well into adulthood. 
72-74 A retrospective study evaluating long-term QOL in 52 germinoma survivors 
into adulthood identified significant problems: only 6 of 44 patients were 
married, 21 patients had no occupation and 7 of 11 formerly employed patients 
had left their jobs.66  
 
The literature on neurocognitive and quality of life outcomes specifically among 
survivors of CNS Germ Cell tumors is limited, and the findings to date are based 
on reports with small sample size and/or retrospective methodology. The 
majority of these reports indicate at least some degree of cognitive impairment. 
75-77 More recently, O’Neil et al 78 reported preservation of neurocognitive, social, 
and emotional functioning in their sample of 20 pediatric CNS Germinoma 
patients treated with chemotherapy and reduced dose ventricular field irradiation. 
Their results did, however, show trends towards lowered performance in 
processing speed scores, and the continued overall preservation remains to be 
seen with longer follow up time. There clearly is a need to assemble 
psychometrically sound data in a sufficiently large sample using a prospective 
design framework to document longitudinal trends in these outcomes.  
 
Since September 2008, a standardized battery of age-appropriate cognitive, 
social, emotional, and behavioral tests is provided by the open COG protocol 
ALTE07C1. The ACNS1123 study will enroll patients onto ALTE07C1 to 
evaluate cognitive, social, emotional and behavioral functioning post-diagnosis. 
The current study will be the first prospective study evaluating neurocognitive 
function longitudinally in a homogenously treated cohort of patients with CNS 
GCT. The resulting longitudinal models will describe changes in neurocognitive 
function. These models will also provide the means of exploring associations of 
covariates such as tumor location, age and the dose/volume of irradiation with 
outcomes. 
 
 
 
 
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3.0 
STUDY ENROLLMENT PROCEDURES AND PATIENT ELIGIBILITY 
 
3.1 
Study Enrollment 
 
3.1.1 
Patient Registration 
Prior to enrollment on this study, patients must be assigned a COG patient ID 
number. This number is obtained via the COG Registry system 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.   
 
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).  
 
 
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 I for detailed CTEP Registration Procedures for Investigators 
and Associates, and CTSU Registration Procedures including: how to download site 
registration documents; requirements for site registration, submission of regulatory 
documents and how to check your site’s registration status. 
 
3.1.2 
IRB Approval 
Sites must obtain IRB/REB approval for this protocol and submit IRB/REB 
approval and supporting documentation to the Cancer Trials Support Unit 
(CTSU) Regulatory Office before they can be approved to enroll patients. 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 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), 
E-mailed (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, in 
addition to marking your submissions as ‘URGENT’ and faxing the regulatory 
documents, 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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Study centers 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. This information will be provided to the CTSU Regulatory 
Office from the CIRB at the time the site’s Signatory Institution accepts the 
CIRB approval. The 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 (i.e., laboratory certifications, 
protocol-specific training certifications, or modality credentialing) must be 
submitted to the CTSU Regulatory Office or compliance communicated per 
protocol instructions. 
 
3.1.3 
Study Enrollment 
Patient enrollment will be facilitated using the Oncology Patient Enrollment 
Network (OPEN). OPEN is a web-based registration system available on a 24/7 
basis. To access OPEN, the site user must have an active CTEP-IAM account 
(check at < https://eapps-ctep.nci.nih.gov/iam/index.jsp >) and a 'Registrar' role 
on either the lead protocol organization (LPO) or participating organization 
roster. 
 
All site staff will use OPEN to enroll patients to this study. It is integrated with 
the CTSU Enterprise System for regulatory and roster data and, upon enrollment, 
initializes the patient position in the Rave database. OPEN can be accessed at 
https://open.ctsu.org or from the OPEN tab on the CTSU members’ side of the 
website at https://www.ctsu.org.  
 
Prior to accessing OPEN, site staff and the results from the rapid central 
pathology screening review have confirmed the patient is eligible. 
• 
All eligibility criteria have been met within the protocol stated 
timeframes. 
• 
All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable). 
 
Note: The OPEN system will provide the site with a printable confirmation of 
registration and treatment information. Please print this confirmation for your 
records. 
 
Further instructional information is provided on the CTSU members' web site 
OPEN tab or within the OPEN URL (https://open.ctsu.org). For any additional 
questions 
contact 
the 
CTSU 
Help 
Desk 
at 
1-888-823-5923 
or 
ctsucontact@westat.com. 
 
 
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3.1.4 
Timing 
Patients must be enrolled before treatment begins. The date protocol therapy is 
projected to start must be no later than five (5) calendar days after the date of 
study enrollment. Patients who are started on protocol therapy on a Phase II 
study prior to study enrollment will be considered ineligible.  
 
Timing for enrollment will begin after the last definitive surgical intervention or 
clinical diagnosis. See Section 3.2.5. 
 
All clinical and laboratory studies to determine eligibility must be performed 
within 14 days prior to enrollment unless otherwise indicated in the eligibility 
section below. 
 
3.2 
Patient Eligibility Criteria 
Important note: The eligibility criteria listed below are interpreted literally and 
cannot be waived (per COG policy posted 5/11/01). All clinical and laboratory data 
required for determining eligibility of a patient enrolled on this trial must be 
available in the patient's medical/research record which will serve as the source 
document for verification at the time of audit.  
 
All clinical and laboratory studies to determine eligibility must be performed within 
14 days prior to enrollment.  Laboratory values need not be repeated if therapy 
starts within 14 days of obtaining labs to assess eligibility. If a post-enrollment lab 
value is outside the limits of eligibility, or laboratory values are >14 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. Imaging 
studies must be obtained as outlined in Section 3.2.3 . 
 
See Section 7.1 for required studies to be obtained prior to starting protocol therapy. 
 
INCLUSION CRITERIA 
 
3.2.1 
Age 
Patients must be ≥ 3 years and ≤ 21 years at the time of study enrollment.  
 
3.2.2 
Diagnosis  
Patients must be newly diagnosed with localized primary CNS NGGCT (Stratum 
1) or localized primary CNS germinoma (Stratum 2). Germ cell tumors located in 
the suprasellar, pineal, bifocal (pineal + suprasellar) and ventricles are eligible. 
Tumors present in the above mentioned locations and with unifocal parenchymal 
extension are eligible. Please see exclusion criteria in Section 3.2.6. 
 
• 
Stratum 1( NGGCT): Patients must have one of the following criteria. 
o 
Patients with serum and/or CSF hCGβ > 100 mIU/mL or any 
elevation of serum and/or CSF AFP > 10 ng/mL or greater than 
 
 
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the institutional normal are eligible, irrespective of biopsy 
results.  
 
o 
Patients with any of the following elements on biopsy/resection 
are eligible, irrespective of serum and/or CSF hCGβ and AFP 
levels: endodermal sinus tumor (yolk sac), embryonal 
carcinoma, choriocarcinoma, malignant/immature teratoma and 
mixed GCT with malignant GCT elements 
 
• 
Stratum 2 (Germinoma):  
Patients must have both serum and CSF markers obtained (unless 
obtaining CSF is medically contraindicated) and must have one of the 
following criteria to be eligible.  
 
o 
Patients with institutional normal AFP (or ≤ 10 ng/mL if no 
institutional normal exists) in both serum and CSF (unless 
medically contraindicated) AND hCGβ 5 - ≤ 50 mIU/ml in 
serum and/or CSF (unless medically contraindicated) (only 1 is 
required to be elevated) are eligible..  No histologic confirmation 
required.   
 
o 
Patients with bifocal (pineal + suprasellar) involvement or pineal 
lesion with diabetes insipidus (DI) AND hCGβ ≤ 100 mIU/ml in 
serum and/or CSF AND institutional normal AFP (or ≤ 10 
ng/mL if no institutional normal exists) in both serum and CSF 
(unless medically contraindicated) are eligible.  No histologic 
confirmation required. 
  
o 
Patients with histologically confirmed germinoma or germinoma 
mixed with mature teratoma and hCGβ ≤ 100 mIU/ml in serum 
and/or CSF and institutional normal AFP (or ≤ 10 ng/mL if no 
institutional normal exists) in both serum and CSF (unless 
medically contraindicated)  are eligible.. 
 
Note: Patients who had more than one surgery/biopsy are eligible.  
 
3.2.3 
Imaging 
Imaging studies must be obtained within 2 weeks prior to study enrollment. 
 
Cranial MRI 
All patients must have a cranial MRI with and without gadolinium at diagnosis/prior 
to enrollment. If surgical resection is performed, patients must have pre-operative 
and post-operative cranial MRI with and without gadolinium. The post-operative 
brain MRI should be obtained within 72 hours of surgery. If patient has a biopsy 
only, post-operative cranial MRI is recommended but not required. 
 
Spinal MRI 
All patients must have a spine MRI with gadolinium obtained at diagnosis/prior to 
enrollment. 
 
 
 
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Note: If the spine study is performed for the first time after surgical resection or 
biopsy, it is recommended to be obtained with and without gadolinium. 
 
3.2.4 
CSF  
 
 
 
3.2.4.1 
CSF Cytology 
Lumbar CSF must be obtained prior to study enrollment unless medically 
contraindicated. If a patient undergoes surgery and lumbar CSF cannot be 
obtained at this time, then it should be performed at least 10 days following 
surgery before study enrollment. False positive cytology can occur within 10 
days of surgery.  
 
Note: Patients with positive CSF cytology obtained prior to 10 days after surgery 
may have cytology repeated to determine eligibility.  
 
 
 
 
3.2.4.2 
CSF Tumor Markers 
Patients must have CSF tumor markers obtained prior to enrollment unless 
medically contraindicated. Ventricular CSF obtained at the time of CSF diversion 
procedure (if performed) is acceptable for tumor markers but lumbar CSF is 
preferred. In case CSF diversion and biopsy/surgery are combined, CSF tumor 
markers should be collected first.  
 
3.2.5 
Timing 
Patients must be enrolled on ALTE07C1 prior to enrollment on ACNS1123.  
 
Patients must be enrolled within 31 days of definitive diagnostic surgery (Day 0) 
or clinical diagnosis.    
 
3.2.6 
Organ Function Requirements 
3.2.6.1 Adequate Bone Marrow Function Defined As: 
- 
Peripheral absolute neutrophil count (ANC) ≥ 1,000/µL 
- 
Platelet count ≥ 100,000/µL (transfusion independent) 
- 
Hemoglobin ≥ 8.0 g/dL (may receive RBC transfusions) 
 
3.2.6.2 Adequate Renal Function Defined As: 
- 
Creatinine clearance or radioisotope GFR ≥ 70 mL/min/1.73 m2 or 
- 
A serum creatinine based on age/gender as follows: 
 
 
 
 
 
 
 
 
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. 
 
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 
 
 
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3.2.6.3 Adequate Liver Function Defined As: 
- 
Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age, and 
- 
SGOT (AST) and SGPT (ALT) < 2.5 x upper limit of normal (ULN) for 
age. 
 
3.2.6.4 Central Nervous System Function Defined As: 
- 
Patients with seizure disorder may be enrolled if well controlled. 
- 
Patients must not be in status, coma or assisted ventilation prior to study 
enrollment. 
 
EXCLUSION CRITERIA 
 
3.2.7 
Mature Teratoma 
 
 
Patients with mature teratoma or completely resected immature teratoma with 
normal tumor markers are not eligible. 
 
3.2.8 
Tumors Outside Ventricles 
 
Patients with tumors located outside the ventricles (basal ganglia, thalamus) are 
not eligible. 
 
3.2.9 
Metastatic Disease 
Patients with metastatic disease by cranial or spinal MRI evaluation or CSF 
cytology (unless medically contraindicated) are not eligible. 
 
3.2.10 Prior Therapy 
Patients must not have received any prior tumor-directed therapy other than 
surgical intervention and corticosteroids. 
 
3.2.11 Pregnancy and Breast Feeding 
 
3.2.11.1 
Female patients who are pregnant are ineligible. 
 
3.2.11.2 
Lactating females are not eligible unless they have agreed not to breastfeed their 
infants. 
 
3.2.11.3 
Female patients of childbearing potential are not eligible unless a negative 
pregnancy test result has been obtained. 
 
 
3.2.11.4 
Sexually active patients of reproductive potential are not eligible unless they 
have agreed to use an effective contraceptive method for the duration of their 
study participation. 
 
 
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REGULATORY 
 
3.2.12 
All patients and/or their parents or legal guardians must sign a written informed consent. 
 
3.2.13 
All institutional, FDA, and NCI requirements for human studies must be met. 
 
 
4.0 
TREATMENT PROGRAM 
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). 
 
4.1 
Overview of Treatment Plan 
 
Induction Chemotherapy  
All patients must begin therapy within 31 days of definitive diagnostic surgery or clinical 
diagnosis and 5 calendar days from enrollment on study. Each subsequent cycle of 
Induction chemotherapy will begin when ANC > 1,000/µL and platelets > 100,000/µL and 
when off filgrastim (G-CSF) for at least 48 hours (if applicable). 
 
Cycle A: (21 Days)  
Carboplatin (600 mg/m2/dose) Day 1  
Etoposide (150 mg/m2/dose) Days 1-3  
 
Cycle B: (21 Days) 
 
 
Ifosfamide (1800 mg/m2/dose) Days 1-5 
Etoposide (100 mg/m2/dose) Days 1-5  
Mesna (1800mg/m2/day) Days 1-5 
Filgrastim (G-CSF) (5 micrograms/kg/day) Days 6-15 or until ANC > 1500/µL 
 
Growing Teratoma Syndrome 
Second-look surgery is strongly recommended in patients with normalization of markers 
who fail to achieve a radiographic CR or PR to induction chemotherapy and in patients 
with increasing size of the mass on MRI scan and negative markers at any time during 
Induction chemotherapy. If a mature teratoma and/or fibrosis are removed, the patient 
remains on protocol and should continue therapy as planned. Response should be 
assessed according to the radiographic and tumor marker response criteria listed in 
Section 10. 
 
 
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Chemotherapy for NGGCT (Stratum 1) 
 
Week 
0 
3 
Evaluation 
            6            9              Evaluation                    12     15         Response Evaluation 
Cycle A Cycle B (MRI/tumor markers)  Cycle A  Cycle B (MRI/tumor markers) Cycle A Cycle B  (MRI/tumor markers) 
 
 
 
Patients will receive 6 cycles of induction chemotherapy consisting of carboplatin and 
etoposide (Cycles 1, 3, and 5) alternating with ifosfamide and etoposide (Cycles 2, 4, and 6).  
The entire length of Induction is approximately 18 weeks unless delay occurs due to 
myelosuppression or unanticipated toxicity.   
 
Following induction chemotherapy, those patients in CR or PR will undergo radiation 
therapy 30.6 Gy WVI with IFR boost to 54 Gy in 1.8 Gy daily fractions. 
 
For those patients with PR, SD or PD and normalization of tumor marker levels in serum 
and CSF, second- look surgery is strongly recommended.  Patients who achieve CR/PR via 
second-look surgery (and have histology consistent with fibrosis, scar or mature teratoma) 
will then proceed to radiation therapy as above. 
 
Patients with positive markers or who have < PR after induction chemotherapy/second-look 
surgery will be removed from protocol therapy.  
 
Patients with residual viable malignant elements (except mature teratoma) on second-look 
surgery will be removed from protocol therapy.   
 
Patients who are unable to undergo a second-look surgery due to safety or other reasons, 
will be taken off protocol therapy if they do not meet criteria for PR/CR (imaging and 
tumor markers).  
 
 
Chemotherapy for Germinoma (Stratum 2) 
Week 
0 
     3 
           Evaluation            
        6 
 
9 
      Response Evaluation  
 
Cycle A      Cycle A       (MRI/tumor markers)     Cycle A          Cycle A                (MRI/tumor markers)  
 
Patients will receive 4 cycles of Induction chemotherapy consisting of carboplatin and 
etoposide.  The entire length of Induction is 12 weeks unless delay occurs due to 
myelosuppression or unanticipated toxicity.   
 
Following Induction those patients in CR/CCR will undergo radiation therapy (see 
guidelines below). 
 
Patients with PR, SD with > 1.5 cm residual and PD with normalization of hCGβ should 
be considered for second-look surgery after completion of chemotherapy. Patients with 
evidence of new lesion(s) and/or increase in tumor markers will be removed from protocol 
therapy. 
 
• 
If findings following (second-look) surgery are consistent with fibrosis, scar, mature 
teratoma or non-viable tumor, patients will receive 18 Gy WVI followed by 12 Gy 
boost to the primary site in 1.5 Gy daily fractions. 
 
 
 
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• 
If findings following (second-look) surgery indicate residual viable malignant 
elements, patients will be removed from protocol therapy. 
 
Patients who have SD or PR with > 0.5 cm (suprasellar) or > 1 cm (pineal) but ≤ 1.5 cm 
residual disease and do not undergo a second-look surgery due to safety or other reasons, 
will receive 24 Gy WVI followed by 12 Gy boost to the primary site in 1.5 Gy daily 
fractions. 
 
• 
Patients who have SD or PR with greater than 1.5 cm residual tumor or PD but 
are unable to undergo a second-look surgery due to safety or other reasons, will 
be taken off protocol.  
 
Radiation Therapy for NGGCT (Stratum 1) 
Radiation therapy will be administered to all volumes in fractions of 1.8 Gy given once 
daily. See Section 10.0 for response definitions. 
 
a. 
CR and PR: WVI to 30.6 Gy followed by IFR boost of 23.4 Gy to a total dose of 
54 Gy. 
 
b. 
Stable disease (SD) or progressive disease (PD): Off protocol therapy unless a 
second-look surgery renders the patient in CR or PR. 
 
Radiation Therapy for Germinoma (Stratum 2) 
Radiation will be administered to all volumes in fractions of 1.5 Gy given once daily.  
See Section 10.0 for response definitions. 
a. 
CR and continuous complete response (CCR):  WVI to 18 Gy followed by local 
boost of 12 Gy to a total dose of 30 Gy. 
 
b. 
PR, SD and PD with normal markers:  If (Second-look) surgery is consistent with 
no viable tumor or mature teratoma, WVI to 18 Gy followed by IFR boost of 12 
Gy to a total dose of 30 Gy will be delivered.  If any viable tumor (including 
Germinoma) is found, patients will come off protocol therapy. 
 
c. 
PR or SD with normal markers: Patients with > 0.5 cm suprasellar or > 1 cm 
pineal but ≤ 1.5 cm residual who do not undergo second-look surgery will be 
treated with WVI to 24 Gy followed by local boost of 12 Gy to a total dose of  36 
Gy. If second-look surgery is not performed and patients do not meet criteria for 
at least PR with ≤ 1.5 cm residual disease, patients will be off protocol therapy. 
 
d. 
Progressive disease (PD):  Patients with PD with normal serum and CSF markers 
after 4 cycles of chemotherapy will proceed to (second-look) surgery. If (second-
look) surgery findings are consistent with mature teratoma or non-viable tumor, 
WVI to 18 Gy followed by IFR boost of 12 Gy to a total dose of 30 Gy will be 
delivered. Patients with any viable tumor (except mature teratoma) will be off 
protocol therapy. Patients with evidence of new lesion(s) and increasing markers 
or patients who do not have second-look surgery will be removed from protocol 
therapy.  
 
 
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4.2 
Concomitant Therapy Restrictions 
4.2.1 
Appropriate antibiotics, blood products, antiemetics, fluids, electrolytes and 
general supportive care are to be used as necessary. Antiemetics may be used per 
institutional guidelines. The routine use of steroids as an antiemetic is 
discouraged. 
 
 
4.2.2  Diabetes Insipidus (DI) 
Patients with DI should have monitoring of endocrine function and consultation 
with an endocrinologist is strongly recommended for guidance during fluid and 
chemotherapy administration.  
 
For COG Supportive Care Guidelines see:  
https://members.childrensoncologygroup.org/prot/reference_materials.asp under Standard 
Sections for Protocols. 
 
4.3 
Stratum 1 (NGGCT) Administration Guidelines for Induction 
4.3.1 
Cycle A (Cycles 1, 3, 5) 
 
CARBOplatin: IV over 15-60 minutes 
Day: 1 
Dose: 600 mg/m2/dose 
 
Avoid use of aluminum containing needles or administration sets. 
 
Medication errors have occurred due to confusion between CISplatin 
(Platinol®) and CARBOplatin (PARAplatin®). 
 
 
Etoposide: IV over 60-120 minutes 
Days: 1-3 
Dose: 150 mg/m2/dose 
 
Infuse diluted solution (concentration  ≤ 0.4 mg/mL) over at least 60-120 minutes; 
slow rate of administration if hypotension occurs. Rate should not exceed 
300 mg/m2/hour (10 mg/kg/hour) (hypotension risk). The use of an in-line filter 
during the infusion is suggested. 
 
Special precautions: Etoposide can be mixed in 0.9% NaCl or D5W. Avoid use of 
large volumes of D5W due to potential development of hyponatremia. 
 
Stability: Leaching of diethylhexyl phthalate (DEHP) from PVC bags occurred with 
etoposide 0.4 mg/mL in 0.9% NaCl solution. To avoid leaching, prepare the 
etoposide solution as close as possible, preferably within 4 hours, to the time of 
administration or alternatively as per institutional policy. Glass or polyethylene-
lined (non-PVC) containers and polyethylene-lined tubing may be used. 
 
 
 
 
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See the Parenteral Chemotherapy Administration Guidelines (CAG) on the COG 
website 
at: 
https://members.childrensoncologygroup.org/_files/disc/Pharmacy/ChemoAdmin
Guidelines.pdf for special precautions and suggestions for patient monitoring 
during the infusion. As applicable, also see the CAGs for suggestions on 
hydration, or hydrate according to institutional guidelines. 
 
See Section 5.0 for Dose Modifications based on Toxicities.  
 
The therapy delivery map (TDM) for Cycle A of Induction is on the next page.  
 
Each cycle of Induction will begin when ANC > 1,000/µL and platelets > 
100,000/µL and when off filgrastim (G-CSF) for at least 48 hours. 
 
 
 
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Page 1 of 1 
 
4.3.2 
Stratum 1 NGGCT Cycle A Induction 
Induction consists of six cycles (Cycle A and Cycle B).  
Cycle A is given during Cycles 1, 3 and 5. 
This Cycle lasts 3 weeks (21 days). 
 
____________________________ 
Patient name or initials 
____________________________ 
DOB 
Criteria to start this cycle: ANC > 1,000/µL and platelets > 100,000/µL and off filgrastim (G-CSF) for at least 
48 hours. Extensive details are in Section 4.0 (treatment overview). This cycle lasts 21 days and the TDM 
for this cycle is on 1 page. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT 
NOTES 
OBSERVATIONS 
 
CARBOplatin 
(CARBO)  
 
IV over 15-60 
minutes 
600 mg/m2/dose 
1 
See Section 5.1.1 if 
renal function is 
abnormal. 
a. History, PE (Ht, Wt, VS) with Neurologic 
Exam, Performance Status 
b. CBC (differential, platelets) 
c. Urinalysis 
d. Electrolytes (including BUN, Calcium, 
PO4, Magnesium, Sodium, Potassium) 
e. Total protein, AST, ALT, albumin, 
bilirubin 
 
OBTAIN OTHER STUDIES AS 
REQUIRED FOR GOOD PATIENT CARE 
 
 
Etoposide 
(ETOP) 
IV over 60-120 
minutes 
150 mg/m2 dose 
1-3 
See admin 
guidelines in 
Section 4.3.1 
 
 
 
 
Enter Cycle #: _____ Ht _________cm 
 
Wt _________kg 
BSA _________m2 
 
Date 
Due 
Date 
Given 
Day 
CARBO 
____mg 
ETOP 
____mg 
Studies 
Comments (Include any held doses, or dose 
modifications) 
 
 
 
Enter calculated dose above and actual dose 
administered below 
 
 
 
1 
____mg 
____mg 
a, b, c, d, e  
 
 
 
2 
 
____mg 
 
 
 
 
3 
 
____mg 
 
 
 
 
4 
 
 
 
 
 
 
8 
 
 
b, d@ 
 
 
 
15 
 
 
b, d@ 
 
 
 
22 
Start Cycle B on Day 22 or when blood count 
parameters are met (whichever occurs later).  
 
 
@ Obtain weekly if clinically indicated. 
 
See Section 5.0 for Dose Modifications for Toxicities and the COG website posted materials for 
Supportive Care Guidelines. 
 
 
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4.3.3 
Cycle B (Cycles 2, 4, 6) 
 
Ifosfamide: IV over 60 minutes 
Days: 1-5 
Dose: 1800 mg/m2/dose 
 
Suggested hydration: Administer 3,000 mL/m²/day (125 mL/m²/hour) using fluid containing 
D5W/0.45% NaCl or 0.9% NaCl. Achieve urine specific gravity ≤ 1.010 prior to start of 
ifosfamide. Monitor for adequate urine output as per institution guidelines. May use diuretics (eg, 
furosemide) to increase urine output. Consider adding potassium and magnesium to prevent 
electrolyte deficiencies. 
 
Etoposide: IV over 60-120 minutes* 
Days: 1-5 
Dose: 100 mg/m2/dose 
 
Note: Infuse as diluted solution (concentration ≤ 0.4 mg/mL); *slow rate of administration if 
hypotension occurs. Rate should not exceed 300 mg/m2/hour (10 mg/kg/hour) (hypotension risk). 
The use of an in-line filter during the infusion is suggested. 
 
Special precautions: Etoposide can be mixed in 0.9% NaCl or D5W. Avoid use of large volumes of 
D5W due to potential development of hyponatremia. 
 
Mesna: IV (short or continuous infusion) 
Days: 1-5 
Total Dose: 1800 mg/m2/day  
 
IV short or continuous infusion: For prophylaxis of hemorrhagic cystitis, the total daily mesna 
dose is equal to 100% of the daily ifosfamide dose. Mesna can be administered in 5 divided doses 
by short intravenous infusion over 15 to 30 minutes. The initial bolus dose of mesna may be 
administered 15 minutes before or at the same time as the ifosfamide dose; subsequent doses are 
given 3, 6, 9, and 12 hours after the start of ifosfamide.   
 
For example: if the ifosfamide dose is 1000 mg, then the total daily mesna dose is 1000 mg; 
200 mg of mesna will be given 15 minutes before or with the ifosfamide dose (Hour 0) and 
4 boluses of 200 mg each will be given at Hours 3, 6, 9 and 12. 
 
This total daily dose of mesna can also be administered as IV continuous infusion. The 
continuous infusion should be started 15-30 minutes before or at the same time as ifosfamide and 
finished no sooner than 12 hours after the end of the ifosfamide infusion.   
 
For example: if the ifosfamide dose is 1000 mg, then the total daily mesna dose is 1000 mg; the 
1000 mg mesna continuous infusion will start 15-30 minutes before or at the same time as the 
ifosfamide and be completed no sooner than 12 hours after the end of the ifosfamide infusion. If 
ifosfamide is administered over 2 hour and mesna is started 30 minutes before the ifosfamide 
infusion, the total mesna infusion will last at least 14 hours and 30 minutes. 
 
 
 
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Use of oral mesna:  
The oral dose of mesna is twice the IV dose. Patients able to tolerate oral mesna may receive the 
last FOUR bolus doses (originally at Hours 3, 6, 9, and 12) orally at 40% of the ifosfamide dose. 
The oral doses will be administered at Hours 1, 4, 7, and 10.   
 
For example: if the ifosfamide dose is 1000 mg, then the first 200 mg dose of mesna will be 
given IV 15 minutes before or with the ifosfamide dose (Hour 0) and FOUR oral doses of 
400 mg each will be given at Hours 1, 4, 7, and 10. 
 
Administer tablets or diluted parenteral solution.  To decrease sulfur odor, dilute mesna parental 
solution before oral administration. The solution can be diluted 1:1 to 1:10 in water, carbonated 
cola drinks, fruit juices (grape, apple, tomato and orange) or plain or chocolate milk.  The most 
palatable is chilled grape juice.  Tablets are 400 mg each and can be divided into 200 mg/0.5 tabs 
so dosing can be rounded up to nearest 200mg. Administer doses on a schedule as determined by 
timing of ifosfamide administration. If a dose is missed, administer dose immediately. Give the 
next scheduled dose according to the original dosing schedule. Do not deviate from the original 
schedule. Notify provider if a dose is delayed or missed. If a dose is vomited within 2 hours of 
administration, repeat the dose orally or switch to intravenous mesna. 
 
Filgrastim: Subcutaneous (preferred) or IV 
Days: Daily, starting on Day 6 and continue for 10 days until ANC > 1500/µL after the expected 
nadir. 
Dose: 5 mcg/kg/dose. 
 
Note: The use of filgrastim is strongly recommended, however, patients receiving PEG-filgrastim 
will not be excluded. 
 
 
See the Parenteral Chemotherapy Administration Guidelines (CAG) on the COG website at: 
https://members.childrensoncologygroup.org/_files/disc/Pharmacy/ChemoAdminGuidelines.pdf 
for special precautions and suggestions for patient monitoring during the infusion. As applicable, 
also see the CAGs for suggestions on hydration, or hydrate according to institutional guidelines. 
 
See Section 5.0 for Dose Modifications based on Toxicities.  
 
The therapy delivery map (TDMs) for Cycle B of Induction is on the next page.  
 
Each cycle of Induction will begin when ANC > 1,000/µL and platelets > 100,000/µL and when off 
of filgrastim (G-CSF) for at least 48 hours. 
 
 
 
 
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4.3.4 
Stratum 1 NGGCT Cycle B Induction 
Induction consists of six cycles (Cycle A and Cycle B).  
Cycle B is given during Cycles 2, 4 and 6. 
This Cycle lasts 3 weeks (21 days). 
 
____________________________ 
Patient name or initials 
____________________________ 
DOB 
Criteria to start this cycle: ANC > 1,000/µL and platelets > 100,000/µL and off filgrastim (G-CSF) for at least 48 hours. 
Extensive details are in Section 4.0 (treatment overview). This cycle lasts 21 days and the TDM for this cycle is on 1 
page. 
DRUG 
ROUTE 
DOSAGE 
DAYS IMPORTANT 
NOTES 
OBSERVATIONS 
 
Ifosfamide 
(IFOS) 
 
IV over 60 
minutes 
1800 mg/m2/dose 
1-5 
See admin 
guidelines in 
Section 4.3.3 
a. History, PE (Ht, Wt, VS) with Neurologic 
Exam, Performance Status 
b. CBC (differential, platelets) 
c. Urinalysis 
d. Electrolytes (including BUN, Calcium, 
PO4, Magnesium, Sodium, Potassium) 
e. Serum Creatinine, CrCl or GFR 
f. Total protein, AST, ALT, albumin, 
bilirubin 
g. Lumbar CSF cytology* 
h. Lumbar CSF Markers (hCG, AFP)* 
i. Serum Markers (hCG, AFP) 
j. Brain MRI with and without gadolinium 
k. Spine MRI with and without gadolinium 
l. Audiogram or BAER 
m. Endocrine function 
* Lumbar CSF should be obtained unless 
medically contraindicated. 
OBTAIN OTHER STUDIES AS REQUIRED 
FOR GOOD PATIENT CARE 
Etoposide 
(ETOP) 
IV over 60-120 
minutes 
100  mg/m2/dose 
1-5 
See admin 
guidelines in 
Section 4.3.3 
Mesna 
(MESNA) 
IV (short or 
continuous 
infusion) 
 
See Section 4.3.3 
1-5 
Administer 
concurrently 
with 
ifosfamide 
 
Filgrastim 
(G-CSF) 
SubQ 
(preferred) or 
IV 
5 mcg/kg/dose 
Daily 
on Days 
6-15 
Start G-CSF on Day 
6 and continue for 
ten days or until 
ANC > 1500/µL. 
 
Enter Cycle #: _____ 
Ht _________cm 
Wt _________kg 
BSA _________m2 
 
Date 
Due 
Date 
Given 
Day 
IFOS 
____mg 
ETOP 
____mg 
MESNA_
__mg 
G-CSF 
____mcg 
Studies 
Comments (Include any 
held doses, or dose 
modifications) 
 
 
 
Enter calculated dose above and actual dose 
administered below 
 
 
 
 
1 
____mg 
____mg 
____mg 
 
a, b, c, d, e, f 
 
 
 
2 
____mg 
____mg 
____mg 
 
 
 
 
 
3 
____mg 
____mg 
____mg 
 
 
 
 
 
4 
____mg 
____mg 
____mg 
 
 
 
 
 
5 
____mg 
____mg 
____mg 
 
 
 
 
 
6 
 
 
 
____mg 
 
 
 
 
8 
 
 
 
 
b, d@ 
 
 
 
15 
 
 
 
 
b, d@ 
 
 
 
21 
 
 
 
 
I$, j$ 
[a,b,c,d,e,f,g,
h,i,j,k,l,m]# 
Indicate date of last  
G-CSF dose ______ 
 
 
22 
Start Cycle A on Day 22 or when blood count parameters are met (whichever occurs later).  
Upon completion of Induction, patients will undergo response evaluation. 
$ Obtain after cycles 2 and 4  
 
 
 
@ Obtain weekly if clinically indicated. 
# Obtain at completion of Induction (after Cycle 6). 
See Section 5.0 for Dose Modifications for Toxicities and the COG website posted materials for 
Supportive Care Guidelines. 
 
 
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4.4 
Stratum 2 (Germinoma) Administration Guidelines for Induction 
4.4.1 
Cycle A (Cycles 1-4) 
 
CARBOplatin: IV over 15-60 minutes 
Day: 1 
Dose: 600 mg/m2/dose 
 
IV: Infuse the diluted solution over 15-60 minutes. Avoid use of aluminum 
containing needles or administration sets. 
 
Medication errors have occurred due to confusion between CISplatin 
(Platinol®) and CARBOplatin (PARAplatin®). 
 
 
Etoposide: IV over 60-120 minutes 
Days: 1-3 
Dose: 150 mg/m2/dose 
 
Infuse diluted solution (concentration  ≤ 0.4 mg/mL) over at least 60-120 minutes; 
slow rate of administration if hypotension occurs. Rate should not exceed 
300 mg/m2/hour (10 mg/kg/hour) (hypotension risk). The use of an in-line filter 
during the infusion is suggested. 
 
Special precautions: Etoposide can be mixed in 0.9% NaCl or D5W. Avoid use of 
large volumes of D5W due to potential development of hyponatremia. 
 
Stability: Leaching of diethylhexyl phthalate (DEHP) from PVC bags occurred with 
etoposide 0.4 mg/mL in 0.9% NaCl solution. To avoid leaching, prepare the 
etoposide solution as close as possible, preferably within 4 hours, to the time of 
administration or alternatively as per institutional policy. Glass or polyethylene-
lined (non-PVC) containers and polyethylene-lined tubing may be used. 
 
See the Parenteral Chemotherapy Administration Guidelines (CAG) on the COG 
website 
at: 
https://members.childrensoncologygroup.org/_files/disc/Pharmacy/ChemoAdmin
Guidelines.pdf for special precautions and suggestions for patient monitoring 
during the infusion. As applicable, also see the CAGs for suggestions on 
hydration, or hydrate according to institutional guidelines. 
 
See Section 5.0 for Dose Modifications based on Toxicities.  
 
The therapy delivery map (TDM) for Cycle A of Induction is on the next page.  
 
Each cycle of Induction will begin when ANC > 1,000/µL and platelets > 
100,000/µL and when off filgrastim (G-CSF) for at least 48 hours. 
 
 
 
 
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4.4.2 
Stratum 2 Germinoma Cycle A Induction 
Induction consists of four cycles. 
Cycle A is given in all four cycles.  
This Cycle lasts 3 weeks (21 days). 
 
____________________________ 
Patient name or initials 
____________________________ 
DOB 
Criteria to start this cycle: ANC > 1,000/µL and platelets > 100,000/µL and off filgrastim (G-CSF) for at least 48 hours. 
Extensive details are in Section 4.0 (treatment overview). This cycle lasts 21 days and the TDM for this cycle is on 1 page. 
DRUG 
ROUTE 
DOSAGE 
DAYS IMPORTANT 
NOTES 
OBSERVATIONS 
 
CARBOplatin 
(CARBO)  
 
IV over 15-60 
minutes 
600 
mg/m2/dose 
1 
See Section 5.1.1 
if renal function is 
abnormal. 
a. History, PE (Ht, Wt, VS) with Neurologic 
Exam, Performance Status 
b. CBC (differential, platelets) 
c. Urinalysis 
d. Electrolytes (including BUN, Calcium, 
PO4, Magnesium, Sodium, Potassium) 
e. Serum Creatinine, CrCl or GFR 
f. Total protein, AST, ALT, albumin, 
bilirubin 
g. Lumbar CSF cytology* 
h. Lumbar CSF Markers (hCG, AFP)* 
i. Serum Markers (hCG, AFP) 
j. Brain MRI with and without gadolinium 
k. Spine MRI with and without gadolinium 
l. Audiogram or BAER 
m. Endocrine function 
* Lumbar CSF should be obtained unless 
medically contraindicated. 
OBTAIN OTHER STUDIES AS REQUIRED 
FOR GOOD PATIENT CARE 
 
Etoposide 
(ETOP) 
IV over 60-120 
minutes 
150 
mg/m2/dose 
1-3 
See admin 
guidelines in 
Section 4.4.1 
 
 
Enter Cycle #: _____ 
Ht _________cm 
Wt _________kg 
BSA _________m2 
 
Date Due 
Date Given 
Day 
CARBO 
____mg 
ETOP 
____mg 
Studies 
Comments (Include any held doses, 
or dose modifications) 
 
 
 
Enter calculated dose above and actual dose 
administered below 
 
 
 
1 
____mg 
____mg 
a, b, c, d, f 
 
 
 
2 
 
____mg 
 
 
 
 
3 
 
____mg 
 
 
 
 
4 
 
 
 
 
 
 
8 
 
 
b, d@ 
 
 
 
15 
 
 
b, d@ 
 
 
 
21 
 
 
i$,j$ 
[a,b,c,d,e,f,g,h,i,j,k,l,m]# 
 
 
 
22 
Start next cycle on Day 22 or when blood count 
parameters are met (whichever occurs later).   
Upon completion of Induction, patients will 
undergo response evaluation. 
 
$ Obtain after Cycle 2. 
 
 
 
 
 
@ Obtain weekly if clinically indicated 
# Obtain at completion of Induction (after Cycle 4). 
See Section 5.0 for Dose Modifications for Toxicities and the COG website posted materials for Supportive 
Care Guidelines. 
 
 
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5.0 
DOSE MODIFICATIONS FOR TOXICITIES 
5.1 
Carboplatin 
 
5.1.1 
Nephrotoxicity 
Patients who have compromised renal function should undergo a GFR (see table 
in Section 3.2.6.2).  If the corrected GFR is <100 mL/min/1.73m2, the carboplatin 
dose should be calculated per the modified Calvert Formula using a target AUC 
of 5.  Please note that the equation below calculates the ACTUAL mg of 
carboplatin to be given and NOT the dose per surface area.  Also note that 
the maximum dose calculated using the modified Calvert Formula must not 
exceed the originally planned dose of 600 mg/m2.  Each final total daily dose 
of carboplatin should be checked to ensure that it does not exceed this 
amount.    
 
Modified Calvert Formula: 
 
Carboplatin Total Dose in mg/day ={(Corrected GFR x surface area) + (15 x surface area)} x AUC 
                                                                                   1.73 
 
Alternately, the equation may also be expressed as follows: 
 
Carboplatin Total Dose in mg/day ={(Uncorrected GFR) + (15 x surface area)} x AUC 
 
Example Carboplatin dosage calculation: 
Example 1: 
 
Surface area = 0.5m2 
 
 
Corrected GFR = 70mL/min/1.73m2 
 
Total dose in mg/day ={ 70 x 0.5  + 15(0.5) }  x 5 
 
 
 
   1.73 
Dose = (20.23 + 7.5) x 5 = 139 mg/day 
 
Double check dose to ensure that it does not exceed 600 mg/m2:  
139 mg ÷ 0.5 m2 = 278 mg/m2  
This does not exceed the max dose of 600 mg/m2, so 139 mg is acceptable. 
 
Example 2: 
Surface area = 1.2m2 
 
 
UN-corrected GFR = 50mL/min 
 
Total dose in mg/day = {50 + 15(1.2)}  x 5 
 
Dose = (50 + 18) x 5 = 340 mg/day 
 
Double check dose to ensure that it does not exceed 600 mg/m2:  
340 mg ÷ 1.2 m2 = 283 mg/m2   
This does not exceed the max dose of 600 mg/m2, so 283 mg is acceptable. 
 
 
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5.1.2 
Ototoxicity 
Careful monitoring of children by expert audiologist and by serial audiometry 
throughout the treatment with carboplatin is recommended as clinically indicated.  
Otoacoustic emissions (OAE) are the clinical methodology of choice for initial 
testing.  If these are normal, patients do not need further evaluation, and should 
be coded as having no hearing loss.  If they are abnormal, then brainstem evoked 
auditory responses (BAER) or tone audiometry should be used to more 
specifically describe the hearing loss.  A decrease in auditory acuity at 
frequencies above 4000 Hz is expected and does not constitute a contraindication 
to further therapy.  For Grades 0, 1 and 2 ototoxicity (CTCAE) no dose 
modification is recommended.  For Grade 3 toxicity, a 50% reduction should be 
made in the carboplatin dosage. For Grade 4 ototoxicity, carboplatin can be 
continued at 50% dose reduction or discontinued at the discretion of treating 
physician and family. 
 
 
5.1.3 
Allergic Reactions 
Carboplatin allergic reactions may be managed with pre-medications such as 
diphenhydramine 1 mg/kg IV (maximum dose 50 mg), ranitidine 1 mg/kg IV 
(maximum 
dose 
50 
mg) 
and 
hydrocortisone 
4 mg/kg IV (maximum dose 100 mg).   
 
5.1.4 
Hematologic Toxicity 
If counts are slow to recover after Cycle A, use filgrastim (G-CSF) during 
subsequent Cycle A. 
 
5.2 
Etoposide 
 
5.2.1 
Nephrotoxicity  
In patients with impaired renal function, the following initial dose modification 
should be considered based on measured creatinine clearance: 
 
 
Measured CrCL 
 
> 50 mL/min/1.73m2 
 
15-50 mL/min/1.73m2 
 
Etoposide Dose 
 
100% of Dose 
 
75% of Dose 
 
Subsequent dosing should be based on patient tolerance and clinical effect.  Data 
are not available in patients with creatinine clearances of < 15 mL/min and 
further dose reduction should be considered in these patients. 
 
5.2.2  Hepatotoxicity 
If the direct bilirubin is between 2 and 3 mg/dL, give 50% of the calculated dose 
of etoposide.  If the direct bilirubin is > 3 mg/dL, hold the etoposide.  Full dose 
may resume when the direct bilirubin has fallen to < 1.2 mg/dL. 
 
5.2.3  Allergic Reactions 
Etoposide allergic reactions may be managed with pre-medications such as 
diphenhydramine 1 mg/kg IV (maximum dose 50 mg), ranitidine 1 mg/kg IV 
 
 
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(maximum dose 50 mg), and hydrocortisone 1-2 mg/kg IV (maximum dose 100 
mg), and by slowing the rate of the infusion. For those reactions, which are 
unable to be controlled with pre-medication and slowing of the rate of etoposide 
infusion, etoposide phosphate may be substituted in the same dose and at the 
same rate. Pre-medication for etoposide phosphate is recommended. 
 
5.3 
 Ifosfamide 
5.3.1 
Hematologic 
No modifications of subsequent chemotherapy cycles will be made for delayed 
recovery of neutrophil or platelet counts, following a prior cycle of Induction 
chemotherapy. 
 
5.3.2 
Hemorrhagic Cystitis 
Microscopic Hematuria 
For transient microscopic hematuria (no more than 2 abnormal urinalyses on 2 
separate days during a cycle of therapy), there is no modification of the 
ifosfamide or mesna dose. 
  
For persistent microscopic hematuria (> 2 abnormal urinalyses during a cycle of 
therapy), increase hydration to 3500-4000 mL/m2/day. In addition, if mesna 
administration is oral or by intermittent intravenous bolus, convert to continuous 
intravenous mesna. 
 
Gross Hematuria 
All episodes of gross hematuria should be evaluated in conjunction with a 
pediatric surgery/urology consult. Further testing, such as cystoscopy, urine 
culture, excretory urogram, and voiding cystogram should be considered based 
on good clinical judgment. 
  
For transient gross hematuria (only 1 episode, which clears to less than gross 
hematuria) during or following a cycle of therapy, hold ifosfamide until 
hematuria clears. When hematuria clears, restart at 50% of the previous 
ifosfamide dose. Use hydration of 3500-4000 mL/m2/day and mesna at 100% of  
ifosfamide dose as a continuous infusion over 24 hrs/day. The ifosfamide dose 
may be escalated back to 100% if tolerated. 
  
For persistent gross hematuria after completion of a cycle of therapy, hold 
subsequent ifosfamide until the urine clears to less than gross hematuria. 
Reinstitute ifosfamide at 50% of the initial dose, with hydration of 3500-4000 
mL/m2/day and the mesna at 100% of the ifosfamide dose administered as a 
continuous infusion over 24 hours. If this regimen is tolerated, the ifosfamide 
dose may be escalated back to the original dose (100%).  
  
For persistent gross hematuria occurring during a cycle of ifosfamide, interrupt 
the ifosfamide. Withhold further ifosfamide until the next cycle of therapy or 
until urine clears.  Reinstitute ifosfamide at 50% of the initial dose, with 
hydration of 3500-4000 mL/m2/day and the mesna at 100% of the ifosfamide 
dose administered as a continuous infusion over 24 hours. If this regimen is 
tolerated, the ifosfamide dose may be escalated back to the original dose (100%).  
 
 
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For persistent gross hematuria on the mesna continuous infusion regimen, 
discontinue the ifosfamide. 
 
 
 
5.3.3    Nephrotoxicity 
In patients with a measured creatinine clearance <10 mL/min/1.73m2, decrease 
dose by 25% (give 75% of initial dose). 
 
5.3.4  Neurotoxicity 
This is an organic brain syndrome that ranges from mild confusion and 
disorientation to seizures, ataxia, and coma. It may be aggravated by impaired 
renal function. It usually, but does not always, resolve spontaneously, and it may 
or may not recur with subsequent doses. If symptoms are mild and transient cycle 
may continue with strict avoidance of potentially aggravating co-administered 
medications such as sedatives and anticholinergic drugs. If Grade 4 neurotoxicity 
occurs during ifosfamide administration, 
investigators may consider administration of methylene blue. Patients who have 
experienced mild symptoms (≤ Grade 2) may receive ifosfamide in subsequent 
cycles. If neurotoxicity > Grade 2 occurs or 
symptoms are prolonged, delete ifosfamide from all subsequent cycles . 
 
 
 
6.0 
DRUG INFORMATION  
See the consent document for toxicities. All other information is available on the COG website in the 
commercial agent monographs manual titled “Drug Information for Commercial Agents used by the 
Children’s Oncology Group.” This manual is provided under Standard Sections for Protocols at: 
https://members.childrensoncologygroup.org/prot/reference_materials.asp. 
 
 
 
 
7.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
Timing of protocol therapy administration, response assessment studies, and surgical interventions are 
based on schedules derived from the experimental design or on established standards of care. Minor 
unavoidable departures (up to 72 hours) from protocol directed therapy and/or disease evaluations (and up 
to 1 week for surgery) for valid clinical, patient and family logistical, or facility, procedure and/or 
anesthesia scheduling issues are acceptable per COG administrative Policy 5.14 (except where explicitly 
prohibited within the protocol). 
 
 
 
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7.1 
Required Clinical, Laboratory and Disease Evaluations During Protocol Therapy 
All baseline studies must be performed prior to starting protocol therapy unless otherwise indicated 
below. Obtain other studies prior to start of phase unless otherwise indicated.   
 
STUDIES TO BE 
OBTAINED 
Baseline 
Prior to 
Each 
Cycle of 
Induction 
(Cycles A 
and B) 
During 
Induction 
(Cycles A 
and B) 
Completion 
of Induction  
(Day 21-35) 
Following 
Second- 
Look 
Surgery 
 
Within 2 
Weeks 
Prior to 
Starting 
RT 
During 
Radiation 
Therapy 
Between 4 -6 
Weeks 
following 
Completion 
of Therapy 
History 
X 
X 
 
X 
X 
 
X (Weekly 
If 
Clinically 
Indicated) 
 
Physical Exam (Ht, 
Wt, VS) with 
Neurologic Exam 
X 
X 
 
X 
X 
 
 
X 
Performance Status 
X 
X 
 
X 
X 
 
 
X 
CBC (differential, 
platelets) 
X 
X  
X 
(Weekly) 
X 
X 
X 
X (Weekly 
If 
Clinically 
Indicated) 
X 
Urinalysis 
X 
X 
 
X 
 
 
 
X 
Electrolytes 
(including BUN, 
Calcium, PO4, 
Magnesium, Sodium, 
Potassium)  
X 
X  
X 
(Weekly if 
Clinically 
Indicated) 
X 
X 
 
 
X 
Serum Creatinine, 
Creatinine Clearance 
or GFR  
X 
 
 
X 
 
 
 
 
Total protein, AST, 
ALT, albumin, 
bilirubin 
X 
X 
 
 
 
 
 
X 
Lumbar CSF 
Cytology4  
X 
 
 
X 
 
 
 
X 
CSF Markers 
(hCG, AFP)6 
X 
 
 
X 
 
 
 
X 
Serum markers (hCG, 
AFP) 
X 
 
X (After  
Cycles 2 
and 4) 
X 
X 
X 
 
X 
Brain MRI with and 
without gadolinium1 
X  
 
X (After  
Cycles 2 
and 4) 
X 
X 
 
 
X 
Spine MRI  
X2 
 
 
X5 
 
 
 
X5 
Audiogram or BAER 
X 
 
 
X 
 
 
 
X 
Endocrine Function 3 
X 
 
 
X 
 
 
 
X 
Pregnancy test (for 
females of 
childbearing 
potential) 
X 
 
 
 
 
 
 
 
1- All patients must have a cranial MRI with and without gadolinium at diagnosis/prior to enrollment. If surgical resection is 
performed, patients must have pre-operative and post-operative cranial MRI with and without gadolinium. The post-operative brain 
 
 
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MRI should be obtained within 72 hours of surgery. If patient has a biopsy only, post-operative cranial MRI is recommended but not 
required. 
2 - All patients must have a spine MRI with gadolinium obtained at diagnosis/prior to enrollment. Note: If the spine study is performed 
for the first time after surgical resection or biopsy, it is recommended to be obtained with and without gadolinium.  
3 -  Endocrine evaluation to include: Cortisol (8 AM), TSH, free T4, IGF1 and IGF BP3. Tanner Stage, LH, FSH, estradiol, and 
testosterone if child has precocious puberty before age 8 in girls or 9 in boys or for all patients age 11 or greater. 
4 - Lumbar CSF cytology should be obtained unless medically contraindicated.  
5 –Spinal MRI with gadolinium is sufficient. 
6 – Lumbar CSF markers must be obtained unless medically contraindicated. If possible determine CSF markers and serum 
markers on the same day. If lumbar CSF markers are contraindicated, ventricular CSF markers are acceptable. In case CSF 
diversion and biopsy/surgery is combined, ventricular CSF should be collected first. 
 
This table only includes evaluations necessary to answer the primary and secondary aims. Obtain 
other studies as indicated for good clinical care.  
 
 
7.2 
Required Observations Following Completion of Protocol Therapy 
 
 
Observation 
 
 
3 Months, 6 
Months, 9 
Months 
 
Every 4 Months 
up to 24 Months 
(Months 12, 16, 
20, 24) and at 30 
Months 
Annually up to 
60 Months 
(Months  36, 48, 
60) 
At Relapse 
Physical Exam with neurologic exam 
X 
X 
X 
X 
Brain MRI with and without 
gadolinium 
X 
X 
X 
X 
Spine MRI with gadolinium 
X 
X 
X 
X 
Serum markers (hCG, AFP)  
X 
X 
X 
X 
Lumbar CSF markers and cytology  
 
 
 
X 
Endocrine evaluation 4 
 
 
X 
 
Audiogram or BAER 
 
X2 
X2 
 
Neurocognitive 
Function 
(See 
ALTE07C1 Protocol and Section 
16.0  
X3 
X3 
X3 
 
1 - Lumbar CSF cytology and markers and serum markers should be obtained  only at time of relapse unless 
medically contraindicated  or if abnormal at completion of therapy. 
2 – Obtain if clinically indicated or if abnormal at completion of therapy. 
3 – Obtain at 9 months (± 3 months), 30 (± 3 months) and 60 months (± 3 months) post diagnosis.  
4 - Endocrine evaluation to include: Cortisol (8 AM), TSH, free T4, IGF1 and IGF BP3. Tanner Stage, LH, FSH, Estradiol, 
and Testosterone if child has precocious puberty before age 8 in girls or 9 in boys or for all patients age 11 or greater. 
 
See COG Late Effects Guidelines for recommended post treatment follow-up:  
http://www.survivorshipguidelines.org/ 
 
 
Note: Follow-up data are expected to be submitted per the Case Report Forms (CRFs) schedule. 
 
 
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8.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA 
8.1 
Criteria for Removal from Protocol Therapy 
a) 
Progressive disease with increasing markers during Induction chemotherapy. 
b) 
NGGCT (Stratum 1) patients with positive markers at the end of Induction 
chemotherapy or who have < PR after induction chemotherapy.   
c) 
NGGCT (Stratum 1) patients with < PR after second-look surgery or any viable 
tumor (except mature teratoma) after second-look surgery  
d) 
NGGCT (Stratum 1) patients who are unable to undergo second-look surgery due to 
safety or other reasons and do not meet criteria for CR/PR (imaging and tumor 
marrkers). 
e) 
Germinoma (Stratum 2) patients with PD and positive markers at the end of 
Induction chemotherapy. 
f) 
 Germinoma (Stratum 2) patients who are unable to undergo second-look surgery 
due to safety concerns and they do not meet the criteria for at least PR with ≤ 1.5 cm 
residual disease without second-look surgery. 
g) 
Germinoma (Stratum 2) patients with any viable tumor (except mature teratoma, 
fibrosis, scar or non-viable tumor) after second-look surgery  
h) 
Refusal of further protocol therapy by patient/parent/guardian. 
i) 
Completion of protocol therapy. 
j) 
Physician determines it is in patient’s best interest. 
k) 
Development of a second malignancy. 
l) 
Patient is enrolled but rechecked labs are outside the limits of eligibility prior to 
starting therapy. (See Section 3.2) 
m) 
Radiotherapy cannot be initiated within 6 weeks after Day 1 of the last cycle of 
Induction chemotherapy or within 31 days after second-look surgery. (See 
Sections 15.2.3 and 15.2.4). 
n) 
Progressive disease with positive or increasing markers at the end of Induction 
chemotherapy, following second-look surgery or during radiation therapy. 
 
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. 
 
8.2 
Off Study Criteria 
a) 
Death. 
b) 
Lost to follow-up. 
c) 
Patient enrollment onto another COG study with tumor therapeutic intent (eg, at 
recurrence). 
d) 
Withdrawal of consent for any further data submission. 
e) 
The fifth anniversary of the date the patient was enrolled on this study. 
f) 
Patient did not receive protocol treatment after study enrollment. 
 
 
 
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9.0 
STATISTICAL CONSIDERATIONS 
9.1 
Study Design 
The primary objective of the NGGCT stratum 1 is to test whether the subset of NGGCT 
patients who have a CR or PR in response to induction chemotherapy or who undergo 
second-look surgery after induction therapy and are found to have only mature teratoma, 
residual scar or fibrosis can be safely treated with 30.6 Gy WVI and IFR boost up to 54 Gy. 
The “intent-to-treat” principle will be followed and any eligible patient who receives dose 
and volume reduced radiation therapy and is evaluable based on response to induction 
therapy will be included in the primary analysis. The number of patients enrolled in stratum 
1 who fail to receive this reduced radiation therapy will also be reported 
 
The primary objective of stratum 2 is to test whether the PFS distribution of localized 
primary CNS germinoma patients who present with serum and or CSF hCGβ ≤ 50mIU/ml is 
sufficient to support continued investigation of the proposed treatment regimen. The “intent-
to-treat” principle will be followed and any eligible patient who receives dose-reduced 
radiation therapy will be included in the primary analysis. The number of patients enrolled in 
stratum 2 who fail to receive this reduced radiation therapy will also be reported. 
 
In addition, for each stratum descriptive statistics will be provided reporting the 
proportion of patients who are classified as local, ventricular, distant or a combination of 
local, ventricular, and/or and distant failures based primarily on imaging evaluation of the 
neuraxis. See Section 15.12. 
 
The first step in assessing primary objective 1.1.3, modeling neurocognitive function, as 
assessed on ALTE07C1, will be to monitor the rate of participation of eligible patients 
treated with dose and volume reduced radiation therapy in stratum 1 and dose-reduced 
radiation therapy in stratum 2. The same monitoring rule described below will be 
independently implemented for Stratum 1 and for Stratum 2. 
 
Assessing neurocognitive function for patients treated on ACNS1123 will be considered 
feasible unless statistical evidence develops that fewer than 80% of patients who are 
eligible and evaluable for assessing primary objectives 1.1.1 or 1.1.2 and who are failure 
free at three years post initiation of therapy can be expected to have both 9-month and 30-
month neurocognitive assessments on ALTE07C1. This rate of success will ensure that 
longitudinal modeling of neurocognitive function will provide viable historical controls 
for subsequent COG trials of these diseases. The rate of also achieving 60-month (5-year) 
neurocognitive assessments is not considered for monitoring feasibility, as the total study 
duration is only expected to be approximately seven years.  
 
The statistical criteria for monitoring neurocognitive evaluations are based on a one-sided 
test (α = 0.025) that the true, unknown, success rate is at least 80% (≥ 80%) with 80% 
statistical power to detect that the success rate is 65%, which would be unacceptable. 
Assuming a binomial distribution, EAST5 was used to calculate the two stopping 
boundaries. If within a stratum, 9 (≤9) or fewer of the first 23 patients evaluable for 
feasibility (39.1%) have both 9 and 30 month evaluations (i.e. patients who are eligible 
and evaluable for assessing the primary objective and are more than 30+ 4 months from 
 
 
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diagnosis), we will recommend to the COG DSMB that consideration be given to closing 
the stratum. The second boundary for recommending closing the stratum will be if 28 or 
fewer (≤28) of the initial 45 patients evaluable for feasibility (62.2%) enrolled in that 
stratum have both 9 and 30 month evaluations (i.e. patients who are eligible and 
evaluable for assessing the primary objective and are more than 30+ 4 months from 
diagnosis). Otherwise accrual to the stratum will continue until the full cohort of patients 
required to address the primary objective assessing the 3-year progression-free survival 
rate has been achieved. 
 
Our ability to address the secondary objectives depends upon whether the proposed 
treatment regimen is effective or not. Secondary objectives will be reported descriptively 
and as exploratory. Other than reports requested by the COG DSMB, secondary objectives 
will only be analyzed at the end of the trial.  
 
1. 
The first secondary objective is to provide Kaplan-Meier estimates of distributions 
of PFS and overall survival for NGGCT patients. 
2. 
The second secondary objective is to provide Kaplan-Meier estimates of the PFS 
and survival distributions of the cohorts of patients who present with a) non 
metastatic CNS Germinoma patients with hCGβ ≤ 50 mIU/ml and  b) non 
metastatic CNS Germinoma patients with hCGβ > 50 mIU/ml and ≤ 100mIU/ml. 
These estimates will only be available to the COG DSMC until the trial is closed to 
accrual. 
 
9.2 
Sample Size and Study Duration 
 
9.2.1 
Stratum 1 NGGCT 
In ACNS0122, COG institutions enrolled 79 eligible patients with localized 
disease over a period of 53 months. Of these 79 patients, 49 (95% lower 
confidence bound = 53%) would have been eligible based on response to 
induction therapy to address the primary study objective of this trial for an 
expected accrual rate of approximately 11.1 patients per year. Thus, we expect 
that approximately 7 years will be required to accrue the required 77 eligible 
patients evaluable for the primary objective.  
 
9.2.2 
Stratum 2 Germinoma 
Based on the publication by Keene et al, the 95% confidence interval estimate of the 
incidence of CNS germinoma in children 4 to <18 years of age is (0.48, 0.91). 67 We 
assume that this estimate holds for 5 to 19 year olds. Canada and US population 
estimates for 5 to 19 year olds are 6.02 and 61.7 million, respectively. Thus, 
annually we estimate that there are 32.5 to 61.6 diagnoses of CNS germinomas in 
patients 5 to 19 years of age. Again based on Keene et al, approximately 77% of 
patients with CNS germinomas will be diagnosed with localized disease and 
approximately 75% will present with serum and CSF hCGβ ≤ 50mIU/ml. 67 
Assuming that 80% of eligible patients would consent to enrolling on this study, we 
estimate that the annual accrual for patients eligible for the primary study objective 
will be between 15 and 28 patients. Since 64.7% of eligible patients are expected to 
be evaluable for the primary objective, annual accrual of eligible, evaluable patients 
will be between 10 and 18 patients. 
 
 
 
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Due to the excellent accrual rate of germinoma patients within the initial 2.5 years 
of study opening (accrual of 80 patients within 27 months), we expect that 
approximately 5 years will be required as originally estimated to accrue the required 
79 eligible patients evaluable for the primary objective. Note that assessing whether 
the accrual rate is adequate should not begin until one year after the protocol has 
been released to COG institutions for submission to their Institutional Review 
Boards (IRB). Receiving IRB approval takes significant time and thus accrual 
during the first year will no doubt be much less than projected; thus, assessment will 
begin with the completion of year two. 
 
9.2.3 
Total Accrual 
Considering 77 eligible, evaluable patients will be required for Stratum 1 and 79 
eligible, evaluable patients for Stratum 2, with a 10% ineligible rate, the 
maximum number of patients expected to be accrued is 275 patients.   
 
As of Amendment #1A, for Stratum 1, the original estimate of the study duration 
was mistakenly based on the fact that all eligible patients enrolled on Stratum 1 
would be evaluable for addressing the primary objective. However, the Stratum 1 
primary objective will be addressed only by eligible patients who achieve an 
objective response and hence qualify to receive reduced radiation therapy. In 
reality, based on the results from the preceding ACNS0122 study, we had 
expected that approximately 62% of Stratum 1 eligible patients would experience 
a CR or PR and would receive reduced radiation therapy. Considering that 77 
eligible patients who achieve a CR or PR and receive reduced radiation therapy 
are required to address the primary objective of Stratum 1, we will need to 
increase accrual to approximately 125 patients.  
 
For Stratum 2, in order to estimate the study duration, there was no information 
on which we could estimate the proportion of eligible patients that would 
experience a complete response or continued complete response and contribute to 
addressing the primary objective. Seventy-nine (79) eligible, evaluable patients 
are required to address the primary objective. Currently, based on the ACNS1123 
data through 31 December 2013, we estimate that approximately 64.7% of 
Stratum 2 eligible patients will experience a CR or CCR, receive reduced 
radiation therapy and contribute to addressing the primary objective. Thus, we 
need to accrue a total of 123 eligible patients to Stratum 2.  
 
Assuming that the expectation for 62% of Stratum 1 eligible patients and 64.7% 
of Stratum 2 eligible patients will contribute to addressing the primary objectives 
is realized, we will need to accrue 248 (125+123) patients and assuming a 10% 
ineligibility rate, the maximum number of patients expected to be accrued is 275.   
 
9.3 
Methods of Analysis 
 
9.3.1 
Stratum 1 NGGCT 
This study will be designed based on the observed outcome for patients treated on 
ACNS0122. Of 102 eligible patients treated on ACNS0122, 79 (77.5%) were 
determined to have localized disease. Thirty-two of the 79 (40.5%) patients 
achieved a CR (N=25) in response to induction therapy or were found on second-
 
 
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look surgery to have a mature teratoma, residual scar or fibrosis (N= 7). Based on 
the ACNS0122 data frozen as of June 30, 2011, the 3-year PFS rate for these 32 
patients is 90.6% (SE=5.2%) and follow-up was current for all patients. No patient 
is censored within two years of initiating therapy and 5 patients continue to be 
followed in their third year. Seventeen of the 79 (21.5%) patients achieved a PR in 
response to induction therapy and the 3-year PFS rate for these patients is 94.1% 
(SE=5.7%) with no patient censored within two years of initiating therapy and 2 
patients continuing to be followed in their third year. The 3-year EFS point estimate 
(95% confidence interval estimate) for the 32 CR and 17 PR patients are 90.6% 
(73.7%, 96.9%) and 94.1% (65.0%, 99.2%), respectively. Thus the 3-year PFS rate 
for these two cohorts of patients treated on ACNS0122 are both excellent and 
similar supporting our decision to combine the groups in our study of reduced 
irradiation. The observed 3-year PFS rate for the combined cohort of 49 patients 
(32+17) is 91.8% (SE=3.9%). 
 
The historical data from the COG trial ACNS0122 shows that for the 102 patients 
with localized NGGCT, all failures have occurred within two years of initiating 
treatment with a single exception of a patient who failed at approximately six years 
post initiation of treatment. In fact, most failures occurred within one year of 
initiating treatment. As indicated above, the outcome for the subset of 49 patients 
treated on ACNS0122 who would have been eligible for treatment on ACNS1123 is 
exceptional with only three failures in the first year and one in the second year of 
follow up. Thirty-eight patients have been followed for more than three years. With 
so few failures in the historical data, the usual time-to-event distributions, 
exponential, Weibull etc., are difficult to characterize and to assess for adequacy of 
fit; so the Study Committee has no estimate of a hazard rate and clearly no estimate 
of median progression-free survival. The binomial distribution appeared to be the 
best distribution on which to design this trial reflecting the fact that with rare 
exception all failures are expected to occur early. The binomial distribution 
parameterized by the 3-year PFS rate is expected to be sufficient to capture virtually 
all failures and reflects the fact that the investigators are confident that all patients 
will be successfully followed for at least three years. This method requires that no 
patient be lost to follow up within the first three years. All patients who fail to be 
evaluated for progression at the 3-year mark will be included in the primary analysis 
as failures. The Principal Investigators are committed that no patient be lost to 
follow up within three years of initiating treatment. 
 
Considering the current results of ACNS0122, a true, unknown 3-year PFS rate of 
0.82 for this reduced therapy approach is considered unacceptable by the study 
team. The sample size calculation will be based on the binomial distribution testing 
that the true, unknown 3-year PFS rate is at most 82% (null hypothesis: ≤ 0.82) and 
powered to detect that the 3-year PFS rate is really 93% (0.93). East 5.3© was used 
to calculate the require sample size of 77 patients. This design will reject the null 
hypothesis if at least 69 patients (≥ 69) are progression free after three years and 
conclude that reduced therapy is acceptable. Due to the discrete distribution, the 
actual type I error rate is 0.0492 (probability of falsely concluding that the treatment 
is effective when the true 3-year PFS rate is 0.82) and statistical power is 0.911 
(probability of correctly concluding that the treatment is effective when the true 3-
year PFS rate is 0.93). 
 
 
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In order for the reduced therapy approach to be considered to have sufficient merit 
for continued investigation, our design requires a statistically significant result – p-
value<0.0492. The null hypothesis must be rejected otherwise this approach will 
have to be reconsidered. 
 
Due to the expected accrual rate, expected low failure rate and three year PFS 
endpoint, even one interim analysis for futility that would stop accrual early is not 
feasible. Note that interim analyses would be restricted to patients who are 
documented failures within three years of initiation of treatment and those patients 
followed for three years failure free. Thus, no formal futility interim analysis is 
planned. However, if 9 patients are documented to have failed (progressed or lost to 
follow up) before three years of follow up and fewer than 77 patients eligible for the 
primary analysis have begun treatment, accrual will be suspended until the COG 
Data Safety Monitoring Board (DSMB) has had the opportunity to review all data. 
 
9.3.2 
Stratum 2 Germinoma 
The outcome for patients with localized germinoma treated with CSI is even better 
than the outcome for patients with NGGCT discussed above.  Huh, Maity and 
Bamberg report 10-year PFS of 96.6% (n=32); 5-year PFS of 100% (n=39); and 5-
year PFS of 88% (n=49), respectively.33-35 The four relapses in the Bamberg cohort 
were all within three years of initiating therapy. Calaminus reported an EFS rate of 
97 ± 2% for 128 patients with localized germinoma treated with CSI. Thus, a 
similar statistical approach is justified for evaluating reduced therapy for patients 
with localized germinoma. The binomial distribution seems most appropriate for the 
design for this stratum, as again the usual time-to-event distributions, exponential, 
Weibull, etc. cannot be well-characterized based on the available data. The 3-year 
PFS rate was chosen as all failures are expected within three years of initiating 
therapy and we will successfully follow all patients for at least three years.  
 
Based on the results of the SIOP-96, SFOP trial and Japanese studies, our approach 
will be considered acceptable if there is statistical evidence that the true, unknown 
3-year PFS rate is greater than 0.87 (> 87%). Thus, a one-sided test will be used 
with a type I error rate of 0.10 (α = 0.10) and 90% statistical power (β = 0.10), if the 
true 3-year PFS rate is 95%. Since this approach offers the potential for superior 
quality of life for surviving patients who are spared exposure to highly effective 
cranial spinal irradiation that has long term consequences for survivors, we have set 
the statistical power at 90%. 
 
The sample size calculation will be based on the binomial distribution testing that 
the true, unknown 3-year PFS rate is at most 87% (null hypothesis: ≤ 0.87) and 
powered to detect that the 3-year PFS rate is really 95% (0.95). This method 
requires that no patient be lost to follow up within the first three years. All patients 
who fail to be evaluated for progression at the 3-year mark will be included in the 
primary analysis as failures. The Principal Investigators are committed that no 
patient be lost to follow up within three years of initiating treatment. East 5.4© was 
used to calculate the require sample size of 79 patients. This design will reject the 
null hypothesis if at least 73 patients (≥ 73) are progression free after three years. 
This approach was selected to minimize the number of patients with this rare 
 
 
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disease that would be required to address the primary study objective with statistical 
confidence even though considerable effort will be required to assure that no patient 
is lost to follow up within three years of initiating treatment. The study team is 
confident that this is possible.  
 
In order for the reduced therapy approach to be considered to have sufficient merit 
for continued investigation, the null hypothesis must be rejected otherwise this 
approach will have to be reconsidered. 
 
Due to the expected accrual rate, expected low failure rate and 3-year PFS endpoint, 
even one interim analysis for futility that would stop accrual early is not practical. If 
at any point in the trial, 7 patients are documented to have failed (progressed or been 
lost to follow up) before three years of follow up and fewer than 79 patients eligible 
for the primary analysis have begun treatment, accrual will be suspended until the 
COG DSMB has had the opportunity to review all data.  
 
9.3.3 
Longitudinal Modeling of Neurocognitive Function (Cognitive, Social and 
Behavioral) 
These analyses will be conducted independently for Stratum 1 (NGGCT) and 
Stratum 2 (Germinoma) patients. To be included in the analyses, patients must 
have the 9-month baseline assessment and at least one of either the 30-month or 
60-month assessments. 
 
The ALTE07C1 standard neuropsychological and behavioral battery focuses on 
three cognitive domains: intelligence, attention, and memory, as well as broad 
domains of social, emotional, and behavioral functioning. Data for all 
assessments will be available as standardized t-scores. The change over time for 
each component of the neuropsychological testing will be estimated using 
Generalized Estimating Equation (GEE); 82 with the standardized t-scores as the 
dependent 
variable 
and 
the 
assessment times 
as 
a 
covariate. 
For 
neuropsychological components for which some patients are missing data at one 
of the three assessments, Weighted GEE 83-84 will be used to address the 
missingness under the assumption that the data are missing at random (MAR). 
 
GEE models will be used to explore associations of changes over time with 
factors such as gender, age at initiation of radiation therapy, tumor location, 
surgical intervention, etc.  
 
 
 
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9.4 
Gender and Minority Accrual Estimates  
The gender and minority distribution of the study population is expected to be: 
 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
8 
3 
11 
Not Hispanic or Latino 
128 
136 
264 
Ethnic Category: Total of all subjects 
136 
139 
275 
Racial Category 
 
American Indian or Alaskan Native 
3 
0 
3 
Asian 
3 
3 
6 
Black or African American 
14 
8 
22 
Native Hawaiian or other Pacific Islander 
3 
3 
6 
White 
113 
125 
238 
Racial Category: Total of all subjects 
136 
139 
275 
 
 
 
 
 
 
This distribution was derived from ACNS0122. 
 
 
10.0 
EVALUATION CRITERIA 
10.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
This study will utilize version 4.0 of the CTCAE of the National Cancer Institute (NCI) 
for toxicity and performance reporting. A copy of the CTCAE version 4.0 can be 
downloaded 
from 
the 
CTEP 
website 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). 
Additionally, toxicities are to be reported on the appropriate case report forms. 
 
Please note: ‘CTCAE v4.0’ is understood to represent the most current version of 
CTCAE v4.0 as referenced on the CTEP website (ie, v4.02 and all subsequent iterations 
prior to version 5.0). 
 
10.2 
General Methodology for Determining Tumor Measurements  
2D (area) tumor dimensions are determined by measurement of the longest tumor dimension 
and its perpendicular for each target lesion. 3D (volume) tumor dimensions are determined 
by measurement of the longest tumor dimension and its perpendicular and the length 
(perpendicular to the plane of the axial measurement) for each target lesion. Regarding MRI 
imaging, the radiologist at each institution may select whatever sequence best highlights the 
tumor (T1 enhanced or T2 weighted or FLAIR images) and the same sequence should be 
used for serial measurements. Response determination will be based on a comparison of a 
2D (area:W x T – see below) 3D (volume; (W x T x L– see below) between the baseline 
assessment and the study date designated in the follow-up Report Form.  Reports for the 
 
 
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follow-up exams should reiterate the measurements obtained at baseline for each target 
lesion.  Newly occurring lesions should also be enumerated in these reports. 
 
Tumor response criteria are determined by changes in size using the longest tumor 
dimension, and its perpendicular +/- length. Either T1 or T2 weighted images are used - 
which ever gives the best estimate of tumor size. The following section describes the 
methodology. (See Figure 10.1 below for illustration) 
 
1. For MRI imaging the longest diameter can be measured from the axial plane or the 
plane, provided the same plane is used in follow ups. This longest measurement of 
the tumor is referred to as the width (W).  
2. The perpendicular measurements should be determined - transverse (T) 
measurement, perpendicular to the width in the selected plane.  
3. The length is then measured as the perpendicular to the plane defined by 
measurements in 1 and 2. 
4. The cystic or necrotic components of a tumor are typically not considered in tumor 
measurements. Therefore only the solid component of cystic/necrotic tumors should 
be measured. If cysts/necrosis composes the majority of the lesion, the lesion may not 
be “measurable”.   
Options: 
 
- 
if the cyst/necrosis is eccentric, the W and 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 
 
Figure 10.1: 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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5. Overall Response Assessment 
The overall response assessment takes into account response in both 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 and new lesions in the 
preceding columns. 
 
 
Target 
Lesions 
 
New Lesions 
 
Overall Response 
CR 
No 
CR 
PR 
No 
PR 
SD  
No 
SD  
PD 
Yes or No 
PD 
Any 
Yes or No 
PD 
Any 
Yes 
PD 
 
CR – Complete Response  
 
PR – Partial Response 
 
 
SD – Stable Disease 
PD – Progressive Disease 
IR – Incomplete Response 
 
The sections that follow discuss the selection and evaluation of each of these types of 
lesions. 
 
 
10.3 
Selection of Target 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. 
In case of a bifocal lesion both lesions should be selected as “target” lesions.  
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). 
 
10.4 
Response Criteria for Target Lesions 
1. 
Response criteria are assessed in 3 (volume) (or 2 (area) if 3 not possible) 
dimensions – the product of W x T x (L).  
2. 
To assess response/progression, the ratio is calculated (x 100 = %): 
 
 
W x T x (L) (current scan)  
 
 
W x T x (L) (reference scan) 
 
3. 
Development of new disease or progression in any established lesions is 
considered progressive disease (PD), regardless of response in other lesions – e.g. 
even when multiple lesions show opposite responses, the progressive disease 
takes precedence. 
 
4. 
For purposes of this study, response criteria for target lesions are: 
 
 
 
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Complete Response (CR): Complete disappearance of visible disease on 
imaging allowing for minimal residual disease/enhancement ≤ 0.5 cm maximal 
dimension in suprasellar or ≤ 1 cm in pineal locations.  
 
Continued complete response (CCR): Continuing absence of radiographically 
identifiable disease allowing for minimal residual disease/enhancement ≤ 0.5 cm 
maximal dimension in suprasellar or ≤ 1 cm in pineal locations. 
 
Partial response (PR): > 0.5 cm dimension residual in the suprasellar area or > 
1 cm residual in case of pineal involvement after completion of chemotherapy, 
but ≥ 65% decrease in the sum of the products of the three perpendicular 
diameters (volume) 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) and residual disease after chemotherapy 
of  > 1.5 cm maximal diameter. 
 
Progressive Disease (PD): 40% or more increase in the product of perpendicular 
diameters (volume) 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 circumstance that 3-D measurement cannot be determined, maximal 
diameter in a 2-D measurement (area) would be used to evaluate response: 
TxW (product of the longest diameter and its longest perpendicular 
diameter)  
 
Complete response (CR): Complete disappearance of visible disease on 
imaging allowing for minimal residual disease/enhancement ≤ 0.5 cm maximal 
dimension in suprasellar or ≤ 1 cm in pineal locations.  
 
Continued complete response (CCR): Continuing absence of radiographically 
identifiable disease allowing for minimal residual disease/enhancement ≤ 0.5 cm 
maximal dimension in suprasellar or ≤ 1 cm in pineal locations. 
 
Partial response (PR): > 0.5 cm maximal dimension residual in the suprasellar 
area or > 1 cm residual in case of pineal involvement after completion of 
chemotherapy, but more than ≥ 50% decrease in 2-D (area) measurement.  
 
 
Stable disease (SD): Decrease in < 50% of all target lesions and residual disease 
after chemotherapy of >1.5 cm maximal diameter. 
 
Progressive disease (PD): Defined as ≥ 25% increase 2-D (area) of target 
lesion(s) or development of any new lesions irrespective of the response of the 
initial lesions. 
 
 
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5. 
Defining Tumor Marker Response 
Patients tumor marker in serum and CSF must remain negative (AFP, hCGβ) or 
become negative (AFP, hCGβ) at completion of chemotherapy.  Patients with PD 
and increasing levels of hCGβ or AFP after completion of 2, 4 or 6 courses of 
chemotherapy will come off protocol. 
 
10.5 
Retrospective Response Review 
MRI imaging for all patients on study will undergo retrospective central review following 
the completion of treatment. Results of the retrospective review will not be returned to 
the site. See Section 14.4 for imaging central review requirements. 
 
 
 
11.0 
ADVERSE EVENT REPORTING REQUIREMENTS  
11.1 
Purpose 
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of patients enrolled in the studies as well as those who 
will enroll in future studies using similar agents.  
 
11.2 
Determination of Reporting Requirements 
Reporting requirements may include the following considerations: 1) the characteristics 
of the adverse event including the grade (severity); 2) the relationship to the study 
therapy (attribution); and 3) the prior experience (expectedness) of the adverse event. 
  
Commercial agents are those agents not provided under an IND but obtained instead from 
a commercial source. In some cases an agent obtained commercially may be used for 
indications not included in the package label.  In addition, NCI may on some occasions 
distribute commercial supplies for a trial.  Even in these cases, the agent is still 
considered to be a commercial agent and the procedures described below should be 
followed. 
 
Determine the prior experience Expected events are those that have been previously 
identified as resulting from administration of the agent.  An adverse event is considered 
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   
 
 
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• 
Myelodysplastic syndrome  
• 
Treatment related secondary malignancy 
 
11.3 
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 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 NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will 
be utilized for AE reporting and are located on the CTEP website at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
All 
appropriate treatment areas should have access to a copy of the CTCAE. 
 
Table B 
Reporting requirements for adverse events experienced by patients on study who have NOT 
received any doses of an investigational agent on this study. 
 
CTEP-AERS Reporting Requirements for Adverse Events That Occur During Therapy 
With a Commercial Agent or Within 30 Days1 
Attribution 
Grade 4 
Grade 5 
 
Unexpected 
Expected 
 
Unrelated 
or 
Unlikely 
 
 
CTEP-AERS 
Possible, 
Probable, 
Definite 
CTEP-AERS 
 
CTEP-AERS 
1This includes all deaths within 30 days of the last dose of treatment with a 
commercial agent, regardless of attribution.  Any death that occurs more 
than 30 days after the last dose of treatment with a commercial agent which 
can be attributed (possibly, probably, or definitely) to the agent and is not 
due to cancer recurrence must be reported via CTEP-AERS. 
 
 
11.4 
Routine Adverse Event Reporting 
Note: The guidelines below are for routine reporting of study specific adverse events on 
the COG case report forms and do not affect the requirements for CTEP-AERS reporting. 
 
 
 
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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 toxicities reported via CTEP-
AERS and all Grade 3 and higher Adverse Events.  
 
12.0 
STUDY REPORTING AND MONITORING  
The Case Report Forms and the submission schedule are posted on the COG web site with each 
protocol under “Data Collection/Specimens”. A submission schedule is included. 
 
12.1 
CDUS 
This study will be monitored by the Clinical Data Update System (CDUS). 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. 
 
12.2 
Data and Safety Monitoring Committee 
To protect the interests of patients and the scientific integrity for all clinical trial research 
by the Children’s Oncology Group, the COG Data and Safety Monitoring Committee 
(DSMC) reviews reports of interim analyses of study toxicity and outcomes prepared by 
the study statistician, in conjunction with the study chair’s report. The DSMC may 
recommend the study be modified or terminated based on these analyses.  
 
Toxicity monitoring is also the responsibility of the study committee and any unexpected 
frequency of serious events on the trial are to be brought to the attention of the DSMC. 
The study statistician is responsible for the monitoring of the interim results and is 
expected to request DSMC review of any protocol issues s/he feels require special 
review. Any COG member may bring specific study concerns to the attention of the 
DSMC.  
 
The DSMC approves major study modifications proposed by the study committee prior to 
implementation (eg, termination, dropping an arm based on toxicity results or other trials 
reported, increasing target sample size, etc.). The DSMC determines whether and to 
whom outcome results may be released prior to the release of study results at the time 
specified in the protocol document. 
 
 
 
13.0 
SURGICAL GUIDELINES 
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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13.1 
Pre-operative Considerations 
The majority of patients with primary intracranial germinoma or NGGCT will present 
with mass lesions in either the pineal and/or suprasellar regions.  Other less common 
locations include the thalamus/basal ganglia and fourth ventricle. Patients with primary 
tumors in the pineal region are likely to present with hydrocephalus. The neurosurgeon 
must consider the following goals in the initial management of patients suspected of 
harboring a primary germ cell tumor. 
 
13.1.1 Neuroimaging 
Cranial MRI 
All patients must have a cranial MRI with and without gadolinium at diagnosis/prior 
to enrollment. If surgical resection is performed, patients must have pre-operative 
and post-operative cranial MRI with and without gadolinium. The post-operative 
brain MRI should be obtained within 72 hours of surgery. If patient has a biopsy 
only, post-operative cranial MRI is recommended but not required. 
 
Spinal MRI 
All patients must have a spine MRI with gadolinium obtained at diagnosis/prior to 
enrollment. 
 
Note: If the spine study is performed for the first time after surgical resection or 
biopsy, it is recommended to be obtained with and without gadolinium. 
 
13.1.2 Medications 
• 
Corticosteroids: Patients with large tumors and those with non-
communicating 
hydrocephalus 
may 
benefit 
from 
high 
doses 
of 
corticosteroids such as dexamethasone (0.25-1.0 mg/kg/day) in divided doses 
every 6-8 hours. Appropriate endocrine tests should be drawn in consultation 
with the pediatric endocrine consultant prior to initiating corticosteroid 
therapy. 
• 
Anticonvulsants: The use of prophylactic anticonvulsants in patients with 
CNS germ cell tumors in typical locations such as the suprasellar and pineal 
regions is not encouraged. Seizures are rare following endoscopic third 
ventriculostomy 
or 
intraventicular 
tumor 
biopsy. 
Prophylactic 
anticonvulsants 
may 
be 
administered 
prior 
to 
craniotomies 
and 
corticectomies depending on institutional policy. 
 
13.1.3 Hydrocephalus 
• 
Most patients with pineal region tumors will present with a non-
communicating hydrocephalus due to obstruction of flow at the level of 
midbrain through the aqueduct of Sylvius. 
• 
A communicating hydrocephalus may arise as a consequence of diffuse 
leptomeningeal metastases. The management of hydrocephalus will relate to 
the severity of symptoms of raised intracranial pressure and the clinical 
response to corticosteroids. 
• 
The preferable management for patients with a pineal region tumor and 
obstructive hydrocephalus is a third ventriculostomy at the time of 
endoscopic biopsy.   
• 
The routine placement of a VP shunt is not recommended. 
 
 
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13.1.4 Tumor Sampling and Resection 
See Section 3.2.2 regarding eligible diagnosis. 
• 
It is highly desirable to first confirm the diagnosis on frozen section in the 
operating room and then to obtain sufficient tissue for flash freezing (biology 
studies) 
and 
formalin 
fixation 
(complete 
immunohistological 
characterization).  
• 
Radical resection for reduction of tumor burden is discouraged given the 
rapidity with which responses are expected with either radiation therapy or 
chemotherapy. 
 
13.1.5 Intra-operative CSF sampling 
• 
For patients undergoing an endoscopic procedure, it is highly desirable that 
intraventricular CSF sample to be obtained prior to biopsy and sent for cytology, 
hCG and AFP. The ventricular CSF should be obtained before fluid is instilled 
for irrigation.  
• 
Lumbar CSF should be obtained (within 10-14 days after surgery if applicable) 
for cytopathology prior to enrollment unless medically contraindicated. 
 
13.2 
Operative Management 
 
13.2.1 Endoscopy 
• 
It is recommended that the endoscope be used for intraventicular tumor 
biopsy and for performance of a third ventriculostomy, if needed.  
 
• 
Normal sized ventricles do not preclude the use of the endoscope for 
tumor biopsy if stereotactic guidance is available. The endoscope should 
be coupled to the frameless navigation system.   The visual 
documentation of seeding, undetectable at the level of sensitivity of 
neuroimaging, will be documented, but will not alter radiation treatment.  
 
13.2.2 Other Operative Approaches 
It is recognized that some tumors may not be easily biopsied by endoscopic 
techniques and alternate approaches may be appropriate, depending on the 
anatomy of the tumor and institutional expertise.  These include the following: 
 
• 
Stereotactic needle biopsy 
Image-guided frame-based techniques are preferred at some sites for 
appropriately selected tumors.  Careful planning of the trajectory is 
essential to minimize the risk of injury to deep venous and arterial 
structures. 
 
• 
Transphenoidal procedures 
The transphenoidal approach may be the preferred method to biopsy a 
isolated suprasellar tumor, especially if a radical resection is not 
required.  The morbidity of this approach is less than a craniotomy.  
 
 
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• 
Open craniotomy 
If the above techniques are not deemed feasible or fail to yield diagnostic 
tissue, an open craniotomy would be appropriate as a means for 
establishing the diagnosis of a germ cell tumor.  The operative approach 
would be determined by the lesion location and geometry. 
 
13.2.3 Ancillary Procedures 
 
• 
External ventricular drain (EVD) 
In some circumstances an EVD may be necessary for monitoring intracranial 
pressure or temporary control of hydrocephalus.   
 
• 
Septostomy 
If the tumor is producing hydrocephalus by obstructing a lateral ventricle at the 
level of the foramen of Monro, a third ventriculostomy may not be possible. In 
such cases, a septostomy may allow a communication to be established between 
the two lateral ventricles and permit a tumor biopsy at the same procedure. 
 
13.2.4 Internal Shunts 
The routine use of permanent internal shunts is discouraged.  However, a 
ventriculo-peritoneal shunt may be necessary in specific circumstances when a 
third ventriculostomy is not feasible or contraindicated, i.e., in the presence of 
tumor deposits on the floor of the third ventricle or communicating 
hydrocephalus. 
 
13.3 
Management of Complications 
• 
Peri-surgical complications include hemorrhage, infection, seizures, and neurological 
injury.  
• 
Significant complications will delay the implementation of adjuvant therapy and may 
preclude protocol eligibility.   
• 
The patient must be ready to begin protocol therapy within 31 days of surgery. 
Readiness assumes significant recovery from peri-operative complications and 
absence of any wound dehiscence, CSF leakage, uncontrolled hydrocephalus or 
uncontrolled life-threatening endocrine deficiency. 
 
13.4 
Second-Look Surgery 
• 
The presence of residual or progressive disease after the completion of induction 
chemotherapy in patients following 4 or 6 (NGGCT) cycles of chemotherapy 
warrants consideration of a “second-look” surgical procedure. 
• 
All differential diagnostic concerns must be considered to include: a non-
germinomatous germ cell component, mature teratoma, a non-protocol tumor and 
scar/fibrosis. 
• 
Appropriate management will depend on narrowing this differential. An open 
craniotomy may be the preferred procedure since a radical resection of residual tumor 
may be therapeutic.4 
 
 
 
 
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14.0 
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). 
 
14.1 
Timing of MRIs 
 
Cranial MRI 
All patients must have a cranial MRI with and without gadolinium at diagnosis/prior to 
enrollment. If surgical resection is performed, patients must have pre-operative and post-
operative cranial MRI with and without gadolinium. The post-operative brain MRI should 
be obtained within 72 hours of surgery. If patient has a biopsy only, post-operative cranial 
MRI is recommended but not required. 
 
Spinal MRI 
All patients must have a spine MRI with gadolinium obtained at diagnosis/prior to 
enrollment. 
 
Note: If the spine study is performed for the first time after surgical resection or biopsy, it is 
recommended to be obtained with and without gadolinium. 
 
To document localized disease, standard cranial MRI with and without gadolinium and a 
spine MRI with gadolinium must be performed at the following time points: 
Brain 
• 
Pre-operative and Post-operative (if applicable) 
• 
Baseline (Prior to enrollment) 
• 
After Cycles 2 and 4 of Induction 
• 
Completion of Induction 
• 
After Second-Look Surgery (if done) 
• 
End of Therapy 
Spine 
• 
A spine MRI obtained preoperatively can be obtained with gadolinium only. If 
the spine study is performed for the first time post-op, it is recommended to be 
performed without and with gadolinium 
• 
Completion of Induction 
• 
End of therapy 
 
14.2 
MRI Guidelines for Brain/Spine Tumors 
For recommended brain/spine imaging (1.5 Tesla), required and optional sequences and 
technical details, see the COG CNS Imaging Guidelines posted on the COG member 
website 
at: 
https://members.childrensoncologygroup.org/_files/reference/RefMaterial/COGCNSImag
ingGuidelines6_4_10.pdf. 
 
 
 
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14.3 
Tumor Response Assessment 
For the response assessments, MRI scans obtained at the time-points during protocol 
therapy (see Section 10.4) will be compared to the baseline MRI scan.  Exception: In 
cases of progressive disease, the reference scan should be the MRI with the smallest 
product observed since the start of treatment). 
 
14.4 
Retrospective Central Review 
A retrospective central review of imaging will be performed for all patients enrolled on 
ACNS1123. Results of the retrospective review will not be returned to the site. Submit the 
following studies that have not already been submitted for the RT on-treatment review with 
their corresponding reports for central review at the completion of treatment or when the 
patient is removed from protocol therapy or at the time of progressive disease/recurrence. 
 
Brain 
- 
Baseline  
- 
Pre and Post Operative scan (if applicable) 
- 
End of Induction 
- 
Post Second-look Surgery 
- 
End of Therapy 
- 
Progressive Disease/Recurrence 
 
Spine  
- 
Progressive Disease/Recurrence 
 
14.4.1 Address Information 
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. 
 
Copies of scans of the required studies for central review should be forwarded to: 
 
IROC RI (QARC) 
640 George Washington Highway  
Building B, Suite 201 
Lincoln, RI 02865-4207 
Phone: (401) 753-7600 
Fax: 
(401) 753-7601 
 
 
 
 
 
 
 
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15.0 
RADIATION THERAPY GUIDELINES 
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). 
 
Radiation Therapy (RT) can only be delivered at approved RT facilities (COG administrative 
policy 3.9).  
 
15.0  
General Guidelines 
The indications for radiation therapy on this protocol will be based on response to 
induction chemotherapy. All patients will receive radiotherapy after induction 
chemotherapy, unless recommended to undergo second surgery. If second-look surgery is 
performed, radiation therapy will be performed following the surgery. The radiation dose 
and fields will be based on both histology and response to induction chemotherapy or 
results from second surgery. This study specifies a 5 mm clinical target volume margin 
and mandates the use of CT-MR registration to define the target volumes. The allowed 
treatment methods are restricted to conformal or intensity-modulated radiation therapy 
using photons or proton beam therapy and electronic data submission is required. 
 
15.0.1 Treatment Planning Specifics 
The guidelines for this study were developed by COG radiation oncology 
investigators and approved by the radiation oncology discipline committee. This 
study stratifies NGGCT to Stratum 1 and Germinoma to Stratum 2. Both strata 
include whole ventricular irradiation followed by boost irradiation of the primary 
site. The prescribed doses to the ventricular and boost volumes are fixed for 
Stratum 1 and vary according to response for Stratum 2. The whole ventricular 
volume should be contoured according to an atlas approved by the radiation 
oncology committee. 
 
15.0.2 Required Benchmark and Questionnaires 
Radiation therapy will be administered using protons or photons. Required 
photon methods include 3D-conformal radiation therapy (3D-CRT) and intensity 
modulated radiation therapy (IMRT). Centers participating in this protocol using 
3D-CRT are required to complete the 3D benchmark; those using IMRT must 
complete the IMRT questionnaire and benchmark or phantom and those using 
protons must complete the proton benchmark and questionnaire. All centers 
participating in this protocol must complete the IROC RI (QARC) CT/MR image 
fusion benchmark. Benchmark materials and questionnaires may be obtained 
from the IROC RI (QARC) (www.qarc.org) and must be submitted before 
patients on this protocol can be evaluated. For information regarding the IMRT 
phantoms, please contact the RPC (http://rpc.mdanderson.org/rpc). 
 
15.0.3 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 
 
 
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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. 
 
15.0.4 Guidelines and Requirements for the Use of Proton Beam Therapy 
Proton therapy may be used to deliver radiation therapy on this protocol.  The 
proton therapy method will be limited to passive scattering and uniform 
scanning. Investigators using proton beam radiation must comply with the 
Advanced Technology Consortium proton therapy guidelines available through 
www.qarc.org.  These guidelines specify the following for the participating 
institution: both passive and scanned beams may be used, but the Radiologic 
Physics Center must review and credential the specific beam line delivery 
parameters. Dose reporting will be in Gy (RBE). Radiation doses shall be 
prescribed protocol specified definitions for gross (GTV) and clinical (CTV) 
target volumes. For set-up uncertainties and target motion, additional margin, 
smearing, range of modulation will be added on a per beam basis. The proton 
institution is required to participate in on-site and remote review according to 
COG guidelines.79-81 
 
  
 
15.1 
Indications for Radiation Therapy  
15.1.1  Stratum 1 
Stratum 1 patients with NGGCT enrolled on this protocol will receive 6 cycles of 
induction chemotherapy.  If there is a CR by neuroimaging or PR with marker 
normalization following chemotherapy, radiation therapy will follow the 6th cycle 
of chemotherapy.  If there is PR, SD or PD to chemotherapy, second-look 
surgery is recommended.  If surgery results in a PR or CR and tumor marker 
normalization, radiation therapy will follow surgery.  If there is <PR or positive 
markers after 6 cycles of induction or if there is residual viable tumor (except 
mature teratoma) at the time of second-look surgery, the patient will be removed 
from protocol therapy.   
 
15.1.2  Stratum 2 
Stratum 2 patients with Germinoma enrolled on this protocol will receive 4 
cycles of induction chemotherapy.  If there is a CR or CCR to chemotherapy, 
radiation therapy will follow the 4th cycle of chemotherapy.  If there is PR, SD, or 
PD after chemotherapy, second surgery is highly recommended. If mature 
teratoma or scar/fibrosis/non-viable tumor is found on second-look surgery, then 
radiation therapy will follow surgery. If surgery identifies viable tumor other than 
mature teratoma, the patient will be removed from protocol therapy.  Patients 
with positive markers after induction chemotherapy will be removed from 
protocol therapy.  
 
If there is SD or PR after chemotherapy (> 0.5 cm (suprasellar) or > 1 cm 
(pineal) but ≤ 1.5 cm residual) and second-look surgery is not performed, 
radiation therapy will follow and a higher dose to the ventricular volume will be 
administered with a subsequent increase in the total dose to the primary site. If 
 
 
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second-look surgery is not performed and patients do not meet criteria for at least 
PR with ≤ 1.5 cm residual disease, patients will be off protocol therapy. 
 
15.2 
Timing 
15.2.1 
It is recommended that all patients be seen in consultation by a radiation 
oncologist at the time of study enrollment. The purpose of the consultation is to 
participate in staging and to review the adequacy of the initial diagnostic imaging 
studies that will be used for subsequent RT planning. 
 
15.2.2  
There are no contraindications to radiation therapy. Patients taking phenytoin 
should be weaned and/or switched to a different anticonvulsant as soon as 
feasible.  
 
15.2.3  Stratum 1 (NGGCT)  
• 
If CR/PR after 6 cycles of induction chemotherapy, radiotherapy should 
commence within 3 weeks of recovery from last chemotherapy (Day 21) and 
no later than 6 weeks after the first day of the last chemotherapy cycle or the 
patient will be removed from protocol therapy (See Section 8.1). 
• 
If PR, SD or PD after 6 cycles of induction chemotherapy, radiotherapy will 
not begin until after second-look surgery. Radiotherapy must begin within 31 
days after surgery. If the patient has positive markers or <PR after second-
look surgery, they will be removed from protocol therapy. If radiotherapy is 
not initiated within 31 days after surgery, the patient will be removed from 
protocol therapy.  
 
15.2.4  Stratum 2 (Germinoma) 
• 
If CR/CCR after 4 cycles of induction chemotherapy, low-dose radiotherapy 
should commence within 3 weeks of recovery from last chemotherapy (day 
21) and no later than 6 weeks after the first day of the last chemotherapy 
cycle. If radiotherapy cannot be initiated by the above-mentioned time 
points, the patient will be removed from protocol therapy. 
• 
If PR, SD, or PD after 4 cycles of induction chemotherapy, second surgery is 
highly recommended. If mature teratoma or non-viable tumor/fibrosis/scar is 
found, then low-dose radiotherapy will commence within 31 days after 
surgery. If the patient is found to have viable tumor other than mature 
teratoma, they will be removed from protocol therapy.  If radiotherapy is not 
initiated within 31 days after surgery, the patient will be removed from 
protocol therapy. 
• 
If PR or SD (> 0.5 cm suprasellar or > 1 cm pineal but ≤ 1.5 cm residual) 
after 4 cycles of induction chemotherapy and second surgery is not 
performed, moderate-dose radiotherapy will commence within 3 weeks of 
recovery from last chemotherapy and no later than 6 weeks after first day of 
the last chemotherapy cycle. If radiotherapy cannot be initiated by the above-
mentioned time points, the patient will be removed from protocol therapy. 
 
 
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15.2.5   
It is preferable to commence radiation treatments on or before a Thursday of any 
given week. Radiation is given 5 days a week, Monday through Friday. 
 
15.3 
Emergency Irradiation 
Patients are not allowed to have received radiation therapy prior to enrollment on this 
protocol and urgent irradiation is not envisioned under any circumstance.  
 
15.4 
Equipment and Methods of Delivery and Verification  
 
Equipment 
Photons 
(any energy) 
IMRT 
(4-10MV) 
Protons 
Linear Accelerator 
X 
X 
 
Proton Beam  
 
 
X 
 
15.4.1 Treatment planning 
CT (volumetric) based planning is required to optimize dose to the PTV while 
protecting normal tissues. Organs at risk within the irradiated volume should be 
contoured including those required. A DVH is necessary to determine target 
coverage and evaluate dose to normal tissues. CT section thickness should be 
≤3mm. 
 
15.4.2 In-room verification of spatial positioning  
15.4.2.1   
Portal imaging is the most common system used to verify patient position, in 
particular when the target volume is believed to possess a fixed spatial 
relationship with visualized bony anatomy. If volumetric imaging is not 
available, orthogonal paired (AP and lateral) portal images (MV or kV) are 
required to verify that the isocenter is in correct alignment relative to the patient 
position. Beamline imaging of the treatment port should be performed when 
feasible. For proton treatment, orthogonal paired kV imaging for daily patient 
positioning and beamline kV imaging for treatment port verification are required. 
 
15.4.2.2   
Volumetric imaging is allowed in this study. This includes in-room kV or MV 
cone beam or conventional CT imaging. Please be able to submit representative 
axial images showing the isocenter and the correct alignment in relationship to 
the patients’ position. For CT tomography where isocenters are not used, a 
printout of the isodoses overlaid on the fused CT images can be printed to 
demonstrate in room verification. 
 
 
15.5 
Target Volumes 
 
15.5.1 General comments 
International Commission on Radiation Units and Measurements (ICRU) Reports 
50, 62 and 78 (www.icru.org) define prescription methods and nomenclature that 
will be utilized for this study. Although the MRI obtained immediately prior to 
 
 
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radiation therapy should be used for treatment planning, the target volumes for 
this study will be determined by the collective information that delineates the 
extent of disease before and after chemotherapy and second-look surgery. 
Patients require a combination of pre- and post-chemotherapy MR sequences to 
delineate the extent of disease and the ventricular volume.  MR pre- and post-
gadolinium contrast T1, T2, and FLAIR sequences should be reviewed. The 
sequences that best define the extent of initial disease and the post-chemotherapy 
ventricular volume should be registered to the treatment planning CT and used to 
determine the whole ventricular CTV and the local field boost GTV. The GTV, 
CTV and PTV and normal tissues must be outlined on all axial imaging slices on 
which the structures exist.  
 
Practical Targeting Guidelines 
 
After following the procedure outlined below, the investigator will have created 
and appropriately named six (n=6) target volumes: Whole Ventricular Volume 
(WVV), Whole Ventricular Volume CTV (WVVCTV), Whole Ventricular 
Volume PTV (WVVPTV), boost GTV (GTV), boost CTV (CTV) and boost PTV 
(PTV). 
 
(1) Obtain a treatment planning CT using a ≤3mm image section thickness. 
Contrast is not required. 
(2) Fuse the appropriate MR sequences  
(3) Contour the GTV to satisfy the protocol requirement to delineate this 
volume. 
(4) Expand GTV geometrically by 5mm to create a CTV for the boost phase of 
treatment.  
(5) Expand the CTV geometrically by 3 or 5mm to create the PTV. Please note 
that a 3mm PTV margin expansion requires daily image guidance and 
intervention prior to treatment. A 5mm PTV margin expansion has no special 
requirements.  
(6) Contour the WVV to satisfy the protocol requirement to delineate this 
volume.        
(7) The WVV is not a volume representing gross tumor and therefore does not 
require a geometric expansion to form the WVVCTV.  However, it is critical 
that the boost CTV be included in the WVVCTV to ensure the boost CTV 
receives the protocol specified dose.  Add the boost CTV to the WVV. Please 
name this volume WVVCTV.  
(8) Expand the WVVCTV geometrically by 3 or 5 mm to create the WVVPTV. 
Please note that that a 3mm PTV margin expansion requires daily image 
guidance and intervention prior to treatment. A 5mm PTV margin expansion 
has no special requirements. 
(9) Please note that the boost volumes must be defined upfront to ensure this 
volume receives the protocol specified dose. 
 
 
15.5.2 Photon definitions for whole ventricular volume, whole ventricular CTV and 
whole ventricular PTV 
  
 
 
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•        A contouring atlas is available on the COG and IROC RI (QARC) websites 
(www.QARC.org). 
 
• 
The whole ventricle volume (WVV) should encompass the lateral, third, and 
fourth Care should be taken to ensure the suprasellar and pineal cisterns are 
included in the whole ventricle volume.  Inclusion of the prepontine cistern is 
optional but should be considered for patients that have undergone a third 
ventriculostomy and for patients with large suprasellar tumors. The whole 
ventricles should be contoured according to the whole ventricle atlas 
available on the COG website and QARC website. The fusion of T2 MR 
sequence obtained just prior to radiation therapy to assist in delineating 
CSF/ventricles is encouraged.  
 
• 
Whole ventricular clinical target volume (WVVCTV):  
The whole ventricular volume represents an area of subclinical microscopic 
disease in the ventricular system and therefore a geometric margin is not 
required to form the WVVCTV.  However, it is critical that the WVV be 
combined with the boost CTV to ensure full dose to the involved field 
boost. Combine the WVV and boost CTV to form the WVVCTV.  The 
WVCTV should not extend outside of the bony calvarium. 
 
• 
Whole ventricular planning target volume (WVVPTV):  
A geometric expansion of 3 or 5 mm should be added to the WVVCTV to 
create the WVVPTV. The PTV has two components, the internal margin 
(IM) and the set-up margin (SM). The IM is meant to compensate for all 
movements and variations in size and shape of the tissues contained within 
the WVVCTV. The SM is meant to account for set-up, mechanical and 
dosimetric uncertainties related to daily patient positioning, treatment 
equipment and software. Given that the WVVCTV is generally confined to 
the intracranial space, the WVVPTV may extend into or beyond bone but is 
unlikely to extend beyond the surface of the patient.  
 
15.5.3 Photon definitions for boost volumes (GTV, CTV and PTV)  
 
• 
Gross tumor volume (GTV) should include any residual tumor present at the 
time of treatment planning and all tissues initially involved or in contact with 
tumor prior to any intervention (surgery or chemotherapy). The GTV is 
defined as the tumor bed at the time of diagnosis accounting for shifts in 
normal tissues displaced by tumor that has responded to chemotherapy or has 
been removed by surgery. This does not apply to areas of parenchymal 
infiltration.  Any region of the brain infiltrated by tumor should be included 
in the GTV. 
 
All diagnostic imaging should be reviewed prior to treatment planning and 
the sequences that best define the full extent of disease should be registered 
for treatment planning. 
 
• 
Boost clinical target volume (CTV) includes the GTV with an added margin 
that is meant to treat subclinical microscopic disease and is anatomically 
 
 
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confined (i.e., the CTV is limited to the confines of the bony calvarium, falx 
and tentorium where applicable or extends up to but not beyond 
neuroanatomic structures through which tumor extension or invasion is 
certain not to have occurred); the CTV margin will be 5mm for all patients. 
When the GTV approaches the boundary of an anatomic compartment, the 
CTV will extend up to and include the boundary. The CTV margin chosen 
for this study requires diagnostic MR imaging data with image section 
thickness ≤ 5mm  
 
• 
Boost planning target volume (PTV) includes a margin which is added to the 
CTV in 3-dimensions to create the PTV. It is geometric and not anatomically 
defined. The PTV has two components, the internal margin (IM) and the set-
up margin (SM). The IM is meant to compensate for all movements and 
variations in size and shape of the tissues contained within the CTV. The SM 
is meant to account for set-up, mechanical and dosimetric uncertainties 
related to daily patient positioning, treatment equipment and software. For 
this study, the PTV margin should be 3 mm. Given that the CTV is generally 
confined to the intracranial space, the PTV may extend into or beyond bone 
but is unlikely to extend beyond the surface of the patient.  
 
15.5.4 Proton definitions for GTV, CTV and PTV 
• 
GTV is the same for protons and photons. 
• 
CTV is the same for protons and photons. 
• 
PTV will be uniquely defined for proton therapy (Section 15.6.4). 
• 
When passive scattering or uniform scanning methods are used, the boost 
planning target volume (PTV) for proton therapy will include a margin which 
is added to the CTV in 3-dimensions. The margin should be consistent with 
the motion control and setup accuracy for the particular type of treatment at 
the treating proton center. The PTV will be used for dose reporting and 
not specifically for treatment planning. The goal of treatment planning will 
be CTV coverage at 100% directly with specific measures taken for each 
specific uncertainty, Specific adjustments will be made to (1) aperture 
margin definitions, (2) smearing of compensator, (3) range of the individual 
beams (depth of penetration), and (4) modulation width of the SOBP. The 
following parameters must be explicitly reported for each beam: range, 
modulation, smearing radius of the compensator, set-up margin (SM) and 
PTV margin. The specifics of dose reporting for the proton PTV and 
recommendations regarding the PTV margin are discussed in Section 15.6.4.  
 
 
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15.6 
Target Dose 
 
15.6.1 Dose Definition  
Photon dose is to be specified in centigray (cGy)-to-muscle. For proton beam, the 
absorbed dose is specified in Gy (RBE), which is the same as ICRU 78 DRBE 
using a standard RBE of 1.10 with respect to water.  
 
15.6.2 Prescribed dose and fractionation for NGGCT Stratum 1: 
• 
The total dose to the whole ventricular PTV prescription isodose surface will 
be 3060 cGy administered in 17 fractions of 180cGy.  The patient should be 
treated with one fraction per day.  All fields should be treated each day for 
photon treatments. It is recommended that at least 2 fields be treated per day 
for proton treatments. Simultaneous integrated boost is not allowed. 
 
The total dose to the boost PTV prescription isodose surface will be 2340 cGy 
administered in 13 fractions of 180cGy.  The cumulative dose will be 5400 cGy.  
The patient should be treated with one fraction per day.  All fields should be 
treated each day for photon treatments. It is recommended that at least 2 fields be 
treated per day for proton treatments. Simultaneous integrated boost is not 
allowed.   
 
Table 15.6.2 Radiotherapy volume and dose guidelines for NGGCT Stratum 1* 
 
Response 
Whole Ventricle Dose 
IF Boost Dose 
Total Dose 
CR/PR 
3060cGy 
2340cGy 
5400cGy 
CR/PR after second surgery 
3060cGy 
2340cGy 
5400cGy 
Mature teratoma/fibrosis/scar 
and CR/PR after second 
surgery 
3060cGy 
2340cGy 
5400cGy 
< PR after second surgery or 
positive markers 
Off protocol therapy 
Off protocol therapy 
Off protocol therapy 
* The dose per fraction is 180 cGy for both whole ventricle and boost dose 
 
15.6.3 Prescribed dose and fractionation for Germinoma Stratum 2: 
• 
The total dose to the whole ventricular PTV prescription isodose surface will 
be 1800 cGy administered in 12 fractions of 150cGy, unless the patient has 
had a PR to chemotherapy and has not undergone second-look surgery, in 
which case the whole ventricular PTV prescription isodose surface will be 
2400 cGy administered in 16 fractions of 150cGy.  The patient should be 
treated with one fraction per day. All fields should be treated each day for 
photon treatments. It is recommended that at least 2 fields be treated per day 
for proton treatments. Simultaneous integrated boost is not allowed. 
 
• 
The total dose to the boost PTV prescription isodose surface will be 1200 
cGy administered in 8 fractions of 150cGy.  The cumulative dose will be 
3000 cGy, unless the patient has had a PR to chemotherapy and has not 
undergone second-look surgery, in which case the cumulative dose will be 
 
 
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3600 cGy.  The patient should be treated with one fraction per day.  All fields 
should be treated each day for photon treatments. It is recommended that at 
least 2 fields be treated per day for proton treatments. Simultaneous 
integrated boost is not allowed.   
 
Table 15.6.3 Radiotherapy volume and dose guidelines for Stratum 2* 
 
Response 
Whole Ventricle Dose 
IF Boost Dose 
Total dose 
CR/CCR 
1800cGy 
1200cGy 
3000cGy 
PR  (> 0.5 cm suprasellar or > 1 
cm pineal but ≤ 1.5 cm residual 
disease and no Second-Look 
Surgery 
2400cGy 
1200cGy 
3600cGy 
Mature teratoma/fibrosis/scar 
found at Second-Look Surgery 
1800cGy 
1200cGy 
3000cGy 
Viable tumor found at second 
surgery or SD/PD > 1.5 cm  and 
no Second-Look Surgery or 
positive markers 
Off protocol therapy 
Off protocol 
therapy 
Off protocol 
therapy 
*The dose per fraction is 150 cGy for both whole ventricle and boost dose.  
 
 
15.6.4 Dose uniformity 
For photons, at least 95% of the protocol-specified dose should encompass 100% 
of the whole ventricular PTV and the boost PTV and no more than 10% of either 
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. Wedges, 
compensators and other methods of generating more uniform dose distributions 
are encouraged. 
 
 
For protons, treatment planning does not specifically use a PTV. All uncertainties 
are taken into account explicitly to create a robust plan that provides full dose 
coverage of the CTV.  For passive scattering and uniform scanning, the aperture 
margin must include the appropriate beam penumbra for the selected beam 
energy, and setup and internal margins (SM and IM).  These margins depend on 
the patient setup techniques used at the treating proton center.  The aperture 
margin may be expanded further if a cold spot occurs near the edge of CTV due 
to insufficient lateral scatter.  The smearing radius for the range compensator 
must be equal to the setup and internal margins (SM and IM). The beam range 
should be equal to the maximum water equivalent depth of the CTV plus a range 
margin.  The main part of the range margin comes from uncertainty in CT 
accuracy and the conversion of the Hounsfield units to proton stopping power 
ratios.  Most proton centers are expected to use 3.5% of the maximum water-
equivalent depth of the CTV and then add another millimeter to account for 
uncertainties in beam range calibration and compensator fabrication.  Additional 
range margin should be applied if internal motion could increase the water 
equivalent depth of the CTV.  The modulation width should be increased 
consistently to ensure proximal coverage of the target volume.  The beam range 
may be adjusted at the discretion of the treating radiation oncologist based on 
 
 
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normal tissue dose concerns. As noted in section 15.5.4, a PTV should be created 
by a uniform expansion from CTV for reporting purposes. The expansion margin 
should be consistent with SM and IM and is typically 3 mm for a static target 
volume when daily imaging is performed. With the planning guidelines provided 
herein, no more than 10% of PTV should receive greater than 110% of the 
protocol dose as evaluated by DVH.  In most cases, at least 95% of the protocol-
specified dose should encompass 100% of the PTV.  A potential exception is 
when the range margin is smaller than the PTV expansion (e.g., 3mm).  As a 
result, the beam may not penetrate deep enough to sufficiently cover the distal 
portion of the PTV.  This may occur for shallow target volumes where the 
maximum depth of the CTV is small and the range margin is small. This scenario 
is not expected for this protocol; however, such incomplete coverage of the PTV 
will not constitute a planning deviation because the plan should be sufficiently 
robust to cover the CTV with the protocol specified dose accounting for all 
uncertainties. 
 
15.6.5 Interruptions, Delays and Dose Modifications 
There will be no planned rests or breaks from treatment, and once radiation therapy 
has been initiated, treatment will not be interrupted except for any life threatening 
infection or severe hematological toxicity defined as ANC < 300/µL or platelets less 
than 40,000/µL during the course of treatment. Blood product support should be 
instituted according to institutional/protocol guidelines.  The reason for any 
interruptions greater than 3 treatment days should be recorded in the patient 
treatment chart and submitted with the QA documentation. There should be no 
modifications in dose fractionation due to age or field size. If one treatment is 
missed during a weekday, it may be made up on the weekend if the institutions 
allows. On weeks on which a holiday falls, radiation therapy may be given 4 days 
that week. 
 
 
15.7 
Treatment Technique 
 
15.7.1 Beam Configuration 
Every attempt should be made to minimize dose to organs at risk without 
compromising coverage of the target volume. Three-dimensional conformal 
therapy (coplanar or non-coplanar) or IMRT are required to minimize dose to 
normal tissues. Treatment techniques utilizing at least 3 fields are required and 5-
7 fields are recommended. IMRT is recommended but not required.   
 
15.7.2 Selection of proton beam arrangements 
For protons, a 3-field technique employing 2 lateral fields and one PA field is 
recommended.  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 15.6.4. 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 components 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.  
 
 
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15.7.3 Field Shaping  
Field shaping for photons will be done with either customized cerrobend 
blocking or multileaf collimation.  Field shaping for protons will be done with 
either customized brass apertures, proton-specific multileaf collimation, or 
through scanning. 
 
15.7.4 Simulation including patient positioning and immobilization 
 
15.7.4.1  Patient positioning  
Reproducible setups are critical and the use of immobilization devices is 
required.  The patient should be treated in the supine position with arms at their 
sides. Consideration should be given to implications for inter and intrafraction 
motion when using non-standard position approaches. 
 
 
15.7.4.2  Immobilization devices 
Standard immobilization devices for the head are to be used.  The methods used 
for localization and immobilization of both patient and tumor are critical. The 
imaging studies should provide a clear assessment of the target volume with the 
patient in the treatment position.  
 
15.7.5 Special considerations  
Anesthesia or sedation may be required in certain patients, such as very young 
patients, to prevent movement during simulation and daily treatments.  
 
15.7.6 Motion Management and Margins to Account for Target Volume Changes During 
Treatment 
Considering motion of normal tissues and target volumes is important. The 
internal target volume (ITV) is defined as the CTV surrounded by the IM 
component of the PTV and is meant to account for potential motion or changes in 
the CTV. The planning organ at risk volume (PRV) includes the corresponding 
organ at risk (OAR) volume surrounded by a margin to compensate for motion or 
physiologic change in the OAR. If adequate clinical data do not exist to define 
the IM component of the PTV or the PRV margin, the following suggestions are 
provided: 
 
• 
A margin matching the PTV margin may be added to any OAR to form the 
PRV. 
• 
Any change in clinical condition or anatomy related to hydrocephalus, VP 
shunt placement, subdural fluid, pseudomeningocele or steroid use should be 
monitored carefully and with repeat imaging when indicated. 
 
 
 
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15.7.7 Treatment Planning Procedures   
Table 15.7.7 
 
15.8 
Organs at Risk 
Planning should be done to minimize dose to the hypothalamus, pituitary, optic nerves, 
optic chiasm, retina, spinal cord, brainstem, and cochlea. Because the boost target volume 
may encompass the suprasellar region, it is possible that the hypothalamus, pituitary, 
optic chiasm and optic nerves may receive the total prescribed dose. No attempt should 
be made to spare these structures when they intersect or are adjacent to the target 
volumes. To avoid exceeding the suggested dose constraints, the dose coverage may be 
adjusted provided the guidelines of Section 15.6.4 are observed. 
 
Following the recommendations of ICRU 62, a margin of 3-5 mm shall be added around 
each of these structures to compensate for geometric uncertainties. The volume, which 
includes this margin, is called the Planning Organ at Risk Volume (PRV). The dose to 
each of these PRV’s shall not exceed 5400 cGy for Stratum 1. It is anticipated that lower 
doses to organs at risk can be obtained for Stratum 2. Sample drawings of these critical 
structures will be available on the IROC RI (QARC) website (www.QARC.org). 
 
15.8.1  Optic Chiasm and optic nerves 
The dose to the optic chiasm and optic nerves should not exceed 54 Gy and 
should be defined on CT or MR and appear on at least two successive images. 
Treatment Planning CT 
Section thickness: < 3mm 
Volume: thoracic inlet-top of head 
↓ 
Register MR Imaging 
Pre-chemo (post-Gd T1WI) 
Post-chemo (T2W1) 
↓ 
Required Contours 
WVV, WVVCTV, WVVPTV (15.5) 
GTV, CTV, PTV (15.5) 
Normal Tissue Contours (15.8) 
↓ 
Radiation Treatment Planning 
Target Volume Coverage (15.5) 
Normal Tissue Dose Recommendations (15.8) 
↓ 
Data Submission to QARC 
Due Day 3 and End of Treatment (15.9) 
Electronic and Hard Copy Data (15.9) 
 
 
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15.8.2  Cochlea 
Each cochlea will be contoured on the CT data as a polygon or circular structure 
within the petrousportion of the temporal bone. The contour should appear on at 
least two successive CT images.  
D50% < 3000cGy – Goal (single cochlea) 
D50% < 2000cGy – Preferred (single cochlea) 
Comment – There is no dose limit for the cochlea. 
 
15.8.3  Brainstem 
The dose to the spinal cord should not exceed 54 Gy. 
 
15.8.4  Optic Globes 
The dose to the optic globes should not exceed 45 Gy and a direct beam should 
be avoided. 
 
15.8.5  Hypothalamus and Pituitary Gland 
There is no dose constraint for the hypothalamus and pituitary gland.  For 
primary tumors that do not involve the suprasellar region, field arrangements that 
minimize dose to these structures for the boost portion of the plan are 
encouraged.  
 
15.9 
Dose Calculations and Reporting 
 
15.9.1  Prescribed Dose 
The monitor units required to deliver the prescribed dose shall be calculated and 
submitted using the RT-1/IMRT Proton Dosimetry Summary Forms. If IMRT is 
used, the monitor units generated by the IMRT planning system must be 
independently checked prior to the patient’s first treatment. Measurements in a QA 
phantom can suffice for a check as long as the patient’s plan can be directly applied 
to a phantom geometry. The daily and total prescribed dose shall be calculated and 
reported on the RT-2 Radiotherapy Total Dose Record. The dose should be 
prescribed to an isodose surface that encompasses the PTV and allows the dose 
uniformity requirements to be satisfied. 
 
15.9.2 Normal Tissue Dosimetry 
The dose to the critical organs indicated should be calculated whenever they are 
directly included in a radiation field. The total dose shall be calculated and 
reported on the RT-2 Radiotherapy Total Dose Record form. The appropriate 
dose-volume histograms should be submitted and RT-1 or IMRT form 
completed. If IMRT is used for the primary tumor, a DVH must be submitted for 
a category of tissue called “unspecified tissue,” which is defined as tissue 
contained within the skin, but which is not otherwise identified by containment 
within any other structure. A DVH for “Body” shall be submitted to enable 
calculation of the required volumes in Table 18.9b. “Body” is defined as the 
outer contour of the patient on the treatment planning CT data set. 
 
 
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Table 15.9a Required DVH data  
 
Required DVH 
Optic Chiasm 
Brainstem 
Spinal Cord 
Right Cochlea 
Left Cochlea 
Hypothalamus 
Pituitary Gland 
Body 
Unspecified Tissue 
 
Treated Volume (mL), Irradiated Volume (mL) and Conformity Index (CI) 
The treated volume (TV) is the tissue volume that receives therapeutic dose. For the purpose of this 
protocol this would include the prescribed whole ventricular dose, the prescribed boost dose and 95% of 
the prescribed doses. This information may be used by the investigators, along with the absolute volume 
of the PTVs, to calculate the conformity indexes (CI) CI100% and CI95%, respectively. The irradiated 
volume (IV) is the tissue volume that receives a dose that is considered significant in relation to normal 
tissue tolerance. The descriptive statistics for these and other tissue volumes maybe used for correlation 
with unusual side effects or to develop practical guidelines for future brain tumor protocols. 
 
Table 15.9b Required Volumetric Information for Stratum 1 
 
Required Volumes (ml) 
TV95% = 51.3 Gy 
TV100% = 54 Gy 
IV35=V35Gy 
IV45=V45Gy 
IV54=V50Gy 
WVV 
WVVCTV 
WVVPTV 
GTV 
CTV 
PTV 
Entire Brain 
Unspecified Tissue 
 
 
 
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Table 15.9c Required Volumetric Information for Stratum 2, all patients except PR without second-
look surgery 
 
Required Volumes (ml) 
TV95% = 28.5 Gy 
TV100% = 30 Gy 
IV15=V15Gy 
IV20=V20Gy 
IV25=V25Gy 
WVV 
WVVCTV 
WVVPTV 
GTV 
CTV 
PTV 
Entire Brain 
Unspecified Tissue 
 
 
 
Table 15.9d Required Volumetric Information for Stratum 2, PR without second-look surgery 
 
Required Volumes (ml) 
TV95% = 34.2 Gy 
TV100% = 36 Gy 
IV15=V15Gy 
IV20=V20Gy 
IV30=V30Gy 
WVV 
WVVCTV 
WVVPTV 
GTV 
CTV 
PTV 
Entire Brain 
Unspecified Tissue 
 
15.10 Quality Assurance Documentation 
 
Digital Submission: 
Submission of treatment plans in digital format (either DICOM RT or RTOG format) 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 QARC web site 
at www.qarc.org under "Digital Data."  Any items on the list below that are not part of 
 
 
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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. 
 
15.10.1  On-treatment Review 
Within three days of the start of radiotherapy, the following data for the whole 
ventricle fields shall be submitted for on-treatment review.  Boost data must be 
submitted prior to the start of the boost, but preferably should be submitted with 
the whole ventricle data at the start of radiotherapy: 
 
Treatment Planning System Output: 
• 
RT treatment plans 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. When using 
IMRT, a DVH shall be submitted for a category of tissue called 
“unspecified tissue.” This is defined as tissue contained within the 
skin, but which is not otherwise identified by containment within 
any other structure. DVHs are included in the digital plan. 
• 
Digitally reconstructed radiographs (DRR) for each treatment field.  
Please include two sets, one with and one without overlays of the 
target volumes and organs at risk. When using IMRT, orthogonal 
setup images are sufficient. 
• 
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 the operative reports for each surgical procedure. 
• 
Copies of the prechemotherapy and postchemotherapy MRI scans 
and radiology reports utilized in defining the initial clinical target 
volume and the local boost volume. 
• 
Pre-operative and post-operative cranial neuroimaging and 
radiology reports for each surgical procedure including second 
surgery after induction chemotherapy. 
• 
Post-chemotherapy (pre-RT) neuroimaging and radiology reports 
when no second surgery was performed. 
• 
Documentation of an independent check of the calculated dose 
when IMRT is used. 
• 
If the recommended doses to the organs at risk are exceeded, an 
explanation should be included for review by the QARC and the 
radiation oncology reviewers. 
• 
Proton therapy: smearing radius of the compensator, set-up margin 
(SM) and PTV margin for each treatment beam. 
 
Forms: 
• 
RT1/IMRT Dosimetry Summary Form (QARC). 
• 
Proton Dosimetry Summary Form (QARC). 
 
 
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15.10.2  Post Treatment Review 
Within one week of the completion of radiotherapy, the following data shall be 
submitted. 
• 
RT-2 Radiotherapy Total Dose Record Form. 
• 
Radiotherapy record (treatment chart) including prescription and 
daily and cumulative doses to all required areas and organs at risk. 
  
 
Electronic submission via sFTP for all data is preferred. Alternatively, the 
supportive data and forms may be sent to: 
 
IROC RI (QARC) 
 
640 George Washington Highway 
  
 
Building B, Suite 201 
Lincoln, RI 02865-4207 
Phone: (401) 753-7600 
Fax: 
(401) 753-7601 
 
Questions regarding the dose calculations or documentation should be directed 
to: 
COG Protocol Dosimetrist 
IROC RI (QARC)  
 
640 George Washington Highway  
 
Building B, Suite 201 
Lincoln, RI 02865-4207 
Phone: (401) 753-7600 
Fax: 
(401) 753-7601 
 
15.11 Definitions of Deviations in Protocol Performance 
In the following table, the GTV, CTV and PTV descriptions and evaluations will applied 
and scored separately to the ventricular and boost phases of treatment.  
 
 
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DEVIATION 
 
Minor 
Major 
Prescription Dose 
 
Difference in prescribed or computed 
dose is 6-10% of protocol specified 
dose 
Difference in prescribed or computed 
dose is > 10% of protocol specified 
dose 
Dose Uniformity 
 
>10% PTV received > 110% 
of the prescription dose 
or 
95% isodose covers < 100% of CTV 
90% isodose covers < 100% of CTV 
Volume 
 
CTV or PTV margins are less than the 
protocol specified margins in the 
absence of anatomic barriers to tumor 
invasion (CTV) or without written 
justification (PTV) 
GTV does not encompass MR-visible 
residual tumor 
Organs at Risk 
 
Dose to any OAR exceeds the goal 
dose stated in Section 15.8 
Dose to any OAR exceeds the 
maximum dose stated in Section 15.8 
 
 
Timing  
Minor Deviation:  Radiation therapy course prolonged 7-14 days. 
 
Major Deviation:  Radiation therapy course prolonged more than 14 days. 
 
15.12 Patterns of Failure Evaluation 
The patterns of failure for patients with localized CNS GCT may be described as local, 
ventricular, distant or a combination of local, ventricular, and/or and distant and are based 
primarily on imaging evaluation of the neuraxis. Local failure is defined as progression of 
known residual tumor or the appearance of tumor at known prior sites of disease that 
were at some point without evidence of disease. Ventricular failure is defined as the 
appearance of tumor at sites within the ventricular system other than known prior sites of 
disease. Distant failure is defined as the appearance of tumor at sites outside the 
ventricles or the primary tumor volume. Distant failure most often occurs in the 
subarachnoid space and may occur at any point within the neuraxis. Although rare, extra-
CNS metastasis represents distant failure. Combined local, ventricular, and/or distant 
failure is defined when evaluation of the entire neuraxis reveals failure at two or three of 
the defined categories. The monitoring of EFS will assess the rate of failure.  
Determining the patterns of failure will require an assessment of tumor recurrence with 
respect to targeting and dosimetry.  
 
 
 
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There is no universally accepted analytical method to assess pattern of failure. For this study, 
the pattern of failure will be assessed qualitatively and quantitatively by registering MR data 
obtained at the time of failure to the dosimetry from the original treatment plan.  
 
 
16.0 
NEUROPSYCHOLOGICAL FUNCTION STUDY 
Note: Patients must be enrolled on ALTE07C1 at the time of study enrollment on ACNS1123. 
 
A separate informed consent for ALTE07C1 must be signed. Please refer to the ALTE07C1 protocol for 
eligibility requirements. 
 
Because of the high risk of neurodevelopmental problems in young children treated for CNS germ cell 
tumors, assessment of functional and neuropsychological status will be completed to obtain information 
about tumor and treatment related morbidity.  The premise of this study is that newer radiation planning 
and delivery techniques are capable of reducing neuropsychological sequelae for all children, including 
the very young.  While it has historically been difficult to obtain neuropsychometric data in a cooperative 
group study, this is now feasible with ALTE07C1.  These data are critical to the success of this treatment 
approach and its acceptance by patients, parents, and the neuro-oncology community. 
 
 
 
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APPENDIX I:  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).  
 
Requirements for ACNS1123 Site Registration: 
 
• 
CTSU IRB Certification (for sites not participating via the CIRB) 
 
 
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• 
CTSU IRB/Regulatory Approval Transmittal Sheet (for sites not participating via the NCI 
CIRB)  
 
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.  
CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
Phone: 1-866-651-2878 
Fax: 
215-569-0206 
E-mail: CTSURegulatory@ctsu.coccg.org (for regulatory document submission only) 
 
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 II:  POSSIBLE DRUG INTERACTIONS 
 
The lists below do not include everything that may interact with chemotherapy. Study Subjects and/or 
their Parents should be encouraged to talk to their doctors before starting any new medications, using 
over-the-counter medicines, or herbal supplements and before making a significant change in diet. 
 
Carboplatin 
 
Drugs that may interact with carboplatin* 
• Antibiotics like gentamicin or tobramycin 
• Anti-seizure medications like fosphenytoin or phenytoin 
• Arthritis medications like leflunomide, tofacitinib 
• Some chemotherapy (be sure to talk to your doctor about this) 
• Other medications like clozapine or natalizumab 
 
Food and supplements that may interact with carboplatin** 
• Echinacea 
 
*Sometimes these drugs are used with carboplatin on purpose.  Discuss all drugs with your 
doctor. 
 
**Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, 
capsules, pills, or dried herbs. All forms should be avoided.   
 
 
 
Etoposide 
 
Drugs that may interact with etoposide* 
• Antibiotics  
• Clarithromycin, erythromycin, nafcillin, rifabutin, rifampin, telithromycin 
• Antidepressants and antipsychotics  
• Aripiprazole, clozapine, nefazodone 
• Antifungals  
• Fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole 
• Arthritis medications  
• Leflunomide, tofacitinib 
• Anti-rejection medications 
• Cyclosporine, tacrolimus 
• Antiretrovirals and antivirals  
• Atazanavir, boceprevir, darunavir, delaviridine, efavirenz, etravirine, 
fosamprenavir, indinavir, lopinavir, nelfinavir, nevirapine, ritonavir, saquinavir, 
 
 
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Stribild, telaprevir, tipranavir 
• Anti-seizure medications  
• Carbamazepine, oxcarbazepine, phenobarbital, phenytoin, primidone 
• Heart medications  
• Amiodarone, dronedenarone, verapamil 
• Some chemotherapy (be sure to talk to your doctor about this) 
• Many other drugs, including the following: 
• Aprepitant, atovaquone, bosentan, deferasirox, dexamethasone, ivacaftor, 
lomitapide, mifepristone, natalizumab, pimozide, sitaxentan 
 
Food and supplements that may interact with etoposide** 
• Echinacea 
• Glucosamine 
• St. John’s Wort 
• Grapefruit, grapefruit juice, Seville oranges, star fruit 
 
*Sometimes these drugs are used with etoposide on purpose.  Discuss all drugs with your 
doctor. 
 
**Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, 
capsules, pills, or dried herbs. All forms should be avoided.   
 
Ifosfamide  
 
Drugs that may interact with ifosfamide* 
• Antibiotics  
• Clarithromycin, erythromycin, nafcillin, rifabutin, rifampin, telithromycin 
• Antidepressants and antipsychotics  
• Citalopram, clozapine, escitalopram, fluvoxamine, lurasidone, nefazodone, 
paliperidone, quetiapine, thioridizine, ziprasidone 
• Antifungals  
• Fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole 
• Arthritis medications  
• Leflunomide, tofacitinib 
• Anti-rejection medications 
• Cyclosporine 
• Antiretrovirals and antivirals  
• Atazanavir, boceprevir, darunavir, delaviridine, efavirenz, etravirine, 
fosamprenavir, indinavir, lopinavir, nelfinavir, nevirapine, ritonavir, saquinavir, 
Stribild, telaprevir, tipranavir 
• Anti-seizure medications  
• Carbamazepine, oxcarbazepine, phenobarbital, phenytoin, primidone 
• Heart medications  
• Amiodarone, dronedenarone, verapamil 
• Stomach and reflux medications 
• Esomeprazole, omeprazole 
 
 
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• Some chemotherapy (be sure to talk to your doctor about this) 
• Many other drugs, including the following: 
• Bosentan, sitaxentan, aprepitant, dexamethasone, lomitapide, mifepristone, 
natalizumab, pimozide  
 
Food and supplements that may interact with ifosfamide** 
• Echinacea 
• St. John’s Wort 
• Grapefruit, grapefruit juice, Seville oranges, star fruit 
 
*Sometimes these drugs are used with ifosfamide 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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APPENDIX III:  YOUTH INFORMATION SHEETS 
INFORMATION SHEET REGARDING RESEARCH STUDY – ACNS1123 
Non-Germinomatous Germ Cell Tumor (NGGCT) 
(for children from 7 through 12 years of age) 
 
Phase 2 Trial of Response-Based Radiation Therapy for Patients with Localized Central Nervous 
System Germ Cell Tumors 
 
1. We have been talking with you about your non-germinomatous germ cell tumor (NGGCT). A 
NGGCT is a type of cancer that grows in your brain. Your tumor is localized meaning it has not 
spread to other areas of your brain, spinal canal or body. After doing tests, we have found that 
you have this type of cancer. 
 
2. We are asking you to take part in a research study to see if localized NGGCT tumors treated with 
chemotherapy and radiation treatments with a smaller dose of radiation will work as well as 
radiation treatments used in previous studies. A research study is when doctors work together to 
try out new ways to help people who are sick. We will talk to you about enrolling on another 
COG study, ALTE07C1. The goal of ALTE07C1 is to learn about the thinking, learning, and 
remembering) of children being treated for cancer. 
 
3. Standard treatment for NGGCT tumors includes chemotherapy to shrink the tumor as much as 
possible followed by radiation treatments. Radiation treatments used to treat NGGCT is usually 
given to the whole brain and is often given to the spinal column as well.  
 
4. Children who are part of this study will be treated with chemotherapy called Induction 
chemotherapy followed by radiation treatments. The treatment on this study takes about 8 
months. It is divided in to 2 stages. In the first stage, you will receive 6 cycles of induction 
chemotherapy. In the second stage, you may receive radiation treatments with a smaller dose.  
You may also have a second surgery before you receive radiation treatments. 
 
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 the 
new treatments work better to get rid of the tumor than the standard treatment and causes less 
damage to your brain.  But, we do not 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.”  One risk to you from this study is that the study treatment may not work as 
well as other treatments to make your tumor get smaller or go away for as long as possible. 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. 
 
 
 
 
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INFORMATION SHEET REGARDING RESEARCH STUDY – ACNS1123 
Non-Germinomatous Germ Cell Tumor (NGGCT) 
 (for teens from 13 through 17 years of age) 
 
Phase 2 Trial of Response-Based Radiation Therapy for Patients with Localized Central Nervous 
System Germ Cell Tumors 
 
1. We have been talking with you about your non-germinomatous germ cell tumor (NGGCT). A 
NGGCT is a type of cancer that grows in your brain. Your tumor is localized meaning it has not 
spread to other areas of your brain, spinal canal or body. After doing tests, we have found that 
you have this type of cancer. 
 
2. We are asking you to take part in a research study to see if localized NGGCT tumors treated with 
chemotherapy and radiation treatment with a smaller dose of radiation will work as well as 
radiation treatments used in previous studies. A research study is when doctors work together to 
try out new ways to help people who are sick. We will talk to you about enrolling on another 
COG study, ALTE07C1. The goal of ALTE07C1 is to learn about the thinking, learning, and 
remembering of children being treated for cancer.  
 
3. Standard treatment for NGGCT tumors includes chemotherapy to shrink the tumor as much as 
possible followed by radiation treatments. Radiation treatments used to treat NGGCT is usually 
given to the whole brain and is often given to the spinal column as well.  
 
4. Children who are part of this study will be treated with chemotherapy called Induction 
chemotherapy followed by radiation treatments. The treatment on this study takes about 8 
months. It is divided in to 2 stages. In the first stage, you will receive 6 cycles of induction 
chemotherapy. In the second stage, you may receive radiation treatments with a smaller dose.  
You may also have a second surgery before you receive radiation treatment. 
 
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 the 
new treatments work better to get rid of the tumor than the standard treatment and causes less 
damage to your brain.  But, we do not 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.”  One risk to you from this study is that the study treatment may not work as 
well as other treatments to make your tumor get smaller or go away for as long as possible. 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. 
 
 
 
 
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INFORMATION SHEET REGARDING RESEARCH STUDY – ACNS1123 
Germinoma Germ Cell Tumor  
(for children from 7 through 12 years of age) 
_____________________________________________________________________________________ 
 
Phase 2 Trial of Response-Based Radiation Therapy for Patients with Localized Central Nervous 
System Germ Cell Tumors 
 
1. We have been talking with you about your germinoma germ cell tumor. A germinoma tumor is a 
type of cancer that grows in your brain. Your tumor is localized meaning it has not spread to 
other areas of your brain, spinal canal or body. After doing tests, we have found that you have 
this type of cancer. 
 
2. We are asking you to take part in a research study to see if localized germinoma tumors treated 
with chemotherapy and radiation treatments with a smaller dose of radiation will work as well as 
radiation treatments used in previous studies. A research study is when doctors work together to 
try out new ways to help people who are sick. We will talk to you about enrolling on another 
COG study, ALTE07C1. The goal of ALTE07C1 is to learn about the thinking, learning, and 
remembering of children being treated for cancer.   
 
3. Standard treatment for germinoma tumors includes chemotherapy to shrink the tumor as much as 
possible followed by radiation treatments. Radiation treatments used to treat germinoma is 
usually given to the whole brain and is often given to the spinal column as well.  
 
4. Children who are part of this study will be treated with chemotherapy called Induction 
chemotherapy followed by radiation treatment. The treatment on this study takes about 6 months. 
It is divided in to 2 stages. In the first stage, you will receive 4 cycles of induction chemotherapy. 
In the second stage, you may receive radiation treatments with a smaller dose.  You may also 
have a second surgery before you receive radiation treatments. 
 
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 the 
new treatments work better to get rid of the tumor than the standard treatment and causes less 
damage to your brain.  But, we do not 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.”  One risk to you from this study is that the study treatment may not work as 
well as other treatments to make your tumor get smaller or go away for as long as possible. 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. 
 
 
 
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INFORMATION SHEET REGARDING RESEARCH STUDY – ACNS1123 
Germinoma Germ Cell Tumor  
 (for teens from 13 through 17 years of age) 
 
Phase 2 Trial of Response-Based Radiation Therapy for Patients with Localized Central Nervous 
System Germ Cell Tumors 
 
1. We have been talking with you about your germinoma germ cell tumor. A germinoma tumor is a 
type of cancer that grows in your brain. Your tumor is localized meaning it has not spread to 
other areas of your brain, spinal canal or body. After doing tests, we have found that you have 
this type of cancer. 
 
2. We are asking you to take part in a research study to see if localized germinoma tumors treated 
with chemotherapy and radiation treatment with a smaller dose of radiation will work as well as 
radiation treatments used in previous studies. A research study is when doctors work together to 
try out new ways to help people who are sick. We will talk to you about enrolling on another 
COG study, ALTE07C1. The goal of ALTE07C1 is to learn about the thinking, learning, and 
remembering of children being treated for cancer.  
 
3. Standard treatment for germinoma tumors includes chemotherapy to shrink the tumor as much as 
possible followed by radiation treatments. Radiation treatments used to treat germinoma is 
usually given to the whole brain and is often given to the spinal column as well.  
 
4. Children who are part of this study will be treated with chemotherapy called Induction 
chemotherapy followed by radiation treatment. The treatment on this study takes about 8 months. 
It is divided in to 2 stages. In the first stage, you will receive 4 cycles of induction chemotherapy. 
In the second stage, you may receive radiation treatment with a smaller dose.  You may also have 
a second surgery before you receive radiation treatment. 
 
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 the 
new treatments work better to get rid of the tumor than the standard treatment and causes less 
damage to your brain.  But, we do not 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.”  One risk to you from this study is that the study treatment may not work as 
well as other treatments to make your tumor get smaller or go away for as long as possible. 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. 
 
 
 
 
 
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